CLINICAL TRIALS YEARBOOK 2015 - Chiltern...CLINICAL TRIALS YEARBOOK 2015 2nd edition Practical outsourcing and oversight: Designing in-depth deals incorporating all necessary aspects

CLINICAL TRIALSYEARBOOK 2015

2nd edition

Practical outsourcing and oversight: Designing in-depth deals incorporating all necessary aspectsMarisa Bower, Director R&D Procurement,Teva Pharmaceuticals & Michael Cox, Senior Outsourcing Manager, Medimmune

Exploring the transformative promise of patient centric R&DKen Getz, Director of Sponsored Programs, Tufts CSDD

Adaptive EDC at field, patient and study arm levelsTerry Katz, Director, Global Data Management and Statistics, Merck Animal Health

Thank you and goodbye to the booklet labelMilad Kelada, Senior Director, Head of Supply Chain, Fibrogen

Developing strategies for effective international trial managementJacqueline Lee, Director, Clinical Operations, Cytokinetics

http://www.barl.ca

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After the success of the launch of the Clinical Trials Yearbook last

year, I am proud to present the 2015 2nd Edition of this topical and relevant

publication. With the pressure on pharmaceutical and biotechnology companies ever growing with regards to clinical trial timelines and budgets, this yearbook presents some unique strategies and technologies that are being developed by companies big and small to optimize clinical trial processes across the industry.

Over 20 clinical events worldwide have placed Arena International in a unique position to bring to-gether industry leaders from trial sponsors, solution providers and academia to contribute to this yearly review of the clinical research industry.

Having been able to attend a number of these events in person, it is clear that the industry is passionate about overcoming challenges within the clinical trial space, be that within clinical monitoring, adaptive designs, patient centric trials, EDC technology implementation, strate-gic outsourcing or complying with increased regulatory requirements. This yearbook covers all of these areas, bringing together many of the latest advancements presented at Arena International events in the last 12 months.

I sincerely hope you enjoy reading this yearbook as much as I, and my team, have enjoyed develop-ing the 2014 and 2015 clinical event series – and as much as the 3000+ delegates have enjoyed attending them this year!

See you at an Arena International event soon!

Kieran Prior Editor, Clinical Trials Yearbook 2015

Editor’s noteCLINICAL OUTSOURCING

4 Practical outsourcing and oversight: Designing in-depth deals, incorporating all necessary aspects to provide a plan of execution and clear responsibilities for all eventualities

10 Establishing the strongest standards in quality control and assurance to ensure effective vendor qualification for small companies

14 To outsource or not to outsource? Exploring quantitative and qualitative issues to consider when determining an appropriate outsourcing strategy

19 Exploring strategies for enhanced vendor selection which avoid the costs associated with a breakdown in sponsor-vendor relationship midway through a trial

23 Exploring best practice strategies in contract development between sponsors and vendors to ensure aligned expectations throughout the trial

25 Ensuring enthusiasm for a fabulous working relationship between small companies and vendors

CLINICAL TRIAL SUPPLY

31 Clinical supply chain challenges: shared perspectives between pharmaceutical, large-cap and emerging biotechnology companies

36 Ensuring in-depth planning takes place within trial supply to meet the demands of the globalization of clinical studies

42 Thank you and goodbye to the booklet label

CLINICAL OPERATIONS

46 Developing strategies for effective international trial management

50 Exploring the emerging advantage of the markets within China and the rest of Asia

59 The transformative promise of patient centric R&D

CLINICAL TECHNOLOGY AND DATA MANAGEMENT

63 Adaptive electronic data capture (EDC) at field, patient and study arm levels

67 Adapting to evolving responsibilities for clinical data management teams

70 Risk assessment of electronic source data for use in research investigation

Contents

EditorKieran Prior

PublisherHannah Toms

Internal WritersKieran PriorRachel Tesfaye

Marketing Manager:Kieron Gradwell

For Yearbook enquiries, please contact:

Kieran PriorT: +44 (0)207 936 6603E: [email protected]

Paul AdamsT: +44 (0)207 936 6948E: [email protected]

Clinical Trials Yearbook 2015 Team:

Practical outsourcing and oversight: Designing in-depth deals, incorporating all necessary aspects to provide a plan of execution and clear responsibilities for all eventualities

ccording to a recent survey of biopharmaceutical

outsourcing professionalsi, the main reason that partnerships fail is because they were not fit for purpose when set up. There are numerous well-documented cases where the value sought from a partnership was never fully realized, rendering the partnership unsustainable.

All this begs the question: how does one go about designing a suitable commercial, legal and governance structure to support the deal that an organization needs? The first step is to investigate those needs.

Ensuring any service levels within the framework are fit for purpose: promoting alignment and expectations among all parties

This starting point is one of the most difficult, as it requires working across a variety of functions such as finance, clinical operations, legal, procurement, and deep within some of these functions. Within clinical operations, for example, it requires asking the

‘make versus buy’ questions of each sub-function such as clinical data management, medical writing, clinical monitoring, project management, and so on. Here are a few questions that can be used as a starting point:

• Is the expense/revenue ratio favourable compared to best-in-class (BIC) providers?

• Is performance in key quality measures favourable compared to BIC?

• Has technology investment kept pace with marketplace?

• Does change management/sponsorship exist?

• Do we have institutional capabilities/experiences that are hard for suppliers to replicate?

• Is the activity important to our customers in the long-run?

• Are the roles being outsourced roles where our company’s future leaders will come from or could come from?

Marisa Bower, Director, R&D Procurement , Teva Pharmaceuticals & Michael Cox, Sr. Outsourcing Manager, MedImmune

iPCMG-US survey included 25 respondents from 10 companies

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& TARGETS

how did we measure success?

MEASURES

GOALS

STRATEGIES

DESIRED

OUTCOMESRE

SULT

S

how can we improve? where do we want to go?

how do we get there?how did we do?

MISSION

Strategic Planning Cycle

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CLINICAL OUTSOURCING

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As functions answer these types of questions, their answers will (1) determine ultimately whether it is advantageous to outsource and (2) allow you to hone in on the specific scope of what should be outsourced. As well as this, a secondary outcome will surface; importantly, this is how do we outsource. These questions’ answers in short will inform the entire outsourcing process in terms of types of vendors needed, which in turn informs the process needed to gather up those vendors into a selection process and ultimately contract with one or more of them.

A final and highly important outcome - something to keep in mind throughout the assessment, selection, and contracting process - is buy-in at the deepest and top-most levels of the organization. Many deals fall through; that is to say, they are not supported by one or more level(s) of an organization, because the appropriate work was not outsourced in the appropriate fashion. A critical component in making sure that the right decision is made first and then executed over time, involves buy-in and support from multiple levels of an organization and across multiple functions of an organization. Never forget that once the deal is done, that is just the beginning. It is important that the governance, escalation pathways and ongoing contacts

all support the execution of the deal and continue to follow many of the key concepts outlined in this article.

Applying principles of investigative negotiation

The concepts of investigative negotiation are straightforward. As a whole, this type of negotiation is, plainly put, making sure to take the time to understand the needs and constraints of the partner with whom you are negotiating across the table. While the concept is simple, implementation can be a struggle, because it combats against natural human instinct. In negotiation, we are driven by putting forward our positions. Investigative negotiation refocuses our time and energy on understanding and negotiating around each other’s interests rather than around each other’s positions.

Before going on, a quick note on positions versus interests. Positions are a counterpart’s stands on the issues. Interests are underlying concerns that would be affected by an

agreement. Positions are based on the best information available to the counterpart. Shifting the discussion to interests, as outlined by the five principles, allows for a more meaningful and faster negotiation as it expands the information available to all counterparts about their respective positions.

The success of investigative negotiation hinges on a few key methodologies, as well as two key principles. The primary methodologies again are commonsensical, and are summarized below:

• Manage the negotiations process; set the framework and review the outcome.

• Start with the end goal in mind and imagine the agreement 12 months out. What issues can you anticipate? How do you measure success? Were the right stakeholders engaged?

• Pave the way for transparency in your agreements to avoid surprises or over-promises. If either party promises things they can’t deliver, it compromises the integrity of the agreement.

"When we started the sourcing process, we knew what we wanted. But when the new Vice President started – all of that changed."

Top 5 Biopharma Procurement Professional

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• Treat alignment as a shared responsibility - if either of the party’s interests are not aligned, it can prolong negotiations.

• Be united in the messaging. Send consistent messages and ensure colleagues associated with both contracting parties have the same information.

There are some common themes in the above that can be noted, which brings us to the key principles to keep in mind. First and foremost, as mentioned above, a major outcome of the alignment and expectations discussions is that buy-in begins there. By actively soliciting from stakeholders what their needs are, and documenting those in numerous ways, especially by including stakeholders in requests for proposals and suggested contracting terms, that buy-in process begins. It is important at each step to go back to the business’ functional owners as information comes in, check it against their needs and adjust as needed. The second key principle is related - engage those same stakeholders in the process. Make sure that legal, finance and clinical operations are all continuously having discussions with supplier counterparts across the negotiating table.

This continues the momentum you start to build, creates synergies that will play out ultimately in operations with any selected vendor, and also helps make sure that alignment is maintained across the board.

Said another way, investigative

negotiations avoid the following pitfalls, which can both kill deals before they are inked, as well as - what is seen in the pharmaceutical industry more frequently - furnish them slow agonizing deaths as their results mix together with business operational groups that are not getting exactly what their business needs. These pitfalls include:

• Neglecting the other side’s problems: neglecting the needs and constraints of suppliers during negotiations, mentioned at the top of this article, formulates perhaps the most common pitfall at the heart of ill-formulated partnerships.

• Letting price bulldoze other interests, such as quality.

• Letting positions take precedent over interests in negotiations and discussions.

• Neglecting BATNA (Best Alternative To Negotiated Agreement), i.e. not considering multiple suppliers’ inputs and capabilities during negotiations.

• Failing to correct skewed visions, e.g. once the suppliers in a market have been reviewed, continuing with certain outsourcing requirements when the data clearly indicates otherwise.

These pitfalls will be elaborated upon below, but one particular is explored here: price. In our modern world, price is a premier driver of many transactions, and rightfully so. Further, as procurement professionals, in negotiations, sometimes talking to our negotiating supplier(s) about their interests and their needs can seem a bit anathema, since the drive to gravitate to positions in negotiations is highly prevalent

in many industries, including the biotechnology sector. However, organizations are notoriously poor in calculating hidden costs, change management costs - which can extend for years and sometimes decades - as well as governance and other costs. With today’s exponentially increasingly regulatory requirements, another major driver that organizations often find challenging is calculating the cost of quality. Within the classic project management triangle of cost, quality and time, the traditionally accepted notion is that there is a directly proportional relationship between the items. However, the opportunity cost of quality often remains unquantified. For example, if a contractual framework is agreed that does not adequately support business needs, quality will suffer, creating additional spend. Remember that when negotiating price and quality together, it is almost always cheaper to do work once, than have to re-do work due to quality issues. In short, making cost-based decisions has a first-row seat in any vendor selection and contracting, but it is highly important to maintain as holistic a view on potential costs as possible.

Identifying how to divide risk and benefits with vendors to facilitate the risk-sharing process

By including the stakeholder in the process, we obtain a negotiations process with dynamic capabilities. This creates a highly adaptable negotiations process. Going back to the second and third bullet points above, by focusing on interests rather than positions, any contract negotiations can adapt to any situation.

When the winds of change blow, some people build walls and others build windmills – Chinese Proverb

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Now, imagine expanding this from the internal business stakeholders to the full set of vendors within the supply chain; for example, having discussions within the business, as well as clinical data management, clinical monitoring and lab suppliers. A central risk in clinical trials is pulling in data on-time. By discussing this interest of data risk together with the full supplier base, suddenly numerous possibilities arise that would not be possible when simply indicating from the business to each supplier separately what the desired position is. It is a matter of brokering these discussions among the suppliers in order to come to reasonable and mutually equitable risk and benefit parameters that make sense for the sponsor business as well as for the supply chain of suppliers supporting the same.

Implementing adaptive strategies within your commercial framework in order to account for a changing environment

This is one of the more difficult outcomes to achieve. Here are a couple of skills to flex that can help, along with the investigative negotiations tactics discussed above, develop adaptive strategies that can be incorporated into the contracting framework.

• Investigate what your counterparts want, as well as why. Firstly, actively listen and inquire to achieve an understanding of what drives and motivates your counterparts at the supplier(s), as well as internal stakeholders. For example, ask for real scenarios that have occurred and would need mitigation, perform informal root cause analysis, then develop

plans in collaboration with all parties involved that will adapt and flex in the relationship framework to mitigate them. Also, guide the dialogue and maintain the framework of your negotiations according to interests rather than according to positions. Bringing this into the conversation in a consistent, across-the-board fashion will yield unanticipated results to the benefit of the overall framework.

• Seek to understand and mitigate your counterpart’s constraints. This methodology facilitates negotiators in overcoming obstacles, tempers attention on trivial differences and focuses dialogue on achieving mutually optimal results. This allows a highly collaborative discussion to take place across multiple stakeholders and companies in order to develop the type of adaptability often needed in today’s clinical trials.

Working with teams to develop a mitigation plan in case of issues during the trial

At this point, the contracts are all signed and work has begun. However, to use a metaphor, no one is doing the dishes and they are piling up in the sink - no one put a dishwashing strategy or risk mitigation plan in place.

If a duly diligent process of stakeholder support gathering and investigative and collaborative negotiations have occurred, then this is a problem that will almost resolve itself. The governance structure of a well-crafted deal will be fit-for-purpose, with the right levels of each supplier having clear corresponding contacts within the sponsor company as well as any relevant other suppliers in the supply chain. The stakeholder

support and buy-in, as well as the ensuing supply chain interactions during negotiations, will have created a strong governance team knowledgeable of each others’ capabilities and key players.

In short, as the framework is agreed, all parties should understand more than just unit pricing of a completed monitoring visit, or penalties and bonuses associated with data quality. All parties, internal business owners and relevant counterparts within the supplier base, should all further, and equally, understand the respective businesses, the escalation pathways for immediate resolutions, and the full governance model that is put in place within the framework to support execution of that framework. This allows for rapid decision making, mutual understanding and quick resolution of a multitude of issues.

In summary

Above is a highly practical approach to identifying organizational needs, parlaying these into outsourcing requirements, selecting the right suppliers to outsource, and finally developing a methodology for negotiating a fit-for-purpose, adaptable framework with one or more suppliers. Some of the elements of the approach require quite a bit of communication and follow-up, translating into a significant amount of work across quite a number of people. However, compare that bit of work with the amount of work to engage a series of suppliers to rescue a deal or a study gone south. The former yields far more effective, and long-lasting, results with a deeper impact on any organization.

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Julie Church-Thomas, Vice President, PCM Trials

esigning a protocol with the subjects in mind up front can make

a significant difference in the success of the trial long term. So much time, energy, and money is spent recruiting eligible patients that it makes sense to address the challenges of participating and staying in the trial at the beginning instead of fixing it down the road.

Utilizing in-home visits to recruit, retain and improve compliance can be a valuable tool. A protocol study design analysis done by a physician at the University of PA, illustrates the willingness of patients to participate in a clinical trial with different protocol designs.

Four of the protocol designs are represented above. As you see by the graph, offering in-home visits had the most significant increase (59% relative gain) in the willingness to participate in the trial.

A group of physicians at Duke University evaluated the

compliance of enrolled subjects in a pancreatic cancer study.

The graph above shows the dosing compliance of enrolled subjects comparing site visits to in-home visits. Over time, the subjects who chose home visits were more compliant than those who had to travel to the site.

Clinical trial services that can be provided in the home setting include activities within the scope of practice of an RN, that can be done with portable equipment, and that have an acceptable risk profile. The most common include assessments, con-meds, vitals, infusions, injections, blood sampling, and processing.

There are a small group of vendors who provide in-home clinical trial visits. The most typical model consists of a central coordination company that sub-contracts with local home health care agencies in close proximity to the site or subject. Their experience in research, hiring practices and operating procedures varies dramatically and so this extra

layer of administration and companies raises questions of risk and overall quality.

PCM TRIALS has a unique model in the U.S. where the company screens, hires, trains and manages all of their own clinical research nurses. All nurses are screened through the FDA, GSA, OIG/HHS, NURSYS and state licensing boards. Each nurse is trained, tested, and certified as a Certified Mobile Research Nurse (CMRN) on an annual basis in the principles of clinical trial research, GCP, Nurse Guidelines and IATA. PCM TRIALS also provides services to support in-home visits such as central pharmacy, equipment procurement and maintenance, and lab kit distribution.

i How Redesigning AD clinical trials might increase study partners’ willingness to participate. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2649726/?tool=pubmedii Feasibility of conducting home-based clinical trials in patients with advanced pancreatic cancer.http://meetinglibrary.asco.org/content/53984-74

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For further information and assistance in evaluating your current or upcoming protocol related to in-home visits contact [email protected] or call 888-628-9707.

U.S., Canada, and International Services Available

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Developing a patient-friendly protocol

Improve Recruitment and Retentionby Mobilizing Your Trial with In-Home Clinical Trial Visits

1.888.628.9707 [email protected]

Our Certified Mobile Research Nurses Set Us Apart

Lower�risk�…�Higher�Quality.�Only�with�PCMTRIALs’�CMRNs�can�sponsors,�CROs�andInvestigator�sites�be�confident�that�homevisits�are�carried�out�with�the�same�quality

and�care�as�on-site�visits.

Clinical Trial Home Visits Can Include:

· Protocol�defined�assessments· Assessment�of�adverse�events· Recording�of�concomitant�medication�

history· Administration�of�investigational�

product�(IV,�injection,�oral,�topical)· Accurate�source�documentation· Blood�draws,�processing�and�shipping· Collection�of�specimens�

(urine,�swabs,�etc.)· Training�for�trial�subjects

PCM�TRIALS’�CMRNs�are��screened,hired,�trained�and�managed�by�PCMTRIALS.�The�CMRNs�are�trained�andtested�annually�in�GCP�principles,�IATAstandards�and��SOPs.

U.S. and Global Services Available

http://www.pcmtrials.com

Establishing the strongest standards in quality control and assurance to ensure effective vendor qualification for small companies

Jeff N. Hunter, Vice President of Operations & Cheryl Kitchen, Quality Assurance Manager, Novan, Inc

or small, clinical-stage biopharmaceutical companies the decision

to outsource clinical programs to contract research organizations (CRO) is commonplace. The process of sifting through many potential CROs to a targeted list of vendors, a few finalists, and ultimately a partner can be daunting. Vendor qualification should begin with the end in mind: to identify, select and manage the CRO the sponsor believes will create the highest opportunity for a successful study outcome.

An integral step in the vendor selection process is the application of quality control and assurance standards. This article will look to explore some approaches to ensure suitably effective standards in quality control and assurance are set.

