[Federal Register: April 28, 2008 (Volume 73, Number 82)] [Rules and Regulations] [Page 22800-22816] From the Federal Register Online via GPO Access [wais.access.gpo.gov] [DOCID:fr28ap08-8] ======================================================================= ----------------------------------------------------------------------- DEPARTMENT OF HEALTH AND HUMAN SERVICES Food and Drug Administration 21 CFR Part 312 [Docket No. 2004N-0018] Human Subject Protection; Foreign Clinical Studies Not Conducted Under an Investigational New Drug Application AGENCY: Food and Drug Administration, HHS. ACTION: Final rule. ----------------------------------------------------------------------- SUMMARY: The Food and Drug Administration (FDA) is amending its regulations on acceptance of foreign clinical studies not conducted under an investigational new drug application (IND) (non-IND foreign clinical studies) as support for an IND or application for marketing approval for a drug or biological product. The final rule replaces the requirement that these studies be conducted in accordance with ethical principles stated in the Declaration of Helsinki (Declaration) issued by the World Medical Association (WMA), specifically the 1989 version (1989 Declaration), with a requirement that the studies be conducted in accordance with good clinical practice (GCP), including review and approval by an independent ethics committee (IEC). The final rule updates the standards for the acceptance of foreign clinical studies not conducted under an IND and helps ensure the protection of human subjects and the quality and integrity of data obtained from these studies. DATES: This rule is effective October 27, 2008. FOR FURTHER INFORMATION CONTACT: Janet Norden, Office of Medical Policy, Center for Drug Evaluation and Research, Food and Drug Administration, 10903 New Hampshire Ave., Bldg. 22, rm. 4200, Silver Spring, MD 20993-0002, 301-796-2270; and Stephen Ripley, Center for Biologics Evaluation and Research (HFM- 17), Food and Drug Administration, 1401 Rockville Pike, suite 200N, Rockville, MD 20852-1448, 301-827-6210. SUPPLEMENTARY INFORMATION: Table of Contacts I. Background II. Overview of the Final Rule, Including Changes to the Proposed Rule A. Acceptance of Studies B. Supporting Information C. Waivers D. Records III. Comments on the Proposed Rule A. Replacement of the Declaration With GCP B. Definition of Independent Ethics Committee C. Local Laws and Regulations D. Acceptance of Studies E. Definition of Good Clinical Practice F. IEC Review and Approval G. Onsite Inspection H. Data From Studies Not Conducted in Accordance With GCP I. Supporting Information 1. General Comments 2. Investigator Qualifications and Description of Research Facilities 3. Detailed Summary of Protocol and Results of the Study 4. Names and Qualifications of IEC Members 5. Summary of the IEC's Decision 6. Description of Informed Consent Process 7. Description of Incentives to Subjects 8. Description of Study Monitoring 9. Description of Investigator Training and Signed Written Commitments J. Waivers IV. Implementation V. Legal Authority VI. Paperwork Reduction Act of 1995 VII. Environmental Impact VIII. Federalism IX. Analysis of Economic Impacts A. Objectives of the Final Rule B. Background on Current Situation Regarding Foreign Studies C. The Final Rule D. Costs of the Final Rule E. Benefits of the Final Rule F. Small Business Impact 1. Nature of the Impact 2. The Affected Industry 3. Alternatives to the Final Rule 4. Outreach 5. Conclusion G. References I. Background In the Federal Register of June 10, 2004 (69 FR 32467), we published a proposed rule that would revise our regulations in part 312 (21 CFR part 312) on the conditions under which we will accept non-IND foreign clinical studies as support for an IND, a new drug application (NDA), or a biologics license application (BLA). As discussed in section III.A of this document, we revised the language used to refer to an application (other than an IND) that may be supported by non-IND foreign clinical studies from ``NDA or BLA'' or ``marketing application'' to ``application for marketing approval,'' which we define as an application under section 505 of the Federal Food, Drug, and Cosmetic Act (the act) (21 U.S.C. 355) or section 351 of the Public Health Service Act (the PHS Act) (42 U.S.C. 262), to make it clear that the regulation also applies to foreign clinical studies supporting abbreviated new drug applications (ANDAs). Previous Sec. 312.120(a) stated that we generally accepted for review non-IND foreign clinical studies provided they were well designed, well conducted, performed by qualified clinical investigators, and conducted in accordance with ethical principles acceptable to the world community. With respect to such ethical principles, Sec. 312.120(c)(1) stated that for a foreign clinical study not conducted under an IND to be used to support an [[Page 22801]] IND or application for marketing approval, the study must have been conducted in accordance with the ethical principles stated in the 1989 Declaration or the laws and regulations of the country in which the research was conducted, whichever represents the greater protection of the individual. Section 312.120(c)(4) set forth the text of the 1989 Declaration. We proposed to replace the requirement that non-IND foreign clinical studies be conducted in accordance with ethical principles stated in the 1989 Declaration with a requirement that the studies be conducted in accordance with GCP. We proposed to define GCP as a standard for the design, conduct, performance, monitoring, auditing, recording, analysis, and reporting of clinical trials in a way that provides assurance that the data and reported results are credible and accurate, and that the rights, safety, and well-being of trial subjects are protected. GCP also would include review and approval by an IEC before initiating a study, continuing IEC review of ongoing studies, and obtaining and documenting freely given informed consent of study subjects. In the preamble to the proposed rule, we provided several reasons for our proposed change in requirements for non-IND foreign clinical studies. First, we noted that standards for protecting human subjects have evolved considerably over the past decade, as evidenced by revisions of the Declaration by the WMA's General Assembly and the issuance of several documents by the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH). We noted that the ICH document ``E6 Good Clinical Practice: Consolidated Guideline'' (ICH E6), which we adopted for use as guidance for industry in 1997 (62 FR 25692, May 9, 1997), includes a definition of GCP that shares many important ethical principles with the 1989 Declaration.\1\ However, we stated that the concept of GCP in ICH E6 provides more detail and enumeration of specific responsibilities of various parties, including monitoring of the trial and reporting adverse events. Although we did not specifically incorporate ICH E6 into the proposed revision of Sec. 312.120, we stated that the standard of GCP that we proposed for Sec. 312.120 was consistent with that in ICH E6 and was sufficiently flexible to accommodate differences in how countries regulate the conduct of clinical research and obtain informed consent, while helping to ensure adequate and comparable human subject protection. --------------------------------------------------------------------------- \1\ICH E6 and other FDA guidances adopted from the ICH are available electronically at http://www.fda.gov/cder/guidance/ index.htm. --------------------------------------------------------------------------- Another reason we stated for proposing to revise Sec. 312.120 was that the adoption of a GCP requirement for non-IND foreign clinical studies would help provide greater assurance of the quality of the data obtained from these studies. Although the Declaration states that it is unethical to enroll human subjects in poorly designed or conducted clinical trials, it does not provide