C H A P T E R

31

Role of Study Director and Study Monitor inDrug Development

Colleen Johnson*, Stephen Frantzy*Toxicology Consultant, Hamilton, Virginia, yMPI Research Inc., Mattawan, Michigan

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Background 747

Study Directors 750

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Description

750 Study Conduct 750 Scheduling 750 Additional Considerations 751

Study Monitors 752

Description 752 Reasons for Using a Monitor 752 Selecting a Monitor 753 Considerations While Monitoring 753

74rehensive Guide to Toxicology in Preclinical Drug Development.

.doi.org/10.1016/B978-0-12-387815-1.00031-9

Study Director Check List 754

Study Monitor Check List 755

Bringing in Experts 755

Regulations 756

Conclusions 756

References 757

In the context of conducting nonclinical studies, thestudy director and study monitor have key responsi-bilities. (Note: For the purposes of this chapter, it haslargely been assumed that the study monitor will bea third party individual.) In fact, the two roles shouldcomplement each other, especially in the eyes of regula-tory agencies such as the Food and Drug Administra-tion (FDA) and the European Medicines Agency(EMA). The study director focuses on the day-to-dayactivities related to performing a nonclinical studywhile the study monitor serves as a bridge betweenthe study director/laboratory personnel and thesponsor and provides a more global evaluation of thestudy.

This chapter discusses the roles of the study directorand study monitor, with a focus on the development ofpharmaceutical products. It also illustrates the mannerin which these scientists interact to most effectivelyaccomplish the goal of providing a well-conducted,

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Good Laboratory Practices (GLPs) compliant nonclinicalstudy for regulatory submission. However, its principlesalso apply to the types of interactions that are importantfor any non-GLP study. This chapter is not intended to bea comprehensive description of responsibilities, butrather to provide both a summary and framework forhow the two jobs allow for a harmonized and stream-lined approach to study conduct. Ultimately, the goal ofboth study directors and monitors is to provide thesponsor with a nonclinical study that is acceptable tonational and international regulatory authorities andallow for ongoing clinical development of the drug.

BACKGROUND

In pharmaceutical development, nonclinical toxi-cology studies are conducted to support clinical trials

� 2013 by Elsevier Inc. All rights reserved.

31. ROLE OF STUDY DIRECTOR AND STUDY MONITOR IN DRUG DEVELOPMENT748

or marketing. The nonclinical studies are designed toaccomplish two main goals:

1. To establish an initial starting dose in humans (basedon the early nonclinical studies) and

2. To define the safety of the drug with respect tomultiple endpoints (e.g., genetic toxicology,reproductive toxicology, pharmacokinetics andmetabolism, etc.), and later to establish information toassist in marketing a safe drug.

Safety is only characterized and understood by estab-lishing toxicity. Sponsors who are new to drug develop-ment sometimes confuse observations of toxicity asbeing an indication of a drug’s limitations, thinkinginstead that a ’clean’ profile is desirable. In fact, theopposite is the case and a successful toxicology studyis one that demonstrates a range of effects, includingtoxic ones.

Only after demonstrating the types of toxicity thata drug produces and the doses and exposures at whichthese effects occur can clinicians and regulators deter-mine what parameters and exposures need to be moni-tored in clinical trials. For this reason, toxicologystudies are performed at a range of doses that will estab-lish minimal, moderate and significant toxicity. Ideally,at least one dose will provide evidence of the types oftoxicity associated with the drug and at least one dosewill produce minimal to no effects. As might beexpected, this ’ideal’ situation is sometimes difficult toachieve, as selecting appropriate doses to produce thedesired range of effects is both a science and an art.Consideration of all available information such as phar-macodynamics and mechanism of action, preliminaryor short-term toxicology data, and findings from other

FIGURE 31.1 Progression of nonclinical studies during drug devel

drugs in the same class is an essential process to select-ing the correct doses to achieve success in study perfor-mance from both a scientific and regulatory standpoint.

The following figure (Figure 31.1) summarizes thetypes of nonclinical data that are needed at variousstages of clinical development. This paradigm is basedon a generic new chemical entity (not an oncology agentor biotechnology-derived product) that will be used fora chronic indication in the clinic.

