Why clinical trials fail before they get even started: the ‘frontloading’ process

Why Clinical Trials Fail Before They Get Even Started: the ‘Frontloading’Process

Jürgen Beck1,*, Peter J. Esser2 and Michael B. Herschel3

1Monitoring Force GmBH, Regina-Protmann-Str. 6, 48159 Münster, Germany2Representative of German Industry and Trade, 1627 I Street, NW, Washington, DC 20006, USA3GlaxoSmithKline GmbH & Co. KG, Theresienhöhe 11, 80339 München, Germany

Copyright © 2004 John Wiley & Sons, Ltd. Qual Assur J 2004; 88, 21–32. DOI: 10.1002/qaj.261

Key Words

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Introduction

Clinical trials are an unavoidable process inthe development of new pharmaceuticals.

Because of the ever increasing regulatory burdenon sponsors and the escalating cost of bringingnew products to market, failure of a study at anystage is not an option – despite the fact that it isvery often a harsh reality. Accordingly, identify-ing weaknesses and possible failing points inadvance of ‘kicking off’ a study is essential.

The Frontloading Process(Definition)

In this article, the frontloading process is definedas the sequence of actions and events between aGo-decision for a clinical trial and the inclusionof the first patient into this trial. Discussing this

*Correspondence to: J. Beck, Monitoring Force GmBH, Regina-Protmann-Str. 6, 48159 Münster, Germany.E-mail: [email protected]

Summary

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22 J. Beck et al.

Copyright © 2004 John Wiley & Sons, Ltd. Qual Assur J 2004; 88, 21–32.

issue in detail is motivated by the ongoing discus-sion about the need to keep clinical trial timelineswithout compromising on quality. However, thisdiscussion seems to focus on the recruitmentphase of the trial. This article stresses the need tofocus on the frontloading process of the trial, i.e.on preparatory phase plan, and its correspondingcommunication and action plans, as well as ontools to use during the frontloading process. Fromthe point of view of a quality-based approach toclinical research, the proper handling of thefrontloading process is a necessity. This is a verypractical approach, but practical approachesseem to gather ground in clinical research [1].

Clinical trials that fail beforethey start: practical view from asponsor

There are trials where experienced clinicalresearch experts have a bad gut feeling evenbefore the first patient has been enrolled. Theremay be an excellent statistician, a famous group ofkey opinion leaders who endorse the trial, regula-tory agencies that approve of it – but it becomes anever-ending story finding patients for it.

The magic triangle of speed, quality, and costneeds to be changed into a square by addinghuman nature. Traits listed here may have someinteresting consequences, though Schopenhauer(German philosopher, 1788 – 1860) would see theconsequences as dire:

Optimism few centres will actually do it.Habits keep those eligibility criteria

that worked in phase II.

Selective listening they will try although theyseem to fail to enrol.

Grandeur maximize it all at once, afterall you are the leader.

Linear thinking if this is so I shall have to bow.

Other traits, Rousseau (French philosopher, 1712 –1778) might have remarked, create opportunities:

Curiosity new ways of recruitment.Sports spirit performance listings.Grace under pressure last minute amend-

ments.Community investigator idea exchange.Sharing financial support for study nurse.

In preparing for a trial, feasibility is an often-used word but a feasibility assessment is hardlydone meticulously. It begins with a critical look atthe protocol. Frequently, limiting patient eligibil-ity starts with recruitment. Among the most fre-quent pitfalls are

● Excluding patients above a certain age, e.g.above 65 years of age.

● Excluding women.● Excluding related disease even if the pri-

mary endpoint is applicable to them as well.

More problems arise with exclusion criteria.Their choice is often based on obtaining a clini-cally pure population, with no concomitant dis-ease and no other drugs taken regularly.Frequently used exclusion criteria whose wisdommay be questioned are

● Inability to co-operate (who knows if theywill?).

● Intake of acetyl salicylic acid preparations.● Relevant cardiovascular, hepatic or renal

disease (what is ‘relevant’?).● Previous diagnosis of cancer (even if

resolved…).● Known allergies.