guidance on how to ensure proper conduct of trials. We proposed the GCP provisions to help ensure data quality and integrity by, among other things, specifying that GCP includes providing assurance that data are credible and accurate and requiring the submission of information on study monitoring and conformance with protocols. Finally, we stated that deleting the reference in Sec. 312.120 to the Declaration was necessary to eliminate the potential for confusion about the requirements for non-IND foreign clinical studies that could result from potential revisions of the Declaration. We noted that the Declaration is a document that is subject to change independent of FDA authority and, therefore, could be modified to contain provisions that are inconsistent with U.S. laws and regulations. We further noted that although revisions to the Declaration could not supersede U.S. laws and regulations, the changes might be confusing for sponsors. We received 32 comments on the proposed rule, which we address in section III of this document. II. Overview of the Final Rule, Including Changes to the Proposed Rule We are revising our regulations in Sec. 312.120 on the conditions under which we will accept as support for an IND or application for marketing approval (an application under section 505 of the act or section 351 of the PHS Act) a foreign clinical study not conducted under an IND. A. Acceptance of Studies Under revised Sec. 312.120(a)(1), we will accept as support for an IND or application for marketing approval a well-designed, well- conducted, non-IND foreign clinical study if it was conducted in accordance with GCP and we are able to validate the data from the study through an onsite inspection, if necessary. Under Sec. 312.120(a)(1)(i), GCP is defined as a standard for the design, conduct, performance, monitoring, auditing, recording, analysis, and reporting of clinical trials in a way that provides assurance that the data and reported results are credible and accurate and that the rights, safety, and well-being of trial subjects are protected. GCP includes review and approval (or provision of a favorable opinion) by an IEC before initiating a study, continuing review of an ongoing study by an IEC, and obtaining and documenting the freely given informed consent of the subject (or a subject's legally authorized representative, if the subject is unable to provide informed consent) before initiating a study. (An IEC is defined in Sec. 312.3 as a review panel that is responsible for ensuring the protection of the rights, safety, and well-being of human subjects involved in a clinical investigation and is adequately constituted to provide assurance of that protection.) GCP does not require informed consent in life-threatening situations under limited circumstances, as specified in Sec. 312.120(a)(1)(i). Section 312.120(a)(2) states that although we will not accept as support for an IND or application for marketing approval a study that does not meet the conditions in Sec. 312.120(a)(1), we will examine data from such a study. We will do so because we require the submission of such data under applicable regulations for drugs and biologics (e.g., Sec. Sec. 314.50, 314.80, 600.80, 601.2 (21 CFR 314.50, 314.80, 600.80, 601.2)) and because the data may have a bearing on the safety of a drug. B. Supporting Information The final rule revises the regulations on the information that a sponsor or applicant who wishes to rely on a non-IND foreign clinical study to support an IND or application for marketing approval must submit to us to demonstrate that the study conformed to GCP. In response to comments, we revised Sec. 312.120(b) to make clear that a sponsor or applicant is not required to duplicate information already submitted in the IND or application for marketing approval. Instead, the sponsor or applicant may either submit the supporting information listed in Sec. 312.120(b) or provide a cross reference to another section of the submission where the information is located (see comment 21 of this document). Under Sec. 312.120(b), the sponsor or applicant must submit the information described in paragraphs (b)(1) through (b)(11). In response to comments, we changed the information requirements in Sec. 312.120(b)(6) and (b)(11) of the proposed rule as noted in the following description. Under Sec. 312.120(b), the [[Page 22802]] sponsor or applicant must submit the following information: The investigator's qualifications (Sec. 312.120(b)(1)). A description of the research facilities (Sec. 312.120(b)(2)). A detailed summary of the protocol and study results and, if we request, case records or additional background data (Sec. 312.120(b)(3)). A description of the drug substance and drug product, including the components, formulation, specifications, and, if available, the bioavailability of the drug product (Sec. 312.120(b)(4)). Information showing that the study is adequate and well controlled (if the study is intended to support the effectiveness of a drug product) (Sec. 312.120(b)(5)). The name and address of the IEC that reviewed the study and a statement that the IEC meets the definition in Sec. 312.3 (records supporting the statement, including the names and qualifications of IEC members, must be maintained by the sponsor or applicant and be available for agency review) (Sec. 312.120(b)(6)). (The proposed rule would have required submission to FDA of the names and qualifications of the IEC members that reviewed the study (see comment 25 of this document).) A summary of the IEC's decision to approve or modify and approve the study, or to provide a favorable opinion (Sec. 312.120(b)(7)). A description of how informed consent was obtained (Sec. 312.120(b)(8)). A description of what incentives, if any, were provided to subjects to participate (Sec. 312.120(b)(9)). A description of how the sponsors monitored the study and ensured that the study was consistent with the protocol (Sec. 312.120(b)(10)). A description of how investigators were trained to comply with GCP and to conduct the study in accordance with the study protocol, and a statement on whether written commitments by investigators to comply with GCP and the protocol were obtained (any signed commitments must be maintained and available for agency review) (Sec. 312.120(b)(11)). (The proposed rule would have required sponsors and applicants to submit copies of any written commitments (see comment 32 of this document).) C. Waivers The final rule includes a provision (Sec. 312.120(c)) under which a sponsor or applicant may request that we waive any requirement in Sec. 312.120(a)(1) or (b). D. Records In response to comments, we included in the final rule a provision on record retention requirements. Section 312.120(d) states that a sponsor or applicant must retain the records required by Sec. 312.120 for 2 years after the agency's decision on an application for marketing approval for a drug or, if a study is submitted in support of an IND but not an application for marketing approval, for 2 years after the submission of the IND. The requirement to maintain appropriate records was implicit in the requirement, in proposed Sec. 312.120(a)(1)(ii), that FDA be able to validate the data from a study through an onsite inspection if necessary, and under the proposed rule, the record retention requirements of Sec. 312.57(c) would have applied to non-IND foreign clinical studies. However, we have concluded that it is appropriate to set forth record retention requirements specifically for these studies in Sec. 312.120(d) (see comment 24 of this document). III. Comments on the Proposed Rule We received 32 comments on the proposed rule. Comments were received from manufacturers, trade associations, advocacy groups, foreign bioethics organizations, and individual health care providers, researchers, and consumers. Summaries of the comments received and our responses follow: A. Replacement of the Declaration With GCP Section 312.120(a)(1)(i) of the proposed rule stated that we would accept as support for