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Introduction to the Study Director

Mary Ellen Cosenza, PhD, MS, DABT, RAC

Amgen, Inc., Thousand Oaks, CA

1.1    Definition of Study Director

What is a Study Director and how does one become a Study Director? These questions are not new and date back to the first draft of the good laboratory practice (GLP) regulations (41 Federal Register [FR] 1976) in 1976. Yet, these questions are still being asked over 30 years later. As with many regulatory definitions, these simple words are open to interpretation which has adapted as the practice has evolved over the years.

The current Regulations (21 CFR 1999; Part 58 Section 58.33) state:

For each nonclinical laboratory study, a 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 control.

The study director shall assure that:

1. The protocol, including any change, is approved as provided in 58.120 and is followed.
2. All experimental data including observations of unanticipated responses of the test system are accurately recorded and verified.
3. 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.
4. Test systems are as specified in the protocol.
5. All applicable Good Laboratory Practice regulations are followed.
6. All raw data, documentation, protocols, specimens, and final reports are transferred to the archives during or at the close of the study.

The GLP regulations were first published in 1978 in Title 21: “Food and Drugs” of the Code of Federal Regulations (CFR) as Part 58: “Good Laboratory Practice for Nonclinical Laboratory Studies” (43 FR 1978), and they applied to all nonclinical safety studies intended to support research permits or marketing authorizations of products regulated by the Food and Drug Administration (FDA). Since then, similar regulations (40 FR 1989) have been published by the Environmental Protection Agency (EPA, 1983) for studies supporting chemicals and pesticides. Internation­ally, these regulations and guidance have been adapted by other agencies including the Organisation for Economic Co-operation and Development (OECD) and the Japanese (PMDA, 2014) regulatory agencies (for drugs and for chemicals). In all of these versions, the scope and responsibilities of the Study Director role are consistent with the FDA regulations. In 1999, the OECD Environmental Directorate issued a consensus document (OECD, 1999) on “The Role and Responsibilities of the Study Director in GLP Studies.” Although not specifically applicable to pharmaceu­tical toxicology studies, this document gives helpful suggestions on the scope, training, and responsibilities of a Study Director in all types of GLP studies.

When the GLPs were first released in 1978 (43 FR 1978) and implemented in 1979, they defined the Study Director as the person having “overall responsibility for the technical conduct of the study, as well as for the interpretation, analysis, documentation and reporting of the results, and represents the single point of study control.” It also stated that Study Directors needed to have “appropriate education, training, and experience, or combination thereof.” These two phrases are the most challenging and provocative parts of the Study Director sections. In addition, the Study Director has strict compliance responsibilities. A review of the history of these sections can help us understand the thinking behind these regulations. For simplicity, the current FDA regulations (21 CFR 1999) and the OECD Consensus Document (OECD, 1999) will be used as the main references in this chapter.

1.2    Regulatory History on the Scope of the Role

To better define the role of the Study Director, we can look at several documents:

• the Good Laboratory Regulations, both the original 1978 final rule (43 FR 1978) and then the subsequent amendments of 1987 (52 FR 1987) and 1999 (21 CFR 1999)
• the preambles to the proposed and final regulations
• the GLP questions and answers documents, several of which were combined and issued as a guidance document in 2007 (FDA, 2007).

There are consistent themes in both the questions and comments from the public to the FDA on this topic and in the responses and comments back from the FDA as well.

When the first draft of the GLPs was released for comment in 1976, there were over 50 specific comments on the scope of responsibilities for the new Study Director role. Many of the comments suggested that the role was too broad and/or suggested that some of the responsibilities listed for the Study Director should be assigned to others (preamble to 1978 final rule). Although some parts were modified in the final rule, the single point of accountability section was not changed. When the GLPs were updated in the late 1980s, the definition and scope of responsibilities were again questioned in the public comments. Again, the FDA confirmed their original intent (52 FR, 1987).

1.2.1    FDA 1976 Proposed Rule (41 FR 1976)

At the time of the GLP proposal (1976), several alternatives to having these regulations were discussed and considered including the licensing of testing facilities, having the FDA conduct all safety testing, and placing full-time agency monitors on-site at testing facilities. Instead, the FDA adopted the GLP regulations largely as we know them today. One of the new “roles” set up as part of the regulations was that of the “Study Director.”

Many of the problems found in the investigations and Congressional hearings that led to the development of the GLPs were attributed to unqualified, insufficient, or improperly supervised personnel. This led to the requirements for education, training, and experience and the documentation of these attributes. The single point of accountability of the Study Director comes from a desire for clear direction and implementation of the protocol (eliminating conflicting instructions).

1.2.2    FDA 1978 Final Rule (43 FR 1978)

The discussion in the preamble to the final rule gives us insight into the thinking behind the final regulations. There were many comments requesting more clarification from FDA on the training, education, and experience needed for study personnel. FDA declined to be more exact as it was felt that these requirements would vary from study to study. This was confirmed in question-and-answer documents when asked about the “minimal” acceptable educational requirements for a Study Director. Here it was also noted that a “wide range of nonclinical laboratory studies and numerous combinations of education, training and experience” would be acceptable (FDA, 1981). It is expected that management and Study Directors would carefully consider personnel qualifications as they relate to each particular study. One can then expect that management would have the final authority on determining if a Study Director had the necessary qualifications for their role. As stated in the preamble: the “Study Director should be viewed as the Chief Scientist in charge of a study.” All of this is further confirmed by Section 58.185, which states, “The final report shall be signed and dated by the Study Director” and “corrections or additions to a final report shall be in the form of an amendment by the Study Director.” This gives the Study Director the final approval of all aspects of the reporting of the study.

There were some additional tasks in the original draft that were changed to be management responsibilities when the final rule was issued in 1978. For those who still think the scope of the Study Director role is too broad, it may be of interest to note that it was even broader in the original 1976 proposed rules and some of the original duties (scheduling personnel, resources, and facilities) were transferred to testing facility management (Section 58.31) in the 1978 final rule. This new section was added, defining the role of testing facility management. This section also gave the authority of assigning and replacing a Study Director during the conduct of a study to testing facility management. Management is also responsible for ensuring that there is a quality assurance unit (QAU), that personnel understand the functions they are to perform, and the testing of test and control articles. One other part that speaks to another aspect of the Study Director's role is Section 58.31(g), which states that management must “Assure that any deviation from these regulations reported by the quality assurance unit are communicated to the study director and corrective actions are taken and documented.” This puts the Study Director squarely in the center of ensuring the compliance of the study and cements the communication pathway between the QAU, the Study Director, and testing facility management.

Several comments to the proposed rule concerned the question of more than one Study Director. It was confirmed in the final rule (43 FR 1978) and in subsequent question-and-answer documents (FDA HFC-30, 1979; FDA, 2007) that there would be...