Too many exclusion criteria become problematicas they do not only limit the number of patientslike a type of funnel, but have a negative impacton the drug approval labelling and prevent thesponsor from gaining knowledge in importantpatient populations before registration. In somecases the limitation, especially in phase II ofclinical development, is justified by reducingvariability; however, there is no publishedevidence that ‘opening up’ the patient populationincreases the variability of the primary endpoint,and, in consequence, really leads to largersample size.

Most often, feasibility is understood as thefeasibility of the investigator site. According toInternational Conferance on Harmonisation(ICH) good clinical practice (GCP) [2], it is thetask of the sponsor to ensure that the site is able toconduct the study. Even at renowned companiesthis meant asking the investigator whether he/shewould be able to come up with x randomizedpatients in y months. Not surprisingly, the answerwas frequently ‘yes’, and this led to the buildingof, as the ‘yes’ answer may have looked less cred-ible, so-called contingency plans. Only recentlyhas it become an established practice in severalcompanies to:

● Ask for historical data, listing real patientsfrom a pre-specified past period, who wouldhave been eligible, possibly with a diseasecharacteristic that might allow for the calcu-lation of real endpoint variability (e.g.haemoglobin A1c).

● Set a time for the investigator to give feed-back on feasibility (as a knock-out criterion).

● Divide the number of patients listed on thefeasibility form given by a figure between 2and 6, depending on the difficulty of thestudy and the task to convince patients toparticipate.

Yet, the mistakes of the past are still committed.The most common are

● Selecting mostly key opinion leaders.● Taking the numbers given by the investiga-

tors for granted.● Paying for feasibility data.● Trusting in ‘centres of excellence’ (who may

have been good in the past…).

There are feasibility factors that are consideredfar less though their impact is high:

● The time to obtain an ethics committee vote.● The time required to obtain trial permits will

most likely increase as maximum times tendto be used by agencies generously, except forin Italy where some people hope that time-lines may speed up agency employees.

● Referral patterns or ‘who has got the patientsfor diagnosis, and who for treatment’.

● Limited resources at the site even if they arenot competing for the same patient group.

● The possibility that the investigator may beready to move house or go on a sabbatical.

● Time to completing the contract with thecentre (mostly a problem in hospitals).

Finding the right investigator fee is yet anotherdifficulty to overcome. One is trapped between arock and a hard stone: fees that are too low whichmay be bordering on ‘unfair’ market value, andon the other extreme, fees that are so high thatthey may be ‘spoiling’ investigators, or evenworse, fees that may be seen as an attempt to cor-rupt institutions. Clearly only those measuresthat exceed standard treatment costs should bepaid for. However, it may be necessary to use adatabase such as PICAS (Data Edge, Inc.) forcomparisons. Such databases provide historicaldata, by procedures involved of standard cost,from different countries; however, apart from theUSA, only few European countries are covered inmuch depth. In addition, some studies may benecessary for approval, but boring for more sci-entifically minded investigators so only a mone-tary inducement may lead to satisfyingrecruitment speed and quality.

In a time of shortening recruitment lines, con-tingency plans are now mostly based on good


The Frontloading Process 23

feasibility data and sound planning. Recruitingextra centres many months after the start of atrial is no longer viable. Each trial should have aclearly defined ‘last intervention point’, i.e. thedate after which no ‘fire brigade work’ would sal-vage the recruitment time any more.

Therefore we suggest the following practicaladvice:

● Plan each study with (more than) sufficientcentres.

● Do not think you save money by restrictingdrug supplies or other trial materials.

● Train investigators how to convince a patientto participate in a trial.

● Make every trial as representative of the realpatient population as you can by eliminatingexclusion criteria and being liberal withinclusions.

The Preparatory Phase Plan

It is essential to establish formal planning, oncethe Go-decision for a clinical trial has been made[3, 4]. This plan has to be a living document andis to include all of the following: regulatory pro-

cedures planned and initiated, InstitutionalReview Board (IRB) or Independent EthicsCommittee (IEC) procedures, any feasibilitycheck measures taken or planned, the progress ofthe selection process of investigator sites, pre-ini-tiation visit planning and actual performance, thestatus of sites’ contracting and last, but not least,a retroactive delay’s planning (see Figure 1).