At the stage detailed below (see Figure A), it is critical to establish the relevant criteria for each respective sponsor used to evaluate prospective CROs.

With the CRO finalists, meeting the vendor’s team at each respective CRO office is essential for effective due diligence. This meeting provides the sponsor with the opportunity to share their development story

and express enthusiasm for the potential product. In return, the sponsor may attain insight into the CRO’s culture, team and commitment. What is the CRO’s attention to detail? Is the CRO team waiting to receive the sponsor when they arrive? Are they organized and efficient with the sponsor’s time?

Some of the issues encountered from a small company perspective include:

• Vendors talk a great game until the work begins.

• Sales teams are sometimes disconnected from service teams, making promises to secure the sale (i.e. specifications in contracts are not always communicated to operations). It is important to ensure the sponsor’s requirements are communicated

F to the right level in the CRO organization.

• ‘Small fish’ syndrome; however, it is important that vendors recognize the quality standards are the same for larger sponsors.

As with most small companies, limited resources make oversight a challenge; therefore choosing the right vendor who is attune to small company needs is critical. The level of due diligence should increase in order to fully appreciate the strengths and weaknesses of the prospective CROs with regard to their compliance with regulations and ability to quickly identify and resolve problems. Quality, trust and relationships, timelines and price should be important principles for evaluating the CRO finalists.

Figure A: Finalists Due Diligence

> 1,100 CROs TARGETS FINALISTS SELECTED

VENDOR

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Quality

Evidence of the CROs adherence to regulations through their quality system is essential. For example: 1) the integrity of the data submitted to the agency in support of an application; and 2) the protection of the rights and welfare of human subjects in clinical research.i An effective way to measure quality is with an audit which typically includes:

• Procedures review

• Records review

• Past history and compliance

• References

The outcome of the audit is a critical source of input for a risk assessment. Risk is defined as an event that has a probability of occurring, and could have either a positive or negative impact to a project should that risk occur. A risk may have one or more causes and, if it occurs, one or more impacts. If certain events occur, there likely will be an impact on the project cost, schedule or performance. Ultimately, what is the risk to the subjects or the risk to achieving the study primary end points if the sponsor selects a particular CRO?

In the following risk matrix (see Figure B), there may be a number of factors, which may vary for each sponsor, of the possible range of outcomes for the X and Y axis.ii iii These include; patient safety, use of electronic systems, site management, monitoring, vendor workflow and process, transparency of communication, regulatory compliance history,

how the CRO is held accountable for their deliverables, among others.iv

The letters correspond to a risk profile that each sponsor can create. The application of the risk assessment is to provide a framework for taking action. The following “grades” offer one example:

• D Grade: Extreme Risk, full vendor qualification audit, plus additional oversight required.

• C Grade: Comprehensive vendor qualification audit, review by web-ex, telecon, document sharing, frequent monitoring recommended.

• B Grade: Reduced vendor qualification effort is acceptable, monitor and react as needed.

• A Grade: Low Risk, an audit may not be required unless risk is elevated.

Trust and relationships; screening for intangibles

Vendor selection is both an art and a science. Trust and

relationships is the art part of the equation. How do you know whether you can trust the vendor? Meeting the prospective vendor team at the bid defense and when at their site is fundamental to establishing a basis for trust. At a recent contractor visit we found compliant records and the vendor employees were open and honest which gave us the confidence to move forward.

Critical to building trust is the aspect of culture. While divergent cultures between the sponsor and CRO can be managed and endured, such a relationship is not optimal and has potential for inefficiency and a negative impact on trust. Based on our experience, if something simply does not feel right, then it probably is not right.iii Seize every opportunity to ask the really tough questions face to face and point out any concerns or deficiencies. Ideally this conversation is held one on one or with a very small group.

Figure B: Risk Matrix

4 B C D D

3 B C C D

2 A B C C

1 A A B B

low 1 2 3 4

Likelihood of study failure - not meeting primary end points - for a prospective CRO

SUBJECT IMPACT

very good

good

critical

catastrophic

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Timelines and price

Timelines and price are constraints faced by most small companies and managing them effectively is the science part of the equation. Timelines should be realistic and based on actual, recent results for clinical programs of similar size and indication. Adhering to timelines requires full participation by both the sponsor and CRO, so encouraging input from CRO functional groups can promote better, creative, more efficient ways to conduct the program. Identify ways that the CRO can be held accountable for deliverables: deliverable-based versus time-based contractsiv.

Naturally, the CRO expects to be paid for their services and the sponsor desires to procure those services at what it considers to be a fair market price. Ensure a financial model (i.e. project based, FTE or hybrid) is compatible with both financial systems.v It may be useful to understand the CRO’s market capitalization as well as capital structure. Is the CRO a public or private company? If privately held, who has controlling interest and is there any significant risk associated with the ownership? What issues have the CRO team experienced recently i.e. layoffs, rapid expansion, high turnover, consolidation, acquisitions, etc.?

Once the best of the CRO finalists has been selected, the work that is to be performed must be agreed upon (see Figure C), with clear expectations in writing before beginning the project. A master services agreement is typical and should include other documents by

reference such as; regulatory standards, a detailed statement of work, CRO’s proposal, project related standards, regulatory expectations, data presentation, and study goals is crucial.

After the project begins, it is important to effectively manage the relationship. This requires a clear understanding of the most critical data, the systems that produce the critical data, and ‘triggers’ that tell the sponsor if the study is on track. For example, a trigger might be a delay in enrollment for a particular site. At that point, there are conversations and possible visits. The situation may require delving deeper and expanding your understanding in order to take effective action. Essentially, triggers are in place to react quickly to ensure proper use of procedures and protocols and other compliance documents required to execute the program.

The criteria sponsors use to select a CRO will vary given differences in culture, resources, personalities, and priorities. The good news is that there are highly competent and worthy CROs eager to partner. Moving from study execution to vendor management is a challenge for

many small biopharmaceutical companies. The sponsors who master this skill set will have a competitive advantage in achieving successful clinical results.vi

REFERENCESi Anderson, Carl, Cathy Tashiro and Laurie Taddonio (May 2007). Vendor Quality Assurance Audits: A Formula for Success. Applied Clinical Trials, 56-60. ii Muchemu, David N (2007). Change Control for FDA Regulated Industries: A Risk Assessment Approach. Bloomington: AuthorHouse. iii Rabe, Fran (2009). Vendor Qualification. Molecular and Cellular Therapeutics, University of Minnesota.iv Hart, Michael J. (June 2014). Managing the CRO Relationship: From Engagement through Delivery. Boston: Clinical Trial Oversight Conference.v Jenke, Dennis (2013). Qualification and Utilization of CRO Partners: Forming a Sensible CRO-Contracting Laboratory Partnership. Baxter Healthcare Corporation. vi Tyson, Gary and Tim Dietlin (June 2004). Working with CROs. Pharmaceutical Executive.

Figure C: Vendor Selected – Now the Work Begins

> 1,100 CROs TARGETS FINALISTS SELECTED

VENDOR

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To outsource or not to outsource? Exploring quantitative and qualitative issues to consider when determining an appropriate outsourcing strategy

Chris Chan, Senior Director, R&D Finance, Fibrogen

uring life’s journey, we encounter challenging dilemmas that have

significant repercussions to our existence. Which college major should I choose? Should I marry this person? Should I bundle my cable and internet? In the life of a development-stage biopharmaceutical company, an equally important decision is what outsourcing strategy to pursue. Given the enormous cost of drug development and the inherent complexity of the development process, this decision may play a key role in determining whether the company ultimately achieves its goals. This article will explore some of the quantitative and qualitative issues to consider as companies try to determine what outsourcing strategy is right for them.

Quantitative factors: which model is most financially beneficial?

Henny Youngman once said, “I've got all the money I'll ever need, if I die by four o'clock.” For companies that plan to live on, money is obviously one of the

biggest factors in determining which outsourcing model to pursue. Most subscribe to the high-level notion that outsourcing is generally more expensive than hiring in-house, but offers greater flexibility to adjust to the roller-coaster resource needs during the course of clinical trials. But the actual nuances are a bit more complex. To better understand these nuances, let’s quantitatively analyze a simple hypothetical example:

Let’s assume that your company is planning a pivotal trial consisting of 300 patients and 30 investigator sites (U.S. only). Over the expected two year study duration from a site monitoring standpoint, you

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expect 60 prequalification visits, 30 initiation visits, 600 monitoring visits (20 visits per site over the course of the trial), and 30 close-out visits. You now want to determine the respective costs of fully outsourcing this job versus hiring in-house monitors.

After receiving proposals from several CRO’s (Contract Research Organizations), the “winning” bid of $2,137,800 is broken down as follows (Exhibit 1).

For the in-house comparison, let’s assume a “fully burdened”

cost of $200K for a CRA FTE (note: “fully burdened” means estimated salary and benefits plus a share of all electricity consumed, coffee ingested, pens chewed, and other overhead costs). Assume 2,000 labor hours per FTE per year (52 weeks x 40 hours per week, less 2 weeks in Hawaii), or 4,000 labor hours over two years. Given that the site visits are expected to total 15,090 labor hours, this equates to approximately 3.8 FTE’s. Ergo, the company would theoretically need to hire 4 CRA’s at a cost of

$800K per year, or $1.6 million over two years.

In this admittedly simplified analysis, hiring in-house would result in a nifty $0.5M savings, or 25%.

But like the first chapter of a mystery in which the spouse’s fingerprints are found on the murder weapon, things are not as simple as they first appear. For instance, there may be additional costs to hiring in-house such as sizable recruitment fees and outplacement/severance payments (if employee transfers to other programs are not feasible at end of study). So let’s refine our analysis by assuming that two of the four hires will require recruitment fees of $50K each, and that two will require severance payments of $50K each at the end of the study. When these costs are factored in, the in-house option only results in a relative saving of only 16%.

Category Activity ResourceHourly Rate

Hours / Unit

Base Unit Price

Units (Visits)

Total PriceBlended Hrly Rate

Total Hours

Site visits PreQual Visits Project Mgr $ 175 1 $ 175

CRA $ 140 14 $ 1,960

$ 2,135 60 $ 128,100 $ 142.33 900

Initiation Visits Project Mgr $ 175 1 $ 175

CRA $ 140 16 $ 2,240

$ 2,415 30 $ 72,450 $ 142.06 510

Interim Monitor Visits Project Mgr $ 175 1 $ 175

CRA $ 140 21 $ 2,940

$ 3,115 600 $ 1,869,000 $ 141.59 13,200

Close-out Visits Project Mgr $ 175 1 $ 175

CRA $ 140 15 $ 2,100

$ 2,275 30 $ 68,250 $ 142.19 480

TOTAL OUTSOURCING COSTS: $ 2,137,800TOTAL OUTSOURCED LABOR HOURS: 15,090

Exhibit 2

Outsource $ $ 2,137,800

Hire in-house $ (assume 4 FTE’s at $ 200K/yr x 2 years) $ 1,600,000

$ saved by hiring in-house $ 537,800

% savings 25%

Exhibit 1

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Now, let’s ponder this fascinating question: in the history of drug development, has it ever occurred that a clinical trial didn’t go exactly as originally planned? More specifically, has any timeline ever proven to be at least somewhat optimistic and reality not quite match those pretty Gantt charts? Because in-house employees are a “fixed cost,” should the study experience delays, the company would still be obligated to pay their salaries for the entire duration. Let’s assume, then, that due to slower than expected site initiations and patient enrollment, the trial takes an additional six months to complete. This would result in incremental internal costs of approximately $400K. Not only would this perfectly reasonable scenario completely negate the cost benefit of hiring in-house, it would result in a $62K cost disadvantage.

The longer the delay, the greater the financial disadvantage of the in-house option. Of course, this hypothetical analysis assumes all outsourcing costs are fully variable. In reality, most outsourced contracts contain at least a portion of fixed costs (usually in the form of surreptitious “monthly management fees”). Nevertheless, the example demonstrates how other macro factors must be taken into consideration when performing any quantitative cost analysis.

Qualitative factors: the world beyond near-term costs

On the first day after joining a new biotech earlier in my career, I flashed a bag of chips to the cashier and asked how much I owed. Cashier: “Nothing.” Me: “I realize I’m cute and charismatic, but I insist on paying for my food.”

Cashier: “No, really. The chips are free. For everyone. So are the cookies, drinks, and fruits. You only pay for the hot foods.” Me: “Is this the cafeteria or the Garden of Eden?” Some companies do not emphasize short-term cost savings as materially as others. The aforementioned biotech, for instance, concluded that having a superior internal workforce was an essential success driver. As such, the strategy was to hire and retain the best in-house talent it could find, and outsource only those functions it deemed to be “non-core.” Additionally, it was willing to pay extra for better

benefits and tasty snacks to keep the workforce happy. For companies believing similarly, the relative cost of outsourcing vs. hiring is obviously much less relevant to their decision-making. Even if salary and other employee expenses are determined to cost significantly more than the outsourcing alternative, they will gladly pay the premium to adhere their philosophy.

Similarly, what if the company places great importance on having direct control over personnel? This pertains not only to having more say in the

Exhibit 3

Exhibit 4

Outsource $ $ 2,137,800


Recruiting and severance costs $ 200,000

$ saved by hiring in-house $ 337,800

% savings 16%

Outsource $ $ 2,137,800


Recruiting and severance costs $ 200,000

Six month delay due to slower than expected enrollment, etc. $ 400,000

$ saved by hiring in-house $ (62,200)

% savings -3%

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way work is performed, but also to having more direct influence on who works on the program. For instance, CRO’s and other vendors have been known to lose key personnel to attrition or, more frustratingly, move them to different (i.e. more potentially lucrative) accounts. If a given CRO is helping your company run a smallish Phase 2 study on a stringently negotiated budget, would it be surprising to find your CRO inclined to migrate its best talent to a new deeper-pocketed customer who promises more and bigger studies? While it’s true that contracts often specify a certain degree of personnel input on the part of the sponsor, that “control” is usually limited to the sponsor being granted opportunity to review and accept new and replacement people. Hiring one’s own in-house key personnel would result in more direct control over personnel.

Additionally, time is also an important qualitative consideration. When hiring in-house, the time it takes to (a) find the right candidates; (b) complete all interview rounds; (c) decide on whom to give offers to; and (d) await target candidates’ arrivals after they give timely notice to and fend off counteroffers from previous employers, could take many months. Even if the company decides to bridge the time gap with consultants, finding good consultants can take time as well. However, CRO’s and service providers have experienced and capable personnel ready to hit the ground running once the contract is signed. If time is recognized as an overriding factor, outsourcing may arguably be the more

advantageous choice, at least during the earlier stages of clinical trials.

It’s interesting to note that even qualitative factors ultimately revolve around financial considerations. Strategies such as ensuring access to superior talent and getting trials started quickly are basically just ways to increase efficiency and hopefully get drug candidates to market as soon as possible. Some companies look at every “time to market” day saved or delayed in revenue terms: if a drug candidate with a limited patent life is assumed to be a $1 billion a year blockbuster, every day saved in the development process may equate to over $2 million in additional revenue and every day delayed the equivalent loss. Taken from that perspective, the incremental expenses associated with many

of the qualitative considerations discussed seem much less material in the big picture.

Conclusion

Deciding on the appropriate outsourcing model is strategically important to any biopharmaceutical company. Because every company (like gentle snowflakes) is different and vary in ideology and personality, their most feasible outsourcing strategies must also respectively vary. Therefore, it is important for companies to fully evaluate all pertinent quantitative and qualitative factors to determine their most appropriate strategy. Some may even discover that with all the immense efforts focused on achieving the worthy goals of successfully developing better treatments for patients and increasing value for shareholders, the difference maker may be free potato chips.

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http://www.woodleyequipment.com

Exploring strategies for enhanced vendor selection which avoid the costs associated with a breakdown in sponsor-vendor relationship midway through a trial

o ensure a successful sponsor-vendor relationship throughout

the life of a trial, it is helpful to carefully consider the following:

• Global reach• Therapeutic area experience• Cost considerations• Niche providers• Interviewing key team members

Global reach

When considering global reach, think about the regions and/or countries you would like to use for a given trial or program. Primarily, it makes sense to conduct the trial in countries that will enroll quickly because enrollment conditions can vary greatly from country to country. It is also important to investigate the regulatory conditions of each country. In some cases, the regulatory environment can present many unwelcome challenges. Checking with your marketing team is also a good idea; typically, it does not make sense to conduct clinical trials in countries where you do not plan to market the compound.

Sometimes, you may not want to use a specific country for a single trial, but you may want to include this country somewhere within the development program for the same compound. If this is the case, it would be smart to work with a CRO that has capabilities in all of the potential countries. Consider a large CRO with a broad global reach if you think that you will ultimately want to include sites across many countries. However, if your marketing strategy is country or region specific, it would be best to utilize a smaller provider that knows the region well and is not required to support a large global infrastructure.

Therapeutic area expertise

A vendor’s therapeutic area expertise is important if the trial design demands a specific understanding of the indication. This is often not the case in regards to scientific expertise, because this usually lies at the sponsor. However, a vendor with a great deal of operational experience in the same indication could prove

T

Rick O’Hara, Associate Director, Clinical Outsourcing, Endo Pharmaceuticals

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very helpful! Ideally, it would be great to procure a provider team that is “fresh-off” a successful trial in the same therapeutic area which is just winding down. For the record, obtaining a team of this type is highly unlikely, but it doesn’t hurt to shoot for the stars. In an effort to obtain the best team for a given therapeutic area, request CVs for all of the key members of the proposed team and verify that these individuals were also team members on the recently completed trial(s). The entire team does not necessarily need to be presented for your trial, but investigating the expertise and experience of the key players (i.e. Project Manager, Lead CRA, Lead Data Manager, Lead Biostatistician) will go a long way toward ensuring success. Also, ask probing questions to verify that previous trials were actually successful (i.e. metrics related to site readiness, enrollment and Data Cleaning, and forecasted vs. actual timelines). Strategic operations and feasibility plans should also be requested as part of your request for proposal (RFP).

Cost considerations

Cost considerations are always important! Contrary to previous assumptions, sponsor funds are limited and should be carefully safe-guarded. Sponsor companies have been increasingly cautious with R&D budgets which means that any funds spent with a vendor should be competitively bid and results oriented. Greater costs do not necessarily equate to better quality and teams should, therefore, seek to verify quality via infrastructure and processes.

These may or may not increase costs, but an increased price alone will not guarantee a high degree of quality.

Vendor pricing should be transparent and the cost/benefit of the services should be easily justified. When a vendor can provide transparent pricing, it is an indication that they truly understand how to efficiently manage their business. It also shows that they employ professional and reliable staff and that they are successful at resource planning. Careful resource planning is crucial for all vendors, especially service providers.

