Investigators and Sites: Answers to Questions about Good Clinical Practice

Earlier this year, Applied Clinical Trials published "Clinical Monitoring: Answers to Questions about Good Clinical Practice," another excerpt from the book, Good Clinical Practice: A Question & Answer Reference Guide. Readers are referred to the July 2003 issue (pages 27-29) to read the full text of the reference guide introduction.

Investigator qualifications

Q.

When is an individual considered "qualified" to conduct a clinical trial? For example, can non-physicians, such as Ph.D.s, Pharm.D.s, D.O.s, or D.D.S.s, be considered qualified to serve as principal investigators?

A. FDA GCP regulations at 21 CFR 312.53(a) require that investigators be "qualified by training and experience as appropriate experts to investigate the drug." The ICH GCP guideline adds that an investigator "should be qualified by education, training, and experience to assume responsibility for the proper conduct of the trial and should meet all the qualifications specified by the applicable regulatory requirements." Although the FDA's GCP regulations make no reference to a medical degree or other specific education or training necessary to qualify as an investigator, the ICH GCP guideline is somewhat more definitive. In Section 2.7 of "The Principles of ICH GCP," the guideline states that "the medical care given to, and medical decisions made on behalf of, subjects should always be the responsibility of a qualified physician or, when appropriate, of a qualified dentist."

In recent informal correspondence on this question, the FDA stated that, "while technically a non-physician can be a principal investigator, this requires that the nonphysician be qualified to personally conduct or personally supervise all aspects of the study. In practice, we have found it very rare that a non-physician can comply with this requirement. In general, where we have seen non-physicians listed on the 1572 as a principal investigator we usually would find an M.D., as a subinvestigator, to perform those study functions requiring the appropriate level of medical expertise. For example, a Ph.D. pharmacologist may be listed as a principal investigator on a pharmacokinetic study with an M.D. as a subinvestigator. Another example might be a clinical psychologist principal investigator with an M.D. subinvestigator." As a general rule, a non-M.D. can be listed on the Form FDA 1572 as the principal investigator, provided that there is an M.D. involved in the study to assume medical responsibility for enrolled subjects.

Frequently in the past, the FDA has been asked specifically about whether nonphysicians can serve as investigators. One of the more definitive declarations of FDA's policy on this subject came in an October 4, 1989, memo (see exhibit below) from Office of Drug Evaluation I (ODE I) Director Robert Temple, M.D., and then- ODE II Director James Bilstad, M.D., which stated: "Qualified individuals who are not M.D.'s can participate in clinical trials either as principal investigators or sub-investigators provided that an M.D. or D.O. (or D.D.S. depending upon the study) is either a sub-investigator or is listed in the IND as an individual who will be responsible for drug administration and evaluation of patient safety."

In a 1983 response to a letter addressing the participation of clinical pharmacists as principal investigators, then-FDA Associate Commissioner for Health Affairs Stuart Nightingale wrote: "In [your] letter you posed the question whether Doctors of Pharmacy (Pharm.D.) may serve as investigators in clinical pharmacological studies of investigational drugs. You noted that you have received varying interpretations of our regulations on this point from different manufacturers who sponsor pharmacological studies. It has long been FDA policy to accept Doctors of Pharmacy as primary investigators of studies of investigational drugs within their areas of expertise. Because such studies may require the diagnosis of disease and the recognition and treatment of adverse reactions or other medical incidents occurring during the course of the study, we have required that a person licensed to diagnose and treat disease be officially associated with the study to be performed. This is ordinarily done by naming such an individual in the Form [FDA-1572] as being responsible to the principal investigator of record. Alternatively, both the Doctor of Pharmacy and the licensed individual may sign the form [FDA-1572] as co-investigators, having equal responsibility in the performance of the study in question."

According to an American College of Clinical Pharmacy (ACCP) commentary appearing in Pharmacotherapy (2000;20(5):599-608), Nightingale then responded to an ACCP request for clarification on whether the above comments applied only to pharmacokinetic studies:

"Doctors of Pharmacy may serve as clinical investigators for both clinical pharmacology studies and clinical trials of a drug provided they do so in conjunction with a person licensed to diagnose and treat disease." In its commentary, ACCP notes that FDA again emphasized "that a physician be a subinvestigator to assess the patient and make medical decisions."

An April 1990 response from then-CDER Director Carl Peck, M.D., to a similar American Association of Colleges of Pharmacy clarification request stated: "You asked whether FDA would consider pharmacists, especially Pharm. D.'s with adequate training and experience eligible to be principal investigators in 1) pharmacokinetic studies and 2) clinical efficacy studies. This question has been addressed on a number of occasions, beginning in 1980 with Dr. Marion Finkel, then director of the Office of Scientific Investigations (now called the Offices of Drug Evaluation I and II), and most recently in a [1989] memorandum . . . from the Directors of the Offices of Drug Evaluation. In 1980 and at present, the conclusion is the same: pharmacists can serve as principal investigators in any clinical trial. Section 506(1) of the Food, Drug, and Cosmetic Act requires that FDA assure that the investigational drug will be provided only to 'experts qualified by training and experience to investigate' a new drug. Whether or not FDA will permit a particular pharmacist to be an investigator in a clinical study will be determined on a case by case basis, and may depend on the type of study (pharmacokinetic study, clinical efficacy study) proposed in the IND."