an IND or application for marketing approval a well-designed and well-conducted foreign clinical study not conducted under an IND if the study was conducted in accordance with GCP. The requirement for conducting a study in accordance with GCP would replace the former requirement in Sec. 312.120(c)(1) that such a study be conducted in accordance with the ethical principles stated in the 1989 Declaration or the laws and regulations of the country in which the research was conducted, whichever represents the greater protection of the individual. At our own initiative, we revised the language used to refer to an application (other than an IND) that may be supported by non-IND foreign clinical studies to ``application for marketing approval'' instead of ``NDA or BLA'' or ``marketing application.'' Under Sec. 312.120(a)(1), we further clarified that an ``application for marketing approval'' means ``an application under section 505 of the act or section 351 of the * * * PHS Act.'' Applications for marketing approval under section 505 of the act include both NDAs and ANDAs. The phrase ``application for marketing approval'' tracks the language used in previous Sec. 312.120. We made these revisions to avoid speculation that this final rule differed in scope from previous Sec. 312.120, which was not our intention. (Comment 1) Several comments expressed support for adoption of the GCP requirement and deletion of the reference to the Declaration, for the following reasons: The proposed changes are appropriate measures to improve public assurance of the quality of the science and ethics supporting data for non-IND studies. Relying on GCP reflects the adoption of ICH E6 as a global standard for the conduct of sponsored clinical research. The 13 principles of GCP set forth in ICH E6 are very encompassing and are in line with the guidelines used for domestic studies. The principles of the Declaration are within GCP and form the basis for the ethical considerations in those guidelines. The change from the Declaration to GCP would update the standards for the acceptance of foreign studies and help ensure the quality and integrity of data obtained from such studies. Applying GCP standards to foreign studies not conducted under an IND brings logical symmetry with FDA regulation of studies conducted in the United States and ends the need to comply with the strict wording of the Declaration, which lacks the detail needed to describe usefully the intended compliance. The proposal to rely on GCP is a more coherent approach to the multitude of complex issues that arise in overseas research than the Declaration provides. (Response) We agree with the comments stating that the requirement to conduct studies in accordance with GCP will ensure that these foreign studies will be conducted in a manner that is comparable to that required for domestic studies conducted under an IND. We also agree that the principles of the Declaration are reflected in the concept of GCP codified in Sec. 312.120(a)(1)(i). We also agree with the comment that application of the GCP standard will protect human subjects while also enhancing the quality and integrity of data generated in these foreign studies. [[Page 22803]] (Comment 2) One comment recommended that we give attention to the current development of international standards for the ethical review of clinical studies, including the work done by the Office for Human Research Protections (OHRP) (of the U.S. Department of Health and Human Services), the European Forum for GCP, the World Health Organization (WHO), and the Strategic Initiative for Developing Capacity in Ethical Review. (Response) We agree that it is important for us to monitor the development of international standards for the ethical review of clinical studies. However, for purposes of determining whether data from non-IND foreign clinical studies can be used in support of an IND or application for marketing approval under Sec. 312.120, we have concluded that it is appropriate to require that these studies be conducted in accordance with GCP for the reasons stated in section I of this document. Although the international standards noted by the comment are important, they are not legally binding on sponsors and applicants under Sec. 312.120, and incorporating these standards into our regulations would present the same problems as codifying a reference to the Declaration, as explained in our response to comment 4 of this document. (Comment 3) Several comments opposed the proposal to delete the reference to the Declaration in Sec. 312.120. Several comments stated that the Declaration represents the international standard or paradigm for the ethical conduct of clinical studies and the protection of human subjects. One comment stated that the Declaration is a living document that remains extremely influential and forms the substance of what people understand as the guiding principles of ethical research. (Response) As stated in the preamble to the proposed rule, we believe that our GCP standard will ensure adequate protection of human subjects while providing the flexibility necessary to accommodate differences in how countries regulate clinical research and obtain informed consent. We acknowledge the prominence of the Declaration among international standards on the treatment of human subjects in medical research, but other national and international ethical guidelines for research, such as the Belmont Report and guidelines issued by the Council for International Organizations of Medical Sciences, also are important. The U.S. Government continues to support the Declaration's underlying principles. However, as discussed in our response to comment 7 of this document, the U.S. Government does not fully support the 2000 version of the Declaration because it contains certain statements that may be inconsistent with U.S. law and policy (e.g., concerning use of placebos in clinical trials). We believe that the requirement to conduct non-IND foreign studies in accordance with GCP, which includes a requirement to protect the rights, safety, and well-being of subjects, ensures adequate protection of subjects without a need for reference to the Declaration. (Comment 4) Four comments stated that our statement in the proposed rule that the Declaration can be modified independent of FDA authority does not provide a basis for deleting the Declaration. These comments stated that we acknowledged that revisions to the Declaration could not supersede U.S. laws and regulations. These comments added that FDA declared in 2001 (in our guidance on ``Acceptance of Foreign Clinical Studies'') that the reference to the Declaration in FDA regulations was to the 1989 version. One comment stated that the possibility that the 40-year-old Declaration might become inconsistent with U.S. ethics regulations is minimal. (Response) The comments appear to misunderstand our statements concerning the effect of modification of the Declaration. As we stated in the preamble to the proposed rule, the Declaration was not established under our authority and is subject to change independent of our control. We proposed to remove from the regulations the 1989 Declaration, which, because it was not the most recent version approved by the WMA, had the potential to cause confusion about the requirements for non-IND foreign clinical studies. The potential for confusion may increase with each subsequent revision of the Declaration. Moreover, initiating a rulemaking to revise Sec. 312.120 each time the Declaration is changed would be burdensome and would not be possible if the changes were inconsistent with U.S. law and policy. For these reasons, the comments' statements regarding modification of the Declaration do not support retaining a reference to the Declaration in Sec. 312.120. (Comment 5) One comment stated that eliminating the reference to the Declaration would damage international medical ethics and undermine the human rights approach and traditional foundations of research ethics in the Declaration, the Nuremberg