Figure 31.1 illustrates that as human studies increasein treatment duration and size, the types and durationof the nonclinical studies also become more comprehen-sive. In general, the design of these various toxicologystudies is well understood by the scientific and regula-tory communities. The one drug-specific variable thatshould be carefully considered for the design of thelonger-term repeat-dose studies is the influence of thedrug’s exposure profile. Exposure differences in thesestudies should be carefully considered when selectingdose levels, particularly when there may be evidencefor saturation of a drug’s metabolic and/or eliminationpathways that can often lead to accumulation andtoxicity outcomes. As described in the 2009 Interna-tional Conference on Harmonisation (ICH) M3(R2) [2]guidance on the nonclinical studies needed for clinicaltrials and marketing authorization of human pharma-ceuticals, the duration of these repeat-dose studiesdepends on the duration of the clinical trials. Animalsmust be treated in the repeat-dose studies for at leastas long as volunteers or patients will be treated in theupcoming clinical trial. For Phase I studies, these dura-tions are generally short (i.e., 28 days), while the PhaseII studies, where efficacy is first studied in patients, aregenerally longer (i.e., 90 days) and the Phase III studies

opment.

FIGURE 31.2 Duration of repeat-dose toxicity studies during the conduct of clinical trials.

BACKGROUND 749

can be longer still (i.e., >90 days). The exceptions areoncology agents or biotechnology-derived productswhere entry into patient populations happens witha reduced nonclinical package. This is detailed inFigure 31.2, which is adapted from the 2009 ICHM3(R2) guidance and specifies the toxicology studydurations during development (ongoing clinical trials).

For ultimate marketing authorization, the followingrepeat-dose studies are needed (Figure 31.3).

As a final note, the nonclinical studies conducted ona pharmaceutical need to use the clinical dosingregimen, including route of administration and treat-ment schedule (i.e., once per day, twice per day). If

FIGURE 31.3 Duration of repeat-dose toxicity studies for marketin

exposure is low via the clinical route, then an alternateroute that maximizes systemic exposure may need to beconsidered. However, any alterations in the dosingroute should be discussed with the regulatory authori-ties prior to initiation of toxicology studies. In addition,it is now expected that toxicokinetic assessments areincluded in all pivotal toxicology studies. These dataare critical during development and for the ultimatesubmission, as comparisons will be made betweenexposures at the no adverse effect doses in animals,and exposures in patients at the clinical dose.

With this understanding of the nonclinical datapackage required at different stages of the drug’s

g authorization.

31. ROLE OF STUDY DIRECTOR AND STUDY MONITOR IN DRUG DEVELOPMENT750

development, the roles and responsibilities of studydirectors and study monitors are discussed below.

STUDY DIRECTORS

Description

A study director is defined as ’the individual respon-sible for the overall conduct of a nonclinical study’according to the Code of Federal Regulations (21 CFRPart 58.3). For any nonclinical study, whether it iscompliant with GLPs or not, the performing laboratory(or contract research organization [CRO]) assigns a studydirector; there is only one study director for a nonclinicalstudy. This individual is responsible for overseeing allelements of study conduct within the testing facility,including, but not limited to: developing the protocol,scheduling the study, obtaining the test article inadequate amounts, ordering animals, meeting with thetechnicians and staff to review the protocol prior tocommencing the study, interacting with the technicianson a regular basis to ensure the study is being conductedto meet the requirements of the protocol, providingupdates to the sponsor, informing the sponsor of anyfindings, working with outside contractors to makesure samples are shipped and received for analysisand that reports are provided, preparing the draft andfinal study reports, interpreting the data to solidify theconclusions of the study, and reviewing and incorpo-rating comments from the study monitor and/orsponsor. As the single individual accountable fora nonclinical study (often referred to as the ’single pointof control’ for GLP expectations), the study director alsobecomes responsible for the work of outside contractorsthat supply critical supportive data for the study.

Study directors bring a unique perspective toa program based on their experience working witha variety of product types, study designs, animalspecies, and dosing methods. This experience can becritical in assisting a sponsor in their consideration ofthe details of the study.

Study Conduct

Once a laboratory has been selected by a sponsor, thefirst step is to determine who the study director will be.This individual can be assigned by the laboratory orrequested by the sponsor. This is followed by the prepa-ration of the protocol. This is a critical process as theprotocol describes how the material will be preparedand dosed, what parameters will be assessed and howoften they will be evaluated during the course of thestudy. Information is shared between the sponsor/studymonitor and study director about the type of study

needed, as well as the type of product being evaluatedand any particular requests from regulatory agencies.For most studies, the general design has been estab-lished or is well understood within the scientificcommunity. Any unique features of the study shouldbe discussed early in the protocol development process,so that they can be incorporated and time allotted in casemore advanced training or specific procedures need tobe followed. In addition, all outside contractors needto be identified and shipping/contact informationprovided for inclusion in the protocol.

