Best Practices & Common Pitfalls to Avoid in Planning & Conducting Global Trials

Focus on: Study Feasibility, Regulatory Considerations, Site Selection and Patient Recruitment

Prepared for

2

Speaker Introductions

As director of project operations, Gwen is responsible for identifying new business opportunities, building strategic partnerships, and managing existing client relations. A seasoned biopharmaceutical professional, she brings more than 16 years of regulatory, preclinical, clinical, and sales experience to the DAC team.

Dan works from DAC’s Boston office identifying income opportunities, building strategic partnerships, and managing contract negotiations. He re-joined the team in 2013, having previously served in the area of strategic and business development under DAC’s former brand moniker, D. Anderson & Company, from 2006 to 2007. Dan has authored many articles for industry publications, is a popular presenter at industry conferences, and has conducted numerous workshops on patient recruitment for clinical trials.

Going Global: Lots of Choices

A.T. Kearney

A.T. Kearney

Patient Pool (30%) Size and availability of suitable patient pool

Cost Efficiency (20%) Cost efficiency of labor Cost efficiency of facilities and

travel

Regulatory Conditions (20%)

Food and Drug Administration visibility

Country’s regulatory laws Strength of intellectual protection

Relevant Expertise (15%) Number of clinical research organizations Number of clinical trials Size and availability of labor force with relevant

skills

Infrastructure and Environment (15%)

Protection of intellectual property Health-care infrastructure Country infrastructure Country risk factors

Country Attractiveness Index Criteria and Weighting

Critical Attributes in Country Selection

Echoes from Global Project Managers

The local ethicscommittee

rejected my recruitment strategies.

The regulatoryagency responded

with a singlequestion and no

details!

Our clinical trial materials are baking in a hot lockersomewhere inside customs.

My highest-enrollinginvestigator is

demanding the latestiPad to keep enrolling.

Patients living only10 miles away have a2-hour drive time to

the site!

Sure, thatcountryenrolled

like gang-busters.

Too bad thedata had

more holesthan Swiss

cheese!

What can go wrong, very well may!!!

Unreasonable and under-vetted protocol design

Poor timing of country/site activation; countries never activated

Incomplete and/or inaccurate feasibility data

Patient pools dry up after study start

Poor communication channels with sites

Cultural differences and communication gaps

Lack of risk mitigation strategies

Lack of customized patient recruitment plan

Scope and budget creep

Unmotivated or angry investigators

Delays, delays, delays

Sure, go ahead, leave it to chance!

Lions, Tigers & Bears ─ Oh My!

Pitfall #1: Study Feasibility & Planning

Realistically evaluate protocol for availability of patients.

Does the target population exist? Analyze disease prevalence & incidence.

Filter site enrollment projections through local representative & data sources.

Determine threat of competing studies.

Clearly understand the standard of care and presentation of disease.

Build in buffers for unexpected time and costs

Protocol should be fully vetted globally before finalization & regulatory submissions:

Complete internal review

Review by outside TA consultants

Full investigator review and feedback

Review by local country representatives

Leverage “big data” to understand prevalence

Consider Socio-economic Profile: Does

your protocol require subjects who have completed 3rd line

chemo-therapy, but you have sites in location’s

where most patients can afford such

treatment

Pitfall #2: Regulatory Submissions

Develop strategic regulatory plan with steps and timelines.

Stagger submissions if needed to ensure all countries activate ASAP and enrollment can begin.

Pre-submission due diligence discussions with regulatory agency

Create a checklist and examples of required documents.

Understand country-specific data acceptance policies.

Major changes will cause major delays.

Apply for more patients and sites than needed.

Hurried submission resulting in missed requirements…

Your application just went to the bottom of the pile!

Local details are the key to global study success

Options: Local Experience; Local Personnel; Local Partner

Logistics: Transportation routes and access points

Customs clearance, taxation, licenses, documentation

Languages spoken and communication channels

Religious , cultural and socio-economic considerations

Familiarity with sites and PI, their experience and reputation

Ethics Committee structure and approval timelines

Customs clearance in

countries like Brazil, India and several Eastern

European countries require

hands-on payment and

receipt of materials by

local representative!