In fact, the preparatory phase plan (PPP)describes the sequence of all actions and events,planned and actually carried out between the greenlight to do the trial and the first inclusion of a studysubject into the trial. However, the PPP being acomplete list of all tasks and actions with theirrequired timelines is not sufficient. As a living doc-ument, it needs to be updated on a regular basis(e.g. weekly) and communicated to all team mem-bers to keep the project in front of people’s mind.

The Feasibility Check

One of the core tasks of the preparatory phasethat needs to be documented and updated in thePPP is the feasibility check. Basically the feasi-bility check deals with the pre-study assessmentof whether or not a site is able to follow a given

24 J. Beck et al.


Figure 1. Preparatory phase plan. The way the preparatory phase is planned is crucial: the focus must be on the first patient inand all (retroactive!) planning must start from there. Different shades (white, grey, black) indicate the immediate need foraction, if the date of a given activity falls into the area: black signalling immediate need for action; grey the need for clone moni-toring and supervision; white means no action needed

protocol. This assessment has two aspects: first,to check the site’s ability to perform all study pro-cedures; second, to check the site’s access to thetargeted patient population. The first aspect israther close to a site inspection and deals withquestions such as.

� Is the Confidentiality Agreement signed sothat a protocol summary can be given to thesite?

� Accessibility of clinical site from airport(ease of monitoring and other visits)?

� Size of the patient pool in the geographicregion of the potential site

� Is there co-operation with referring insti-tutes? If yes, will sufficient documentationof medical history be supplied?

� Distance from clinical site for the majorityof patients (Driving distance? Overnighttravel? Any possible attendance problemfor visits?)

� Investigator and staff’s experience in clini-cal research and GCP? Also, are investiga-tor’s and sub-investigator’s CV’s available?

� How much time will study staff be able tospend on study procedures?

� Number of studies currently ongoing withthe same indication

� Interfering studies?� Motivation of staff: is there interest in par-

ticipation?� Staff Resource: clinical research coordina-

tor’s (CRC) assignments (what is the typicalnumber of studies assigned to CRC’s at thisinstitute), who allocates assignments andduties? Are there any additional support staff(i.e. phlebotomist, data entry associate, regu-latory associate, administrative support)?

� Institutional contract procedures: Whichdepartment executes contractual proce-dures, do they insist on the use of their owncontract templates, what is the typical turn-around time?

� Communications: International phone andfax lines, email?

� Physical space and resources: Clinic space,space for clinical research associates(CRAs) during monitoring visits?

� Time of principal investigator (PI), sub-investigators (sub-I) and CRC allocated tomeetings with monitoring staff during visits?

� Equipment (based on what is actuallyneeded)

� Pharmacy and medication handling, labaccess and facilities

� IRB/IEC: Submission – approval turn-around time (typical experience with otherstudies)? IRB/IEC fee? Internal or externalIRB/IEC?

� Agreement to monitoring intervals andaudits

� Provisions for archiving� Does the investigator have a ‘repository’ of

patients or does he/she enroll patients asthey come along? In both cases: What timeburden can he/she cope with?

The other aspect of the feasibility check is morespecifically targeted on whether or not thepatients defined by the protocol inclusion andexclusion criteria are available at the site. Here,the approach of site inspection and questioningdescribed above definitely fails. It is not veryhelpful to ask an investigator how many patientsfitting into these criteria he/she expects to be ableto include within a given period of time. Anyinvestigator interested in the trial is likely toover-estimate his/her recruitment potential. Wesee the consequences on an almost daily basis:once the trial is started, the gap between plannedand actual recruitment widens steadily, until therequest for opening new sites is made.

This can be prevented by taking the secondaspect of the feasibility check seriously. The onlyway to assess this second aspect of feasibility is tocheck the site’s patient database by a ‘caserecord form like tool’ (CRFLT), which basicallysummarizes the key information of the inclusionvisit. The investigator has then the possibility togo through his/her patient database and docu-ment potentially eligible patients in the CRFLT,though this documentation must occur in acompletely anonymous way. However, it can bemonitored and source data verified, if this isappropriate for the indication, if there isIRB/IEC approval for this pre-study activity,



and, of course, patient informed consent issought and obtained.

