A Practical Guide To Study Directing

A Practical Guide to Study Directing Alan P. Brown Drug Safety Research & Development, Pfizer Global Research & Development, Ann Arbor, Michigan 48105, USA

Summary The Good Laboratory Practice (GLP) regulations are designed to provide regulatory guidance and oversight of nonclinical studies that prospectively study the effects of test articles in test systems under laboratory conditions to determine their safety. These regulations are designed to assure quality, accountability, and reliability of safety data, and provide guidelines for improving the scientific validity of the studies. A key element of the GLP regulations is with respect to the role of the Study Director, who is the individual assigned as the single point of study control and has overall responsibility for the entire nonclinical study. Experience has shown that unless responsibility for the proper conduct of a study is assigned to a single individual, the potential exists for personnel to receive conflicting instructions, and for study events and issuance of the final report to occur in an uncoordinated fashion. While serving as the Study Director can be a challenging position with numerous demands and expectations, it is a role that allows an individual the opportunity to combine project management with technical and scientific skills in the pursuit of a single goal. Individuals who serve as Study Directors in the nonclinical laboratory typically represent a diverse range of educational and professional backgrounds, and oftentimes learn to become Study Directors on the job. The goal of this paper is to provide a concise description of the Study Director’s responsibilities and give guidance for planning, initiating, and completing a nonclinical study. While this paper focuses on test articles that are evaluated in the pharmaceutical/biotechnology industry and regulated by the US Food and Drug Administration (FDA) GLPs, much of the information presented should apply to other GLP and non-GLP studies. Copyright r 2009 John Wiley & Sons, Ltd. Key Words: Study Director; GLP; Good Laboratory Practices; nonclinical laboratory; toxicology; US FDA

Introduction and Responsibilities The US FDA Good Laboratory Practice (GLP) regulations (Section 58.33) state the following. ‘‘For each nonclinical laboratory study, a *Correspondence to: Alan P. Brown, PhD, DABT, NAMSA Inc., 6750 Wales Road, Northwood, Ohio, USA. E-mail: [email protected]

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scientist or other professional of appropriate education, training, and experience, or combination thereof, shall be identified as the Study Director. The Study Director has overall responsibility for the technical conduct of the study, as well as for the interpretation, analysis, documentation and reporting of results, and represents the single point of study control. The Study Director shall assure that:

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a)

b)

c)

d) e) f)

The protocol, including any change, is approved as provided in 58.120 and is followed. All experimental data, including observations of unanticipated responses of the test system are accurately recorded and verified. Unforeseen circumstances that may affect the quality and integrity of the nonclinical laboratory study are noted when they occur, and corrective action is taken and documented. Test systems are as specified in the protocol. All applicable Good Laboratory Practice regulations are followed. All raw data, documentation, protocols, specimens, and final reports are transferred to the archives during or at the close of the study.’’ [1]

The role of the Study Director in the conduct of nonclinical studies designed to assess safety of various test articles is oftentimes challenging and dependent upon that individual’s managerial, technical, and scientific capabilities. Individuals who serve as Study Directors typically have not received formal education in this endeavor, and many times have other professional responsibilities within an organization. Training and mentoring of Study Directors usually occurs ‘‘on the job’’ and is dependent upon the level of organization and experience of the laboratory personnel interacting with that individual. This paper is intended to serve as a practical resource to provide guidance to Study Directors for the initiation, conduct, and completion of nonclinical studies. This guide is intended to be useful to all Study Directors, regardless of experience level, and is applicable for the majority of studies conducted in a nonclinical laboratory, irrespective of scientific discipline or study design. Although emphasis is placed on the conduct of nonclinical studies for the biopharmaceutical industry and regulated by the US Food and Drug Administration (all cited references to GLP refer to these regulations), Copyright r 2009 John Wiley & Sons, Ltd.