The internal team will often generate a great deal of passion for one CRO or another, based on an effective bid defense, good chemistry or past experience. These are all important components, but they should not automatically trump the importance of appropriate pricing. Even the happiest of Sponsor teams will turn sour on a CRO midway through a trial if

they feel like they are paying too much. An unjustifiable budget makes it tough to pass the “red face” test when confronted by senior management. This is especially when the trial experiences set-backs or delays which almost always seems to be the case. In addition to transparent pricing, the CRO should be able to accomplish the following:

• Easily map their proposed budget into your preferred bid grid

• Commit to mutually agreed fixed price units

• Commit to one (1) comprehensive Project Management Unit!

• Commit to a deliverables-based milestone payment schedule

Niche providers

Niche Providers or Functional Service Providers (FSPs) can serve as a perfect solution. An example of this would be if you have a consistent need for a specific function that does

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not currently exist in-house (i.e. IRT or investigator grant payments). These are functions that the sponsor may choose not to develop in-house so it makes sense to partner with an FSP. Other examples of ideal FSP solutions might be a data management FSP in a lower-cost geography, or a region-specific team of monitors. Successful implementation and utilization of FSPs like these could result in substantial savings.

The up-side of partnering with a niche provider or an FSP is that these vendors usually employ very seasoned staff. They are also likely to have more experience within that specific function than a standard CRO, so they have probably built a strong infrastructure and processes. The down-side of partnering with niche providers or FSPs is that their service offerings can be somewhat limited. This might require that a sponsor may end up working

with several disconnected FSPs at the same time, which could result in an administrative nightmare.

Overall, it is most important to select the correct vendor for the trial at hand. You shouldn’t “fall in love” with your CRO. Successful relationships with CROs are always a plus, but that specific CRO may not be the appropriate solution for all of your trials. Force-fitting a CRO on a given clinical trial team could create unexpected negative consequences.

Clinical teams should also be careful not to be distracted by shiny baubles. There are many innovative vendors that are proposing new and unique solutions; these solutions may be appropriate for your trial, but in many cases, they can be more trouble than they are worth. Before pursuing a new and innovative solution, ensure that it is compatible with your current clinical trial systems and processes.

Interviewing key team members

Requesting to interview key team members is a perfectly reasonable expectation. As the team prepares the RFP, they should identify the ideal skill-sets and qualities that they would like to see in key roles (i.e. PM, DM, Statistician, etc…). This way they will have an additional tool with which they can compare proposals. And once the final candidates are identified the key team member interviews can help to make sure the best vendor is selected. Including a “key personnel” clause in your contract verbiage is also a good idea. This will highlight to the vendor that this position(s) is crucial which will help to align expectation throughout the entire trial.

In closing, careful consideration of all of the topics listed in the beginning of this article will significantly help to ensure a successful sponsor-vendor relationship throughout the entire trial.

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Clinical R&D Consultancy Traditional and Adaptive Clinical Studies Biometrics Pharmacoepidemiology Pharmacovigilance Expanded Access Programs

The orchestra that hits the right tone

ICTA Headquarters - 11, rue du Bocage - 21121 Fontaine-les-Dijon - France - Phone: +33 (0)3 80 53 40 00 - Fax: +33 (0)3 80 57 10 22ICTA UK - Unit A4 Whitecrook Business Centre - Whitecrook St - Clydebank, Glasgow G81 1QF - UK - Phone: +44 141 952 1630ICTA GmbH - Lebacher Strasse 4 - 66113 Saarbrücken - Germany - Phone: +49 (0) 681 99 63 409 - Fax: +49 (0) 681 99 63 111

INTERNATIONAL CLINICAL TRIALS ASSOCIATION

International Full-Service CRO

www.icta.fr - [email protected]

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Exploring best practice strategies in contract development between sponsors and vendors to ensure aligned expectations throughout the trial

hen planning your project or study you need to carefully think

about the collaborations needed; what do you need, when do you need it, who should do it for you, and how should these things be done? A potential vendor will need to carefully listen and fully understand what a sponsor is asking, whilst a sponsor needs to fully comprehend what exactly the vendor can offer. This will lead to and help you prepare an effective outsourcing strategy.

As a sponsor you will need to seek collaborations both internally and externally when developing a contract, in order to promote an open forum for negotiation. Depending on your study/investigation plans you may need to seek collaborations internally with R&D, marketing, regulatory departments, as well as different regional offices of your organisation. On an external side of things; you may need to focus on collaboration with scientific input, from the project leader, study manager or someone with CRA/monitoring capability. Depending on your needs and what the vendor is offering you, this could lead to agreements about preparing the CIP, searching for countries and sites for study start up, creating CRFs, setting up data management processes, statistical analysis plan, study management and monitoring.

The next step in the contract process, once the needs and requirements have been duly identified, is to be extremely specific. It is important to fully understand what is expected from both parties; you as a sponsor should consider a vendor’s therapeutic speciality, size, organisation, geographical representation and local knowledge and set up a detailed specification and create the ‘Request for Proposal’. The vendor will review this and revert back to you with a proposal and if you are in agreement, you should decide whose templates to use and begin development of the Work Order and the Contract. At this stage, questions still need to be asked to ensure transparency between sponsor and vendor to explore any potential training needs that may need to be considered.

It is important, in regards to liability and responsibility to avoid any confusion during the study. For the Work Order, for example, create a Gantt-chart, define tasks and deliverables and indicate responsibilities. Ensure that these include measurable milestones and timelines but remember that there will always be changes during the study. These changes should be defined in ‘Change Notifications’ which should include all aspects that could have an impact on the responsibilities,

Johan Ivarsson Blechert, Clinical Research Manager, Cochlear Bone Anchored Solutions

timelines and costs for example. Eventually these ‘Change Notifications’ will be gathered in a Change Order to the original Work Order. In this way the sponsor and vendor will have full control over what has happened during the course of the study.

To further strengthen the liability and responsibility it is imperative to continue with close communication. This can be done by ensuring main ‘channels’ for communication are set up; for example by arranging study meetings in a regular and effective way that suits both parties with detailed minutes taken.

Throughout the collaboration, encourage honesty to ensure sponsor expectations are clear and vendors are open about any challenges that they may encounter. Promoting and encouraging open communication during meetings and other communications is essential to explain your positions so both parties are aware of the strong and weak points. Also, be clear about the reporting and expect that problems and issues are presented in a clear and constructive way. It is always beneficial to look for solutions instead of pointing the finger and ending up in ‘blame situations’ as this will take energy and focus from the study.

W

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From a sponsor point of view you always need to consider contract negotiations strategies to maximise the value for service at the lowest possible cost. In this process vendor evaluations are an important part of the negotiation process. These evaluations are critical for the outcome of the study in respect of budget and quality, so remember to involve the necessary stakeholders in the decision making process. The process of evaluation and negotiation with a potential vendor can involve a number of different processes, for example; bid defence meetings, on-line auctions, team-scoring, customer references and previous experience. Once the sponsor has decided on carrying out a vendor audit, it is a must to fully know what the vendor is capable of and if the cost is reasonable.

When considering effective negotiating strategies it is worth looking at the vendor size and what overhead costs they have – what are the effects that this may have? Should a small sponsor avoid a larger vendor? Also important are the pass-through costs; this can provide the sponsor a signal of how efficient the vendor is and if some tasks should be taken care of by the sponsor if possible. It is also important to remember to check the need for sub-contractors at any point, to avoid or minimize unforeseen costs.

For all studies and projects it is important to try to predict problem areas, to enable contingency plans to be developed by both the sponsor and the vendor. Risk Management is an important part of the prediction of risks and

therefore the necessary planning required. Risk Management is the process that enables identification, assessment, planning and management of the foreseen risks associated with a study or project. Often sponsors and vendors are successfully using Gantt-charts when considering the risks in terms of; how likely they will occur, what impact they will have, what contingency should be put in place and the responsibility of monitoring the risks and implementing the contingency.

Finally when going into a collaboration and contract between a sponsor and a vendor remember to have a clear idea of what you as a sponsor want to do; be extremely specific, carefully decide responsibilities and encourage working with risk management processes.

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● Full-service Contract Research Organization● Phase I-IV Services● Local Knowledge/Global Presence

The premier source for outsourced drug development solutions.

The Partner that Shares Your Mission

[email protected] I www.pharm-olam.com(713) 559-7900

http://www.pharm-olam.com

hy should vendors want to work with small pharmaceutical

companies? What’s in it for them? How do you know it’s going to be a good fit in the short term, and could there be longer-term benefits? These were the types of questions that were addressed in the May 2014 Outsourcing in Clinical Trials East Coast meeting, and

Ensuring enthusiasm for a fabulous working relationship between small companies and vendors

this manuscript summarizes and expands upon some of the key thoughts expressed by the author and by some of the audience members during the question and answer session.

The presentation explored ways in which vendors and small pharmaceutical companies should evaluate working together to enable successful clinical trials of various

magnitudes, from small, focused studies to large studies that may span the globe.

From a sponsor’s perspective, there are many vendors from which to choose. A component of setting your trial up for success is evaluating the competitive landscape to determine which vendor is the best for the trial and your company. Relationships with vendors may be pre-existing or may be new. While an informal network influences which vendors may be considered early in the process, eventually a more formal evaluation including a broader group of vendors may ensue. A request for proposal (RFP) and phone calls or meetings prior to and after delivery of the RFP is often part of the process. Letting your prospective vendors know what is most important to you enables them to showcase their ability to meet the demands of your study. Confirming that your prospective vendors are in a competitive process is appreciated, and allows each vendor to address the marketing claims of the others. Ideally, vendors will demonstrate with their proposals that their products and services

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Ruth Ann Subach, Director, Clinical Operations, TrevenaThe opinions presented are those of the author and may not be held by Trevena, its investor, or partners.

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are a good fit for the study and their business model is a good fit for the sponsor.

Once you’ve narrowed down to a couple of vendors, the job of the sponsor focuses further on ensuring the most suitable vendor is selected to ensure their skill set is complementary to the needs of the trial. Comparing and contrasting of vendors continues in greater depth as you are evaluating the responses to the scope of work. In some cases, it is important to determine if the vendor has specifically done the type of work that you are intending to do, exploring not only services but therapeutic areas as well.If they have not, it is extremely critical to ensure that they have done similar types of studies or can transfer knowledge from other types of studies to yours. What I have found most revealing is when a vendor under consideration comes to you with innovative solutions to challenges that you have presented.

For example, for one study, I evaluated vendors who had the capability to provide software for a study-specific pharmacodynamic test. This was a new type of vendor to evaluate and required additional time on my part to understand the technical capabilities and compliance considerations. All of the vendors that were evaluated could have provided the services, however one vendor was able to communicate to us in “our language” to best describe how they were going to develop and implement the

tool for use in the study. This group demonstrated flexibility with regard to developing the tool, and worked with our primary clinical research organization(CRO) and with each of the sites at the investigator meeting to ensure that the tool was easily understandable and fit into the sites workflow. The collaborative nature allowed us to develop a tool that was successfully used in the study.

Understanding the vendor’s relationship with other vendors that have already been awarded work on the same project is important as well. Often times their feedback about these relationships can prove to be helpful from understanding how a vendor works operationally but also how they function as part of a team.

Strategies that smaller companies can use to outsource their trials on a larger, global scale are numerous, and evaluating a vendor’s ability to work globally can be challenging. It is important to demand specific metrics about countries the vendor has worked with, and how recently. Vendors should demonstrate proficiency in all aspects of study start-up, maintenance, and close-out in the countries that you are intending use, and provide information about recent challenges and regulatory or ethics approval of clinical trials in the region.From the standpoint of clinical trial feasibility, vendors should be able to demonstrate that the type of study that you are planning to conduct has been conducted in the countries that you are considering, and that

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the vendor has access to the sites/investigators that have relevant experience.The vendors should offer access to medical experts within these countries in order to fully understand the standard of care in the disease area and how that may impact your clinical trial. Lastly, the ability to stay on top of day-to-day changes in political and economic environments should be demonstrated by the vendor, as world events having nothing to do with medicine can alter the course of clinical trial conduct within a region within in a rapid timeframe. As studies increase in number of countries or regions, the complexity of project management increases; mechanisms to ensure consistency in global and regional messaging should be developed, utilized, and evaluated frequently to ensure adequacy.

Establishing enthusiasm from the vendor team to ensure they are invested in your trial is a goal for most sponsors.I believe it is the sponsors who must be the most enthusiastic people on the team; so how do you spread that enthusiasm? By building direct relationships with the people on the vendor team! These relationships are very important in establishing and maintaining a sense of responsibility from each of the people involved in the study.The strategy that I enjoy most is to meet my team members face-to-face and get to know them as people and team contributors. I also enjoy explaining the interesting parts of the trial,

how the trial fits into the development of the drug, and how the drug may potentially influence the treatment of patients in the future. I ask for their input into the trial and I ask them to spend time thinking about the trial as if they were employed by the sponsor. I am often able to determine quickly if the person working on the study is able to view the trial from that perspective. I have found that when people from a particular vendor are able to think this way, the vendor’s corporate culture encourages them to think this way, and it is an indicator of a successful business relationship.I have also found that studies are more challenging to conduct when team members cannot find at least some enthusiasm for the trial or some ability to put themselves into the “sponsor’s shoes”.

Working together is a two-way street. What might be the advantages to vendors of working with a smaller pharmaceutical company, and how should vendors maximize on these relationships? Each vendor should ask themselves, from a both a scientific and business perspective, “why would we want to work with a small company that may only have one or two clinical studies?”

This is a great question. Clearly the larger pharmaceutical companies will have the potential for larger numbers of clinical trials, and in some cases, larger companies will

establish preferred provider relationships to guide the interactions. However, when working with smaller companies, you may have the opportunity to work with a tight knit team of people who are engaging in innovative research and may stretch the boundaries of activity beyond the status quo. You may have the opportunity then to participate in unique or groundbreaking types of studies, and to contribute directly to something new. It’s true that some sponsors may be “one hit wonders”… but it’s a small world. You’re bound to run into team members again, and having performed a spectacular job in the face of an uncertain future with a company, you’ve gained the respect and trust of people who will be working elsewhere in the future.

In summary, teamwork and clear communication, regardless of the size of the pharmaceutical company and vendor, are the keys to success, both in the near- and long-term future.

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Matthew Voicheck, Assistant Director, CentralSource, Myoderm

Alleviating the pain of independent site sourcing

W

Matthew Voicheck, Assistant Director, CentralSource, Myoderm

Matt has over a decade of industry experience and leads CentralSource, Myoderm’s revolutionary turnkey drug sourcing, distribution, and management solution for clinical trials.


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hen sponsor companies require clinical trial sites to source commercial

drugs and ancillary supplies independently, it can impact the outcome of clinical trials. Sites often lack the expertise, time, resources and processes for efficient and effective supply chain management. It is critical that sponsors evaluate these challenges and optimize their sourcing strategies to minimize risk and maximize success.

Identifying the risks

Independent site sourcing can be challenging. Trial sites, especially in emerging markets, oftentimes lack the trusted supplier network to source the initial and ongoing supply of commercial drugs and ancillary products. And, the opportunity for volume cost savings is lost.

The risk of not obtaining these products leaves trials in jeopardy of disruptions and delays due to missed doses or dropped patients. Even when supply is successfully sourced by independent sites, trial integrity is at risk due to lack of standardization from site to site.

Ensuring product integrity is crucial. Sponsors need to understand sites’ storage capabilities and capacities, and clearly communicate expectations. Storage at clinical sites is often at a premium, especially for cold chain products.

Ongoing inventory management at clinical sites can be challenging as well. Relying on sites to ensure proper supply levels is only one piece of the puzzle – products stored at the sites require staff to monitor expiration dating and recalls, handle those recalls, and keep detailed records for lot traceability.

Centralization for simplification

The complexities involved with independent site sourcing pose an obvious threat to clinical trials. But there are alternative solutions that can alleviate these challenges and minimize risk.

Pooling commercial drugs and ancillary products at a central warehouse is one option. This takes the burden of sourcing off the individual sites and places the responsibility with an experienced sourcing specialist, giving sponsors control over purchasing and approval.

Centralization mitigates the risk of not being able to obtain the product needed and reduces costs by taking advantage of a specialist’s volume purchasing power. Consolidated storage and shipping provides additional cost savings.

Utilizing centralized storage improves inventory management. With established resupply levels,

trial sites can be supplied on an ongoing, as needed basis, throughout the length of the trial. And, the standardization of products from site to site, with the centralized monitoring of expiration and recalls, protects trial integrity and enhances patient safety.

Choosing an experienced sourcing partner is integral to the success of a centralized sourcing program. Larger IMP distributors do not typically have the streamlined processes and capabilities, which is why it is important to identify a sourcing and distribution specialist with deep expertise.

The value of centralized sourcing is clear. The benefit it provides, along with the risk it eliminates, is why an increasing number of sponsor companies around the world are using this option.

myoderm.com

For us, they’re not hard to find.Myoderm knows what’s at stake for our clients, so we scour the world for the comparators they need for clinical trials. Our ability to locate restricted and hard-to-find drugs is unmatched. And we can handle both one-time shipments or the ongoing management and delivery of drugs and supplies to local trial sites. That’s why eight of the world’s top ten pharma companies place their trust in us. You will, too.

© 2014 Myoderm. All rights reserved.

MYO-140_Corp_WordSearch_JCS_210x297.indd 1 1/10/14 3:17 PM

http://www.myoderm.com


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http://www.bappharma.com

harmaceutical and biotech companies both big and small are

finding that a greater proportion of the clinical trial budget is being apportioned to the clinical trial supply chain. Arena International’s recent Clinical Trial Supply East Coast Conference, that took place in Princeton, NJ in October 2014 offered two days of shared learning's and challenges associated with the growing complexity and sourcing requirements to support the increasing complexity and challenges of global trials. Contrary to assumed differences based upon company size, the discussions highlighted common threads, challenges and proposed actions to develop streamlined and program responsive supply chain management strategies. The ongoing challenges of sustaining timely supply of both comparator drugs and drug product to meet both complex regulatory challenges and trial designs emerged as an area that should be treated as a critical strategic imperative. Among the key considerations the speaker faculty at the event focused on the following aspects:

Clinical supply chain challenges: Shared perspectives between pharmaceutical, large-cap and emerging biotechnology companies

Albine Martin, Executive-in-Residence, John Hopkins University

Maximizing the efficiency of drug product and comparator drug supply in a manner that minimizes overage and waste

Early planning processes emerged as a common concern differentiated only by internal or external stakeholders and influencers of the supply chain. In the case of the emerging company; success at this stage was overwhelmingly dependent upon developing a strategic relationship with its Contract Manufacturing partner and Contract Research Organization. With the larger and well resourced biotechnology and pharmaceutical sponsors, the need for including supply chain planning with internal stakeholders during the trial design and budgeting stages was noted as critically important. The typical challenge was one of effective communication across functional areas which may be historically stove-piped between the strategic and tactical functions within these organizations. However, the complexity of trials and risk of supply now requires much closer and more proactive interaction between teams to communicate to the supply

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management functions in "real time". Close integration between the clinical operations, supply logistics and program management teams surfaced as an absolute requirement to minimize delays and maximize efficiency of supply. The pinch points should occur with a minimum of 6 months prior to the inception of the program and then on an ongoing basis particularly as studies transition and demand curves change due to trial outcomes or events within individual countries.