The advantage of monitoring the CRFLT isobvious: as with any study document, monitoringincreases data validity dramatically. For theCRFLT this means, according to past unpub-lished experience by one of the authors (JB), thatfrom all patients identified by the CRFLT about20–30% are included if the CRFLT is not moni-tored, while this percentage reaches 90%, if mon-itoring takes place. Monitoring the CRFLT hasanother major advantage. Since the investigatoris forced by the monitoring of the CRFLT to iden-tify patients really eligible to participate in thetrial before he/she is selected as a site, he/she is inmost cases very motivated to identify as manypatients eligible as possible to qualify for the trial.Once these patients are identified and havealready given informed consent to participate inthe pre-study, it is highly probable that they lateron sign up for the trial, if and when the site isselected and opened. A monitored feasibilitycheck puts the patient selection into a phase whenthe investigator is highly motivated to find asmany eligible patients as possible.

The Selection Process

Another major activity of the preparatory phaseand to be covered by the PPP is the selectionprocess, i.e. the formal way to select – or not – agiven site for participating in a given trial. Theselection process varies from trial to trial, butit should in any case be established beforehand. The key aspects of any selection processinclude:

● The results of the feasibility check.● At least two visits to the site during the selec-

tion process.● A named team on site.● A binding agreement of the selection terms.

The impression a site makes on a sponsor orContract Research Organization (CRO) variesand site motivation and interest in doing a trialmay depend on confounding influences withoutany relationship to the trial. A ‘good’ day may

make it and a ‘bad’ day may kill it and themonitor doing the feasibility check may not haveany clue as to what is really happening.Therefore it is somewhat hazardous to select asite based on just one visit. The more visits thesponsor/CRO conducts, the higher the probabil-ity to eliminate confounding influences and toget a realistic picture of the site with regard toits interest in and its capability to perform thetrial. Two visits per site should be the minimumprior to selection.

In most trials, it is important to have an expe-rienced and motivated site team and not begin-ners or uninterested people. If the decision on thesite team is left open till the initiation visit, anotherwise properly selected site may turn into adisaster, simply because the expected site teammay not be available. At the end of the selectionprocess a named team should be agreed on, spec-ifying to what extent the PI participates in studyactivities, and the identity of sub-Is and CRCs.Only if the team is known, a proper selection canbe done.

Finally, it must be stressed that the terms onwhich a site is selected should be put down in abinding agreement. The site’s agreement to moni-toring intensity and frequency, to make specificequipment available, etc., should be assured inthis way.

Retroactive Delays’Planning

The planning of delays with an early-alert systemto detect time-critical deviations early in the studyis another major aspect of the PPP. Planningshould depart from the point in time when thefirst patient in (FPI) is expected and, with properplanning, this date should not be deviated from.All other dates for initiating or finishing activitiesare calculated from this corner date. Since thereare always deviations from plan for the multitudeof activities in the preparatory phase, the toolused to supervise the retroactive delays’ planningshould be able to give categories of how criticalthese deviations are for keeping the FPI date. Anexample is shown in Figure 1. In a supervision

26 J. Beck et al.


system different shades (white – grey – black) orcolours may be used to depict the differing needfor action with a given deviation from plan.

The Communication Plan

There is need for a formalized communicationplan that outlines what and how information iscommunicated within and outside the project.There is always critical information that needs tobe communicated. Potentially critical communi-cation scenarios need to be identified beforehandand the sponsor/CRO team must be trained todevelop a standardized behaviour strategy to dealwith communication in critical situations. A wayto train team members on communication strate-gies is through role-playing, which allows theteam to practice using the actual communicationmethod in a simulated situation. The basis forrunning a communication plan, i.e. the way howto communicate critical information effectively isto enhance team building, which facilitates per-sonal contact between team members.

The communication plan must also include agrid of who will communicate to whom on whatmatter (see Figure 2).

The Action Plan

In addition to a communication concept, the trialteam has to develop an action plan which is avail-able and ready for implementation if and whenspecific events occur. The action plan must estab-lish exactly what needs to be done if and whenspecific situations appear. Quite obviously, eventsthat might put the trial at risk of failure need tobe anticipated.