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the guidance provided here is consistent with the role and responsibilities of the Study Director in GLP studies as described in the OECD (Organization for Economic Cooperation and Development) Principles of GLP [2]. Although the qualifications and training required for an individual to serve as a Study Director may vary and are the responsibility of test facility management to determine, general guidances should be considered. In regard to formal education, a degree in the biological sciences (e.g. BS, MS, DVM, PhD, MD) is generally required although in certain circumstances appropriate training and professional experience may be sufficient for an individual without a degree in the biological sciences. Management should assess prior professional experience when determining which aspects of a formal training program are most applicable for an individual becoming a Study Director. This individual should clearly document in their training record or file the ability to collect, interpret, evaluate, and report experimental data as evidenced by formal education, academic and/or industrial research, publications, certifications, professional experience, and completion of any relevant training programs. In addition to understanding the regulatory and scientific requirements for directing studies, Study Directors also need to successfully manage, communicate, and interact with numerous individuals who are involved with the design and conduct of the study. The various managerial and interpersonal skills necessary for successful study directing have been described elsewhere [3]. As per Section 58.31 of the GLP regulations, ‘‘For each Nonclinical laboratory study, testing facility management shall: (a) Designate a Study Director as described in 58.33, before the study is initiated. (b) Replace the Study Director promptly if it becomes necessary to do so during the conduct of a study.’’ [1] For both assignment and replacement of a Study Director, management should ensure that the assigned person has the appropriate qualifications, training, interest, and resources to direct the study. Management has the ultimate reQual Assur J 2009; 12, 40–50 DOI: 10.1002/qaj

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sponsibility for ensuring that the testing facility is effectively organized and that work is carried out to a high standard, in accordance with GLP regulations and facility standard operating procedures (SOPs) and practices. Before any study activity is undertaken, the Study Director should ensure that management has committed adequate resources, in terms of personnel and equipment, to perform and complete the study in a timely fashion. SOPs should be in place for procedures/operations to be conducted in the study. The laboratory’s SOPs should be detailed enough to adequately describe/instruct how to perform the intended task, yet clearly written to avoid confusion and allow efficient work to occur [4]. Facility management should ensure that personnel involved in the study are adequately trained to perform the tasks expected of them and that the equipment to be used in the study has been appropriately calibrated, serviced, and maintained. Although the Study Director is not directly responsible for instituting these conditions for the study, he/she accepts responsibility for the study following issuance of the protocol.

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Studies intended to support safety and characterize the toxicity of a test article need to comply with GLP regulations. This includes the majority of genetic toxicology, safety pharmacology, and general toxicology studies performed in support of applications for research or marketing permits of biopharmaceutical agents. Exceptions to this rule may include screening genetic toxicology studies, dose range-finding studies, and investigative or exploratory studies. Study design and rationale, parameters to be evaluated, and doses to be tested should be discussed between the Study Director, Sponsor, project team representative, and other relevant individuals. If unique assays or procedures are to be included, planning should occur to ensure that appropriate resources, training, and procedures are available to properly conduct the study. Dose-level selection is a key aspect in protocol preparation and should be determined as soon as possible so that test/control article requirements can be determined, materials ordered, and appropriate analytical methods/ information made available.

Test and Control Articles Initiating and Directing the Study Study Objectives The Study Director, in consultation with the Sponsor or project team representative should discuss the objective(s) of the study, whether GLP compliance is required, and the appropriate study design. Section 58.3 of the GLP regulations state: ‘‘Nonclinical laboratory study means in vivo or in vitro experiments in which test articles are studied prospectively in test systems under laboratory conditions to determine their safety. The term does not include studies utilizing human subjects or clinical studies or field trials in animals. The term does not include basic exploratory studies carried out to determine whether a test article has any potential utility or to determine physical or chemical characteristics of a test article.’’[1] Copyright r 2009 John Wiley & Sons, Ltd.

