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Mark P. Mathieu is a writer and editor with PAREXEL International Corporation.
Vernette J. Molloy, MBA, RN, is vice president of GCPA, Inc., Fairfax Station, Virginia.
Douglas R. Mackintosh, DrPH, MBA, MSHyg, is president of GCPA, Inc., Fairfax Station, Virginia.
A new reference guide clarifies uncertainty surrounding this sometimes misunderstood document.
A new reference guide clarifies uncertainty surrounding this sometimes misunderstood document.
This excerpt from Good Clinical Practice: A Question & Answer Reference Guide, second edition, is presented with the permission of the guide's publisher, Barnett Educational Services (www.barnettinternational.com). The book answers more than 300 frequently asked questions, but it is not intended to provide specific regulatory or legal advice. Readers should consult their company's standard operating procedures (SOP), clinical and regulatory departments, and legal counsel for guidance when applying GCP standards in clinical research.
FDA officials responsible for the agency's good clinical practices (GCP) program emphasize that few, if any, GCP-related areas generate as much industry uncertainty as the Form FDA 1572-Statement of Investigator. Through this seemingly mundane form, a clinical investigator must provide a study sponsor with information on the education, training, and experience that qualifies him/her to conduct a particular study as well as his/her commitment to conduct the proposed study in accordance with the protocol and federal regulations.
Over the years, several factors have contributed to industry uncertainty regarding the 1572 and its use, among them the fact that, today, the 1572 has both mandatory and practical, nonmandatory uses. Complicating matters has been lingering uncertainty regarding the 1572's use at non-U.S. study sites, and questions about what U.S. sponsors can and should require of foreign-based investigators who may be reluctant to sign the 1572, which is often viewed as a formal contract.
In developing the May 2004 second edition of our new text, Good Clinical Practice: A Question & Answer Reference Guide we invested considerable time and effort to explore and resolve many of the long-standing and troublesome questions regarding the 1572. The series of questions below, which is excerpted directly from the text, addresses several of these questions.
Q: Because it is used for a few different purposes, there is uncertainty in some cases about the Form FDA 1572-Statement of Investigator, in particular when its use and submission is mandatory. What is the 1572's regulatory purpose, and in what ways is the form used in practice?
A: The 1572 itself declares that, "No investigator may participate in an investigation until he/she provides the sponsor with a completed, signed Statement of Investigator, Form FDA 1572." And FDA regulations at 21 CFR 312.53(c)(1) add that, "Before permitting an investigator to begin participation in an investigation, the sponsor shall obtain the following: (1) A signed investigator statement (Form FDA-1572)...." Therefore, the Form 1572 is a document that an investigator must submit to the study sponsor.
Through the 1572 Form and the attachments typically sent with it, an investigator provides a sponsor with, among other things, information on his or her education, training, and experience (CV or other statement of qualifications) that qualifies him or her to undertake the clinical investigation, information on the relevant facility, IRB, and subinvestigators, protocol information, and the investigator's commitment to conduct the study in accordance with the protocol and FDA regulations.
So where is there uncertainty about the 1572's use? In many cases, companies submit the completed and signed 1572s to the FDA in the original IND and subsequently when new investigators are added to a study. IND applicants and holders do this as a convenient way of fulfilling an FDA requirement at 21 CFR 312.23(a)(6)(b), which calls for a clinical trial protocol submitted in an IND to provide "the name and address and a statement of the qualifications (CV or other statement of qualifications) of each investigator."
Because this has become such a common practice, some incorrectly assume that this is an FDA requirement. In fact, the IND form (Form FDA 1571) explicitly gives sponsors the option of fulfilling 312.23(a)(6)(iii)(b) by submitting either "Investigator data [21 CFR 312.23(a) (6)(iii)(b)] or completed Form(s) FDA 1572."
In informal correspondence on this issue, the FDA stated that, "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 information required under 21 CFR 312.23(a)(6)(iii)(b)."
Q: Since it is such common practice for companies to provide the 1572 and accompanying CV and other information to the FDA in the original IND and subsequently when a new investigator is added to the study, has that become an agency expectation or even a de facto requirement?
A: None of several Center for Drug Evaluation and Research review divisions contacted recently claimed that the submission of the 1572 was a divisional expectation. And most did not express even a preference in terms of the format (i.e., a 1572 or alternative format) in which IND applicants should provide investigator qualification-related information.
It is important to note, however, that there are differences between some CDER review divisions, and that applicants should ask about a division's policy in this area. Under a 1992 policy, for example, the Division of Oncology Drug Products asks that sponsors of commercial INDs (i.e., those submitted by industry) not submit either the 1572 or the investigator's CV for new investigators because such submissions are "inefficient and cumbersome." Rather, in its "no CV letter," the division asks all IND holders to submit summary information, including "the minimum qualifications of investigators selected for the protocol...and a statement that each investigator meets or exceeds those qualifications" (see sidebar, "Division of Oncology Drug Products' 'No CV Letter'").
In the letter, the Division of Oncology Drug Products emphasizes to applicants that, "You are, of course, also required to maintain the information provided to you by the investigator on the form FDA 1572, which is to be retained by you. In addition, you must maintain in your files a current C.V. of each investigator which must be updated as investigators are added. Only upon request of the Agency, will you be required to submit the current C.V. for a specific investigator."