A protocol, once signed, becomes the road map forthe study. However, it is not set in stone and protocolamendments must be created as details of the studyneed to be refined or changed to meet the sponsor’sneeds or to accommodate unexpected findings. Thegoal is to have all the details finalized prior to studyinitiation, but this is not always possible. Still, keepingthe number of amendments/changes to a minimumshould be a priority so that there is limited opportunityfor confusion or missed data collection. Ideally, changesshould be made well enough in advance so that the tech-nical staff can incorporate them seamlessly into theirstudy-specific procedures.

After or as the protocol is developed, the moretangible elements of the study start to take place:ordering and receiving animals and obtaining the testarticle. These ideally need to occur between 2 and 3weeks prior to initiation of dosing so that there are nodelays in the program.

Scheduling

All activities and endpoints assessed in a nonclinicalstudy follow a schedule that is prepared in advance,generally during protocol development, by the labora-tory’s scheduling group. Although changes to the studyschedule are possible and do occur, these can be difficultto incorporate while balancing the timing of the multipleother studies also being performed by the laboratory.Should or when a sponsor requests changes to the studyschedule, the study director needs to then work with thescheduling group to integrate all new activities given theavailability on the master schedule for the facility. Anychanges need to be communicated in an expeditedmanner to the technical staff. Reasons for re-schedulingcan include test article availability, ongoing develop-ment of supportive methodologies, a scheduling changeat an outside contractor, need for expedited reviewof the data, etc. These changes can either move up orpush back a study start or can impact the timing ofcritical study events after study initiation.

The responsibilities of the study director are manifoldand require attention to detail. Although a studyschedule provides the framework, the study director

TABLE 31.1 Regulatory Guidance Frequently Asked Questions

The Study Director isoften asked:

• Where do I go to find the applicableregulatory guidance documents?

• Which guidances do I apply to mystudy?

• What role does an anticipatedduration of clinical treatment play in

STUDY DIRECTORS 751

and technicians work together to make it happen. Beingaware of the various activities and being present for thecritical ones is both an expectation of the sponsor andfrom the regulatory agencies under GLPs. Furthermore,regular communication on study progress and potentialproblems is essential. Given themultitude of responsibil-ities, interactions between study directors and studymonitors are akey to the successful completion of a study.

study selection?

• What role does API (activepharmaceutical ingredient) purityplay in my study?

• What part does the sponsor play inthose studies conducted at a CRO?

Additional Considerations

Throughout this chapter, there are many references toregulatory compliance and the guidances that dictatethe standards to which study directors and laboratorystaffs are held. However, interpreting the intent behindwhat is written in specific sections of these guidancesis often a subject for great debate. Because of theseimprecise and sometimes even vague passages in theregulations, the laboratory conducting a study and itsquality assurance unit can find themselves in a difficultsituation in attempting to follow their interpretation ofthe guidance’s intent versus the view from the sponsorcompany. Ultimately, the laboratory must balanceprotecting itself from receiving a 483 citation, or inextreme situations, an FDAwarning letter, which couldresult from Agency inspections and their subsequentfindings with the needs of the sponsor. For thesereasons, it is important for a CRO and its managementto work together with the sponsor to try to resolve anyunclear situations to everyone’s mutual satisfaction;this is often easier said than done.

One example of this can occur when the bioanalysisof plasma samples from a toxicokinetics (TK) bloodcollection in a toxicology study and the subsequent TKdata analysis for exposure parameters are conductedby either the sponsor’s internal lab staff or by a third-party lab. If the protocol states that the sponsor orthird-party lab will conduct both plasma and TKanalysis, but the actual TK data analysis is outsourcedto yet another party, the protocol has to be amended sothat the study director and the lab where the studywas conducted are aware of the changes in responsibil-ities. Should this not happen, a GLP deviation wouldoccur and this would be listed in the final report in orderto avoid a 483 citation for the primary (tox) lab. In thisparticular circumstance, it is better to take a GLP devia-tion and to cite it in the final report than to risk questionslater in an audit of that study by the FDA.