The test article is commonly referred to as test substance and is typically the drug or experimental compound under study. Oftentimes, the test article is the most variable element to the nonclinical study and it is common for the test facility and Study Director to have various questions regarding this aspect of the study. The control article is also referred to as control substance and is administered to the test system for establishing a basis for comparison with the test article. Typically, the control article is the vehicle that is used to formulate and deliver/ apply the test article to the test system. Adequate supplies of the test and control articles for completion of the study should be available in the test facility at least several days prior to initial use of the material. Documentation of identity, strength, purity, and composition of the test article is required by the GLPs (Section 58.105), and should be Qual Assur J 2009; 12, 40–50 DOI: 10.1002/qaj

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determined and documented in a certificate of analysis, analytical test report (ATR), or properties memo prior to study initiation. This information should provide the ‘‘percent active moiety’’ or the portion (%) of bulk substance, by weight, attributed to the active drug substance or active pharmaceutical ingredient (API). It is important to ensure that this information is or will be available for the test article lot(s) to be used in the study. Test articles may exist as salts or contain non-active components; therefore, it is important to consider the portion (%) of bulk substance comprised by the API when considering dosage formulations. Analytical information/characterization may not be available for experimental compounds being tested in non-GLP studies early in development. Therefore, it may be appropriate to assume 100% active moiety, with corrections made for salts in these circumstances. Typically, the control article is the vehicle used to deliver the test article to the test system. Studies may use standard excipients for vehicle formation. An excipient is a material added to the active drug substance to produce a formulation and is a component of the vehicle. The laboratory must document the preparation of the vehicle. When marketed products are used as excipients in the formation of a vehicle, those products will be characterized by their labeling. When unique control articles/vehicles are to be used, laboratory personnel should be consulted so that availability of the vehicle can be determined and GLP compliance maintained. The type of vehicle to be used for delivering the test article to the test system should be selected well in advance of the study and approved by the Study Director. Depending upon the study design, vehicle selection may occur by default (e.g. DMSO for in vitro genetic toxicology studies). It is important for the vehicle selected to have minimal effects on the test system. GLP-regulated studies require the following (Section 58.105): ‘‘The stability of each test or control article shall be determined by the testing facility or by the sponsor either: (1) before Copyright r 2009 John Wiley & Sons, Ltd.

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study initiation, or (2) concomitantly according to written standard operating procedures, which provide for periodic analysis of each batch.’’[1] Prior to study start, the certificate of analysis, ATR, or properties memo will indicate the purity (percent active moiety, i.e. potency) of the test article. The Study Director should request that a sample of each lot of test article used in the study be submitted for analysis following completion of the dosing phase. Stability of commercially available materials used as control articles can be documented by their labeling. If the test article lot was manufactured under GMP (Good Manufacturing Practices) conditions and certified as such, there may be a retest date for reanalysis of the lot. This retest date should have been based upon prior stability information for the test article. If the retest date will occur after completion of the dosing phase, then stability can be assumed and no additional testing for that lot is required (if applicable, please indicate in the protocol). The Study Director should be aware if special handling and/or storage conditions are required for the test or control articles, and should communicate such information to the laboratory staff. Although it is preferable that a study use a single lot of test article, this may not always be possible. The requirements for stability testing are applicable for each lot used in the study. Each lot of test article to be used in the study should be indicated in the protocol and/or amendment(s). Section 58.113 of the GLP regulations indicate that for each test or control article that is mixed with a carrier (i.e. vehicle or diet), tests by appropriate analytical methods be conducted: a) To determine the uniformity (i.e. homogeneity) of the mixture and to determine, periodically, the concentration of the test or control article in the mixture. b) To determine the stability of the test and control articles in the mixture as required by the conditions of the study either: before study initiation, or concomitantly according to written SOPs which provide for periodic analysis of the test and control articles in the mixture [1]. Verification of stability and homogeneity of the Qual Assur J 2009; 12, 40–50 DOI: 10.1002/qaj