Pitfall #3: Inadequate Local Analysis

Ensure mix of KOLs with lesser-known, competent, enthusiastic PIs

Consider location in country: PI’s in Tier 2 and 3 cities often perform better

Some markets justify an on-site visit and inspection

Verify facilities, equipment and drug storage facilities.

Consider availability of critical support resources, departments and personnel (IRB, local lab, diagnostics; etc.)

Capture metrics on past performance for similar studies.

Ensure no participation in competing studies.

Consider catchment area of subjects around site.

Determine subject referral network and process in advance.

Determine sites willingness to implement certain recruitment procedures.

Consider accessibility and convenience factors for subjects.

Pitfall #4: Site Feasibility

Re-conduct site feasibility if there is 3+ month delay from site selection to activation.

Critical to develop expertise in regards to the recruitment landscape

Consider developing a proactive recruitment plan – Every country is unique

Which recruitment materials require EC approval & approval timelines

Typical utilization rates for the various recruitment strategies by sites

The ways in which patients can be engaged at the investigative site

Understand how patients first learn about clinical trials

Identify common stakeholders in the consent decision process

Which types of initiatives prove successful when supporting sites – only gained from hands on experience

Engage CRAs, as they provide a critical link with the investigative site

Involve local expertise and network of various groups to enhance recruitment and increase effectiveness

Pitfall 5: Patient Recruitment

Pitfall #6: Investigator Relations

Proactively address investigator concerns with protocol.

CTAs should be performance-driven.

Consider need for local representation.

Ensure fair allocation of site grant to PI.

Be sensitive to regional compensation differences.

In-person sponsor visits have many benefits.

Consider critical site support personal availability.

Determine availability of onsite CRC or through contract.

Be wary of investigator leveraging and strong-arming: Establish performance incentives up front. Determine if sites are open to training. Gauge willingness of PIs to refer patients. Set aside funds for investigator recognition. Consider mid-study rejuvenation meetings. Have backup sites contracted, approved and

ready.

Re-conduct site feasibility if there is 3+ month delay from site selection to activation.

Access to Patients Predicts Success

53% of investigators were highly successful if their number of matching patients was high.

High matching was defined as 6% or more of their insured patient population.

13

LOW Match MEDIUM Match HIGH Match25%30%35%40%45%50%55%

40%

47%

53%

% Who Are Highly Successful

Metrics Support a Data-Driven Approach

LOW # of Trials MEDIUM # of Trials

HIGH # of Trials0%

10%

20%

30%

40%

50%

60%

18%

28%

52%

% Who Are Highly SuccessfulExperience Helps Predict Success

52% of investigators were very successful if they conducted a high number of trials.

The percentage of successful investigators was sharply lower if trial count was low/medium.

Feasibility (graphic)– Indication: Ovarian Cancer– Institution Type: Public & Private– Enrollment Period: 10 months – Phase: III– Countries: 5 incl. Brazil and India– Sites: 7 in Brazil and India– Patients Per Mo: +500– Est. Enrollment: 160-180

- Initial feasibility based on the draft protocol was encouraging to the Sponsor.

- Brazil and India would carry 40% of target, reducing timeline by 3 to 4 months.

- The sponsor program manager planned country visits to inspect sites.- Following receipt of the full protocol, several challenges became apparent:

- Subjects must have completed 2nd line chemo and be platinum-resistant.

- Subjects required to take home study drug requiring temperature control.

- Subjects were to complete a specialized quality of life survey

Case Study: Pitfalls Re-shape a Study

Actual Study– Institution Type: Private Only– Enrollment Period: 9 months – Phase: III– Countries: 12– Sites: 6 (Brazil, India)– Patients Per Mo: 95-100– Est. Enrollment: 60-70

- Requirement to maintain cold chain:- Extreme high temperatures are common in both countries.- Specialized temperature-controlled boxes would be supplied to subjects- Patients would need to have refrigerators in their residence (or AC)- Temperature loggers or visits from social workers to monitor compliance

- The Sponsor was unaccustomed to some sensory elements of both countries.- Private centers more aesthetically appealing to Sponsor despite fewer

patients.- QOL questionnaire translations were both time consuming and costly.

Challenges Emerge: - 2nd line chemo requirement

inappropriate for some cities- Large OC population- Diagnosis poor- Socioeconomic challenges

severely limit patient pool- While care at government centers

is free, chemo is usually not

Case Study: Pitfalls Reshape a Study