Study directors regularly field the same types ofquestions from sponsors as they prepare to conductstudies. These questions provide excellent opportunitiesfor the study director to offer guidance that can helpensure the success of the study or studies being con-ducted. Table 31.1 below summarizes some of thesetypical questions.

The use of appropriate regulatory guidance docu-ments is covered elsewhere in this text (e.g., the ICHM3 (R2) guidance) and briefly later in this chapter.

One question that often arises is the purity of the APIthat is used in preclinical studies, particularly in theearly development stages (e.g., dose ranging and pre-IND toxicity studies) of the program. This is often over-looked and its importance is underestimated until itbecomes an issue which can lead to an interruption(i.e., clinical hold) of a compound’s clinical develop-ment because an impurity(ies) is/are not qualified firstin toxicology studies. Typically, the strategy in earlydevelopment stages should be to conduct nonclinicalstudies using the ’dirtiest’ lots of material (e.g., thosehaving the most impurities). This means that carefulconsideration should be given to the level of purityused in the preclinical studies, starting with smaller,non-GMP qualified lots that tend to be not as pure asthe larger kg-scale lots that are manufactured inhighly purified, GMP-compliant campaigns for clinicaluse. It is important to note that these pre-GMP lots ofmaterial still need to be characterized and the levelsand types of impurities determined. Using the lowerpurity, smaller quantity lots can avoid the unantici-pated situation of potentially exposing clinical subjectsto those ’impurities not yet tested in nonclinical animalstudies’, which can lead to being placed on a clinicalhold by the Agency. While it is possible to qualifyimpurities at any stage of development, careful plan-ning will certainly help limit delays in both the costand timing of the program.

Some additional considerations for a sponsor toaddress to ensure that a high-quality study will beconducted can include:

1. Are you providing the CRO with sufficiently detailedoutlines so that all important study design aspectswill be included in the study(ies) being planned? Youcan expect that a competent CRO will ask critical

31. ROLE OF STUDY DIRECTOR AND STUDY MONITOR IN DRUG DEVELOPMENT752

questions to make sure that no design features areassumed;

2. Is sufficient information being provided to determinewhether a study segment will be conducted ata sponsor’s lab or will go to a third-party/subcontract lab? How/when an important studysegment that is not done at the CRO is beingscheduled will be critical to avoid timing/cost issues,sometimes even when done in the sponsor’s lab;

3. Are sponsor expectations for report metrics beingcommunicated clearly to the CRO?; and

4. How much compound will you ’burn through’ inpreclinical studies and will sufficient API supplybecome an issue later, in longer-term studies? This iswhen getting enough API to the CRO on time iscritical to avoid timing/cost issues.

These questions and their proactive answers canoften make a considerable difference to how smoothlythe study will run.

Finally, it must be reiterated that a successful toxi-cology study is one that demonstrates a range of effects,including toxic ones, and that this is the expectation forboth safe and effective drug substances by FDAandotherregulatory agencies around the world. Sponsors in drugcompanies, particularly in small pharma/biotech firms,need to carefully balance observed toxicities in a givenstudy with the overall program objectives. This meansthat they should separate the requirement todemonstratetoxicity from becoming a perception of the drug’s limita-tions. The misconception that a ’clean’ drug profile isdesirable can often be a competing objective from boardsof directors and funding/venture sources that quicklybecome nervous at any occurrence of an ’unexpectedfinding’. Thus, a successful companyneeds to align fund-ing objectives with safety expectations from reviewingagencies in order to obtain their approval to conducthuman clinical trials.

STUDY MONITORS

Description

Perhaps the best way to describe a study monitor is tosay that he or she acts as the eyes and ears of the sponsor.Being the point of contact and representative for thesponsor requires an understanding of what is best forboth the sponsor and the study. As a result, it is essentialto understand the overall goals of the sponsor, not simplyfor the study, but ultimately for the submission of the datato a regulatory agency. For example, being aware of thecorporate objective for timing of a submission is criticalwhen working with the laboratory and the sponsor, asthere are times when the target is not feasible given the

time required to complete a nonclinical study or studiesand coordinate the data for the submission. Alternatively,it is important to understandwhether there are particulartoxicity flags that the sponsor is concerned about. Thesegoals should ideally be understood in advance, particu-larly if there is a short turn-around between completionof the study and submission to an agency, or if specificfindings could terminate a study or program. Keep inmind too that the addition of a recovery period may beimportant or even critical to the successful outcome ofthe study, both from the perspective of reversal of effectsobserved during the dosing period or for the appearanceof a delayed effect that takes longer than the dose phase toobserve clinically or microscopically. This and anyspecific requests of a regulatory authority need to beincorporated from the beginning into the study design,as it is oftentimes not possible to make these changeswhile the in-life phase of a study is under way due to aninsufficient number of animals.