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test article in the vehicle (i.e. formulation) should be conducted prior to initiation of a study or series of studies using the same test article and vehicle. For example, the laboratory could prepare 2 or 3 concentrations of a test article formulation spanning a range of concentrations (e.g. 0.1, 1, and 200 mg/mL) and the formulations then evaluated by analytical means for determination of homogeneity and stability up to approximately 28 days (depending upon intended length of use and frequency of preparation). This testing is also required for formulations that are solutions. The Study Director is responsible for being aware of these results and planning dose concentration and preparation frequency accordingly. Storage conditions should be consistent and supported by stability data. In the event that stability and homogeneity information is not available at the time of study initiation, the Study Director can arrange to have these analyses conducted on the dosage formulations used in the study. This requires analyses to be initiated on the day of formulation preparation. An alternative approach is to have stability and homogeneity testing occur simultaneously or after study conclusion, using nonstudy formulations. The caveat is that verification may not occur for the concentrations or vehicle used in the study. Stability and homogeneity analyses of a test article formulation need not be repeated for different lots of test article unless the test article form has changed (e.g. significantly different crystal form, different salt form); the concentration range is outside of the established range; the method of preparation and storage are different or the vehicle used has changed. Verification of stability and homogeneity is not required for non-GLP studies. Dosage formulations used in a GLP study are required to be periodically analyzed to determine test and control article concentrations. The frequency for the analyses will be dependent upon the duration and type of study, and/ or test article formulation. SOPs should stipulate that measured concentrations of test article should be within7X% of intended concentraCopyright r 2009 John Wiley & Sons, Ltd.

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tion (typically710%). More frequent evaluations of dosage formulation concentrations may be warranted for formulations that periodically fall outside of this range. In the event that a formulation is initially measured to be outside of the intended range, notification of the Study Director should occur and SOPs should dictate the course of action for investigation. Although dosage formulation analyses are not required for non-GLP studies, analyses are recommended when using a test article formulation for the first time or when concerns exist regarding the formulation.

Protocol Development The Study Director should take appropriate steps to assure issuance of the final protocol at least 3 days prior to the start of the first pretest event. Some laboratories may require protocol issuance prior to animal receipt into the facility. Although exceptions to this guidance may exist (in vitro genetic toxicology studies for example), protocols must be issued prior to initiation of pretest activities because data are collected during the pretest period. In addition, final protocols need to be issued with enough time so that all groups and individuals involved in a study are fully able to prepare and perform study-related activities. This is a GLP requirement as stated in Section 58.31(e) and (f). Many testing facilities have protocol templates for a majority of studies typically conducted by the laboratory. A protocol template should be selected that most closely resembles the study to be conducted. Templates are often designed with enough flexibility to provide an adequate guide for the generation of most study protocols. Previously issued protocols can be used as a reference for the generation of a new protocol; however, current templates should be used because practices, procedures, and information may have been updated. Protocol templates should contain procedures, parameters and assays for which current SOPs exist and resources are available for their performance. If a procedure (e.g. intrathecal administration in monkeys) or parameter (e.g. Qual Assur J 2009; 12, 40–50 DOI: 10.1002/qaj

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measurement of serum testosterone in mice) is required for the study but not present in a protocol template, it should not be assumed that SOPs, training, and/or equipment or resources are currently available. The Study Director should discuss with the appropriate colleagues the necessary steps required for implementation of these procedures. Statistical tests indicated in the protocol templates are often applicable to the current study design and parameters. If changes to the study design are required, consult with a statistician to determine the appropriate statistical tests for the study and whether those tests can be performed. Study Directors using vertebrate animals should be familiar with The Guide for the Care and Use of Laboratory Animals, National Research Council, 1996 [5]. This document provides guidance for the housing, care, and handling of laboratory animals and provides the basis for animal husbandry practices in many test facilities. Animal Welfare Act regulations require that procedures used in animal studies receive prior approval by the Institutional Animal Care and Use Committee (IACUC). Procedures to be conducted in study animals are described in an Animal Use Protocol (AUP) and reviewed by the local IACUC. The Study Director needs to ensure that an approved AUP is available for the intended study and includes the procedures to be used. If an AUP is not available, then the Study Director may have to prepare and/or assist with the preparation of a new AUP, and submit the protocol to the IACUC for review and approval. A clinical veterinarian should be consulted regarding preparation of a new AUP. If minor changes to an existing AUP are warranted (e.g. additional animals are needed for a study), then an addendum to an existing AUP may be the only requirement. The draft protocol should be distributed for review with enough time to allow adequate review and revision prior to study events. The draft protocol should be sent to the Sponsor, project team representative, study personnel, and test facility management for review. If the Copyright r 2009 John Wiley & Sons, Ltd.