Electronic Tools and EarlyAlert Mechanisms

Finally, modern information technology (IT) helpsdramatically to gather and to evaluate all relevantinformation during the preparatory phase of aclinical trial. It is not mandatory, but extremelyhelpful to have a set of instruments availablewhich supervise and control the frontloadingprocess. The proper IT tools can help the trialmanager to do her/his job. In order to do this, thetools need to be simple and easy to work with. Thisis especially important to consider, since the use ofcomplicated IT tools can become so time-consum-ing that other trial related activities may suffer.



Figure 2. Communication plan

Nevertheless, while IT tools can be very usefulthe teleconference between the sponsor andinvestigators and between groups of investigatorsshould not be disregarded as it is simple toarrange and cost-effective.

Legal Aspects

Business failures, such as a breakdown in negoti-ations towards a finalized clinical trial agreement(CTA), and true legal failures, such as thosewhich carry the risk regulatory sanctions and/orcivil litigation, are generally preventable, givenadequate and timely legal frontloading.

The overall welfare and ultimate success ofcomplex or large clinical trials depends in signifi-cant part on a number of small, yet key legal ‘vic-tories’ achieved during the earliest stages of thepre-trial process. Presented here is a briefoverview of those legal considerations that shouldalways be a part of the frontloading process, asseen from the vantage point of the sponsor. Theterm ‘sponsor’ refers here solely to industrysponsors, e.g. small, medium and large pharma-ceutical and biotechnology companies, ratherthan public sponsors. The term ‘frontloading’ inthis context refers to preparatory measuresundertaken during the times span commencingwith the finalization of preclinical studies andconcluding with IRB/IEC approval and executionof the CTA.

Frontloading From a LegalPoint of View – A Two-StepProcess

Because sponsors are increasingly outsourcingcertain roles, a legal framework for a trial and itscomponents must be built upon a solid founda-tion of planning and coordination. The coopera-tion of the sponsor, and more particularly thesponsor’s legal team, whether in-house or exter-nal, with all other parties involved in planningand execution of the trial is essential.

Frontloading in this context can and should beviewed as a two-step process. The first step

involves addressing general logistics, in particu-lar those with any possible legal consequences.Only then can the frontloading process continueon the second step, in which obvious legal (i.e.contract) and regulatory matters may be tackled.

Logistics, or the ‘Pre-legal’Steps

Teambuilding: In an increasingly global and com-petitive environment, successful legal frontload-ing requires first and foremost the establishmentof an effective network. The sponsor, in concertwith the sponsor’s representatives where a CROor similar service is utilized, can best promoteteam building by way of initial group meetings.Such a meeting generally facilitates cooperationon the part of all key parties involved in a trial,and also serves as a venue for disseminating com-prehensive background information on allaspects of the study, ranging from the protocol tobackup procedures. Detailed minutes of theseand subsequent meetings can serve as evidencethat all key parties were informed fully of all legalregulatory requirements impacting the trial.

Bridging knowledge gaps: As is increasinglythe case with large, multicentre, multinationalstudies, the study team may well be composed ofgroups and individuals scattered across the globe,with varying levels of experience, exposure to dif-fering legal and regulatory frameworks, and his-tories of prior cooperation. Effective frontloadingdemands the aforementioned team building andinitial briefings, as well as regular subsequentcontact with the clinical coordinator as the focalpoint and that legal experts receive regularupdates and provide relevant feedback. Thesponsor should be receptive to all inbound sug-gestions from foreign study teams, as critical reg-ulatory issues may be overlooked, particularlyduring periods of implementation of new regula-tions.

Timelines: Bureaucratic intransigence can eas-ily kill the participation of a single site or evencripple an entire trial. It is essential that this verypreventable risk be mitigated by setting timelinesfor all aspects of contracting well in advance of

28 J. Beck et al.


study initiation. A suggested reference point forthe commencement of contract template draftingis 6 months before patient recruitment is antici-pated to start. To the extent that feasibility checksmay have been or are currently being conducted,it is useful to refer to past experience with studycentres to customize CTAs. While flexibility withrespect to timelines is of course mandatory in thefrontloading process, it cannot be emphasizedenough that an execution copy of a finalized CTAshould be provided to the site and/or PI withoutdelay.