Perhaps the most effective assistance that a studymonitor can provide is to ensure that all parties, labora-tory and sponsor, are on the same page with respect toconducting each study. In this way, the number of’surprises’ or unrealistic expectations should beminimized.

It is important to note that the ’eyes-on’ role of a studymonitor is not restricted to on-site visits. Rather, moni-toring occurs both in person and remotely. In fact, mostof the monitoring will likely occur remotely, through e-mails, teleconferences, secure on-line data sites, andother technologies, since a full-time, on-site individualis generally not a financially feasible option. While avail-able current technologies allow for regular oversight ofstudies, there are times when a complete understandingof a study can only be obtained by being on site. Deci-sions about the timing and frequency of such visitsshould be discussed before the study starts, so that theycan be coordinated with the study schedule.

Reasons for Using a Monitor

The question can reasonably be asked why there isa need for a study monitor, since a study director actu-ally runs the study. As noted above, the study directoris responsible for the day-to-day in-house activities ofa study. In comparison, a study monitor providesa different level of input or oversight that is focusedless on these details and more on a global or higherlevel view. There are times when stepping back fromthe details can provide a perspective on the data thatis not immediately evident when dealing with theday-to-day activities.

There are several reasons why a sponsor may elect tohave a monitor be involved in a study. The first is time. It

STUDY MONITORS 753

is a time-consuming effort to regularly be involved withand oversee a nonclinical study. If the sponsor hasmultiple other obligations and projects that limit theirtime and availability, then a study monitor can step inand serve this role. The second is experience. Not allsponsors have the expertise in-house to oversee a labora-tory and the details of a study. This is particularly truefor companies that either do not have a nonclinicalgroup or whose nonclinical group is small and/orincludes less-experienced scientists. The third is thedecision to have a new or fresh perspective on a studyso that it is not affected by previous work on the devel-opment program. Although these are just a few reasons,it is likely that all three as well as others could play a rolein the decision to select a study monitor.

Selecting a Monitor

Once a decision has been made to include a studymonitor in a program, the question becomes how toselect the correct individual. This is ultimatelya personal preference on the part of the sponsor.Certainly, experience plays a critical role in the decision,but in addition having ’good chemistry’ (personalityand ability to interact with a variety of individualswith a large range of study-specific responsibilities) iskey. Recommendations from other colleagues whohave worked with study monitors can be extremelyvaluable.

Because the monitor will serve as the liaison betweenthe lab and the sponsor, will observe activities on-site,will relay any findings to the sponsor, will assist inmaking decisions during the conduct of the study,and will review reports (amongst other things),a balance of technical expertise and good communica-tion skills is needed. Having a level of sensitivity inhow to communicate certain findings does not hurt,especially when corrections or changes need to bemade. A spirit of collaboration and not competition isanother useful characteristic in identifying a goodstudy monitor and should not be underestimated orundervalued.

A well-qualified study monitor should have experi-ence with the types of studies that they are being askedto oversee, along with knowledge of the protocol andany relevant regulations. Previous interactions withthe laboratory can be very helpful, but are not essential.Being able to assess the overall quality of the laboratoryand personnel is important. Although most studiesproceed with little to no deviations, mistakes or errorscan occur. By working closely with the study directorand laboratory staff, the monitor can help to diminishthese complications or assist in expediting a resolutionon behalf of the sponsor. This rapid and proactive

response is facilitated by a good working relationshipwith the study director.

Whether through an on-site visit or remote communi-cations, a confidence needs to be established betweenthe study director and monitor such that there are nodelays in understanding how the study is progressing.This becomes particularly important if unexpected find-ings are obtained or if adjustments need to be made tothe design/conduct in the middle of the study. Whileit is not always possible, a face-to-face visit with thestudy director at the facility can provide the most effec-tive way to begin or mature this relationship. This can beparticularly effective as well when the conclusions of thestudy report are nearing a finalization stage and mayneed to be discussed.