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study is a GLP-regulated study, the draft should also be sent to the Quality Assurance Unit (QAU). Three to 5 business days (depending upon study complexity) is an adequate period for review. The draft protocol and any proposed changes should be discussed with key study personnel. Comments provided to the Study Director should be considered and/or included in the protocol. The protocol is officially issued when the Study Director signs the protocol. The GLP regulations consider the study initiation date to be the date that the protocol is signed by the Study Director.

Protocol Amendments Changes or revisions to an issued protocol are called protocol amendments. Section 58.120 of the GLPs states: ‘‘All changes in or revisions of an approved protocol and the reasons therefore shall be documented, signed by the Study Director, dated, and maintained with the protocol.’’ [1] Issuance of a protocol amendment is the responsibility of the Study Director, and needs to occur in a prospective fashion (i.e. before an action or procedure is to occur). Protocol amendments should not be issued for procedures or acts that have already occurred. Amendments generally should not be used when an unforeseen event occurs in the study requiring a unique response unrelated to other processes indicated in the protocol. In this case, the Study Director should accurately document the unforeseen event and unique response in the study data. The protocol amendment should clearly indicate the reason for the change and this should be a rational or scientifically justified reason. Reasons can include the following: 1) To add, remove, change, or correct an item that currently exists in the protocol regarding study conduct (not a typographical error). 2) To clarify an item or procedure in the protocol. 3) To change the name(s) of responsible parties identified in the protocol. 4) To terminate a study. The Study Director should consider whether the amendment should be reviewed for clarity/content prior to issuance, by individuals Qual Assur J 2009; 12, 40–50 DOI: 10.1002/qaj

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involved with the study. The effective date provided in the amendment indicates when the amendment is considered ‘‘active’’, and not necessarily the date that the amendment is signed. Only the Study Director is required to sign the amendment which should occur in a reasonable and timely manner. A well written amendment instructs study personnel as to what they should do on a study and why, and documents decisions made by the Study Director and the reason for those decisions. If a study is to be terminated, a protocol amendment is required; otherwise, the study will be maintained on the Master Schedule and considered active.

Study Director Involvement The testing facility should develop or utilize a Study Director notebook or log as a means by which Study Directors can document their involvement in the study and awareness of study events. This notebook or log could be comprised of hardcopy/paper records or laboratory notebook, or could utilize electronic records that are 21 CFR Part 11 compliant [6]. Entries in the notebook should be signed and dated. As examples, the notebook could provide a readily available means for documenting the following: 1) Activities conducted by the Study Director, phases of the study observed, and data reviewed. 2) Interactions with study personnel, Principal Investigators on multi-site studies, and review of contributing scientist reports. 3) Awareness of unforeseen events, animal treatments, animal morbidity or mortality, and/or deviations from the protocol or standard operating procedures. 4) Provide clarification to other recorded study data. 5) Document interactions with the Quality Assurance Unit (QAU) and review of the QAU audit report. Study Director Notebook entries should be limited to a brief description of the topic of the audit, the date, and individuals in the QAU that were involved. Entries should not describe the audit report contents. There may be cases where alternate means for study documentation are more appropriate. This may include Copyright r 2009 John Wiley & Sons, Ltd.