Feasibility: Catastrophes can be readilyaverted when frontloading, from the sponsor’slegal point of view, gives due deference to explor-ing the capabilities and competencies of potentialpartners at the investigator level. This importantprerequisite can serve to alert all critical partiesof inadequacies in terms of facilities, technicalcapabilities, and investigator experience.Conducting due diligence on basic compliance ofthese potential partners with general acceptedindustry standards in the recent past is one verysimple means avoiding potentially inadequatepartners, and thereby avoiding issues of liabilityand indemnification down the road.

Legal Considerations

Background: The Federal Food, Drug andCosmetics Act of 1938, found in Title 21 of theUnited States Code, and implemented by Title 21of the Code of Federal Regulations (CFR) [5]defines the legal and regulatory environment forclinical trials. Other conventions relating toissues such as GCP and patient privacy providean additional overlay of guidance for trials. TheDeclaration of Helsinki [6] and regional agree-ments such as the European Union Directive onGood Clinical Practice in Clinical Trials (ClinicalTrials Directive 2001/20/EC) [7] provide yetanother set of guidelines and/or planned regula-tion of trials. It is essential that the frontloadingprocess, from a legal point of view, be conductedby individuals with in-depth knowledge of theseand additional legal and regulatory strictures,and that those ‘frontloaders’ do their utmost to

communicate the intent and meaning of the legal-ities to their colleagues. Concurrently, it is essen-tial that the frontloaders keep an eye on new legaland regulatory developments in view of the factthat initial delays may cause the study to ‘kickoff’ under a changed regulatory scheme.

In terms of an overall legal climate affecting clin-ical trials, legal frontloading must take into accounta number of risk factors. These include the presenttrend towards increasing internationalization orglobalization of trials, a major emphasis oninformed disclosure, a heightened awareness of andenforcement of patient privacy rules, and the ever-present threat of patent litigation. Furthermore,the notoriety attached to clinical trials as a result ofa handful of tragedies that occurred in the recentpast has attracted the interested of the plaintiffs’bar in clinical trials [8]. Moreover, many sites,while generally not reluctant to cooperate in trials,have increasingly begun to review their own stan-dard operating procedures (SOPs) with regard toparticipation in trials. Figures 3 and 4 demonstrate



Figure 3. The regulatory environment

Figure 4. Clinical trials – present legal climate

the overlap of the regulatory and legal environ-ments impacting clinical trials.

True legal frontloading can be broken downinto two categories, namely, generalities and risk-centred details.

Generalities: These include reviewing opera-tional documents at the first opportunity foradequacy of content and their effective controland management by those involved in clinicaloperations. Among other generalities arereviewing background and resource materialsfor the latest developments regarding consentdocumentation, and careful planning and pre-liminary drafting of the protocol in anticipationof institutional and regulatory approval. Moredetail should be devoted to practical issues suchas planning for the provision of study drugs,securing the most favourable terms on intellec-tual property, clarifying publication provisions,and ensuring compliance with all applicableregulations.

Details: Issues which may not at the time ofpublication have been given sufficient emphasisin practice, particularly on the part of Europeansponsors, include patient privacy in the formof the Health Insurance Portability andAccountability Act (HIPAA) [9]. Because imple-mentation is ongoing, sponsors with minimalprior contact to the United States are still some-what unfamiliar with the myriad requirementsimposed by HIPAA, and may find suggested con-tract language on HIPAA daunting. Accordingly,it is incumbent upon the sponsor’s representa-tive, for example legal counsel to a CRO, to briefthe sponsor in detail on issues such as this and tosee to it that all study documents and proceduresincorporate all relevant aspects of HIPAA.

Another area which requires utmost attentionto detail in the early stages of planning is informedconsent. Proper drafting is essential to avert prob-lems with institutional and regulatory review ofconsent documentation. The informed consentdocumentation should be carefully drafted andcritically reviewed to ensure that all informationcontained therein is clear and presented in such amanner as to be easily understood by the patient.Details include providing the best possible trans-lation of informed consent documentation where

applicable, and subjecting the informed consenttext to critical review for clarity.