Code, and the Universal Declaration of Human Rights. One comment stated that deleting the reference to the Declaration might send a message that FDA no longer supports high standards of ethics in research involving human subjects in foreign countries. One comment stated that the policy of unilaterally deciding not to rely on one of the most respected ethical documents is worrying. One comment stated that dismissing the relevance of the Declaration would encourage every other country to do the same. (Response) We disagree with these comments. We remain firmly committed to protecting the rights, safety, and well-being of subjects in both foreign and domestic research, and this commitment is reflected in Sec. 312.120, our IND regulations, and our guidance documents, including ICH E6. We do not believe that deleting the reference to the Declaration in Sec. 312.120 will damage international medical ethics or result in harm to research subjects because sponsors and applicants will need to comply with GCP, which includes protection of human subjects. It is also worth noting that the United States is not alone in declining to adopt the Declaration as the standard to apply. For example, the European Union (EU) recognizes the importance of the Declaration, noting in Directive 2001/20/EC on the implementation of GCP in the conduct of clinical trials that the ``accepted basis for the conduct of clinical trials * * * is founded in the protection of human rights and the dignity of the human being with regard to the application of biology and medicine, as for instance reflected in the 1996 version of the Helsinki Declaration.'' Nevertheless, Directive 2001/20/EC does not incorporate the Declaration in the articles of the directive. Similarly, we do not believe that codification of the Declaration in our regulations is needed to ensure that foreign studies used to support U.S. drug applications are conducted in accordance with high ethical standards. (Comment 6) Several comments stated that they preferred the Declaration over GCP (as described in ICH E6) as a standard for ethical principles. Several comments stated that the Declaration is produced by the WMA, which is comprised of 82 national medical associations, whereas ICH documents are the product of the regulatory authorities and pharmaceutical industries of the United States, the EU, and Japan. One comment stated that the Declaration is independent of any one nation and represents a consensus, albeit sometimes uneasy, between many different parties with many diverse interests. One comment stated that the ethical principles in the 2000 [[Page 22804]] Declaration were produced under an international and democratic process conducted by the WMA. One comment stated that it is improper for FDA to dismiss the views of the academicians, researchers, and clinicians who comprise the WMA and who have adopted the Declaration provisions. (Response) Although we appreciate the significance of the Declaration, we do not agree that the manner in which it was adopted makes it the most appropriate standard for the conduct of clinical studies. In fact, our regulations do not require that studies conducted in the United States under an IND be conducted in accordance with the Declaration. Furthermore, although we have not incorporated ICH E6 into our regulations (see comment 9 of this document), we disagree with the comment's characterization of the process for developing ICH guidelines. Twenty-seven countries (the United States, Japan, and the 25 member-states of the EU) participate in the ICH process, and Canada, Switzerland, and the WHO are observers. In addition to input from regulatory authorities and drug manufacturers, there is considerable opportunity for public health organizations, consumers, researchers, academicians, and others to comment publicly on proposed ICH guidelines, both before their adoption at the international level and before they are incorporated into the regulatory framework of individual ICH countries. Finally, by deleting the reference to the Declaration, we are not dismissing the views of WMA members regarding the protection of human subjects. Instead, we simply conclude that it is most appropriate and effective to ensure that studies are properly conducted by requiring compliance with GCP, as defined in Sec. 312.120(a)(1)(i). (Comment 7) In objecting to the deletion of the reference to the Declaration, several comments cited the United States' objection to paragraphs 29 and 30 of the version of the Declaration adopted in 2000 (paragraphs 29 and 30). Paragraph 29 states: ``The benefits, risks, burdens and effectiveness of a new method should be tested against those of the best current prophylactic, diagnostic, and therapeutic methods. This does not exclude the use of placebo, or no treatment, in studies where no proven prophylactic, diagnostic or therapeutic method exists.'' Paragraph 30 states: ``At the conclusion of the study, every patient entered into the study should be assured of access to the best proven prophylactic, diagnostic and therapeutic methods identified by the study.'' Several comments were critical of the United States' objection to paragraphs 29 and 30 and expressed concern about its impact on research subjects. On the other hand, one comment expressed opposition to paragraphs 29 and 30. (Response) Compliance with the GCP standard will ensure adequate protection of human subjects in foreign clinical studies while accommodating differences in local authorities' regulation of these studies. As stated in our response to comment 3 of this document, we cannot endorse the 2000 version of the Declaration. We believe that paragraph 29 is inconsistent with U.S. law and policy because it would impose a standard for the design of clinical trials that is different from the standard of ``adequate and well-controlled investigations,'' which the act requires us to apply. Paragraph 30 invokes issues of health care policy that are not directly related to FDA's mission of ensuring that medical products are safe and effective. In addition, we do not believe that this rulemaking is the proper forum for debating or resolving issues concerning particular paragraphs of the Declaration, such as use of placebo controls or continued access to therapy after a study is concluded. (Comment 8) Several comments stated that deletion of the reference to the Declaration will have an adverse impact on the populations of developing countries, who are vulnerable to abuse, exploitation, and negligence because of their relative poverty and lack of education. One comment stated that the proposed rule is consistent with FDA's purported purpose of weakening items in the Declaration related to protection of human subjects in developing countries. One comment stated that deletion of the Declaration would imply that FDA believes that non-U.S. study populations do not need access to study results or that non-U.S. populations could be studied and put at risk only to identify medical products that would benefit the U.S. population. (Response) We do not agree that deleting the reference to the Declaration will have a negative impact on research subjects in developing countries or result in less protection for subjects in foreign studies. Human subject protection is essential to GCP as defined in revised Sec. 312.120, which, among other things, requires the protection of the rights, safety, and well-being of trial subjects, and review and approval of studies by an IEC. We do not believe that referencing the Declaration in our regulations would provide additional protection to the populations of developing countries beyond the protections set forth in revised Sec. 312.120. (Comment 9) Several comments stated that ICH E6 is concerned primarily with procedural and technical issues, not overarching ethical issues. One comment stated that GCP does not encompass the range of concerns about the protection of human subjects that is provided for in the Declaration. One comment stated that while the Declaration focuses on