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forwarding email messages (with time and date indicated), and signed and dated faxes or memos to the study file. It is important to remember that good study documentation is an important element in the conduct of nonclinical studies, and when in doubt, it is best to document. Timely documentation of awareness of study events is important for demonstrating Study Director-control of the study and commonly evaluated during study audits by the QAU and external auditors (e.g. FDA).

Study Start Prior to the start of the in-life phase of a study, a meeting should be held by the Study Director with key individuals who will be involved with the conduct of the study (typically the in-life portion of the study). The purpose of the meeting is to review the study goal(s) and protocol, and to ensure that the primary individuals involved with conducting the study are prepared to do so. This meeting should occur prior to any pretest activities and animal assignment to the study. Before the meeting, the Study Director should review the study schedule for accuracy and to ensure that protocoldirected events are scheduled appropriately. Topics that should be presented and discussed at the meeting include: study protocol and schedule, animal assignment, test article and dosage formulations, unique procedures, etc. It is the Study Director’s responsibility to assure that the test systems are as specified in the protocol. This means assuring that animals are available and meet the requirements (age, sex, body weight, clinical status) as specified in the protocol. It is recommended that pretest data be reviewed prior to animal assignment/ randomization to the study. If animals are to be excluded from randomization or assignment to the study, documentation of the animal(s) and reason(s) for exclusion should be made. The laboratory staff should document the return of large animals to the stock colony, as well as the disposition of unassigned (extra) rodents. The Study Director’s involvement during the course of the study should include observing Qual Assur J 2009; 12, 40–50 DOI: 10.1002/qaj

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study procedures and reviewing data to ensure that the protocol and applicable SOPs are being followed, and to familiarize themselves with study data and any response(s) of the test system to the test article(s). This is particularly relevant during the in-life phase of the study. Phases of the study for observation include (but are not limited to) the following: dosage formulation, dosing, clinical observations, physical and ophthalmic examinations, electrocardiography, measurements of heart rate and blood pressure, blood collection, necropsy, laboratory assays, and analytical procedures. Depending upon the study design and/or responses of the test system to the test article(s), more or less frequent observations of protocol procedures may be warranted. The Study Director should document their observation of any study procedure. The Study Director has overall responsibility for the interpretation, analysis, documentation, and reporting of study results. Therefore, familiarity with study data is essential. Data which should be reviewed in a timely fashion include (but are not limited to) the following: study records, test/control article dosage formulation and potency analyses, animal room environmental reports, and responses of the test system to test/control articles as directed in the protocol (i.e. data for parameters to be measured or evaluated). The Study Director should document their review of study data. Frequent communication with personnel involved in a study will help ensure that the study is conducted as per the protocol, help prevent issues or events from arising that may have a negative impact on the study, and demonstrate Study Director-control of the study. Interactions with the clinical veterinarian(s) are important when toxicologically significant responses occur and/or animal treatments are considered [7]. Section 58.33 of the GLPs states: ‘‘The Study Director shall assure that: unforeseen circumstances that may affect the quality and integrity of the nonclinical laboratory study are noted when they occur, and corrective action is taken and documented.’’ [1] Unforeseen circumCopyright r 2009 John Wiley & Sons, Ltd.

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stances include (but are not limited to): protocol and SOP deviations, out-of-range conditions for animal housing or equipment, equipment problems or failures, data loss, outof-range values for dosage formulation concentrations, animal treatments not indicated in the protocol, significant or unanticipated mortality, and facility failures (e.g. utilities, computer systems). The Study Director is responsible for documenting awareness of the event(s) in a timely fashion, and to ensure that corrective action has, will, or can be taken, and that any corrective action is documented. Many potential unforeseen circumstances have an SOP-directed response; therefore, the Study Director should document awareness of the event. Means for documentation include the Study Director’s notebook or log, or memo or email stored in the study file.