Yet other ‘standard’ terms appearing in theCTA must receive detailed treatment. Amongthese candidates are insurance and indemnifica-tion provisions, publication issues, and languagedetermining the allocation of intellectual prop-erty rights. The latter are extremely important,bearing in mind the fact that any developmentaldrug has the potential to become a ‘blockbuster’.Moreover, the desirability of keeping the researchpipeline full advocates devoting significant front-loading effort to negotiating the most favourableterms on intellectual property protection andretention.

Additionally, providing for intellectual prop-erty coverage at the earliest stage of CTA draftingis essential as the United States Patent andTrademark Office is currently in what might bestbe described as a state of general chaos. With thepatent process mired in bureaucracy, it stands toreason that the parties to a CTA conclude theagreement with all speed in anticipation of newdiscoveries. Nonetheless, the practitioner and thesponsor should both recognize that patent termrestoration may be used to ‘close the gap’ withregard to time lost to the trial process and to thepatent office [10].

Negotiating

The frontloading process, and ultimately thetrial, need and should not be compromised bypoor negotiating skills or time pressure. One issuecommonly encountered in terms of legal front-loading is that, for a variety of reasons, such asthe inadequate allocations of resources, adminis-trative overkill or sheer habit, a CTA presentedby the sponsor to a site may be reviewed by a con-tract generalist rather than clinical specialists.Frustration sometimes results, as the sponsor maythen be presented with a ‘counteroffer’ consistingof a ‘standardized’ or form contract, generally acompilation of those boilerplate terms preferredby the institution’s legal representative. In thealternative, the study site may insist at the onseton the use of such a form or standard contract.

30 J. Beck et al.


Situations such as this can and should beturned to the sponsor’s advantage – frontloadinghere involves in-depth communications and a will-ingness to be confrontational, yet fair, if only toobserve deadlines, but more importantly to dis-pose of undesirable and often inapplicable clauses– the ‘boilerplate’ – and to supplant these withterms the sponsor can justifiably claim are state ofthe art and on-point. There is no such animal as a‘standard clinical trial agreement’, and that theseasoned sponsor and/or legal specialist under-stands that all such ‘standard agreements’ pre-sented by institutions are frequently so alteredfollowing an exchange between legal representa-tives of both sponsor and site as to be whollyunrecognizable from the original template.

A caveat to the foregoing: the ability to recog-nize the futility of trying to negotiate certain stan-dard or ‘boilerplate’ CTAs is also required foreffective legal frontloading. Advocacy must beweighed against the sponsor’s overall willingnessto assume risks such as potentially losing adesired study site.

Nonetheless, the following two examples repre-sent, using the example of patent rights, the fruitof successful negotiations with respect to contractterms more favourable to the sponsor:

Example 18. (a) It is expressly agreed that neither the

Sponsor on the one hand, nor the Institution andthe Investigator on the other, transfers by opera-tion of this Agreement to the other party heretoany patent right, copyright or other proprietaryright which either party hereto owns as of theEffective Date, except as specifically set forthherein. (b) Institution agrees that any inventions,discoveries, or improvements (‘SponsorInventions’) arising out of work performed here-under that . . .

Example 24.1 The Sponsor shall be entitled to file in its

own name patent applications in respect of anyInventions. At the Sponsor’s request, theInvestigator and the Institutions shall provide theSponsor with such assistance as is reasonable toobtain and secure patent protection in respect ofany Inventions, including the execution of legaldocuments related thereto, provided that all

expenses related thereto, legal or otherwise, shallbe paid by the Sponsor.

In essence, both passages, taken from two sep-arate CTAs, concluded with two North Americaninstitutional sites lead to the same endpoint, withroughly the same outcome – beneficial terms forthe sponsor. However, the first example is clear,concise and not open to interpretation. The sec-ond example is abbreviated, as the original pas-sage continues on for several pages. Effectivefrontloading, in terms of contract drafting to pre-vent issues arising with contract interpretation,should always emphasize clarity and brevity.