The emerging company on the other hand relies heavily on third parties, including its CMO and potentially its CRO to support these planning stages. These outsourcing partners must be provided with an understanding of the business and investor goals and embrace the fact that the sponsor often lacks the expertise and breadth of experience to support the planning and execution stages. Likewise, the sponsor must be willing to embrace this type of exchange and expose its external partners to the status of individual sites and any adverse events which impact trial design or original assumption sets.

Sourcing of comparator drugs is becoming more challenging and must be considered with equally important and early planning

In addition to communication the tools and approach for high quality advanced planning and forecasting system was highlighted. The importance of adequate lead times must also account for supplier backorders, regulatory delays, distribution to specific geographic sites to meet the labeling requirements.

Estimating global supply at the onset of the trial must be kept current with a clear process of ongoing updates so supply management can implement a "just in time" inventory plan or have adequate lead times: at least a couple of months to respond to country specific requirements.

Key considerations for effective adaptation to program changes in a manner that continues to secure supply of drug product

The emerging company viewed its drug product management strategy as a "make or break" decision point as it can represent a significant percentage of its financial resources with little or no margin for error. Cost combined with manufacturing lead times especially for biologics led both the emerging and large biotech company to adopt a strategy of holding reserve supply in the form of Drug Substance which can be converted to Drug Product with shorter lead times. Establishing a strong partnership with the CMO

was especially vital and viewed as a long term relationship by the emerging partner especially for a first in man drug product. Since trial size was going to be variable, the plan had to include small lot manufacturing of drug product for Phase 1 with the expectation to optimize and scale as the trials advanced. Sponsors with large global trials added a product "relabeling" strategy to manage drug supply as they obtained extended stability data.


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This allowed substantial flexibility in securing supply across different sites and countries. The complexity of managing this supply increases with multiple dosing requirements and comparator drugs which need to be matched and accompanied by individual quality assurance and release documents to confirm chain of custody. The importance of the partnership model with the CMO included visibility to all raw material costs, longevity of the technical team, ability to troubleshoot and address unforeseen issues during the engineering runs and translate the learning's to the final cGMP drug product.

Exploring factors to optimize selection of vendors and managing expectations and deliverables

Vendor selection criteria may indeed vary based upon the skill sets and requirements defined by the sponsor but the goal of achieving a partnership with this partner was identified as a uniform goal. A partnership defined by common goals such as continuous improvement to achieve cost savings, accessibility to decision makers, high quality project management and ability to adapt to change will sustain a mutually beneficial relationship. These factors have to be supported by technical

capabilities and services such as product packaging, IVRS capability and knowledge about implementing alternative packaging or delivery of drug product globally. The vendor should have the capability to interface with the clinical sites to implement the most effective supply chain strategies in order to minimize waste and rationalize inventory levels held as finished product. Likewise the sponsor should implement an objective process for evaluating and selecting vendors such as; vendor scorecards, standard RFP templates and a management system that is based upon clearly communicated roles and responsibilities.


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Our teams at Fisher Clinical Services know that every day brings another opportunity for a life-saving, world changing breakthrough. We conduct these trials under the highest quality standards and we’re driven by a deep appreciation for all that is at stake. For more than 25 years we have been solely dedicated to servicing the unique requirements of clinical trials across the world.

http://www.fisherclinicalservices.com/about-us/

etting serious about reducing clinical trial costs means changing

your mindset and adopting new processes that will put power back into your hands.

We know that studies are costly and are becoming increasingly complex. These trends are driving up the costs of traditional supply chain services that depend on study forecasts, which often fail to predict and efficiently respond to unplanned study changes. This article will offer you three innovative approaches to supply chain management in which you can adopt to combat these growing complexities in a manner that will keep your study’s costs low and predictable.

Package and label supplies as needed

A clinical trial’s timeline plays an important role in not only the overall cost and budget, but it can significantly help or hinder the launch of a new drug. With traditional packaging and labeling, a typical lead time is eight weeks. Applying methods that will allow you to package and label clinical supplies only as needed can provide significant time-savings between protocol approval and First Patient In. These revolutionary processes are allowing trials to get up and running in just a few weeks. More importantly, these methods allow

Reduce clinical trial costs by streamlining the supply chain

drug products to be shipped to sites as soon as the first site is ready.

Implement flexible scheduling

We can expect there will be unexpected changes that will directly impact your study’s budget. These changes could include ending the trial early, expiry of drug, or new countries added. This often means medication that is already paid for will not be used or will need to be reworked. Consider adopting a clinical supply and distribution model that allows you to prepare medication as needed versus committing your entire drug supply upfront. Utilizing a flexible supply model will nearly eliminate expenses due to drug waste and rework when unplanned changes occur.

Contracting services in weeks vs. months ahead of your study

Contracting clinical supply companies typically occurs four to six months before you actually need the supplies. The problem with sizing and signing a contract months before a study starts is that things will change. If your trial is expected to take one year to enroll 120 patients, not all 120 patients will be enrolled on the first day. Moreover, if each patient is expected to take medication for twelve months (one kit per month for twelve months), not all 1,440 kits are needed at the trial’s start,

nor should you be willing to spend money on kits that may never be used. Choosing to work with companies who can engage your study’s needs in weeks versus months before the start of your trial will ensure that your contract scope and price reflects what you will actually need and pay - allowing your study to stay within budget.

Managing clinical trials will not get simpler and it's likely that costs will continue to climb. Mitigating these trends by introducing some or all of the methods outlined in this article is something you can do. Is it time for you to evolve the way you manage your trials?

Want to learn about how CSM's clients are experiencing average savings of 180% by adopting these methods? Read the case study.

About Gerald Finken R.Ph., M.S.

Gerald Finken is the founder of CSM and a 32-year veteran of the biotechnology and pharmaceutical industries. Finken is a licensed pharmacist in seven states and has been recognized with the Elan Innovative Pharmacy Practice Award. He is a member of many industry associations including the American Pharmacists Association and the American Association of Pharmaceutical Scientists.

Gerald Finken R.Ph., M.S., Founder and CEO, CSM

G


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[email protected]

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Kieran Prior, Writer, Arena International

Ensuring in-depth planning takes place within trial supply to meet the demands of the globalization of clinical studies

ith more and more pharmaceutical, biotechnology and

medical device companies launching trials on a global scale, alongside the ever-increasing costs associated with a clinical trial; it has become essential for clinical supply teams to implement effective planning strategies as early as possible to promote reduced costs, deadline adherence and higher levels of efficiency.

Getting started early

On top of the increased costs and budgets required, sponsor companies are finding their timelines are getting tighter so starting the planning process as early as possible is the only way to meet these looming deadlines. There needs to be close communication with the clinical development and operation teams, to be kept aware of lead candidates and pipelines so comparator sourcing and demand forecasting process can begin at the earliest opportunity. It is invaluable to find out the planned locations for clinical trial sites so appropriate vendors can be found, distribution pathways can be identified and regulatory requirements scrutinized. For

example, for temperature-sensitive products; specific storage requirements can be premeditated and transit timelines can be estimated so an effective cold chain distribution strategy can begin to be put together.

Putting the wheels in motion at this early stage can provide an insight into potential bottlenecks that may arise once the trial begins, so they can be acted upon before they occur. If problems do come up, such as potential issues with comparator or placebo availability or sourcing or impossible regulatory hurdles to contend with; these must then be addressed across the

W teams to identify how they can be overcome and if necessary avoided.

This may also identify some potential ‘shortcuts’ that may be able to be implemented; such as supplying multiple trials concurrently, utilising drug pooling and just-in-time labeling strategies. It is of course important to bear in mind that changes to the trial are inevitable and, as much as preparation is necessary, flexibility is key and this needs to be kept front of mind throughout the preparation process and beyond.

Capitalizing on partnerships

Effective planning relies on a complex network of parties being involved throughout the supply chain; from the protocol management stage, where CROs and clinical operations teams need to be involved, through to the production planning stage where recognising the CMO perspective is imperative to fully understand the processes taking place, all the way through to material management and exploring challenges faced by packaging and labelling teams, distributors and couriers.


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Getting your vendor involved at the earliest opportunity can provide a huge advantage when putting together your clinical supply pathway. Working with vendors in the planning stage can provide the opportunity to capitalize on their geographical and regulatory knowledge, and their input can actually help shape the clinical supply strategy. They may be able to provide recommendations on other partners and potential study sites whilst keeping you in the loop on any new technologies or regulatory changes that may affect your trial.

These external teams and partners may also be an invaluable source of expertise and experience; they may have specific knowledge of a regulatory pathway, having run a trial in a particular region recently before. This sort of information should be something that is taken into account very early on, and so it should be incorporated into your vendor selection questionnaire to ensure any companies you partner with can be of value to you in this way.

As working with these vendors can provide a key knowledge source, it is important that vendor sourcing and selection is carried out effectively and the right set of vendors is found for your trial. Of course it is important for you to do this quickly to meet trial timelines, but due time and care must be taken to ensure the correct vendor with the appropriate expertise is found.

Working in emerging markets

The number of trials taking place in emerging markets,

such as Eastern Europe, India and China, is growing at a phenomenal rate and working in these regions, from both a large and small company perspective, demands effective analysis of the supply chain to deal with a number of different challenges these markets can produce. The challenges can include aspects such as; coping with greater transit times and costs from distribution hubs, dealing with under qualified staff during the supply chain, increased variance in temperature (especially for biologics) and more complex regulatory landscapes.

The sponsor must, naturally, take responsibility of the quality and safety of their products and so must ensure that any manufacturing sites that they are using across the globe are operating to US and EU GMP standards, on top of any local requirements that may be in place. This alone can cause issues in terms of

potential language barriers and so identifying these possible issues early on can perhaps give organizations sufficient time to hire a fluent speaker of a particular language to improve understanding and reduce the risks of any possible misinterpretations with this essential requirements. To ensure sufficient standards are met, audits may need to take place on these manufacturing sites; yet another reason to have a ‘native tongue’ as part of your team.

Emerging markets can also offer another challenge altogether for temperature sensitive products which will also have to be taken into account in the planning stage of the trial. In some regions, there may be more cases of your product being left ‘on the tarmac’ for elongated timelines. On top of this, some countries may not have the infrastructure or knowledge to effectively utilise advanced temperature monitoring technologies.


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All these challenges and more, not just in emerging markets, but in traditional clinical site locations as well, can lead to a huge amount of wastage within clinical trial supply with the industry considering 50% overage levels as normal; so reducing clinical supply overage can really lead to some huge savings within the clinical trial supply chain.

Effective forecasting

Forecasting is clearly a key tool in reducing overage and minimizing wastage, and can be the key to meeting clinical supply chain budgets. There are multiple factors that must be taken into account to accurately forecast trial demand; a lot of information from the trial protocol can be invaluable. This can include

information treatment groups, dosing definitions and study geography, which in turn can help supply teams to fully understand patient enrolment timelines, and therefore implement an effective forecasting strategy.

Utilizing ‘Just-In-Time’ strategies can be effective as a way of minimizing wastage, and when taking this approach, the vast array of technologies available need to be taken into account. There are modelling technologies that can take into account different variables such as patient recruitment levels, site shipment quantities and site quantities.

With the variety of technologies and strategies available within this space, due care needs to be taken to ensure you find the right

‘fit’ for your trial. It is clear though, that harnessing the power of effective forecasting can make an immeasurable difference to overall clinical supply costs.

To conclude, there are a great variety of factors that have to be included when planning a clinical trial, from highly technological aspects to forecasting and ‘Just-In-Time’ modelling, to effective operational strategies to ensure clear communication and reduced misinterpretation. It is clear that in-depth planning can make or break a clinical supply chain budget, and taking the time early on in the trial can prevent unforeseen circumstances that may lead to increase trial budgets or timelines.


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B&C Group has developed a wide range of specialized Clinical Trial Supply services to ensure the successful conduct of your clinical trials. These services include drug Sourcing, Primary & Secondary packaging &Labeling, Qualified Person expertise, sample collection Kit assembly, Warehousing & Distribution, Transport and Storage or Archiving of clinical trial material and biological specimens. Through our unique combination of services and global coverage (global depot network in 18 countries across the 5 continents), we offer efficient and tailor-made solutions to support the full clinical supply chain.

B&C group is also your preferred partner for centralized biological sample management, biorepository and biobanking activities.

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Sue Lee, Technical Portfolio Manager, World Courier Management

Meeting clinical trial logistics demands within emerging markets

hen it comes to clinical research, an already small world continues

to grow even smaller. In no area is this more evident than site selection for clinical trials. North America, Western Europe and, to a lesser extent, Australasia once served as prime locations for the majority of research. But these Western markets are approaching saturation, which has led to a lack of naive patients who are available and willing to take part in trials. Companies have thus turned to new global locations to run trials; an effort made far easier due to the huge improvements that emerging markets have made in investigator and patient identification, as well as regulatory initiatives.

India and Brazil serve as prime examples of rapidly evolving markets for clinical research. Both countries have seen significant investment in infrastructure programs to improve the way they handle clinical trial applications, including trial review, and the granting of import licenses and permits. IMP supplies can be imported relatively quickly to allow trials to occur concurrently with those in Western Europe and North America.

Other global regions have seen a similar rise in attractiveness as clinical sites. Companies have realized significant cost reductions by performing trials in Eastern Europe, Latin America and Asia. In Russia and China, for example, it’s possible to reduce operational costs by conducting trials in large hospitals, which have patient catchment areas that number in the millions and can speed up patient recruitment.

National regulations have also spurred on the increase in the geographic disbursement of clinical trials. Many countries now require trials to be conducted within their borders prior to the drugs’ introduction in those countries. China spent approximately 66.8 USD billion on pharmaceuticals in 2011, so local trials within that country are vital to any global pharmaceutical company’s long-term growth and success.

For clinical trial logistics, does it even matter how far down the route of emergence each country is? Every country represents challenges in logistics; ensuring temperature control, arranging customs clearance and regulatory release. Every country is also different.

Every shipment can be different. There are times when shipping into North America and getting shipments through FDA and USDA requirements presents more issues than sending to Sub-Saharan Africa.

With many obstacles in arranging shipping, most of which require knowledge of local practices, from how to address the package to what storage options are available in individual airports, one could argue that being first to enter a market offers a distinct disadvantage. First entrants must forge ahead into a country to find out about customs requirements, regulatory requirements and the practicalities of the supply chain.

Should we be concerned about how far a country has emerged? For a company’s financial standing and positioning in the global marketplace, it absolutely matters. For logistics and study set-up, it matters much less, as every country along the spectrum will have special needs. The greatest tools in our arsenal are healthy amounts of patience and persistence. With these tools the industry can forge into previously uncharted territories.

W


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Milad Kelada, Senior Director, Head of Supply Chain, Fibrogen

Thank you and goodbye to the booklet label

s in any other profession, we find that certain trends and

protocols are followed to serve certain purposes. However, when these are already exhausted, the spirit of the time dictates the need to provide more effective strategies. Strategies that still serve specific purposes, but are more targeted towards a goal that is serving a desired end that facilitates the flow of operation, and at the same time, are quality assured. As for the how of it, we start to study the drawbacks of the previous system and put into consideration all these drawbacks. After careful analysis of these we start implementing new alternatives that would take the place of older systems and present new more efficient ones that are globally compatible.

Within the age of Technologic Revolution, and following the fast pace of development, we are compelled to think and present suitable alternatives. Zooming closer into our profession, after careful analysis and consideration, we reach the conclusion that the booklet label should not be the only solution to creating flexibility around global studies. Going further into detail, we offer a new way to label our supplies. As we discuss the suggested method in this article we will discover that we can label our supplies in a manner that will prove to be in

compliance with global regulatory requirements. Furthermore, as the article unfolds, potential Health Authorities’ concerns will be addressed.

There are several reasons that lead to the idea of coming up with this innovation.

Let us shed some light on these reasons and discuss them one by one so we can comprehend the necessity of reaching that solution.

First, globally speaking, we find that, as we all know, a challenge or competition (avoiding the word conflict!), is arising among participating countries concerning their position in the booklet label. We find that most of the countries tend to prefer to be located in the first page of the booklet label, or in the base label. Why? Because placing it there makes it is easier for the patient to view. The risk of losing pages from the booklet ought to be put into consideration as the patient consequently might not be able to see them. So, we sense the pressure from these countries and this influences the decision as to where they would like to be located in the booklet label.

Second, dealing with the issue from the side of the Health Authorities, inquiries started to arise. These inquiries were

A


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concerning the risk the patient is exposed to in case their page is lost. The patient is trying to handle a 20-25 page booklet - needless to say that these pages might even get more in number based on the nature of the study and how many more countries would be participating. In order to get the information the patient needs, he/she has to go through numerous pages to finally reach what they are looking for. The process is long and tedious; both issuing the booklet from one side and also handling it from the patient side. Worthy of notice is that the cost of the booklet label compared to a single panel label would be much higher. In addition, the lead-time for a booklet compared to a single panel label presents a considerable difference

Third, and equally important, we study the issue from the side of the clinical groups. 90% of the time the clinical groups are not ready to supply a complete list of the countries participating in the study. So we either delay the beginning of the study altogether or start the study with the first one or two countries available at the time, which will increase the waste factor.

Another potential situation that might occur is the desire to add more countries after the study is started and that will require us to either revise the booklet label to include these countries or to repackage including a new booklet for these new countries added. Other scenarios might crop up; for example, one of the participating countries requesting a change of text on the label due to a change in their regulations or due to any errors that were not caught at the time of booklet approval.

The study may have two booklet labels at the same time. For example, the first one is 25

pages and the second booklet, after adding the new countries, may be 29 pages. It will be very hard (almost impossible) to keep all the countries’ positions the same in the booklet labels (i.e each country stays on the same page, even though we have increased the number of pages due to the preference of some countries to be on the base label. In this case, we reach the conclusion that there would be a gap in performance. The operation of this procedure in this manner does not actually form a compatible system that would be totally relied on. The flow of performance is interrupted by several factors that would be a hindrance to the implementation of an effective, more efficient and quality assured operation to ensure patient safety.

Based on the previously mentioned discussion we found out that necessity is the mother of invention. We had to come up with a new form of label presentation. This new presentation would be packaging our supplies using a single panel label. However, the single panel label would still yield to the traditional manner. In this


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sense, it would be split in two halves. One would be base label coding panel carrying the USA (English) requirements. The other (JIT applied part) would include regulatory requirements for each country participating and local regulations translated into the local language to comply with Annex 13.