Multi-Site Studies The OECD Principles of GLP describe requirements for multi-site studies [8]. Studies in which study activities or phases (except for test article characterization before the study begins) occur at more than one site and the sites are geographically remote, organizationally distinct, or otherwise separated are considered ‘‘multi-site’’. Different departments of an organization located at one geographical location are not considered ‘‘multi-site’’. An example of a multi-site study is where all study work and data generation are to occur at Tox Labs Inc., Chicago, Illinois with the exception of toxicokinetics analysis which will occur at Tox Labs Inc., Milwaukee, Wisconsin. The testing facility is the laboratory that uses the test article in the test system (e.g. Tox Labs Inc., Chicago, IL) and the test site is the laboratory where phases of the study are conducted (e.g. Tox Labs Inc., Milwaukee, WI). The Principal Investigator is the individual responsible for the phase(s) of the study conducted at a test site and serves on behalf of the Study Director. The study protocol and any amendment(s) need to be provided to the Principal Investigator and test site QAU. Protocols for multi-site studies need to include Qual Assur J 2009; 12, 40–50 DOI: 10.1002/qaj

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the following: 1) Name and location of the test site(s) and phases of the study to be conducted there. 2) Identity of the Principal Investigator at each test site. 3) Location of archives for raw data and specimens. 4) The role of the respective QAU’s. 5) SOPs which may be applicable to each site. 6) The means by which the Study Director will interact/communicate with the Principal Investigator and how data generated by the test site will be provided to the Study Director for inclusion in the final report. It is important that unforeseen circumstances (e.g. protocol or SOP deviations) that occur at a test site are communicated to the Study Director. The Study Director is responsible for reviewing the results of any QAU audits that occur at a test site. The Principal Investigator will issue a contributing scientist report along with a QA statement for the phase(s) of the study conducted at the test site and this report will be included as an appendix to the final research report for the entire study.

Completing the Study Preparing the Final Report The Study Director is responsible for ensuring that all aspects of the final report accurately reflect the protocol, amendments, and data generated in the study. The required components of the final report are indicated in Section 58.185 of the GLP regulations [1]. The Study Director should periodically review the study file to assure that all data to be included in the final report are available. Summary data and individual animal data should be reviewed for accuracy and interpretation, and are required to be reported. A thorough evaluation of the data is necessary for determining toxicologic or biologic significance of the results, and for deriving conclusions from the study. Contributing scientist (see below) or Principal Investigator reports should be reviewed, along with the data, and discussed with the individual preparing the report. It may be helpful to review a final, previously issued research report for a Copyright r 2009 John Wiley & Sons, Ltd.

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related study as guidance for preparing the draft study report. Section 58.185 of the GLP regulations state that the final report shall include: ‘‘The signed and dated reports of each of the individual scientists or other professionals involved in the study.’’ [1] Signed and dated contributing scientist reports are required for inclusion in the final report (in the appendices), and need to be signed prior to issuance of the final report by the Study Director. A contributing scientist is an individual who was responsible for analyzing and interpreting study data. Individuals who worked on a study or served in a supervisory capacity would not necessarily be considered a contributing scientist. For a general toxicology study, contributing scientists typically include the clinical veterinarian, study pathologist, clinical pathologist, toxicokineticist, and statistician. The Principal Investigator role in a multi-site study can be equivalent to that of a contributing scientist. The abstract of the report is the most widely read portion of the study report and deserves special attention. The abstract is the principal means by which the study findings are communicated. The abstract often serves as the foundation for subsequent summary documents; therefore, it is imperative that it be written in a clear and concise manner, and accurately describes test article-related effects and study conclusions. It is very important that accurate presentation of unforeseen circumstances that may have affected the quality or integrity of the data be mentioned in the final report along with the assessed impact on the study. Typically, this involves protocol deviations. When mentioning these occurrences and their impact, brevity is recommended. In general, SOP deviations would not necessarily need to be mentioned in the final report unless the deviation had a significant or negative effect on performance of the protocol or data generation (e.g. data not collected due to failure to follow an SOP for a piece of equipment). Following completion of the draft report, the report in its entirety should undergo a scientificQual Assur J 2009; 12, 40–50 DOI: 10.1002/qaj

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peer review. Reviewers could comprise Study Director/facility management, contributing scientists, and the Sponsor and/or project team representatives. The Study Director should critically review the comments and consider incorporating changes into the final draft of the report if they offer acceptable improvements. However, it is important to recognize that the Study Director is responsible for the final report along with overall interpretation, analysis, and reporting of the results.