researchers' ethical conduct and the primacy of patient welfare, ICH E6 focuses on the relations between researchers and pharmaceutical sponsors. One comment stated that ICH E6 is designed to improve data quality but is unconcerned with ethics. (Response) We disagree with the comments. Most importantly, we note that the definition of GCP contained in Sec. 312.120 is the standard that will apply to these studies, rather than the procedures set forth in ICH E6. The regulation requires, among other things, that the rights, safety, and well-being of subjects be protected, that an IEC review and approve (or provide a favorable opinion on) each study before initiation, and that subjects give informed consent. As for ICH E6 itself, protecting the interests of human subjects is one of its two fundamental purposes, along with helping to ensure the quality of data from clinical studies. The first paragraph of the introduction to ICH E6 states that compliance with GCP ``provides public assurance that the rights, safety, and well-being of trial subjects are protected, consistent with the principles that have their origin in the Declaration of Helsinki, and that the clinical trial data are credible'' (p. 6). In addition, the first principle of GCP listed in ICH E6 (section 2.1) is that ``[c]linical trials should be conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki, and that are consistent with GCP and the applicable regulatory requirement(s)'' (p. 8). Sections 3.1 and 4.3/4.8 of ICH E6 address the responsibilities of institutional review boards (IRBs)/IECs and investigators, respectively, concerning matters related to the care and treatment of research subjects,\2\ including provisions on informed consent and medical care of subjects. Thus, although ICH E6 does address procedural issues, ethical issues are another principal focus of the document. --------------------------------------------------------------------------- \2\ICH E6 at pp. 10-11, 14-15, 17-21. --------------------------------------------------------------------------- (Comment 10) Several comments recommended that FDA simply add to the regulations a requirement to comply with GCP rather than delete the reference to the Declaration. One comment stated that it understood the [[Page 22805]] need for data standardization and urged us to add GCP requirements without eliminating the reference to the Declaration. One comment stated that international studies, as they have been conducted in the past, can comply with both documents. Another comment stated that adherence to both documents would not cause the quality of these foreign studies to suffer. Several comments stated that the GCP guidance does not address conflict of interest or the need to publish results, which are both included in the Declaration. These comments stated that the two documents are complementary and that the regulations could require that affected studies comply with both documents. (Response) For the reasons stated previously in this document, it is no longer appropriate for Sec. 312.120 to require compliance with the Declaration, either the 1989 version, the current (2000) version, or some other future or past version. Moreover, we believe that because of the requirement in Sec. 312.120 that acceptable foreign studies be conducted in accordance with GCP, which includes ensuring that the rights, safety, and well-being of trial subjects are protected, a specific reference to the Declaration will not enhance protection of human subjects. Nor do we believe that Sec. 312.120 should address conflicts of interest or the need to publish study results. Other FDA regulations address conflicts of interest in these foreign studies (for example, the provisions on financial disclosure by clinical investigators in part 54 (21 CFR part 54) are applicable to studies submitted in support of an NDA, ANDA, or BLA under Sec. 314.50(k), 21 CFR 314.94(a), and Sec. 601.2(a), respectively). With respect to the publication of study results, we note that section 801 of the Food and Drug Administration Amendments Act of 2007 (42 U.S.C. 282(j)(3)) provides for publication in a results data bank of the results of ``applicable clinical trials'' under certain circumstances. In addition, we strongly encourage sponsors to seek publication in peer- reviewed journals. B. Definition of Independent Ethics Committee We proposed to add, under Sec. 312.3, a definition for IEC. We proposed to define IEC to mean a review panel that is responsible for ensuring the protection of the rights, safety, and well-being of human subjects involved in a clinical investigation and is adequately constituted to provide assurance of that protection. An IRB, as defined in Sec. 56.102(g) (21 CFR 56.102(g)) of this chapter and subject to the requirements of part 56 (21 CFR part 56), is one type of IEC. (Comment 11) Several comments stated that the proposed definition of IEC differed from the definition in ICH E6, and requested that we provide clarification of the term ``adequately constituted'' in the definition of IEC. One comment suggested either defining ``adequately constituted'' as ``if its composition and membership complies with [part] 56, subpart B of this chapter,'' or omitting ``adequately constituted'' from the definition of IEC, making it consistent with the definition in ICH E6. Other comments suggested defining IEC as in section 1.27 or 3.2 of ICH E6. (Response) The requirement in Sec. 312.3 that the IEC be ``adequately constituted'' emphasizes the importance of the IEC having appropriate expertise to perform its critical role in the protection of human subjects. As described in the preamble to the proposed rule, we would consider an IEC to be adequately constituted if it ``includes a reasonable number of members with the qualifications and experience to perform the IEC's functions (see, e.g., section 3.2.1 of the Good Clinical Practice guidance [ICH E6])'' (69 FR 32467 at 32468). Such an ``adequately constituted'' IEC is responsible for ensuring the protection of the rights, safety, and well-being of human subjects involved in a clinical investigation. Although the definition of an IEC in ICH E6 does not include the term ``adequately constituted,'' ICH E6 defines an IEC as being ``constituted of medical/scientific professionals and nonmedical/nonscientific members whose responsibility it is to ensure the protection of the rights, safety and well-being of human subjects'' (section 1.27). We view our proposed definition of IEC as consistent with the definition of IEC in ICH E6 but at the level of specificity and detail appropriate for regulation. We recognize that the organization and membership of IECs may differ among countries because of the local needs of the host country, but we believe that such variation should not affect an IEC's ability to perform its functions. Our regulations must be sufficiently flexible to accommodate differences in how countries regulate the conduct of clinical research, including the composition of an IEC. Therefore, we will not specifically define IEC membership in the regulations or require that an IEC comply with the requirements in subpart B of part 56, or with the recommendations for membership in ICH E6. However, we would consider an IEC that is constituted to comply with part 56 or with ICH E6 to be ``adequately constituted.'' In fact, the definition of IEC in Sec. 312.3 clarifies that an IRB, as defined in Sec. 56.102(g) and subject to the requirements of part 56, is one type of IEC. For these reasons, we decline to omit ``adequately constituted'' from the definition of IEC in Sec. 312.3. C. Local Laws and Regulations (Comment 12) Some comments stated that the proposed rule would delete the provision in former Sec. 312.120(c)(1) requiring that foreign clinical research be conducted according to the laws and regulations of the country in which the research was conducted, when such laws provided for greater protection of human research subjects than the principles of the Declaration. Some comments stated that