Furthermore, the study of each country can start independently from the rest of the participating countries. All of these countries’ specific labels will be governed and monitored by the IXRS and the CRO system to ensure compliance.

In a nut shell, following the above method, the drug inventory would be flexible to go anywhere, to any

country, at any time. The process this way is definitely facilitated to a much greater extent without taking the pains of issuing a booklet that could create confusion and be a burden on both the manufacturer and the patient.

From the clinical point of view, this enables us more flexibility to add any new country at any time. Moreover, we can start the study for any newly added country within 2/3 weeks in the most.

So, what is really required to improve the process is not to package a single panel label operation for each single country but to improve the process and develop a new way for packaging and utilizing the JIT operation

in the best way possible. In other words, dividing the clinical supplies label into two halves as previously explained is a good solution. This way we will cut the lead time line from 3-4 months into a week or maybe even less. The lead timeline to print booklet labels would not be required.

We hope that in this article the need for the label presentation innovation is clarified. The discussion presented makes it crystal clear why this move was a necessity. As mentioned in the opening idea, we have to move forward to fulfill what is needed to reach the optimum level required for a smooth, accurately implemented, and quality assured performance.


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Making supplychain integrity

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© Copyright 2013 Packaging Coordinators, Inc. All Rights Reserved.

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AndersonBrecon (UK) Limited trading as Packaging Coordinators, Inc. is a company registered inEngland and Wales with company number 02543975 and VAT registration number GB 549 7026 19whose registered of� ce is at The Broadgate Tower, Third Floor, 20 Primrose Street, London, EC2A 2RS

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Jacqueline Lee, Director, Clinical Operations, Cytokinetics, Inc.

rom a clinical operations perspective at a US-based pharma/

biotech company, conducting international clinical trials can be a bit more challenging than conducting a domestic clinical trial, but with appropriate planning and organization it can be an exciting experience while being effective at the same time.

Once you have a study design and protocol in place, there are many things to consider. You must look at your company’s internal resources and determine what expertise you have versus what expertise you need. That will be vital in determining which tasks you can take on and which tasks require outsourcing. The majority of US-based companies that conduct international clinical trials require some sort of outsourcing, and determining the appropriate outsourcing model is extremely important. There is the ‘full-service model’ (all-inclusive CRO), the ‘functional model’ (a specific vendor for each service need and function), the ‘hybrid model’ (company control with access to SOPs and expertise of a full-service CRO), and the ‘risk-sharing model’ (strategic partnerships with shared risk and shared reward).

Whichever outsourcing model is chosen, it is extremely helpful to actively engage the CRO (or multiple CROs) in the clinical

Developing strategies for effective international trial management

trial development and start-up phase as early as possible. From the perspective of a US-based pharma/biotech company, it is important to choose a CRO that can properly inform you about the national regulatory requirements to ensure compliance and meet the timelines associated with various international submissions. There are often substantial differences when managing an international clinical trial versus a domestic one (e.g., patient reimbursement policies); therefore, capitalizing on their expertise is invaluable. It is important to be able to answer the question “Do you do want a CRO from the Unites States to manage your sites in Europe?” Sometimes the uniqueness of the CRO can offer valuable advantages that should not

be overlooked but the most important thing to remember is that candid communication up front regarding strategy and expectations is vital to the selection of the appropriate CRO for your international trial needs.

Once the CRO is chosen, the real teamwork effort begins. Teamwork is critical in building a collaborative relationship and I believe that is vital for effective trial management. In an international clinical trial, this can be the most challenging component because of geography, cultural differences, and even language barriers. You can’t necessarily control the successful outcome of your clinical trial but you can control the success of your relationship with your CRO.

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CLINICAL OPERATIONS

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The best way to start building a relationship with your CRO is to make the CRO an extension of your internal team. Begin with a face-to-face kick-off meeting and build a rapport to create structure with flexibility. Set mutual expectations and areas of responsibility but be willing to shift them as needed during the course of the trial. And don’t forget the power of laughter in developing a positive relationship!

While managing the ongoing clinical trial, it is important to create an environment that is open to suggestions and creative thinking not only from the CRO, but also from the clinical sites and the site monitors. Collaboration is a skill set and the art of ‘listening’ is a powerful tool. When a sponsor maintains total power and control, they leave little room for learning and progress. Sometimes a simple question from a site, a monitor, or a CRO can lead to a productive discussion that leads to improvement in the conduct of a clinical trial. Always remember to be open to suggestions.

While it isn’t always logistically possible to schedule multiple face-to-face meetings between the sponsor and the CRO or sites in a clinical trial that is conducted internationally, regular teleconferences with your CRO and site investigators are critical to effective communication. Even occasional sponsor visits to the sites can be extremely effective in the successful conduct of a clinical trial and should be factored into the overall study budget whenever possible.

Managing international clinical trials can present challenges, but by focusing on good communication and the development of positive relationships with your sites, your vendors, and your monitors, can mean the difference between success and failure. When sites are happy and feel as though they are an important part of the team, they focus on study recruitment and are eager to enter data and resolve queries in a timely manner. When monitors are happy and feel as though they are an important part of the team, they are more willing to step up to help meet critical data monitoring deadlines throughout the study. When CROs are happy and feel as though they are an important part of the team, they make themselves available to meet the needs of the study and are more likely to adopt the ‘whatever it takes’ attitude.

Data cuts for interim analyses and database lock can be especially challenging in any clinical trial. They often become

even more challenging in an international trial because of time zone differences and various country holidays that interrupt work flow. Every effort in the beginning that is devoted to developing a collaborative team and positive relationships (as well as maintaining them) will be well worth it in the end.

If CROs can continue to deliver dependable, quality service at a competitive cost, US-based biotech companies can expect to see increased reliance on outsourcing models to support global clinical development. If we nurture and value the relationships with our CROs and vendors, we can maximize the benefits of the services they provide. And if Sponsors can maintain positive and collaborative relationships with sites and site monitors in spite of geographical distances, the conduct and overall management of international clinical studies will be far more efficient. Remember that true synergy increases effectiveness and equals success!

CLINICAL OPERATIONS

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major component to a well-executed clinical trial is an effective

enrollment strategy. However, with so many implementation variables to consider, knowing where to start can be challenging. Narrow your considerations by taking these five steps towards a better patient recruitment strategy.

1. Identify the right target audience. A common misconception is that the patient population and the target audience of a recruitment plan is always one and the same. While sometimes this can be true, target audiences of recruitment campaigns are segmented components of a greater patient population. Specific protocol criteria may seek a patient population of males and females 50 years of age and over, but a target audience must be defined from these criteria by narrowing demographics within that population, then comparing with syndicated market research to further refine their concentrated locations, beliefs, and behaviors. Distinguishing a target audience allows you to select tactics and an integrated strategy that reaches potential patients/subjects more directly and effectively with better results.

2. Provide site support. Many recruitment plans offer methods for driving patient referrals to sites without including a plan for how sites are to inform, engage, and manage those referrals. Successful patient recruitment does not end with patient-facing

Five steps to maximizing your patient recruitment strategy

Julie Ross | Executive Vice President, CRO, Advanced Clinical

support; a comprehensive patient recruitment strategy includes the means for enhancing overall enrollment by strengthening study awareness among site staff and lifting the burden for sites to manage their own approaches to identifying and enrolling patients. Empower sites by providing tools that enable quick access to protocol information, that allow straightforward communication with referring physicians and the greater community, and that streamline study messaging to make it easier to educate and engage potential participants.

3. Integrate with clinical operations. We live in an era of highly fragmented information consumption, which is the reason why integrated marketing is more essential now than ever. Today, for a large patient recruitment program to be most effective, it must be comprised of proven integrated marketing strategies. As these campaigns become increasingly more integrated, there is a greater need to centralize the orchestration of recruitment services to ensure seamless execution at the site level. When selecting patient recruitment services, be sure that there is a clearly defined roll out strategy at the point of start-up, which includes a plan for training and communicating with sites and operations teams throughout the study.

4. Incorporate balanced buy-in. While patient centricity is often seen as a discussion topic in the field of clinical research,

there is more to be seen of patient centricity in writing within protocol and recruitment strategy development. Before deciding on a plan for recruitment, it is important to not overlook the value of assessing patient insights in conjunction with feedback from external sources in the field including general HCPs, potential investigators, and monitoring teams. Allow the expectations and concerns of these entities to inform the enrollment plan in order to ensure all stakeholders will buy-in to the strategy once executed.

5. Include a contingency plan. Recurring challenges to clinical research – such as strict inclusion and exclusion criteria, long enrollment duration, budget constraints, and lack of effort from sites – may not manifest until well beyond the planning and start-up phases. While unforeseen challenges to recruitment are unfortunately inevitable, deciding on a recruitment strategy that includes a contingency plan at the onset of a study saves valuable time on planning and decision-making when action is needed most.

Unique protocol specifications require a specific plan to recruit and retain patients for every individual study. While no two recruitment plans are exactly the same, these five steps are a cohesive approach to maximizing the effectiveness of each strategy.

A

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Adam Dion, Industry Analyst, Pharma, GlobalData Healthcare

Exploring the emerging advantage of the markets within China and the rest of Asia

lobalData believes the dynamics of pharmaceutical

outsourcing and location decisions in emerging markets are changing. Cost reduction is being augmented, and will gradually be eclipsed by footprint growth and capacity building as the major factors shaping outsourcing decisions. This is especially true when it comes to emerging markets. CROs are realizing that the ability to be on the ground closer to their customers is a key building block to establishing sustainable, long-term relationships with sponsors. With the economic balance shifting from mature markets in the west to the emerging markets, the need for a strategic partner in these regions is vital to overcome market access obstacles across regulatory, clinical and regional domains. Further, while the US and European drug markets are witnessing the full brunt of the patent cliff, pharmaceutical firms are seeking new regions to bolster sales. And with more R&D being outsourced, contract research organizations are partnering at an increasing rate with domestic service providers to expand access to growing patient populations with high unmet treatment needs.

In the analysis below, GlobalData scanned the CRO sector within China and the rest of Asia to see

what partnerships and operations activities have taken place.

China

The Chinese CRO market has been rapidly growing over the last few years as Big Pharma looks to tap into the region’s burgeoning drug market. However, pharmaceutical companies and service providers are entering China (and also India) with caution, and for good reason. Both countries have lax standards around patient safety, which is of concern to pharmaceutical companies looking to conduct clinical trials. While both India and China offer access to large pools of treatment-naive patients and cheap labor, each country’s regulatory structure lacks the transparency seen with the US and EU agencies, and both are riddled with hurdles. China and India offer byzantine regulatory regimes making each country far more complicated than originally thought. As a result, the labor savings in China and India is commonly juxtaposed with longer approval timelines for bringing a drug to market. This is beginning to change how pharmaceutical companies and CROs do business in these regions.

The Raleigh, North Carolina-based PRA International formed a joint venture with WuXi to offer clinical research services for the Chinese market. The clinical

Goperations of WuXi and PRA in China have combined to operate as an independent CRO, and are jointly owned by their respective companies. While two competitors joining forces seems like an odd relationship, the partnership does make good business sense. The joint venture agreement allows PRA to offer its broad platform of Phase I–IV clinical trial services in China, Hong Kong, and Macau, while WuXi contributes its operational experience, and local regulatory knowledge in dealing with China’s highly centralized and bureaucratic State Food and Drug Administration (SFDA).

On a separate but parallel track, service providers are deepening their investments in China. For example, Quintiles announced that it had established a regional headquarters in Shanghai to significantly expand lab testing capabilities. To support its growth strategy in China, the company is devoting $14 million to build a new 43,000–square-foot facility in the Feng Lin Science Park, expected to accommodate more than 450 employees. Quintiles will also engage the Shanghai Clinical Research Center (SCRC), one of the leading research centers in China, as a strategic partner to help local and international biopharmaceutical companies develop new and better medicines to serve China’s enormous unmet medical needs. The Quintiles-

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SCRC collaboration follows the launch of Kun Tuo, Quintiles’ local CRO, built to help domestic and global biopharmaceutical companies achieve successful registration of medicines in China. Kun Tuo provides a full range of services and customizable offerings in key therapeutic areas, along with vaccines, and late-phase studies and even clinical trial management for medical devices and diagnostics. Quintiles anticipates its growth plan for China will double its staff in the region by the end of 2014, as the company looks to provide its customers with the solutions they need to succeed in one of the world’s most dynamic marketplaces.

WuXi teamed up with a number of biopharmaceutical companies to help with drug commercialization efforts. The company partnered with AstraZeneca’s MedImmune division to develop MEDI-5117, a biologic for treating rheumatoid arthritis and other inflammatory diseases. The two companies initiated Phase I trials of the drug and WuXi will eventually market the drug in China. Both companies have equal ownership of the venture, and once MEDI-5117 is on the market, AZ will have the option to buy the full rights; in the meantime, WuXi will earn revenue based on services provided. WuXi also signed a deal with Ambrx and Zhejiang Medicine Company (ZMC) to develop and commercialize ARX-788, Ambrx’s Antibody Drug Conjugate (ADC) targeting HER2-positive breast cancer. WuXi has been tapped for preclinical development of the toxin, antibody and the ADC; meanwhile, ZMC will receive commercial rights to ARX-788 in China and Ambrx has retained rights outside of China and will receive royalties on sales

of the product in China. These agreements serve as examples of how WuXi is working to build long-term drug development partnerships with leading biopharmaceutical companies to help to accelerate the development of novel medicines.

Rest of Asia

Singapore is often considered the nucleus for clinical research in the Asia-Pacific region - with mainland China and the Korean peninsula to the north and Australia and Oceania to the south, Singapore is a natural hub for clinical outsourcing. The government of Singapore promotes translational and biomarker research and it has put in place laws protecting intellectual property and adheres to Good Clinical Practice (GCP) guidelines, offering a sense of security and assurance to pharma clients looking to conduct trials in the country. However, with a small patient pool, clinical trial opportunities in Singapore (and small countries like it) are limited to mostly Phase I/II trials, leaving the heavily populated countries of China and India to grab the bulk of late-stage trials where large patient numbers are required.

Countries like Taiwan, Cambodia, and the Philippines are beginning to hold their own in Asia as key locations for clinical trial outsourcing. Companies such as Parexel and Chiltern have opened new locations in Taiwan, attracted by the country’s tax incentives and streamlined drug-approval process. Taiwan has a solid healthcare system, a highly educated population and an impressive R&D market, making the country appealing for pharmaceutical outsourcing. DKSH is a leading market

expansion services provider with a specialized focus in Asia. DKSH signed two five-year deals with pharma giants Bayer Healthcare and Bristol-Myers Squibb to help grow their presence in Asia. The drugmakers will lean on DKSH’s substantial infrastructure to drive business. DKSH has 680 business locations in 35 countries – 660 of them in Asia – offering its pharma clients custom-made offerings centering around regulatory submissions and registrations, market entry studies, as well as importation, customs clearance, logistics, distribution and invoicing and credit management services.

Outside of China, South Korea is one of the fastest-growing emerging markets for clinical trial work. According to Outsourcing-Pharma.com, the number of clinical trials initiated in South Korea increased from 206 in 2006 to 513 in 2009 a 150% increase over the four year span. While Korea’s pharmaceutical industry is competitive in terms of chemical and synthesizing technologies, it is considered less competitive in drug screening, safety evaluation, and clinical development. Therefore, companies have found partnering to be an ideal way in which to become more involved in R&D. To enhance its bioanalytical service offerings in Korea, Quintiles announced an exclusive partnership with BioCore, a leading Seoul-based bioanalytical CRO. BioCore is South Korea’s largest provider of bioanalytical liquid chromatography-tandem mass spectrometry services, and was South Korea’s first GLP-compliant certified bioanalytical CRO, and the first to be certified by Korea’s Food and Drug Administration. Under the two-year agreement, BioCore will provide Quintiles

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with liquid chromatography and mass spectrometry services. The partnership with BioCore is part of Quintiles’ plan to add local capabilities as needed in order to gather high-quality bioanalytical data earlier in clinical development, which is crucial for biopharmaceutical companies making informed decisions that increase their probability of success in more expensive later-stage trials.

The government of South Korea is also putting forward incentives to spur investment dollars into the country’s clinical trials market. One government initiative is the Korea National Enterprise for Clinical Trials (KoNECT), collaboration between the South Korean government and a number of global CROs to provide life sciences groups with clinical resources, training and support. Icon and KoNECT will collaborate on a series of educational

events for local and multinational pharmaceutical companies, investigators and industry executives. Programs will aim to further enhance the already high standards for clinical research in South Korea, including creating therapeutic focused seminars. In addition to KoNECT, the Korea Drug Development Fund (KDDF) is a consortium of three health-related Korean ministries, established to help Korean drug companies develop and commercialize healthcare products for the global market. Parexel was the first CRO chosen by the KDDF to help emerging companies to advance their promising new therapies. Parexel will provide to KDDF a broad range of drug development and consulting services specifically tailored to meet the needs of Korean companies and will span the entire drug development continuum.

Lastly, the Philippines remain an untapped market with a solid population base, but it has its fair share of shortcomings. The Philippines’ problems include poor intellectual property protection, lagging R&D investment and a rampant counterfeit drug market. However, the country has a rather straight-forward regulatory process; the majority of Filipino researchers are either US or EU-trained, and English is one of the country’s official languages, and the primary language for medical record keeping. The Philippines also has some major therapeutic advantages for research – many of the country’s health issues include heart disease, cancer, diabetes, and kidney disease – all important therapeutic areas for drug development. The Philippines is also prime territory for testing vaccines and drugs to treat tropical diseases, like tuberculosis.

Figure 1: Top contract research organizations, APAC revenue (2013 vs. 2012)

$98

QUINTILES $774

CMIC $447

COVANCE $370

EPS $305

CATALENT $270

PAREXEL $243

ICON $148

WUXI $127

CHRIVER

INC $80

PATHEON $60

PRAH $56

AMRI $52

$100 $200 $300 $400 $500 $600 $700 $800 $900

Source: GlobalData Analysis of

Company SEC Fillings,, 2013 & 2012

$

All values in $USD Millions.

2013

2012

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Practical planning for the Clinical Trial Lifecycle: “Expect the best, plan for the worst, and prepare to be surprised.”i

he numbers may vary by source, but there is widespread

agreement that most clinical trials experience significant delays during their life cycleii. Variable expenses increase with every month the trial timelines are extended and the delay of product launches could mean the loss of millions of dollars in potential revenue.

Clinical trial planning and execution is one of the most complex project management activities in any industry, involving timelines spanning across years, multiple vendors and contributors, tens of millions of dollars, and variables often beyond the control of the sponsor. Every trial is different, the landscape keeps evolving, and there are always surprises. How do you plan appropriately for the successful execution of clinical trials knowing that you will experience unexpected barriers and delays? How do you manage the expectations of investors and Board members who want you to go faster while spending less?