Completing the Final Report Following all revisions of the draft report, the report should be submitted to the QAU for auditing (for GLP studies). The role of the QAU is to ensure compliance of the study and the testing facility with the GLP regulations, and to certify that the final report accurately reflects the raw data and protocol. The QAU will evaluate adherence with the protocol and applicable SOPs, whether study data were collected according to the protocol and SOPs in a GLP-compliant fashion, Study Directorinvolvement in the study, and whether quality processes are in place and functioning. QAU comments and/or questions will be provided to the Study Director following completion of the study audit(s). It is the Study Director’s responsibility to evaluate each comment and to ensure that a response indicating the action(s) taken/not taken for each comment in the audit is provided. Once the Study Director and the QAU have agreed that acceptable responses to the audit have occurred, the report should be ready for issuance. The contents of a QAU audit, including audit findings, should not be documented or reported in the study file or records, but maintained by the QAU only. This includes audit reports received in multi-site studies. At this time, a signed Quality Assurance (QA) statement will be issued by the QAU, which will be incorporated in the final research report. This statement will indicate the dates and phases of the study that were audited for GLP compliance, but will not indicate audit Copyright r 2009 John Wiley & Sons, Ltd.

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findings. The Study Director signs the report last, and once that occurs, the report is final and issued. Non-GLP studies will go through this procedure except that auditing and issuance of a QA statement by the QAU will not occur. An occasion may arise in which a change is necessary to be made in a final, issued report. Corrections and/or additions to an issued report need to occur by issuance of a report amendment by the Study Director. The amendment should clearly identify the portion of the final report that is being changed and the reason for the change. The amended pages and/ or additional pages are included in the Final Report Amendment. The QAU should conduct an audit and issue a signed QA statement for the Final Report Amendment. Following issuance of the final report, all draft copies of the report and any draft part thereof should be destroyed. The Study Director is responsible for ensuring that all raw data, specimens and samples have been submitted to the archives and should verify this process with the various laboratory groups involved in the study.

Conclusions The GLP regulations are designed to assure quality, accountability, and validity of scientific data in which test articles are evaluated in nonclinical studies to determine their safety. A key element of the regulations is with respect to the Study Director, who is designated as the single point of control and has overall responsibility for the study. While this role has numerous challenges and expectations, it is a position with significant responsibility. As science, technology, risk assessment and regulatory expectations change and evolve, new opportunities for Study Directors will develop. By combining managerial, scientific, and communication skills in a single position, the Study Director plays a pivotal role for achieving the study objectives. Serving as a Study Director involves a journey of continuous learning; Qual Assur J 2009; 12, 40–50 DOI: 10.1002/qaj

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hopefully the guidance provided in this document will help lead those individuals on the path to success.

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2. OECD Series on Principles of GLP and Compliance Monitoring Number 8 (revised). Consensus Document, The Role and Responsibilities of the Study Director in GLP Studies, 1999. 3. Rose CA and Mayer DE. The regulatory and business roles of a study director. Qual Assur J 2005; 9:

Acknowledgements

273–282. 4. Robinson

The author would like to acknowledge the following individuals from Pfizer Inc, Ann Arbor, Michigan who provided critical information and editorial support in the development of this guide: Dr. Charles Rothwell, Dr. Scott Clipper, James Poteracki, and Kathryn Perez.

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Disclaimer The views expressed in this paper represent those of the author and do not necessarily represent official policy of Pfizer Inc.

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Copyright r 2009 John Wiley & Sons, Ltd.

Qual Assur J 2009; 12, 40–50 DOI: 10.1002/qaj