Finally, a study monitor needs to have experiencewith regulatory agencies and understand their expecta-tions with respect to what constitutes a well-conductednonclinical study. This is particularly important should,or when, unexpected events occur during the course ofa study (e.g., terminating a dose group early in a carcino-genicity study, placing animals on a drug holiday,decreasing a dose). Rapid interactions and agreementsto alterations in studies with agency personnel are some-times required. Here is where experience is critical.These agreements/decisions cannot be facilitatedwithout an understanding of what the regulatoryauthorities expect and a means to communicate withagency scientists (i.e., based on previous interactions).Reviewing guidance documents provides a sense ofthe agency’s perspective/requirements, but only regularand recent interactions will enable a study monitor tomake the most appropriate recommendations to thesponsor and study director. The recent interactions areparticularly important as feedback and recommenda-tions on the design of studies is generally first communi-cated in this environment, often months or years beforeit becomes formally recognized in an official agencydocument.

Considerations While Monitoring

There are no formal or informal regulations govern-ing or guiding the study monitoring process eventhough it is an expectation of the regulatory agencies.This allows each monitor to establish his or her ownindividual processes and procedures for overseeingstudies. However, because each monitor may considerdifferent elements of the study of different impor-tance, it can be challenging to have a consistentapproach to this process. The following table (Table31.2) lists some of the notable things to consider whenmonitoring.

A final question to consider is when to conduct an on-site monitoring visit: pre-study, during dosing, at

TABLE 31.2 Study Monitoring Considerations

The degree of monitoring depends on the significanceof study.

• For example, a range-finding study likely needs input for dose selection,discussion of observations, and recommendations for dose escalation,which can occur remotely whereas a pivotal repeat-dose study will likelyrequire an on-site visit and regular interactions with the study director toensure that the study progresses with a limited number of unexpectedevents.

Study monitoring is part experience and part intuition. • There are times when you need to go with your ’gut’ in regards to makingdecisions about a study or pursuing explanations for findings.

When observing, the monitor should be present, butnot disruptive to the daily activities (e.g., dosing, datacollection, etc.).

• In other words, it is most helpful to observe without getting in the way ofnormal study-related procedures.

Questions are good and demonstrate hands-oninteractions.

• Questions can be a key source of information taken from the technicianswho observe the animals at each dosing or data collection time point.

It is not helpful to monitor the minutia. • Throughout the course of a study, isolated, aberrant results may occur.Knowing which are important to follow up on and which are not will focuseveryone’s attention in the right direction.

Be knowledgeable and helpful. • Know what you know and what you don’t know.

Don’t offer previews of what the study staff shouldexpect to observe.

• When interacting with technicians, allow them to communicate theirobservations on the study without biasing them or directing them ina specific manner.

TABLE 31.3 Study Director Check List

The Study Director: • Is responsible for all aspects of thestudy conduct

• Acts as a ’single point of control’on all GLP-compliant studies

• Is responsible for all study designchanges and writing of formalamendments to the study protocol

• Assures that all applicable GLPsare followed

31. ROLE OF STUDY DIRECTOR AND STUDY MONITOR IN DRUG DEVELOPMENT754

necropsy? Any or all of these times will provide usefulbut different insight into the progress of the study. Inaddition, the occurrence of unexpected findings isanother opportunity to observe and communicate thefindings. Under perfect circumstances, the on-site visitis scheduled in advance, but should adverse eventsoccur it is imperative to get on site as quickly as possible.Having said this, the location of the laboratory playsa major role in the extent of on-site monitoring. Someinternational locations can be difficult to access so thisneeds to be considered by the sponsor when selectingthe CRO.

• Assures that Should readcorrective action is conveyed anddocumented in a timelymanner toall affected study staff

• Is available for weekend andholiday study decisions

Additional StudyDirector Roles:

• Approves the study plan• Assures arrival of the test article• Approves and issues

amendments to andacknowledges deviations from thestudy plan

• Visits the study room regularlyand documents those visits

• Liaises with (and is readilyavailable to) each of the PrincipalInvestigators on a study

• Ensures that all staff are aware ofrequirements of the study anddocuments these expectations

• Ensures that a final report isprepared

STUDY DIRECTOR CHECK LIST

Before initiating a nonclinical study, several itemsneed to be in place to ensure a high-quality study willbe conducted for the sponsor. These most often include,but are not limited to, a study protocol, chemistryconsiderations, dose formulation and plasma analysis,dose administration, proper selection of the test species,arrival of the test article, or API when dealing withpharmaceutical substances.