Subinvestigators

Q.

What is a subinvestigator, and how does a subinvestigator relate to a principal investigator? Since subinvestigators conduct important trial-related tasks (e.g., make clinical decisions), must a subinvestigator meet the same "training and experience" qualifications as an investigator? Can nurse coordinators, ARNPs, PAs, Pharm.D.s or Ph.D.s be subinvestigators? And who must be listed as subinvestigators on the FDA Form 1572-Statement of Investigator? Can subinvestigators be investigators that recruit patients at other offices or sites, or must a subinvestigator work at the same office/facility as the investigator?

A. Under FDA regulations (21 CFR Section 312.3(b)), an "investigator" is "an individual who actually conducts a clinical investigation (i.e., under whose immediate direction the drug is administered or dispensed to a subject). In the event an investigation is conducted by a team of individuals, the investigator is the responsible leader of the team. 'Subinvestigator' includes any other individual member of that team." Block #6 in the Form FDA 1572-Statement of Investigator asks for the "names of the subinvestigators (e.g., research fellows, residents, RNs) who will be assisting the investigator in the conduct of the investigation."

In essence, a subinvestigator is any other member (i.e., other than the investigator in charge of the study) of the study team who makes clinical decisions during the study. The ICH GCP guideline defines subinvestigator as, "any individual member of the clinical trial team designated and supervised by the investigator at a trial site to perform critical trial-related procedures and/or to make important trial-related decisions (e.g., residents, research fellows, RNs)." The implication, then, is that the subinvestigator will have a clinical degree and training.

Since the investigator signs the Form FDA 1572 while the subinvestigator does not, it is the investigator who assumes all of the commitments specified in the form, including ensuring "that all associates, colleagues, and employees assisting in the conduct of the study(ies) are informed about their obligations in meeting the above requirements." Confusion frequently arises about who should be listed as subinvestigators on the 1572. Normally, these are the people who make study-related medical decisions regarding the diagnosis and treatment of the disease under investigation. Those who are responsible for completing study paperwork need not be listed on the 1572.

Today, however, FDA officials continue to acknowledge that "subinvestigator" is among several trial-related terms that could use further clarification, despite agency attempts to clarify this area in the past. In the preamble to its 1987 IND regulations, for example, the FDA specifically responded to a request that the agency define the term "subinvestigator," and that it clarify whether the term includes non-physicians, nurses, technicians, and other assistants to the clinical investigator. "Studies frequently are conducted by a team of individuals who share responsibility for designing and conducting the investigation," the agency stated. "The principal investigator is the responsible leader of that team. Subinvestigators include all other professionals who assist the principal investigator in the design and conduct of the investigation. Subinvestigators would not include those technicians and other [assistants] who assume no responsibility for the conduct of the study."

In recent informal correspondence regarding this question, the FDA stated that, "in general, if individuals involved in the conduct of the study are performing functions within the scope of their professional license they would be deemed to be qualified. A subinvestigator may, but does not necessarily have to have the same credentials as the principal investigator . . . However, the investigator is responsible for fulfilling all of the commitments listed in Block #9 [Commitments of Form FDA 1572] at all of the remote sites. If the investigator cannot realistically accomplish these responsibilities, it would be preferred if the subinvestigator at a remote site sign a separate 1572 as investigator for that site."

As a practical matter, NPs, PAs, and other care providers who make clinical decisions regarding study subjects should be listed as subinvestigators. The same advice applies to clinicians who write orders for, or "prescribe," the study drug for each subject. Some sponsors request that pharmacists who prepare a study drug based on patient characteristics such as weight or body mass index also be included as subinvestigators.

Revising the 1572

Q.

When must the 1572 be revised for changes in study personnel?

A. A revised 1572 is required in the following scenarios:

• A change in the principal investigator for the study.

• The addition of a new subinvestigator.

• The addition of a local lab or health care facility to which study patients make visits.

• A change in the IRB or IRB's name.

In recent informal correspondence on this issue, the FDA stated that ". . . regarding when a 1572 must be revised, that really is more of a matter for the sponsor to decide for themselves. People seem to obsess over the 1572. We wonder how many people realize that the 1572 is not even required to be submitted to the FDA. In theory, we could never even see it. In practice, however, the 1572 is typically submitted to the IND by the sponsor as an efficient means to provide the information required under 21 CFR 312.23(a)(6)(iii)(b) which requires the sponsor to provide, among other things, the following [in an IND submission]: (b) The name and address and a statement of the qualifications (curriculum vitae or other statement of qualifications) of each investigator, and the name of each subinvestigator (e.g., research fellow, resident) working under the supervision of the investigator; the name and address of the research facilities to be used; and the name and address of each reviewing Institutional Review Board.

"Likewise, the sponsor is required to file an amendment to their IND under 312.30 when certain changes are made. One of the changes requiring an amendment is the addition of a new investigator (312.30(c)), in which case the sponsor must submit the same information as described above. Again, a sponsor may elect to provide the 1572 for a new investigator as a means to report this information."

It is worth noting that, within industry, there are different approaches to reporting certain types of study personnel changes. Some companies, for example, report changes such as an inactivated subinvestigator immediately, while other firms wait and batch this change and perhaps others in a submission used to report a more significant change, such as the addition of a new subinvestigator (see Q&A 3.1).