deleting the reference to compliance with local laws of the host country supported the notion that FDA could accept data collected in violation of those laws. (Response) We do not agree that deletion of this provision will lead to FDA accepting studies not conducted in accordance with local laws. Sponsors, IECs, investigators, and research sites and/or institutions are all responsible for complying with the local requirements for conducting research, including any requirements that may be more stringent than the requirements in Sec. 312.120. A host country may deny a sponsor's request to conduct research in the country if the sponsor does not comply with local requirements, or may stop a study that is in progress in violation of the host country's laws. New Sec. 312.120 sets forth U.S. standards for acceptance of foreign clinical studies in support of an IND or application for marketing approval, including that the study be conducted in accordance with GCP. We are confident that these standards provide for the protection of human subjects, and we will accept a study only if these standards are met. In addition, sponsors or applicants that currently conduct clinical trials in accordance with ICH E6 would comply with local requirements because ICH E6 states that one of the principles of GCP is that clinical trials be conducted consistent with the applicable regulatory requirements (i.e., any laws and regulations addressing the conduct of clinical trials of investigational products of the jurisdiction where a trial is conducted). (Comment 13) One comment stated that although proposed Sec. 312.120 referenced general GCP standards, it did not clarify whether GCP as interpreted by the host country was at all relevant to acceptance of data or whether the [[Page 22806]] ethics committee that must be used was one approved by the host country. (Response) The host country's interpretation of GCP is relevant to these non-IND foreign clinical studies because the host country requires the sponsor to comply with its laws. However, we will only accept data from studies that we determine were conducted in accordance with GCP as described in Sec. 312.120(a)(1)(i). As to whether the IEC must be approved by the host country, if a host country requires by law that the host country approve the IEC, the sponsor would need to comply with that requirement. However, we will not specifically require in Sec. 312.120 that an adequately constituted IEC be approved by the host country. We do not believe that such approval is essential to ensuring the quality of data or the protection of human subjects. Therefore, this matter is left to the discretion of the host country. (Comment 14) One comment recommended including a provision in Sec. 312.120 to continue to allow a sponsor to document that the study was conducted in a country where the laws and regulations already provide for strict adherence to the principles of GCP, which would clearly provide for the assurance of protection of human research subjects and quality of clinical data. As support for this approach, the comment stated that clinical trials conducted in Europe must now meet the requirements of the EU Clinical Trials Directive and its implementing guidance for the conduct of clinical trials under GCP. (Response) We believe that the supporting documentation required under Sec. 312.120(b), combined with an onsite inspection if necessary, will provide us with the ability to determine if a foreign clinical investigation was conducted in accordance with GCP. If the country adheres to the principles of GCP and the study complied with those principles, this should be reflected in the documentation submitted to us. Therefore, it is not necessary to add a provision as suggested by the comment. D. Acceptance of Studies (Comment 15) One comment stated that the proposed rule should be consistent with FDA's 1998 guidance ``FDA Approval of New Cancer Treatment Uses for Marketed Drug and Biological Products'' (New Cancer Treatment Guidance). The comment stated that section III.B of the New Cancer Treatment Guidance allows certain data to be submitted to us without additional data collection, auditing, or analyses by a pharmaceutical company submitting a marketing application, depending on the quality and credibility of the institutions providing such data. (Response) We do not agree that this rule and the New Cancer Treatment Guidance concern the same issues. Although the guidance addresses the submission of certain data without the applicant being subject to auditing, this is applicable only to data from studies conducted by independent cancer clinical trials organizations that have well-established and publicly available procedures for research data management, monitoring, and auditing, and a track record of high- quality research (e.g., U.S. National Cancer Institute-sponsored cooperative cancer research groups and other highly credible organizations that have no commercial interest in study outcomes). The guidance does not address the submission of foreign clinical data and is limited in scope to drugs for treating cancer. We will not accept foreign clinical studies in support of an IND or application for marketing approval except as set forth in Sec. 312.120. (Comment 16) One comment recommended including the following statement in Sec. 312.120 to reduce the potential regulatory burden: ``The information to be provided in support of the IND does not need to be submitted to FDA throughout the study. The supporting information may be provided at the time the clinical study report is filed to the FDA in support of an NDA and/or made available upon request.'' (Response) We do not agree that including such a statement in Sec. 312.120 is necessary because the submission and reporting requirements are already clear. Information required under Sec. 312.120 to be submitted in support of an IND or application for marketing approval would be submitted at the time the application is submitted to the agency. Once an application is pending before the agency, the applicable reporting requirements for INDs, NDAs, ANDAs, or BLAs under part 312, 314, or 601 (21 CFR parts 314 and 601), apply. E. Definition of Good Clinical Practice For the purposes of Sec. 312.120, we proposed, in Sec. 312.120(a)(1)(i), to define GCP as a standard for the design, conduct, performance, monitoring, auditing, recording, analysis, and reporting of clinical trials in a way that provides assurance that the data and reported results are credible and accurate and that the rights, safety, and well-being of trial subjects are protected. We also proposed to require that GCP include oversight by an IEC and obtaining informed consent of subjects. The final rule clarifies the limited circumstances in which GCP would not require informed consent. The proposed rule stated that GCP does not require informed consent in life-threatening situations when the IEC reviewing the study finds that the conditions present are consistent with those described in Sec. Sec. 50.23 or 50.24(a) (21 CFR 50.23 or 50.24(a)), or when the measures described in the study protocol or elsewhere will protect the rights, safety, and well-being of subjects and ensure compliance with applicable regulatory requirements. We explained in the preamble that this provision would be consistent with the GCP guidance, which recommends that a legally authorized representative provide informed consent or that the requirement of informed consent be waived under such circumstances. In the final rule, we have made more explicit two conditions that were implicit in the proposed rule: The IEC review must occur before initiation of the study and the IEC must find that informed consent is not feasible. In addition, we deleted the provision referring to the IEC ensuring compliance with applicable regulatory requirements. Upon reconsideration, we recognized that the reference to ``applicable regulatory requirements'' was not clear. We had not described the requirements we considered to be applicable, and without