The sponsor who is cognizant of ‘local rules’, orin-house procedures on the part of study sites thatmay impact negotiations will be best equipped tonegotiate the CTA. In the case of a foreign spon-sor, it is extremely advantageous to employ a legalteam with international expertise to navigate andexplain local clinical and regulatory practices.By keeping communications channels open, thesponsor may avert mundane problems such asdelays on the part of an overwhelmed institutionalcontracting team and the like.

A final point on legal negotiations: in terms ofreaching an agreement on a CTA, a sponsor’sresources and the ability to ‘give and take away’the benefits of a trial often trump any chance thelegal counterpart at a potential site may have tonegotiate advantageously. This imbalance ofpower should be exercised judiciously in view ofthe fact that the sponsor’s goal should be to estab-lish a solid and lasting working relationship.

Conclusion

The sponsor engaged in this aspect of frontload-ing, where the boundaries between legal and logis-tical issues become amorphous, must proceed infull awareness of the fact that the trial is most vul-nerable before reaching the point at whichpatient recruitment commences. However, itshould also be clear that this is precisely the pointat which problems are most readily addressedand future complications are most preventable.

It is essential that those charged with the keylegal aspects of the frontloading process do their



utmost to make their ‘teammates’ aware of the legaland regulatory issues impacting clinical trials. Athorough understanding of and constant updatingon the evolving regulatory environment is essentialto the success of the study. Frontloading effectivelyinvolves holding all ‘partners’ to a high standard ofcompliance and continuing legal and regulatoryeducation. The impending deadlines for implemen-tation of the EU clinical trials directive [7], whichwill of course add an additional regulatory overlayto multinational trials, will stand as a good bench-mark for the effectiveness of legal frontloading inthe near term.

Daniel Webster is credited with having oncesaid, ‘wisdom begins at the end’. The sponsor andthe sponsor’s representatives would do well toalways bear this in mind at the earliest planningstages of a study. Just as case law is built upon afoundation of precedent, so a successful trial willtake cues and borrow methodology from a recordof past successes. However, new methodologyshould be tried and further improved, forinstance, rather than relying on classical projectcharts, the ‘theory of constraints’ approach exem-plified by Goldratt [11] should be introduced aswell. In contrast to traditional critical path plan-ning, Goldratt uses a concept of moving con-straints and different sorts of buffers which lendsitself to more reasonable logistic modeling.Attention and adherence to a timeline, addressingproblems before they can truly manifest them-

selves, and carrying a study to the point of suc-cessful patient recruitment are all hallmarks ofsuccessful frontloading from a sponsor’s legalpoint of view.

References

1. Holt P. The art of the practical? It’s in purpose and processes.

GCPj 2003; 1100(6): 3–4.

2. ICH Guideline for Good Clinical Practice (E6).

http://www.ich.org.

3. Warlow C. How to do it. Organise a multicentre trial. Br Med J

1990; 330000(6718): 180–183.

4. Farrell B. Efficient management of randomised controlled trials;

nature or nurture. Br Med J 1998; 331177: 1236–1239.

5. 21 Code of Federal Regulations. http:// www.fda.gov.

6. Declaration of Helsinki. http://www.wma.net/e/ethicsunit/

helsinki.htm.

7. Directive 2001/20/EC on the Implementation of Good Clinical

Practice in the Conduct of Clinical Trials on Medicinal Products

for Human Use. http://europa.eu.int/eur-lex/pri/en/oj/dat/ 2001/

l_121/l_12120010501en00340044.pdf.

8. Foubister V. Lawsuits over clinical trials have doctors wary, but

not quitting research yet. American Medical News, 2001; AApprriill.

9. Health Insurance Portability and Accountability Act (HIPAA).

http://www.hipaa.org.

10. An ‘official guidance’ document issued by the U.S. Food and

Drug Administration on Patent Term Restoration. http://www.

fda.gov/cder/about/smallbiz/patent_term.htm.

11. Goldratt E. Das Ziel. Campus, 2002.

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Documents

Why clinical trials fail before they get even started: the ‘frontloading’ process