Q: Occasionally, European clinical investigators and sites are reluctant to sign the FDA Form 1572-Statement of Investigator. Is this ever acceptable for studies conducted under INDs and, if so, what is done in lieu of the 1572?AFor a variety of reasons (e.g., the need for an IRB, which some countries do not have), some foreign investigators may refuse to sign the FDA Form 1572-Statement of Investigator, in part because they do not want to enter into a contract directly with the FDA (U.S. government). All study investigators who will participate in studies under an IND must sign the 1572, however. In such scenarios, then, trial sponsors must find other investigators who are willing to sign the form.
But does this mean that, if a sponsor has an IND under which it is studying a specific drug, then investigators at all non-U.S. sites conducting studies involving that drug must complete sign a 1572?
A: Not necessarily. Only those sites involved in studies specifically included under the IND are required to sign a 1572.
In a February 2004 informal response to this question, the FDA stated the following:"There is no FDA requirement that study sites outside of the United States operate under a U.S. IND. FDA regulations (21 CFR Parts 312.120 and 314.106) [establish the criteria under which the agency will accept] non-U.S., non-IND studies/data for purposes of FDA review in support of applications (IND or NDA). The decision to operate under an IND at non-U.S. sites is therefore discretionary on the part of the study sponsor.
"HOWEVER, should a sponsor make the decision that non-U.S. studies/sites [will be conducted] under a U.S. IND, then all FDA IND regulatory requirements must be met. This includes submission of the 1572 with its investigator certification that U.S. IND requirements are understood and will be met.
"On the other hand, a sponsor may decide and indicate that a study's non-U.S. sites [will not be conducted] under a U.S. IND. In this case, elements of IND regulations (beyond provisions for FDA's acceptance of non-U.S., non-IND studies/data under 312.120/314.106) are not FDA-enforceable requirements per se. That is, there is no FDA regulatory requirement for completion of a 1572 when a sponsor has designated the non-U.S. study or sites as 'non-IND' (although a sponsor may still request completion of the 1572 as part of an internal SOP-and FDA, of course, expects SOPs to be followed).
"The distinction, then, is whether the sponsor has chosen/committed to operate its non-U.S. sites under U.S. regulations (in which case, the 1572 and all IND requirements must be met at non-U.S. sites) or as non-IND (in which case the FDA regulatory requirement for a 1572 does not apply)."
Under a June 2004 proposed regulation, the agency proposed to revamp its sometimes-vague regulatory standards for non-U.S. clinical trials by specifically referencing its good clinical practice regulations as the FDA expectation for such studies. Although U.S. GCP standards have long been the expectation for non-U.S. clinical trials conducted under INDs, the agency has traditionally accepted foreign studies that were not conducted under an IND if they conformed to either the Declaration of Helsinki or national requirements, whichever afforded the greater protections to study subjects. While the proposed rule would make U.S. GCP the standard for all clinical studies to be used in supporting U.S. regulatory applications, it would not affect the 1572-related requirements discussed above.
Excerpted from Good Clinical Practice: A Question & Answer Reference Guide, available from Barnett Educational Services (www.barnettinternational.com or 800-856-2556, x2200) $24.95.
Douglas R. Mackintosh,DrPH, MBA, MSHyg, is president andVernette J. Molloy,MBA, RN, is vice president of GCPA, Inc., Fairfax Station, Virginia.Mark P. Mathieuis director of publications with Barnett Educational Services.
SIDEBAR: Division of Oncology Drug Products' "No CV Letter"
Sponsor name and address
Attention: sponsor representative
Dear Dr. [name]:
The Division of Oncology Drug Products is recommending changes in the policy regarding documentation of investigator qualifications. The changes are intended to streamline the process of submitting and maintaining records regarding qualifications for principal and participating clinical investigators conducting trials under Investigational New Drug Applications (INDs).
Currently, the most prevalent method of complying with those parts of 21 CFR 312.23(a)(6)(iii)(b) and 312.30(d)(1)(iii) pertaining to investigator qualifications is to submit the investigator's curriculum vitae (C.V.). This method has proven to be inefficient and cumbersome. Consequently, the Division requests that C.V.s not be submitted for commercially sponsored INDs.
Instead, for IND submissions that pertain to investigator qualifications, you should include a cover letter along with the completed Form FDA 1571 that provides the following for each clinical protocol submitted, including those in the original submission:
a. The clinical protocol title and number (if applicable);
b. minimum qualifications of investigators selected for the protocol. For example, medical degree, board certification, etc.;
c. a statement that each investigator meets or exceeds those qualifications; and
d. the name and address of each investigator and those subinvestigators working under the supervision of the investigator.
You are, of course, also required to maintain the information provided to you by the investigator on form FDA 1572, which is to be retained by you. In addition, you must maintain in your files a current C.V. of each investigator which must be updated as investigators are added. Only upon request of the Agency, will you be required to submit the current C.V. for a specific investigator.
This policy applies only to appropriate submissions sent to the Division of Oncology Drug Products and may not be appropriate for other Divisions within the Center for Drug Evaluation and Research. This policy does not alter your obligations under 21 CFR 312.53 or other regulations concerning the conduct of clinical investigations. Please note that 21 CFR 312.53(a) states that "A sponsor shall select only investigators qualified by training and experience as appropriate experts to investigate the drug."
Your compliance with this policy is appreciated and will result in a more manageable system of processing IND submissions.
Richard Pazdur, M.D.
Director, Division of Oncology Drug Products
Office of Drug Evaluation 1
Center for Drug Evaluation and Research
cc: Orig. IND
R/D initialed by/SCSO