additional clarity, the phrase did not provide additional protections for subjects in the study. Therefore, we decided that the provision would be clearer without this phrase. (Comment 17) Several comments requested confirmation that compliance with ICH E6 would be adequate to assure compliance with Sec. 312.120 and questioned whether citing compliance with ICH E6, rather than submitting the supporting documentation required under 312.120(b), would be acceptable. One comment requested that we waive requirements in the proposed rule for any study conducted in EU member states, provided the member can submit a EudraCT (a database of clinical trials in the EU) number, and for any studies that have been conducted in Japan under Japanese Good Clinical Practices. One comment stated that the rule should explicitly require following ICH E6 because imposing a U.S. standard ``consistent with'' an international standard seemed insufficient. One comment recommended that if Sec. 312.120 does not specifically require following ICH E6, we should acknowledge in the final rule or subsequent guidance that ICH E6 should be taken into account as one GCP [[Page 22807]] standard that we find acceptable, and describe in what ways the standard set forth in Sec. 312.120 differs from that in ICH E6. (Response) As noted in the preamble to the proposed rule, we have already incorporated many of the principles of GCP into our existing regulations. However, we have not specifically incorporated all of ICH E6 into our regulations, and we will not do so in Sec. 312.120, for several reasons. First, for one of the same reasons that we deleted the reference to the Declaration from Sec. 312.120, we do not believe that it is appropriate to reference in a regulation a document that is subject to change independent of our control. Second, although we adopted ICH E6 in 1997 for use as guidance for industry, there are other international documents that provide acceptable standards for GCP. Specific incorporation of ICH E6 into Sec. 312.120 would constrain our ability to accept data from non-IND foreign clinical studies from countries that use other comparable GCP standards. Finally, ICH E6 contains a level of detail and specificity that is not appropriate for regulations. We believe that the GCP standard in Sec. 312.120 is appropriate because it provides sufficient flexibility to accommodate differences in how countries regulate the conduct of clinical research, while still ensuring adequate and comparable human subject protection. Therefore, we do not require that sponsors or applicants follow ICH E6, but a study conducted in compliance with ICH E6 would meet the GCP requirements in Sec. 312.120. However, for the agency to evaluate such a study, the information required under Sec. 312.120(b) must be submitted. It would not be adequate to simply submit a statement that ICH E6 or Japanese GCP were followed, or to provide only a EudraCT number. F. IEC Review and Approval Proposed Sec. 312.120(a)(1)(i) stated that GCP includes review and approval (or provision of a favorable opinion) by an IEC before initiating a study and continuing review of an ongoing study by an IEC. (Comment 18) One comment stated that the requirement for review and approval by an IEC does not guarantee protection of the participants unless the guidelines that the IEC must follow are stated explicitly and are not weaker than the Declaration. (Response) We disagree. Although Sec. 312.120(a)(1)(i) requires review and approval of a clinical study before initiation, the regulation does not specify the procedures that the IEC must follow because different procedures offering equivalent human subject protection may be followed in different countries. As previously stated, we believe that the GCP standards in Sec. 312.120, including the requirement for review and approval by an IEC, are and should be sufficiently flexible to accommodate differences in how countries regulate the conduct of clinical research, while ensuring adequate and comparable human subject protection. G. Onsite Inspection Proposed Sec. 312.120(a)(1)(ii) would have required, as a condition of acceptance of a study submitted under this section, that we be able to validate the data from the study through an onsite inspection if we deem it necessary. (Comment 19) One comment recommended that we give attention to the current development of national and regional (e.g., European Medicines Agency) inspections outside the United States and the role they might play in providing public assurance for the quality of data and the protection of human subjects. (Response) Although this rule does not address the process for conducting inspections outside the United States, we can review and consider information from inspections by foreign authorities. However, if deemed necessary, we are also able, under Sec. 312.120(a)(1)(ii), to conduct an onsite inspection to validate the data from a study. H. Data From Studies Not Conducted in Accordance With GCP Proposed Sec. 312.120(a)(2) stated that although we will not accept as support for an IND , NDA, or BLA a study that does not meet the conditions of Sec. 312.120(a)(i), we will examine data from such a study. (Comment 20) One comment requested that we clarify the meaning of proposed Sec. 312.120(a)(2). The comment asked if this provision means that a sponsor should submit studies conducted on the investigational product but differentiate studies that comply for FDA review of safety and efficacy, or that we will review noncompliant studies as supportive. (Response) The provision states that we ``will not accept as support'' for an IND or application for marketing approval a study that does not meet the conditions of Sec. 312.120(a)(1) (i.e., a ``noncompliant'' study). Nonetheless, a sponsor or applicant of an IND or application for marketing approval must submit all studies and other information required under applicable FDA regulations for drugs and biologics, including ``noncompliant'' studies. We would review information from ``noncompliant'' studies because they might have bearing on the safe use of the product. In the application, a sponsor or applicant should identify any studies that do not meet the conditions of Sec. 312.120(a)(1). I. Supporting Information Proposed Sec. 312.120(b) would have required a sponsor or applicant submitting a non-IND foreign clinical study in support of an IND, NDA, or BLA to submit, in addition to information required elsewhere in parts 312, 314, or 601, supporting information that describes the actions taken to ensure that the research conformed to GCP. 1. General Comments (Comment 21) Some comments stated that certain of the proposed requirements for submission of supporting information in Sec. 312.120(b) are not entirely consistent with guidance provided in other relevant ICH documents. One comment requested that we confirm that conducting a study in accordance with ICH E6 and reporting and submitting the study according to ICH E3 (``Structure and Content of Clinical Study Reports''), ICH M4 (``Common Technical Document for the Registration of Pharmaceuticals for Human Use''), and FDA's corresponding guidance documents satisfies all the requirements of proposed Sec. 312.120(b). In addition, the comment requested that in cases where the requirements in Sec. 312.120(b) differed from ICH E3 and M4 standards, we consider modifying the requirements, thereby allowing sponsors to submit IND and non-IND studies according to a single standard. (Response) Conducting a study in accordance with ICH E6 and reporting and submitting the study according to ICH E3, ICH M4, and FDA's corresponding guidance documents would not satisfy all the requirements of Sec. 312.120(b). The supporting documentation required in Sec. 312.120(b) must describe the actions the sponsor or applicant took to ensure that the research conformed to GCP. This supporting documentation will supplement information required elsewhere in parts 312, 314, or 601. If any of the supporting information is already included