There is no single approach that works best. However, there are

guiding principles that will help focus your planning efforts and outputs.

• Planning never ends; it evolves and adjusts.

• Planning needs an owner.

• Planning requires performance measures, escalation and timely decision making.

• Planning must be realistic and transparent.

These tenets apply throughout the clinical trial life cycle with emphasis depending on study stage and audience for the information.

There are three common themes related to delays that we see in virtually every clinical trial and should be addressed in the planning process.

1. Getting out of the gate late. Start up delays during site selection, regulatory document completion, and institutional contract/committee approvals are a very common source of frustration for the study team.

2. Clinical Drug Supply putting the brakes on study start. In the words of Roseanne Roseannadanna: “It’s always something.” Drug

supply shortages, insufficient documentation for QP release, importation restrictions and customs barriers are just a few examples.

3. Enrolment off track. There are a number of root causes of enrolment delays, including impractical protocol design elements and low/non-enrolling sites.

These issues are not easily avoided via quick fixes, but understanding, measuring, and assessing the operational risks will allow you to develop proactive strategies and timely contingency plans.

In this article, we include our top five tips for planning in each of the stages leading up to study start up. While the strategies and processes related to vendor selection and investigational product supply chain management are critical, many articles have addressed these topics in detail, so we will only touch on them briefly.

Planning for funding

As a sponsor seeking investors (or budget approval), it is a fine balance between defining high level scientific and protocol

T

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By Lisa Guttman, Leslie Guerreiro, and Kris BentvelsenPartners and Owners, Practical Clinical Inc.

strategy while accounting for operational cost drivers to develop a realistic budget forecast. Most sponsors underestimate the cost of clinical research and end up requesting additional funding later. How do you avoid this pitfall with limited resources and, often, minimal or no experience with trial execution?

There is a temptation at this stage to make premature decisions regarding study design, regional involvement, and start up timelines. While the pressure to commit to deliverables is significant, we caution sponsors against putting the cart before the horse. The critical outputs at this stage are a draft cross-functional Clinical Study Plan, preliminary

budget forecast, and strategy for outsourcing. Get expert input and start with the end in mind. Know where you want to go before proceeding to the next stage because you need to be prepared to answer many questions from vendors who want to help you refine your plan moving forward.

Top 5 guidance points for planning for funding

1. Assign an experienced project manager as owner of the cross functional plan.

2. Consult with experts and get a second opinion where necessary – scientific and medical advisors, regulatory agencies, biostatistics, and clinical operations teams. Ensure team members and roles are clearly defined.

3. Ensure your investigational product manufacturing, sourcing and timelines are in order.

4. Educate yourself and your Board of Directors/investors about clinical research, ICH E6 sponsor obligations, and manage expectations.

5. Use benchmarks for budgeting - tap into modeling and planning tools from experts and/or vendors who will identify key budget drivers and draw on extensive data sources.

Planning for decision making

This stage is extremely busy and may span many months, which is why it is critical to have your sponsor and virtual expert team well-defined. Key deliverables include a protocol synopsis leading to a draft protocol,

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Today’s complex clinical trials demand effective planning, risk management and sponsor oversight to increase operational success and meet your submission goals.

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regulatory meetings, and RFPs for vendors. You should have a good grasp of the activities on the critical path for study start up. There is a lot of input and data to discuss and review before finalizing the protocol and related plans, selecting vendors, and making decisions about operational design.

Top 5 guidance points for planning for decision making

1. Ensure your sample size accounts for screen failures, dropouts, endpoint ineligible patients, and loss to follow up.

2. Develop a potential vendor list focusing on track record and fit. Send out a well-defined RFP, including expectations, roles and responsibilities. Seeking input from experts and vendors will be an iterative process as you incorporate data from multiple sources.

3. Work with potential CROs to design feasibility. Speak to potential sites in addition to reviewing feasibility questionnaire data. Be open, realistic, and flexible about region and site selection strategies.

4. Develop a Risk Mitigation Plan.

5. Allow at least six months to ensure investigational, companion, and comparator products are ready for packaging, labeling, distribution, and importation.

Planning for execution

You are now preparing for study start up. Vendors are selected, contracts signed, and team members assigned. The protocol is final and many operational documents will be drafted for regulatory submissions and

study management. Your expert team should be prepared for decisions that require your input and approval. You may need to refine feasibility assessments if the protocol has changed significantly since the draft.

Top 5 guidance points for planning for execution

1. Carefully review and approve proposed team member qualifications and experience, especially vendor Project Managers and CRAs.

2. Establish team communication, roles and responsibilities related to reviews and approvals. Have clear expectations for deliverables.

3. Develop the Quality Oversight Plan.

4. Develop a Dashboard based on the communication needs of the Board and investors. Identify the various sources of trial performance data and develop your analytics process. Measure what matters.

5. If your study is blinded, define the unblinded team member(s) on the sponsor side and at all vendors and ensure communication and escalation processes are documented.

As you execute your trial, you will encounter some of the barriers you identified in your Risk Mitigation Plan and maybe some that will surprise you. Defining and assessing performance measures and implementing sponsor oversight early will allow the team to trigger contingency plans and adjust course. There are no guarantees in drug development, but thoughtful planning and smart execution can improve the likelihood of your clinical trial’s operational success. i Denis Waitley, motivational speaker and authorii Cutting Edge Information, “Clinical Operations Benchmarking Per-Patient Costs, Staffing and Adaptive Design”, 2011

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Alexander Artyomenko, Director, Late Phase Clinical Operations, Medpace

Implementing a risk-based monitoring approach: aligning sites, sponsors and CROs

isk-based monitoring (RBM) continues to get more recognition

across the industry. Regulators recommend and welcome a more formalized approach, supported by substantial data obtained from multiple studies. Still, there is sometimes a misconception that RBM implies a reduced level of monitoring, or that it may present additional risks to subject safety or data integrity.

Risk-based monitoring is based on a quality risk management concept. As with a more generic risk management process, it has a continuous cycle of risk identification, risk analysis, risk control and risk review. Following this cycle infers continuous improvement in the process.

Unlike the ‘traditional’ monitoring model, where on-site monitoring activities drive the process and require the most time, centralized monitoring forms the foundation of RBM. Continuous centralized data monitoring applies a targeted approach to on-site activities based on the key quality and risk indicators, or signals found within the data. Not only are we able to apply the monitoring effort where and when it is most required, but using the targeted source data verification, we can focus on specific items while being physically on-site.

From a high-level Sponsor perspective, there are key requirements for an effective RBM implementation:

• To effectively coordinate various aspects of RBM implementation,

a leader is needed. This could be a medical expert or a clinical trial manager, playing an integral part in leading the study.

• Because risk factors which could influence the study come from various areas, input from different functional groups is required. RBM processes are cross-functional and require collaboration, communication and process management across the organization.

• Subject safety and data integrity must be maintained at all times. Both on-site and remote components of data monitoring and analysis should be adequately designed to ensure this.

Partnering with your CRO

Your CRO should have established processes and a solid technology platform to support this adaptive approach. Comprehensive RBM training ensures that all functions are acutely aware of the role-specific RBM requirements, and the team is able to tailor the monitoring and risk management accordingly. Other functions such as data management and statistics will see increased roles in RBM. CRA work is evolving as well, with RBM directing the monitor to specific points and identifying priorities, thus ensuring data quality and patient safety is maintained at all times. Everyone involved in site management or analyzing the study data remotely keeps in close communication to enable informed decision-making regarding the site’s performance and to trigger appropriate actions to rectify

R any issues detectable either by centralized or on site monitoring.

Investigators are also reacting differently to the introduction of the RBM concept. While some would see this as a relief, praising less frequent monitoring visits, which may distract from their clinical work, others would miss that detailed guidance by a CRA. When using RBM, it is important to set expectations with the investigators, where sites take full ownership of the data they provide. Establishing internal standards for clinical trials at the site helps with improving the processes and data quality. Also, as any centralized data review activities depend on the data availability, timely data entry is of paramount importance, and should be agreed to with the sites early in the process.

To ensure successful RBM implementation, all parties should work cohesively and share the same understanding and willingness to change, even though it may mean stepping out of the comfort zone and a ‘we have always done it this way’ thinking. Having an experienced partner who is able to guide the process and advise on the optimal strategy could be a critical differentiator and a key success factor.

About Medpace

Medpace is a global full-service clinical research organization providing Phase I-IV core development services for drug, biologic, and device programs. Visit Medpace.com

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Experts. Experience. Execution.RISK BASED MONITORING

“I attended the Medpace webinar on Risk Based Monitoring and it was an excellent presentation. Well thought-out and 10 times better than most of the presentations on

RBM that I have seen.”Director of Clinical Operations /US Pharmaceutical Company

What You'll LearnRealizing the potential of Risk-Based Monitoring (RBM) requires coordination and collaboration across functions within both the Sponsor and CRO organizations. Drs. David Orloff and Alex Artyomenko will lead a discussion to explore the cross-functional perspectives and process alignment between Sponsor and CRO: • Medical: influences on overall risk profile of the study, such as complexity of the design and challenges of specific indications. • Regulatory: navigating international regulatory landscape while applying the RBM principles. • Operational: taking a holistic approach to build a customized monitoring program • Data management: new challenges for data collection, analysis and technology requirements.

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Study ProtocolsInformed Consent FormsPatient Reported Outcome forms Summary of Product CharacteristicsPatient Information Leaflets

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The transformative promise of patient centric R&D

Ken Getz, Director of Sponsored Programs, Tufts CSDD

takeholders throughout the drug development enterprise have

caught the patient centricity bug and it is highly contagious. Sponsors, CROs, investigative sites, technology solution and service vendors, and ethical committees are all getting in on the movement, seeking new ways to enhance study volunteers' participation experiences and to engage study volunteers and the broader health care community as partners in the research process.

This contagion is generating a large number of initiatives that touch all aspects of clinical trials; from design and planning, through study conduct and trial completion. Organizations widely believe that patient centricity holds the potential to transform traditional drug development R&D – a paradigm that has been highly productive but also highly risky, costly and inefficient.

STraditional drug development

The number of new molecular and biologic entities in the R&D pipeline, for example, has been rising 7% annually and now exceeds 10,000 active drug candidates. And for each of the last several years, the total number of new drugs and biologics approved by regulatory agencies in the United States, European Union and Japan has generally met or exceeded historical approval patterns of the past two decades.

Despite historical efforts to improve drug development risk, the high uncertainty of successfully bringing a drug from discovery to commercialization is low and getting worse. Recent Tufts Center for the Study of Drug Development (CSDD) research indicates that only 11% of drugs that enter clinical testing will be approved in the United States and Europe, down from a 16% success rate ten years ago.

Source: Tufts CSDD <csdd.tufts.edu>

Clinical Development Success Rates

1980s

21.3%

1990s

19.1%

2000s

16.4%

2010s to date

11.3%

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Clinical phase durations are no faster today than they were in the early 1990s. Despite the implementation of numerous new practices and technology solutions intended to accelerate clinical development cycle times, the opposite has occurred. The average clinical phase duration is 6.8 years and has increased 15% during the past decade. Longer clinical phase durations are in large part a function of the therapeutic classes that dominate research activity (e.g., oncology and CNS) as drugs targeting these diseases require more time to demonstrate safety and efficacy.

Tufts CSDD research has also shown that development inefficiencies are a function of rising protocol design complexity. The average number of procedures per protocol, average number of eligibility criteria, average number of investigative sites and countries where clinical trials are conducted simultaneously, have all increased dramatically during the past ten years creating more demanding protocols both scientifically and operationally.

Operating inefficiencies are a major contributor to longer development cycle times but perhaps the largest contributor is poor study volunteer recruitment and retention rates. A recent Tufts CSDD study of several hundred global clinical trials found that sponsor companies must typically double the planned enrollment period to give investigative sites enough time to recruit study volunteers and complete a given clinical trial. Even though study durations are extended, one out of every ten (11%) investigative sites,

on average, in any multi-center global clinical trial will fail to enroll a single patient and one-out-of-four (39%) will under-enroll. The other half of sites in a given multicenter study will either eventually meet the enrollment target or will exceed it.

It is estimated that one out of every 200 people in mature markets (e.g., European Union, United States) would need to participate in clinical trials today if the clinical research portfolio were to be successfully completed. The failure of the drug development enterprise during the past two decades to elicit support and commitment from the public and patient communities and to engage them as partners in the clinical research process has played an instrumental role in challenging recruitment and retention effectiveness. National and international public opinion polls show that public confidence and trust in the clinical research enterprise has eroded. A notable percentage of the public believes that pharmaceutical and biotechnology companies are not transparent and do not share complete information about investigational treatments or inform the public quickly when safety concerns about a drug are uncovered.

The cost of R&D is high and rising. Total spending worldwide on pharmaceutical R&D will reach an estimated $140 billion (US$) in 2014, representing a 4.9% compound annual growth rate during the past ten years. 12 to 15 years of capitalized investment is required to bring a drug through R&D and into the marketplace. The average capitalized cost to bring a single

drug through R&D and into the marketplace now exceeds $ 2 billion. Each successful drug must cover its own direct costs (30% of the total) plus all of the costs associated with the high number of failed drugs and the opportunity cost of capital amortized over the R&D period. Today, most approved drugs are targeting smaller market opportunities forcing sponsors to implement a number of strategies to recoup high development investment (e.g., charging higher prices, generating revenue across multiple indication areas simultaneously, introducing companion diagnostics).

Putting the patient at the center of R&D

The current R&D operating environment is clearly inefficient, extremely risky and costly. A new paradigm is critically needed to drive higher levels of efficiency and to mitigate drug development risk. The concept of a patient centric R&D paradigm is compelling and potentially transformative and disruptive.

Under traditional drug development, pharmaceutical and biotechnology companies have vied to innovate in an insular and secretive manner. Sponsors have largely sought the development of medical interventions internally with a singular focus on performing great science to gather and analyze proprietary, competitively sensitive data. In this approach, patients are subjects; contract research organizations (CROs) and investigative sites are service providers, and health care payers and providers are consumers of newly launched products.

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Patient centered R&D seeks to engage patients and the health care community as partners in the R&D process. R&D innovation is an open process where precompetitive information and drug development risk is shared among a broader community of external partners including academic and basic research groups, co-development sponsors, development operations alliances, and patient advocacy groups.

Patient centered R&D strives to minimize research activity that does not target critical unmet medical needs as defined by the patient communities that innovations serve. In this paradigm drug development sponsors aspire to obtain commitment from study volunteers to support and to take ownership for clinical trials from design through to completion with the expectation that whatever is learned – both positive and negative results – will be shared openly to advance collective knowledge about disease and how to treat it.

As part of the patient centricity movement, clinical research professionals look to conduct not only great science, but also more feasible clinical trials that enhance study volunteer participation experiences and reduce the burden of participation. In this approach, contract research organizations, investigative sites, health care providers and payers each play important roles as R&D partners and supporters helping to ensure that patient participation experiences are positive and that patient medical needs are met.

Patient centric initiatives

During the past 24 months, as more organizations have turned their attention to this new paradigm, we have seen rapid proliferation of initiatives touching all aspects of clinical development. Sponsor organizations are partnering with patient advocacy groups and forming precompetitive alliances to better understand unmet medical needs, to collaboratively set research agendas, to generate financial and community backing of R&D initiatives, and to solicit input into protocol designs to improve feasibility.

Sponsors and CROs are establishing stronger relationships with a variety of health care delivery systems to leverage electronic health information. In doing so, companies hope to identify areas where medical interventions can be improved and better targeted, and to find and reach patients who might benefit by participating in clinical trials more rapidly and efficiently. Pharmaceutical companies and their contract research partners are piloting electronic informed consent forms and the use of wearable devices to improve the study volunteer experience and to simplify the collection of outcomes data in real time.

Sponsors and CROs are also piloting new approaches designed to make study participation more convenient. Telemedicine and home nursing networks, for example, are being used on select clinical trials to give patients the opportunity to

participate in their own homes or in closer proximity to their residences and workplaces. By improving convenience, sponsors and CROs hope to increase study volunteer retention rates.

Partnership under a patient centric R&D model requires transparency and disclosure of clinical trial results to study volunteers and patient communities. A growing number of sponsors are now routinely disseminating clinical trial results, in lay language non-technical summaries, to volunteers at the completion of clinical studies.

Ultimately, patient centric drug development is expected to accelerate drug development cycle times, improve efficiency, and to spread R&D risk across multiple stakeholders through higher levels of clinical trial feasibility; better patient recruitment and retention rates; and broader support among all stakeholders impacted by new medical interventions. But it is early days and there is little to no information demonstrating real impact.

Over time, as more is learned, select initiatives will take hold and many will not. Some patient centric initiatives will deliver sufficient return on investment to affirm their becoming standard practice; some will be used on an as needed basis; and others will prove too costly with limited to no measurable benefit. At a minimum, the patient centricity movement is inspiring the drug development enterprise to challenge and transform the current R&D paradigm at a time when it is essential that it do so.

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http://www.rws.com/services/life-sciences-translations/clinical-trials

http://www.pharmaquest-ltd.com

daptive experimental designs have become ubiquitous throughout

the pharmaceutical industry, especially in therapeutic areas such as oncologyi,ii. Adaptions enable a sponsor to seamlessly move between development stages and/or tailor the study to those treatments that have positive patient clinical response. FDA’s Critical Path Initiative (FDA, 2004iii, 2006iv) is a bold supporter of these designs. This article will explore if our current data management systems support trial adaptions.

First, we should examine what data management systems do well. All, including Excel spreadsheets, allow data to be entered, held until needed, and then enable extractions. Advanced systems track who entered each data value and when it was entered, which are requirements of 21CRF11v. Evaluating the data against pre-defined ranges or a set of predefined responses,

Adaptive electronic data capture (EDC) at field, patient and study arm levels

Terry Katz, Director, Global Data Management and Statistics, Merck Animal Health

Aand providing queries when the ranges are exceeded, provides timely data cleaning opportunities.

Modern electronic data capture (EDC) systems contain web-based remote access which enables sites to enter their own data. As compared to classic paper-based studies with subsequent double-keyed data entry, web portals enable on-going data review, which timely meets the ICH E8 provisionvi that “emerging animal toxicological and clinical data should be reviewed and evaluated by qualified experts to assess their implications for the safety of the trial subjects.”

Why allow a trial to adapt?

ICH E8 asks for data review and “in response to such findings, future studies and, when necessary, those in progress should be appropriately modified in a timely fashion to maintain the safety of trial participants.”

ICH focused on safety, but the FDA Critical Path Initiative and the EMEA Reflection Papervii moved trial adaption for efficacy into a mainstream regulatory accepted practice. In return, regulatory agencies expect controlled adaptions. For static protocols, this requires protocol amendments as opposed to protocol deviationsviii after observing something outside the trialix, such as conclusions from other studies with the same compound or public disclosure of competitive products.