It is incumbent upon the study director to explain allof the risks to the sponsor if not all elements of a studyare in place prior to starting. The following is a shortlist (Table 31.3) that details the major responsibilities ofthe study director, principally as it applies to GLP-compliant studies, but it usually applies for the conductof non-GLP studies as well.

TABLE 31.4 Check List for Study Monitors

Study Initiation

and Set-Up

Four weeks prior to study start:

• Select CRO and ensure contracts are in place• Schedule study

Three weeks prior to study start:

• CRO to identify study director• Prepare and review protocol• Identify contractors/principal investigators and inform them of the study schedule• Address test article characterization (e.g., identification, stability, etc.)• Discuss dose formulation/preparation• Determine status of analytical/bioanalytical work (e.g., dose formulation, plasma/serum analyses,

antibody analyses, etc.)

Two weeks prior to study start:

• Approve protocol (prior to animal receipt)• Work with study director to estimate test article needs and ensure appropriate amounts are shipped to

CRO• Ensure that animal order is placed• Confirm that animals have been received in good health

One week prior to study start:

• Ensure that animals are acclimating• Confirm that pre-study assessments have been conducted• Finalize formulation preparation with pharmacy• Attend study pre-initiation meeting

In-Life

Activities

• Observe dosing and/or review regular updates from study director• Confirm the collection of critical study parameters (e.g., blood samples, formulation samples, in-life

assessments)• Regularly discuss study status and findings with study director and sponsor• Visit on-site to observe study-related activities, review study administration and pharmacy books, analyze

available data• Address any deviations with study director and sponsor• Review data as they become available• Ensure samples are shipped to outside contractors on a timely basis (this may need to occur at regular

intervals during the study)

Post-Mortem

Activities

• Observe necropsy and/or receive update from study director• Review preliminary data• Coordinate any final sample shipments to outside contractors• Alert outside contractors to study timelines• Review reports from outside contractors

Reporting • Review draft report• Communicate findings/changes with sponsor• Ensure that all principal investigator reports are received by study director

BRINGING IN EXPERTS 755

STUDY MONITOR CHECK LIST

There are four main stages during the life cycle ofa study that a monitor can focus on (Table 31.4,Figure 31.4).

The activities of the study monitor will intersect withthe activities of the study director to a certain extent, but

FIGURE 31.4 Life cycle of a nonclinical study.

will also be unique in other ways. The following table(Table 31.4) provides a list of various tasks to considerin each of the study phases. Although the study monitormay not be involved at all stages, an understanding ofeach of these elements is extremely helpful.

BRINGING IN EXPERTS

No matter what your level of experience may be,there are times during the performance of a study thatan expert may be needed. It is critical to know when toinvolve such a specialist and who to contact. These

31. ROLE OF STUDY DIRECTOR AND STUDY MONITOR IN DRUG DEVELOPMENT756

individuals can be a part of the CRO team or an outsideconsultant or group.

Perhaps themost often utilized expert is a pathologist.Pathology peer review groups or even individualpathologists are often employed to conduct blindedreviews of slides, provide insight into a mechanism, orsimply confirm the observations of the study patholo-gist. Not every study requires such input, but somesponsors as a matter of policy involve a peer reviewfor the more pivotal studies, such as carcinogenicitystudies. Other areas for which experts are commonlyused include neuropathology, reproductive toxicology,electrocardiography and ophthalmoscopy.

REGULATIONS

As the drug development process has matured overthe years, the regulations that relate to nonclinicalstudies have expanded. Both the study director andstudy monitor need to be aware of existing guidelinesand how to implement them in order to perform a studythat meets both national and international regulatoryrequirements.

GLPs refer to the principles that govern the conductof nonclinical studies. These were implemented in theUnited States (US) by the FDA following investigationsinto the quality and reliability of certain data submittedto support product registrations. GLPs were officiallyadopted by FDA as a final rule in 1978 [1]. In Europe,under the auspices of the Organisation for EconomicCo-operation Development (OECD), they were offi-cially adopted in 1981 (c.f.[3]). The OECD GLPs weredeveloped by an expert working group which includedrepresentatives from 17 countries, including the US.Since their adoption, revisions or updates to these prin-ciples have been published as scientific technology andmethodologies have advanced, but the core principlesremain the same. In general, nonclinical studies per-formed by US-based laboratories are in compliancewith the FDA GLPs and those performed outside theUS are in compliance with the OECD GLPs. As bothsets of GLPs define the same requirements or expecta-tions, they allow global acceptance of nonclinicalstudies as long as they are performed in compliancewith one of these systems.