Adaptive trials (FDA, 2010; EMEA, 2007) are designed to pre-plan alternative paths for the trial from the design stage. These may include gate-keeping steps for early stopping rules, sample size re-estimation, adding new geographic areas, or dropping one or more experimental arms. The protocol defines the requirements space such as the number of interim data looks, maintenance of blinding by using Independent

i Berry, DA, Adaptive clinical trials in oncology, Nat Rev Clin Oncol. 2011 Nov 8;9(4):199-207. doi: 10.1038/nrclinonc.2011.165.ii Berry, Donald, Adaptive Clinical Trials: The Promise and the Caution, 2010, Journal of Clinical Oncology, http://jco.ascopubs.org/content/29/6/606iii FDA Critical Path Initiative (2004), http://www.fda.gov/ScienceResearch/SpecialTopics/CriticalPathInitiative/ucm076689.htmiv FDA Critical Path Opportunities List (2006): http://www.fda.gov/downloads/ScienceResearch/SpecialTopics/CriticalPathInitiative/CriticalPathOpportunitiesReports/UCM077258.pdfv FDA (2014), Part 11, Electronic Records; Electronic Signatures — Scope and Application, http://www.fda.gov/regulatoryinformation/guidances/ucm125067.htmvi International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceutical for Human Use, ICH Harmonised Tripartite Guideline, General Considerations for Clinical Trials E8, http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E8/Step4/E8_Guideline.pdfvii EMEA, Committee for Medicinal Products for Human Use (CHMP), Reflection Paper on Methodological Issues in Confirmatory Clinical Trials with Flexible Design and Analysis Plan, 2007, CHMP/EWP/2459/02, http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500003616.pdfviii Mehta M, Kurpanek, K, et al, The Life Cycle and Management of Protocol Deviations, Therapeutic Innovation & Regulatory Science, (2014), http://dij.sagepub.com/content/early/2014/04/17/2168479014530119.full.pdf+htmlix FDA Guidance for Industry, 2010, Adaptive Design Clinical Trials for Drugs and Biologics, http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM201790.pdf

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Data Monitoring Committees, and the criteria to continue or adapt. These preplanned adaptions eliminate guess work and uses controls that are statistically prudent like group sequential or Bayesian methods.

Data management in adaptive trials

When incoming data from a trial is reviewed in aggregate up and beyond monitoring of Case Report Forms [CRF], it is considered an interim review by the guidelines. Clinical and Statistics are very dependent on Data Management to act in a manner that supports or enhances data collection and availability to enable a timely aggregate review as the first step in implementation of an adaption.

Key success criteria for a data management system to support adaptive trials include:

• Tools to rapidly collect clinical data

• Tools to display clinical data

• Standards to enable quick modification to protocol and database

• Implementation efficiency to enact preplanned adaptions

Consider a car’s GPS unit as an example of an adaptive trial. The starting point and ending point are defined by the user, and the best set of roads is pre-selected by the tool. During the drive, new data on the car’s position is constantly being collected, processed, and plotted. If the driver deviates from the GPS plan, the unit recalculates directions based on both the initial parameters and the new data, and adapts to a new route. Better units can gather external

data like traffic, and propose adaptions before hitting the traffic jam. But, being warned just a mile early doesn’t help if the next exit is 4 miles ahead. Likewise, “temporary” speed zones are not considered (even if the road repair is years long) and the GPS may misleadingly provide the default speed limit, resulting in a higher likelihood of a traffic violation.

While a GPS can adapt on-the-fly, clinical trials are more restrictive and need layers of approval from the sponsor, Institutional Review Board (IRB), and possibly regulatory agencies. Gathering those approvals at trial start will allow the adaptions to occur when the criteria are met, without sequentially moving though the various gatekeepers.

Rapid data collection has not always been a forte of clinical trials, but EDC, with its remote access, greatly improves the timeliness of data entry by allowing an administrator at the clinical site to directly transcribe into the database. Conceptually, site administrators could enter data each day, but realistically, time lags of days or weeks occur. Consistency checks can now be directly sent to the site for resolution including “pop-up” queries issued to the site keyboarder immediately upon typing data outside of the predefined ranges.

While the current state of the art is quite an advance over paper based trials, it can use a few boosts to support adaptions.

Improvements to data collection and examples of field-level adaptions:

Most EDC are web-based

systems, and theoretically could be used bed-side. This would completely erase the entry lag, and allow the pop-up queries to be addressed by the Investigator in real time. Data quality would improve since an unusual value for a vital sign could be flagged and corrected while the patient is still present.

What if the system also had an adaptive field-level operation? For example, if the systolic blood pressure of a controlled hypertensive patient was >160mmHg, instead of a simple query to confirm the high BP result, the system could instead adaptively ask the Investigator to collect multiple blood pressures matching the American Heart Association guidelinesx. This provides clinical information that was preplanned in the protocol, but only enacted when the relevant criteria was met. The database would have already been designed to handle the adaption, and the statistician and clinician already defined how to analyze this data.

Data management systems could be used to monitor a patient’s weight, and when it drops by 10% from baseline, enact the protocol adaption of a re-calculation of chemotherapy quantity. Time-to-event efficacy criteria, such as complex RECISTxi progression criteria, can be automatically implemented without the need for the physician to manually review the entire patient casebook.

Data managers with today’s systems often design 2 or more copies of the same CRF to handle one different data collection field. For example, at 0, 6, and 12 hours, vital signs

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plus temperature are collected, but at 3 and 24 hours only vital signs. To reduce complexity and costs, a single CRF could be designed with a field-level adaptive operation that displays the temperature field only on the correct visits, and either leaves the space blank or provides a grayed-out field [Fig. 1] so the Clinician explicitly knows at which time the temperature is to be collected.

Mobile tools

Laptops are portable but investigators rarely take them into the patient examination room, possibly due to time-related issues, patient objections and ease of use reasons.

One solution is to use mobile tools like tablets or smartphones. These tools are less intrusive than laptops and enable a clinician to enter data while maintaining their focus on the patient. However, small screen

size and resolution means the sponsor and regulatory agencies need to downsize the number of variables.

Existing mobile tools like eDiaries and ePRO allow patients to collect their own data between visits. Upon entering the waiting room, this data can be loaded into the web system and accessed by the investigator during the visit. Even better would be a routine upload to the web database from the patient’s home before the visit, so the investigator can review the patient’s progress in real time, jump on adverse events, and have adapted treatment plans waiting for the patient on examination day. This changes the clinical care from reactive to proactive, with the hospital staff prepared to implement the adaption.

Even newer mobility tools are reaching the consumer market.

Home blood pressure, fitness bands, portable pulse oximeters, EKG patches and electronic scales are all now available with Bluetooth connection to smartphones. Uploading to the EDC system would be a logical next step; however, these Apps and devices are not necessarily validated in a manner required by FDAxii or EMAxiii,xiv. While fine for home monitoring, they may not be sufficient for regulated clinical trials.

Patient-level adaption in data management systems

Data Management systems also can accommodate patient-level adaptions.

Patients are encouraged to complete a trial, but occasionally they withdraw. For paper studies, the unused CRF pages are either marked as not applicable or ignored after some type of early withdrawal form is completed. EDC systems often are a bit inflexible with edit checks expecting entry into fields after the withdrawal has occurred. Data managers manually remove expected eCRF pages or mark as not applicable within the EDC. Alternatively, building a single switch into the database to turn off all visits after the current day would be ideal, possibly auto linked to the disposition page.

Patient-level adaption could be triggered at preplanned phases during the study. For example,

x Pickering, T., Hall, JE, et al, Recommendations for Blood Pressure Measurement in Humans and Experimental Animals, Part 1: Blood Pressure Measurement in Humans, A Statement for Professionals From the Subcommittee of Professional and Public Education of the American Heart Association Council on High Blood Pressure Research, Circulation. 2005;111:697-716, http://circ.ahajournals.org/content/111/5/697xi Eisenhauer, E.A., Therasse, P., et al, New response evaluation criteria in solid tumours: Revised RECIST guideline (version 1.1), European Journal of Cancer 4 5 ( 2 0 0 9 ) 2 2 8 –2 4 7, https://www.eortc.be/Recist/documents/RECISTGuidelines.pdfxii Mobile Medical Applications, Guidance for Industry and Food and Drug Administration Staff, September 2013, http://www.fda.gov/downloads/MedicalDevices/.../UCM263366.pdfxiii EUROPEAN COMMISSION, DG HEALTH AND CONSUMER, Directorate B, Unit B2 “Health Technology and Cosmetics”, Guidelines on the Qualification and Classification of Stand Alone Software Used in Healthcare with the Regulatory Framework of Medical Devicies, MEDDEV 2.1/6, January 2012xiv MHRA, Guidance on medical device stand-alone software (including apps), http://www.mhra.gov.uk/Howweregulate/Devices/Software/index.htm

Figure 1: Novel design of a CRF to detail requirements of certain visits

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when a patient completes a specified number of treatment cycles or has a pre-planned clinical event, the EDC system could seamlessly move that patient into the next study Epoch, such as invoking a new randomization (for a randomized withdrawal trial) or placing the patient into a treatment maintenance phase.

Adaption at the study arm level

Adaptive trials focus on moving seamlessly through development phases, dropping study arms in pick-the-winner designs, etc. These are triggered when a sufficient number of patients reach the criteria for the protocol adaption to occur. All previous discussion of the need for rapid data collection is amplified since these changes have a much higher magnitude of risk. If data collection is biased towards one region, for example, the action to close a treatment arm may be premature if there is an underlying regional effect.

From the EDC operational perspective, opening the next study phase or closing a treatment arm is minimally different than an early patient withdrawal. Gatekeepers, such as Independent Data Monitoring Committees (DMC)(FDA, 2006xv; EMEA, 2005xvi) and Sponsor Steering Committees, depend on delivery of sufficient efficacy and safety data from all treatment arms, and all regions, to render a well based decision. Rapid collection of high quality data is a must, which is aided by the

field and patient-level adaptions discussed earlier.

One additional challenge for adaption at the study level is communication with the IWRS, drug inventory, and other systems. EDC adaption is a major step, but interoperable or integrated peripheral systems improve the likelihood that all systems can be designed to adapt simultaneously.

Conclusion

This article examined some key success elements for adaptive clinical trials by pre-planning EDC adaptions. Examples of field-level, patient-level, and study arm-level adaptions were shown, with increased risk associated with higher order

adaptions. Early data retrieval at bedside and by mobile tools greatly enhances the data collection and quality. Using common database standards and “single-switches” improves data management’s implementation of changes. Ensuring uniform rapid data collection from all sites mitigates premature study-level decisions which could be inadvertently biased based on underlying regional differences.

The ability to design an EDC with all planned adaptions was shown to be implementable. A greater implementation challenge is how to link the EDC adaptions to the IWRS and other systems since study-level adaptions depend on the interoperability of multiple complex systems.

xv FDA, Guidance for Clinical Trial Sponsors, Establishment and Operation of Clinical Trial Data Monitoring Committees (March, 2006), http://www.fda.gov/downloads/regulatoryinformation/guidances/ucm127073.pdfxvi EMEA, COMMITTEE FOR MEDICINAL PRODUCTS FOR HUMAN USE (CHMP), GUIDELINE ON DATA MONITORING COMMITTEES, EMEA/CHMP/EWP/5872/03 Corr, 27 July 2005

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Rachel Tesfaye, Writer, Arena International

To ensure high-quality, reliable, and statistically thorough data from

clinical trials, clinical data management (CDM) professionals should be proactively involved in all stages of the clinical trial from preliminary discussions about data collection options to the development of data pooling tools based on the clinical trial protocol. As a result, they should have adequate process knowledge that helps maintain the quality standards of CDM processes. Several processes in CDM including Case Report Form (CRF) design, CRF annotation, database design, data entry and validation, data extraction, and database locking are assessed for quality at regular intervals during a trial. Currently, there is an increased demand to improve the CDM standards to meet the regulatory requirements and stay ahead of the competition by means of faster commercialisation of product. With the implementation of novel regulatory compliant data management tools, CDM teams can meet these demands, whilst allowing companies to meet requirements to submit data electronically. CDM professionals should meet appropriate expectations and set standards for data quality and also have a drive to adapt to the rapidly changing technology.

At Arena International’s 14th annual European Clinical Data Forum, that took place in Brussels in March 2014, Dainius Ulpis of Mitsubishi Pharma delved into the current landscape for CDM professionals and explored new opportunities and concerns for the future that are detailed in the article below:

Team structure and the role of the clinical data manager

Full understanding of a CDM professional’s role and responsibilities as well as the Program Manager’s (PM’s) role are key components, not only in the successful execution of a trial, but also in the creation and submission of regulatory documents. Companies need to fully appreciate what is involved in the move to more technical responsibilities, in order to determine the best way to deal with this transformation process.

The role of a CDM professional’s role is changing, and teams need to be restructured to adapt to this change. The traditional data management role was a CDM professional looking at a computer screen and spreadsheets for 8 hours a day. Now, the ‘new data manager’ has more of a communicative role; where different vendors have to be managed and monitored. Some longstanding skills, such as data review are less important now, and the spotlight is on communication skills and data integration.

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Adapting to evolving responsibilities for clinical data management teams

When recruiting for data managers, there are many questions that need to be considered before any hiring decisions are made. For example, when dealing with a wide range of job requirements and expectations, should you hire ‘green’ and train people up or look for experiences and integrate their knowledge bases? Once these employees are on board, how best can they be retained? What specific skills and achievements should be highlighted in performance reviews?

It is essential that CDM professionals are kept up to date with changes in technology that may drive changes in processes and procedures. Companies need to have training structures in place, and understand to what level CDMs need to be trained on particular software, based on frequency of use and current knowledge and expertise.

It has been recognised that every clinical trial benefits from standardising data management processes, systems and data structures. Standardised internal processes help ensure that data is collected and managed in the same way across groups and studies which ultimately improves the quality when data is pooled. These standardised systems support unified data management processes across studies and ensure that data can ultimately be managed from end to end.

Working with a myriad of different software platforms

Where sponsors keep their data management in-house it is important to do a cost-benefit analysis. For example, cloud based services sell an aspect of

data management that is very efficient in theory; however for your department the benefit must out way the cost. It is valuable to get a weigh overview of how the technology is moving forward and consider where it will be in a year and how any changes may affect your processes. Technology is evolving and the industry needs to keep up. It is essential to know all the development processes for data management software platforms and not just the data management angle.

Training comes hand in hand with new technology. For newer technologies that are now really coming into play over paper records, you want to be able to remove some elements of the programming to simplify things as much as possible. Within Electronic Data Capture (EDC) the most important thing is to make sure the appropriate data capture tool is used here. The output data in a CDISC compliant model is already programmed to

do this and it is an ultimate goal for a lot of companies to have this built in for all EDC systems. As a sponsor, you need to select the appropriate technology and ensure that vendors need to be CDISC compliant.

Case study: At Mitsubishi Pharma, shortening the path from raw data structures to CDISC compliant structures proved to be an efficient way of saving in terms of cost and time spent for the review of data and its specifications (the metadata). For example, eliminating the intermittent step of only partially CDISC-compliant data structure reduced the number of review cycles by half, effectively saving about 20-25 working days of in-house data management time. It is important to mention that such an approach has a potential to create further efficiencies as it promotes better transparency in data mapping which is a good practice and regulatory requirement in its own way.

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As a result, data enquiries coming from the statistical analysis team or clinical reviewers can be tackled much quicker and more efficiently. Overall, this path-shortening solution was a result of careful deconstruction and formalisation of the existing data mapping process.

Automating the clinical data process

Some believe there is not enough automation when it comes to processing data. Currently a number of responsibilities are done by outsourcing companies when the industry should be able to use automated in-house systems. This would reduce the costs and should increase the quality of clinical data.

As the industry is maturing and moving towards new and more advanced technologies this should be a capability. The way to move forward with this is to commission a standard on database design. At the moment it is not just about collecting and storing the data; it needs to be re-configured. This may be a challenge as there are uncertainties regarding whether all data managers are aware of the correct terminology and these standards.

The whole chain must understand that when you process this information it is the responsibility of the clinical team as a whole. Adaptive screening is a new approach and provides better interaction between the data manager and the production of data matrices with the data screening and monitoring. Advancing the data management side of things can be used to help monitor increasing demands and productivity. You can provide

matrices to the monitors to identify the investigational site on, i.e. the centres, which may be most at risk. This means the monitors can focus on the critical sites, allowing them to be more effective. These matrices have the enrollment rates, the number of queries to the site, the number of documents reported by the site and information on any strange or unusual behaviour detected in the data. For example, if you had a certain patient profile in all centres except one, it would clearly identify the centre that is not aligned and monitors can then go in and more closely investigate the date.

For a successful CDM infrastructure it is imperative that all aspects of the Clinical Data Manager’s role are supported; from the team structure to automating new software platforms and adopting new

regulatory requirements. Globally, the benefits of supporting the evolving role of a clinical data manager allow for more efficient data and study management. As a result, trials are managed more efficiently and time is decreased for the following: database lock, statistical analyses, final study reports, regulatory submissions and ultimately, market launch. Furthermore, time is utilized more effectively, man-hours and costs are reduced, and the process of clinical research, data management, biostatistics and project management are streamlined. Nevertheless, in order to accomplish this, companies must be willing to take the necessary steps to reassess their workflow and resource allocations as they move to implementing and executing more proficient clinical trials.

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Yiannis Karageorgos, Senior Protocol Data Manager, Bristol-Myers Squibb

Risk assessment of electronic source data for use in research investigation: How to assess if data collected on systems that are under the site’s control are reliable? - Operational structures and regulatory perspectives

n the aftermath of the CDISC eSource Data Interchange Document,

the eClinical Forum (eCF, http://eclinicalforum.org/ ) has been working since 2006 to aggregate functional and quality criteria applicable to electronic source systems using the predicate Regulatory and International Standards references. After reflectively reviewing them, the Forum successfully compiled and disseminated these User Requirements in the form of:

1. Functional Profiles (approved by ANSI, HL7 and the EuroRec institute in Europe)

2. Detailed and acclaimed Practical Considerations white papers

Further to the eCF historical members (Pharmaceutical Sponsor or CRO companies), this work leveraged direct and decisive input by major Healthcare System (EHR-S) vendors, academia, regulatory agencies and standards development organisations

(CDISC, HL7, HITSP, ISO TC 215, CEN TC 251).

The cross-functional and multidisciplinary team and its associated deliverables are known as the Electronic Health Records for Clinical Research project (EHRCR, http://www.eclinicalforum.org/ehrcrproject/en-us/home.aspx). This work became a key reference for any researcher or project manager wishing to understand the challenges of the use of electronic systems for storing research source data; it directly influenced regulatory thinking when it comes to managing data acquisition related risks and is referenced as such extensively in the Society for Clinical Data Management eSource White Paper - released in the beginning of June 2014.

It all sprung from one foundational requirement:

Good clinical practice requires that clinical trial data can be verified against its source.

Guidance from the EMA and FDA in 2010 states that sponsors should be responsible for the compliance of systems to GCP, if used to originate clinical research source data. That included hospital systems - despite the fact those systems are not governed by the clinical research regulations and applicable legislation. This places a new type of burden on both sponsors and investigators. According to this interpretation, they are responsible for evaluating every EHR system which contains source data for a clinical trial, regardless of whether the system was conceived for this purpose or not. At the same time the minimal legal requirements associated with quality, validation and security of healthcare systems are far from being uniform between the ICH geographies; sometimes even regional/district requirements might differ within the same state or country.

I

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The FDA in particular clearly states that those systems that are not under the sole control of the sponsor or the Investigator are not subject to 21 CRF Part 11 requirements. This apparent “contradiction” is not meant to deter from the use of electronic systems; it actually underpins that the purpose of evaluating electronic source systems is not to impose the strict requirements of GxP, which in many cases are beyond the original system requirements and therefore currently unfeasible at large scale. In the US, those systems are otherwise governed by a different set of laws (under 45 Code of Federal Regulations - Section 170 in particular). All major regulatory agencies have rather confirmed that risk assessments with an impact on the protection of patients’ rights and safety must focus on the corroboration of the reliability of the source clinical data and reproducibility of their “chain of custody”. So sponsors, alongside the regulators themselves need to prioritize those sites which present the most “worrisome” negative concurrence of system and process shortcomings in order to assign the right level of monitoring, auditing (and, why not, inspections). This paradigm shift should render obsolete the need for exhaustive “forensic” visual verifications of paper notes.

Those who have been vocal in the preparation and dissemination of the Agencies’ current thinking when it comes to Risk Based Monitoring also defined eSource expectations.

The challenge is of course how to create consistent and comparable risk indicators on systems that are so disparate

and multiform and, what’s more, not consistently regulated nor subject to the same technical standards among ICH countries.

Funnily enough, what generated anguish among the technical experts on semantic interoperability between electronic systems for the past 25+ years, provided a solution when it comes to risk characterization:

While the technical interoperability standard references are vast and not always consistent between the US and Europe (thus rendering direct data interchange between systems impossible to implement at large scale now), the mapping of the EHR-system functional/quality criteria to clinical research requirements was both feasible and actually already compiled and made publicly available by the EHRCR team.

In looking in the User Requirements created for what was called “Tier-0” for allowing systems to be interoperable, the EHRCR team realized that they were simple, granular and consistent enough to be transcribed to a short questionnaire that sites and system vendors could be expected to be able to respond to now.

What’s more, these questions show the common denominator between the regulations and standards which apply to electronic healthcare and clinical research systems, without necessarily expecting or imposing first-hand verifications by the monitor, auditor on inspector against every single criterion. Study nurses, CRAs or GCP auditors are usually not informatics engineers anyway, but precisely because the same questions will be consistently asked, the “scoring” obtained by aggregating the information on a specific protocol or program site population allows for an objective comparison and prioritization of underperformers or otherwise suspicious sites.

It then became self evident that the advantages of sharing this information among research sponsors and CROs (in line with applicable data protection regulations of course), far outweigh any apprehension related to competitive intelligence: an understaffed, unqualified, or fraudulent site often impacted the development programs of more than one sponsor. Sharing the same data even with the regulatory agencies in the interest of transparency and even considering joint audits/inspections has been hailed as a step in the right direction.

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However, a common, comparable eSource quality assessment would not only be a “policing” tool for sponsors and regulators. Further to the obvious benefit of not having to fill in multiple such initiation assessments for every new study, clinical program or sponsor, the sites themselves will be able to more easily obtain (through vendor pre-fills and Healthcare Certification schemes) the answers to difficult technical questions as well as gain insight to how they perform compared to other research centres.

Ultimately, regulatory compliance when it comes to secondary uses of clinical data will definitely be a significant competitive advantage for EHR-system vendors; in particular because this type of objective quality benchmarking comes without any aggressive commercial connotations.

What next? An online assessment and a database for QA

The Investigator eSource Readiness Assessment Tool (eSRA) is currently in the process of being digitized and will be freely available through a website, hopefully within 2014 or early 2015. By design it aims to identify the parties involved in quality risk assessment of systems and processes associated with Source Data collection at the site and meets the objective of reproducibility of the chain of custody. By default it can become essential to Site Initiation - and provide the cornerstone for an overall Site Risk Assessment. The Tool attracted positive attention and remarks by the FDA eTeam and the EMA GCP Inspectors Working Group to whom it

was presented last year. Both agency representatives groups acquiesced to its value but also stressed their expectation that the eCF actively works towards operationalising its finalisation, availability and use, in a manner to decrease the extent of any possible additional administrative overheads for Investigators and site personnel.

Further to the functional criteria, organized as granular statements, the eSRA Tool will be accompanied by role specific handbooks (Sponsor/CRO/Monitor, Site, EHR vendor) including:

• Usage Instructions

• Comprehensive Regulatory and Technical References (regardless of whether they are binding or guidance-only)

• Glossary of terms

• Definitions of concepts associated with eSource Appropriateness

The questions associated with the system characteristics and version, as well as implementation and customization brought at the site’s request, allow for fully comparable risk evaluations grouped in the following 5 compliance groups:

• Identify records which will be a source for clinical research protocol(s)

• Establish the existence of an electronic audit trail

• Describe access controls (data privacy, security, documentation of consents and authorisations)

• Copy/Backup, disaster recovery, data integrity

• System development & maintenance - triggers for reassessment.

The tool actually also provides “tips” (suggestions and the context) for acceptable workarounds in case of system or process shortcomings. It therefore constitutes a convenient baseline for Corrective and/or Preventive action (CAPA) wherever appropriate.

The timeliness of adjustments on tools and associated site processes will not only help determine eSource quality; it will contribute to the emergence of a collective learning curve for sites and those who monitor them with huge benefits starting with recruitment and initiation but also retention of the higher quality sites.

The creation of consistent, corroborated and comparable data will also provide an additional non-negligible by-product: A dataset or registry of eSource quality. As this dataset will gain in size and representability, it is highly likely to become the first stop for all Quality “Analysts” (be it Pharmaceutical or Academic research sponsors, Government/Regulatory investigators, Drug Payers and Patient Advocacy groups).

In all cases the eCF is committed to actively seek regulatory and industry perspectives in maintaining and subsequently releasing each version of the common assessment tool. Most importantly, this effort discreetly but steadily presages a realistic and non-invasive transition to an integrated eHealth/eClinical environment. One which we can start to trust.

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Business Development

Manager

VP/Director

CxO

Delegate profiles; distribution of attending delegates

Clinical Trial Supply Southeast Raleigh/Durham, NC, July 8-9, 2015

Clinical Trial Supply East Coast Princeton, NJ, October 21-22, 2015

Clinical Trial Supply Southern California San Diego, CA, November 10-11, 2015

Clinical Operations in Oncology Trials (West) San Francisco (Burlingame), CA, April 15-16, 2015

Clinical Operations in Oncology Trials (East) Boston, MA, July 14-15, 2015

Clinical Operations in Oncology Trials (Europe Amsterdam, The Netherlands, November 17-18, 2015

Clinical Data Integration and Management Princeton, NJ, March 31 - April 1, 2015

Copenhagen, Denmark:- OCT Nordics- CTS Nordics

Amsterdam, Netherlands:- CTO

Cannes, France:- CTS Europe

Germany:- OMDT Europe- OCT Europe

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ACRO is a locally owned, full-service clinical research organisation based in South Africa whose services include the management of phase I-IV clinical trials, research training, capacity building and clinical trial auditing. With a strong South African focus and presence, ACRO works across the African continent with staff in both East and West Africa.

www.acro.co.za

Advanced Clinical is a full-service CRO with flexible FSP and talent management solutions that works in all areas of clinical development including preclinical development, translational medicine, and Phases 1-4. Our flexible solutions are offered through multiple outsourcing models designed meet each specific client’s needs.

www.advancedclinical.com

Appletree CI Group is a niche CSO (Clinical Service Organization) specialized in ophthalmology, dermatology and medical device investigations as well as in global regulatory affairs services. With presence in 11 European countries and 50 permanent staff, we are able to facilitate your clinical development and regulatory projects.

www.appletree-cig.com

ARIANNE is a clinical CRO conducting clinical trials (I-IV) globally with a focus on North America and Emerging regions including Middle East and North Africa. ARIANNE offers site monitoring, project/data management, safety monitoring, biostatistics, medical writing, regulatory and consulting in oncology, cardiovascular, respiratory, inflammatory, diabetes/obesity, ophthalmic and infectious disease.

www.ariannecorp.com

Cellular Technology Limited (CTL) specializes in cell mediated immunity. We offer automated image analyzers (ImmunoSpotR), serum -free reagents (for use in e.g. ELISPOT, measuring NK activity), and cryopreserved PBMCs. Our CLIA certified laboratory services includes: cryopreservation of samples, GLP compliant testing (using e.g. ELISPOT, ELISA, FACS), and customized assay development/validation.

www.immunospot.com

Europital is an international organization dedicated to Medical Management and Scientific Research. We provide our expertise in a flexible end-to-end model tailored for the needs of our clients. Via our services and creative solutions, we support private companies and governmental institutes in achieving and maintaining high-quality and efficient work standards.

www.europital.com

Outsourcing and Clinical Operations

DIRECTORY OF SERVICES

Directory of servicesPlease find below all services and solution providers featured in the Clinical Trials Yearbook.

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ICTA is an international CRO with 30 years of experience in clinical R&D, pharmaco-epidemiology, and EAPs for drugs, cell/gene therapies, diagnostics, medical devices and vaccines.ICTA’s international teams provide a full-service in traditional and adaptive clinical trials from Early Phase to Late Phase across a broad range of therapeutic areas.

www.icta.fr

Medpace is a leading global full service clinical research organization providing Phase I-IV core development services for drug, biologic, and device programs. Medpace has assembled the industry’s most experienced and therapeutically focused teams to execute at every level of the company’s operations, providing complete and seamless drug development services in over 40 countries.

www.medpace.com

In-home clinical trial visits with PCM TRIALS’ own Certified Mobile Research Nurses is available throughout the U.S. and with our partners in Canada and overseas. The management team in Denver, Colorado supports in-home visits through project management, quality assurance, clinical oversight, development of source documents and training and coordination with nurses, subjects, sites, labs, pharmacies, etc. Contact [email protected] or 303-628-9707.

www.pcmtrials.com

Translation and linguistic validation

PharmaQuest are specialists in the translation and linguistic validation of PRO measures. We stand out in our field by providing a responsive and personal service along with genuine expertise, and as part of the RWS Group we also offer the scope and resources of a global industry leader.

www.pharmaquest-ltd.com

Helping Create A Healthier WorldPharm-Olam

Pharm-Olam International is a multi-national contract research organization offering a wide range of comprehensive, clinical research services to the pharmaceutical, biotechnology and medical device industries. From Phase I to Phase IV, Pharm-Olam focuses on delivering the highest quality data, achieving targeted enrollment and meeting projected timelines.

www.pharm-olam.com

Practical Clinical are experts in clinical trial planning, execution, and oversight. As a seamless member of your sponsor team, we work with you to develop plans and solutions that are realistic, sustainable and practical to implement. In the complex world of clinical research, practical makes perfect sense.

www.practicalclinical.com


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Language services provider to major life sciences clients and CROs worldwide; from Regulatory Affairs, clinical trials, medical devices, manufacturing and PROs

• In-house, qualified subject-specialist translators

• 200+ languages using mother tongue translators

• All major document types and formats.

• Security cleared for handling confidential documents

www.rws.com/services/life-sciences-translations/clinical-trials

Venn Life Sciences is a full service European Clinical Research Organisation providing clinical trial management and resourcing solutions to pharmaceutical, biotechnology and medical device organisations. With dedicated operations in France, Germany, the Netherlands, the UK, Ireland and Europe wide representation - Venn specialises in rapid deployment and management of multisite projects.

www.vennlifesciences.com

Woodley Equipment is a specialist global supplier of medical and laboratory equipment rental and purchase solutions to the Clinical Trials Industry. Woodley is the supplier of choice to many of the largest companies in Clinical Research, as well as partner to many small and medium sized companies around the World.

www.woodleyequipment.com

Clinical Trial Logistics and Supply

B&C Group is an integrator specialized in logistics, packaging/labelling and biorepository services for Clinical Trials. We offer worldwide services through our global depot network. Our services: Sourcing, Primary & Secondary packaging, Labelling, QP support, Sampling Kits design/assembly, IMPs Warehousing & Distribution, Transport and Storage of clinical trial material and biological specimens.

www.bnc-group.com


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BAP Pharma is a specialist supplier of comparators for Clinical Trials with a global reach. We are passionate about providing an exemplary service for our customers and deploy robust processes with experienced personnel to ensure that risk is minimised and clinical trial supplies can proceed as planned. We work with our clients in a strategic partnership to provide the optimum sourcing solutions to meet their needs.

www.bappharma.com

We offer global clinical trial services that focus on helping the healthcare industry successfully develop new medications and treatments. Partnering with investigators and organizations, we aid in the logistical design and successful execution of their clinical pharmaceutical trials. At BARL our clinical trial supply services are known for being dedicated, accurate, timely, and for going that extra mile. With experience in the full management of small to large scale clinical trials, our services will strategically help you design and execute your clinical research trial.

www.barl.ca

Be4ward is a niche consultancy company helping pharmaceutical and medical device companies improve their labelling and artwork capabilities. We help clients define the most efficient business processes, organisation design and, being completely independent, help them select and implement the most appropriate service providers and IT systems to meet their needs.

www.be4ward.com

As one of the leading manufacturers of temperature monitoring systems, Berlinger & Co. AG has provided the pharmaceutical and other industries for over 25 years with reliable and easy to use temperature monitoring systems. Whether simple indicators, reusable or single-use loggers, dry ice or long-term monitoring, we have the right solution for any requirement. Our devices are used hundred thousand of times by operators all over the world.

www.berlinger.ch

BioCision is a life science research and development company that develops products and solutions for process standardization through application of advanced thermal regulation principles and technologies. By comprehensively addressing temperature stability, BioCision strives to improve the success of therapeutic discovery and development and enable effective care delivery.

www.biocision.com

Bracket eClinical offers a suite of configurable and extensible products in the Clinical IRT and eCOA/ePRO arena supporting clinical trial requirements form phase I through IV. Our vision is to set the industry benchmark for enabling our customers to achieve competitive advantage through the use of clinical technology solutions.

www.BracketGlobal.com


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Since 1997, CSM has been solving complex clinical trial supply problems for biotech and pharmaceutical companies such as limited drug supply, time constraints, and mid-study changes. We offer a unique blend of traditional and innovative services that can significantly shorten timelines, reduce costs, and improve outcomes for clinical studies

www.csmondemand.com

Durbin is a leading global provider of supplying comparators, standard of care, rescue medication and ancillaries for clinical trial supply Durbin prides itself on its sourcing network regularly purchasing from 64 different countries and distributing to over 180. Durbin partners with Pharma and Biotech in order to provide low cost long term supply solutions.

www.durbin.co.uk

For more than 25 years, Fisher Clinical Services has exclusively focused on serving the packaging and distribution requirements of clinical trials across the world. As clinical trials require increasingly complex supply chain support, the company’s purpose-built integrated facilities provide the global presence, information systems, and flexibility to allow unparalleled visibility and control of GMP activities from protocol design through to the investigator site.

www.fisherclinicalservices.com

Myoderm is a global leader in the sourcing, distribution, and management of pharmaceuticals for clinical trials. We offer two unique sourcing solutions: GlobalSource, which provides global sourcing and distribution of pharmaceuticals for clinical trials; and CentralSource, a turnkey service for sourcing, warehousing, and distributing rescue, concomitant, and standard-of-care therapies directly to clinical sites.

www.myoderm.com

The global healthcare industry trusts PCI for the development solutions that increase their products’ speed to market and opportunities for commercial success. PCI brings the proven experience that comes with over four decades in the healthcare business. Leading technology and continued investment enables us to address our customers’ needs throughout the drug development life cycle.

www.pciservices.com

www.peli.com

www.pelicanbiothermal.com

Pelican/Peli BioThermal delivers a comprehensive suite of temperature-controlled packaging solutions globally that reduce payload risk, total distribution costs and environmental impact. By providing clients with asset management tools which optimize the use of a broad range of reusable and single-use shippers, our scientific packaging technologies assist clients and business partners with the safe transport of thermal sensitive materials that ultimately save lives.


http://www.csmondemand.com/index.aspx?utm_source=Arena%20International%20Events%20Group&utm_medium=Clinical%20Trials%20Yearbook%202014&utm_content=Yearbook%20Directory&utm_campaign=Closed-Placement-Exploration

www.peli.com

www.pelicanbiothermal.com

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Sensitech Inc. enables global leaders in the life sciences market to track, monitor and protect the quality and integrity of their temperature-sensitive products across complex supply chains. Through its logistics security division, FreightWatch International, Sensitech also provides real-time cargo transparency and security solutions, mitigating risks such as theft, diversion, and chain of custody.

www.sensitech.com

World Courier designs world-class logistics and supply chain programs in complete alignment with customers’ business goals. With 2,000+ associates across 50+ countries in 140+ company-owned offices, we deliver ultimate peace of mind for the transport and storage of time- and temperature-sensitive products, with unsurpassed knowledge, global reach and flawless supply chain execution

www.worldcourier.com

Venn Life Sciences is a full service European Clinical Research Organisation providing clinical trial management, IRS, data management, statistics and resourcing solutions to pharmaceutical, biotechnology, academia and medical device organisations. With dedicated operations throughout Europe, Venn specialises in rapid deployment and end to end management of multisite projects.

www.vennlifesciences.com

Clinical Data Management


Looking to advertise in the 3rd Edition of the Yearbook?

With a global reach and a repeat source of information for leading industry professionals the Clinical Trials Yearbook will be your best source of increased brand awareness and visibility in the industry.

To enquire about advertising opportunities for the next Clinical Trials Yearbook please contact:

Paul [email protected]: + 44 207 936 6948

Interested in contributing to the Clinical Trials Yearbook 2016?

We are always looking for new and interesting case studies to include in the publication.

If you would like to provide an article for the 3rd Edition of the Yearbook, please get in touch with the Editor:

Kieran [email protected]+44 (0)207 936 6603

Documents

CLINICAL TRIALS YEARBOOK 2015 - Chiltern...CLINICAL TRIALS YEARBOOK 2015 2nd edition Practical outsourcing and oversight: Designing in-depth deals incorporating all necessary aspects