It is important to clarify that GLPs refer to theprocesses and procedures that are in place to supportthe performance of nonclinical studies; they do notdescribe study designs. Detailed criteria have been out-lined for testing facilities and their operating procedures,personnel, equipment, record keeping, test and controlarticles, and other related parameters. Today, it isexpected that any pivotal nonclinical study supporting

either ongoing clinical trials or a marketing authorizationwill be performed in compliance with GLPs.

In an effort to harmonize global requirements fornonclinical studies, ICH developed a series of guidelines[2]. The ICH guidances are the most comprehensive andinternationally recognized set of documents addressingthe nonclinical aspects of pharmaceutical development.However, like GLPs, these generally do not outlinespecific details on study design. Rather, these providedirection on the overall types and timing of nonclinicalstudies as well as more expanded commentary on thesestudies. The key guidelines fall under the safety cate-gory and address carcinogenicity, genetic toxicity, toxi-cokinetics, reproductive toxicity, safety pharmacology,immunotoxicology, and photosafety as well as durationof chronic toxicity studies, biotechnology-derived prod-ucts and oncology products. The focus is on criteriaand/or recommendations for a particular safety endpointor data interpretation and not generally on study design,although study details are specified for the reproductivetoxicity endpoints. By developing the guidances in thisway, accommodations for technological advances withinthe scientific community as well as specific requirementsfrom regional regulatory authorities can be incorporatedinto the nonclinical studies.

In addition to the ICH guidelines, both FDA andEMA prepare separate supplemental guidances thatassist in or describe specific expectations for variousnonclinical studies or types of pharmaceutical products.FDA prepares documents entitled ’Guidance forIndustry’ and EMA prepares documents entitled ’Notefor Guidance On’. These documents are easily accessibleon the websites for each agency.

There is no singular location where one can finddetailed protocols of currently accepted study designsfor nonclinical studies to support the developmentof a pharmaceutical. This is because the details ofthe studies are constantly evolving based on Agencyrequests or needs. However, OECD has publisheda series of guidelines for the testing of chemicals thatdo outline in detail the design of a wide variety ofnonclinical toxicology studies. This is a good startingpoint for understanding what a regulatory agency willexpect. In addition, experienced CROs and scientistsare aware of the trends in this area, specifically as theyrelate to pharmaceuticals, and can provide specific guid-ance to sponsors with questions.

CONCLUSIONS

The roles of the study director and study monitor areinterconnected and effective execution of a nonclinicalstudy therefore involves a good working relationshipbetween these two individuals (Figure 31.5).

FIGURE 31.5 Collaboration between study directors and studymonitors.

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There are several keys that make this happen. The firstis communication. Regular, ongoing, and rapid accessi-bility of study directors and study monitors can circum-vent many potential problems and facilitate the overallstudy performance and outcome. The second is collabo-ration. Understanding that both parties are workingtoward the same goal and are on the same team can alle-viate any uncertainties and misunderstandings that mayarise. The third is certainty/decisiveness.When decisions

need to be made during the course of the study, clearsuggestions or proposals are necessary so that thesponsor can, along with the study director and monitor,determine the best path forward.

When study directors and study monitors are in sync,not only do nonclinical studies progress smoothly butany unexpected events are dealt with quickly and ina manner that meets the mutual expectations andrequirements of the CRO and the sponsor. Such an envi-ronment creates the ideal setting for accomplishing theultimate objective of providing reliable nonclinicaldata to support the clinical development and marketingauthorization of pharmaceuticals.

References

[1] Federal Register (FR). Nonclinical laboratory studies. Goodlaboratory practice regulations 1978;43(247):59986e60025.

[2] International Conference on Harmonization (ICH). Guidanceon Nonclinical Safety Studies for the Conduct of Human ClinicalTrials and Marketing Authorization for Pharmaceuticals. M3(R2)2009.

[3] Organization for Economic Co-operation and Development.OECD principles on good laboratory practices (as revised in1997). In: OECD Series On Principles Of Good Laboratory Prac-tice And Compliance Monitoring; 1998. Number 1.