in another section of the IND or application for marketing approval, the sponsor or applicant would not be required to submit this information more than once. We revised Sec. 312.120(b) to clarify that, in submitting the description of the actions taken to ensure that research conformed [[Page 22808]] to GCP, the sponsor or applicant is not required to duplicate information already submitted in the IND or application for marketing approval. Instead, the description submitted must provide either the supporting information required in Sec. 312.120(b)(1) through (b)(11) or a cross-reference to another section of the submission where the information is located. In some cases, it would be necessary to supplement studies submitted according to ICH E3 and M4 with additional information to adequately describe the actions the sponsor or applicant took to ensure that research conformed to GCP. ICH E3 provides advice on structuring and reporting data from a clinical trial, and ICH M4 provides advice on the organization of information in an application. These documents, unlike ICH E6, were not developed to address GCP. 2. Investigator Qualifications and Description of Research Facilities Proposed Sec. 312.120(b)(1) would have required submission of the investigator's qualifications, and proposed Sec. 312.120(b)(2) would have required submission of a description of the research facilities. (Comment 22) One comment stated that we were imposing an additional regulatory burden by requiring a description of the investigator's qualifications and a description of the research facilities. The comment stated that the information provided should be similar to that currently provided to FDA by sponsors for studies conducted under an IND. (Response) We do not agree that the rule would impose any additional regulatory burden related to investigator's qualifications and description of research facilities. Section 312.120(b)(1) and (b)(2) of the final rule are unchanged from previous Sec. 312.120(b)(1) and (b)(2), so there is no greater or lesser regulatory burden compared to what was previously required. In addition, we believe that assessment of the qualifications of the investigators and the adequacy of the research facilities are important factors in determining the reliability of the data generated by the study. IND sponsors are required to submit information about investigator qualifications and the name and address of the research facilities (whether domestic or foreign) to be used for each protocol (Sec. 312.23(a)(6)(iii)(b)). This rule does not require more information about investigator qualifications from sponsors of non-IND foreign studies. However, we generally are less likely to be familiar with the research facilities in which those studies are conducted. Therefore, we believe that it is appropriate to require a description of the research facilities for these studies to help us determine the adequacy of the facilities and to prioritize the need for an onsite inspection. 3. Detailed Summary of Protocol and Results of the Study Proposed Sec. 312.120(b)(3) would have required submission of a detailed summary of the protocol and results of the study. In addition, the sponsor or applicant would have been required to submit case records maintained by the investigator or additional background data, such as hospital records or other institutional records, if requested by FDA. (Comment 23) One comment recommended that we modify the requirement in proposed Sec. 312.120(b)(3) to allow sponsors to follow ICH E3, in which annex I, ``Synopsis,'' provides the template for the detailed summary of the protocol. (Response) We do not agree that submitting only the Synopsis from annex I of ICH E3 would be adequate to meet the requirements in Sec. 312.120(b)(3) because the synopsis would not provide sufficient detail about the study protocol or results. Therefore, we have not modified the requirement as suggested by the comment. Although following ICH E3 is not required, an integrated, full clinical study report submitted in accordance with ICH E3 would be acceptable for meeting the requirements for providing summaries of the study protocol and results in Sec. 312.120(b)(3). In addition, sponsors and applicants must submit information required elsewhere in parts 312, 314, or 601. (Comment 24) One comment indicated that the reference to ``hospital records'' in Sec. 312.120(b)(3) suggests that we could request hospital records instead of a description of medical records maintained by an investigator, which might lead to data privacy concerns. One comment stated that the requirements for recordkeeping by investigators described in ICH E6, which it said were comparable to the requirements for investigator recordkeeping in Sec. 312.62, should be included in the final rule. (Response) Proposed Sec. 312.120(b)(3) was unchanged from previous Sec. 312.120(b)(3). If we need source documents such as hospital records to verify data, these records must be available during an onsite inspection or provided upon request. If the necessary records are not available, we might not accept the study as support for an IND or application for marketing approval. We believe that informed consent documents should notify subjects that regulatory authorities will have direct access to the subject's original medical records for verification of clinical trial procedures and data, which is consistent with ICH E6, section 4.8.10(n). However, if a sponsor or applicant cannot disclose foreign records because it is prohibited by foreign law, the sponsor or applicant and FDA would need to agree upon an alternative validating procedure if the agency is to rely on the data. With respect to investigator recordkeeping, this rule does not address individual investigator responsibilities, but rather describes the requirements for sponsors or applicants who are submitting non-IND foreign clinical studies in support of an IND or application for marketing approval. Sponsors or applicants are responsible for ensuring that their investigators meet their responsibilities. As originally proposed, the retention requirements in Sec. 312.57(c) for records and reports required under part 312 would have applied to records required under this rule. However, we decided to clarify the record retention requirements applicable to records required under this rule and incorporate the provision directly into Sec. 312.120. Accordingly, we have added the following provision at Sec. 312.120(d): A sponsor or applicant must retain the records required by this section for a foreign clinical study not conducted under an IND as follows: (1) If the study is submitted in support of an application for marketing approval, retain records for 2 years after an agency decision on that application; (2) if the study is submitted in support of an IND but not an application for marketing approval, retain records for 2 years after the submission of the IND. This record retention provision is similar to the requirements set forth in Sec. 312.57(c). 4. Names and Qualifications of IEC Members Proposed Sec. 312.120(b)(6) would have required submission of the names and qualifications for the members of the IEC that reviewed the study. (Comment 25) One comment stated that although the requirement to provide names and qualifications of IEC members is in current Sec. 312.120(c)(3), the regulation should allow for situations where it is impossible for a sponsor or clinical investigator to obtain this information. One comment stated that because of privacy concerns, some IECs only provide sponsors with letters to confirm that the constitution of the IEC is in agreement with GCP. The [[Page 22809]] comment stated that ICH E6 requires that the investigator files include the IEC composition to document that the IEC is so constituted, and that this information is available in sponsor files. The comment recommended that as an alternative we consider requiring the name and address of each IEC that approved a study. One comment requested allowing a statement from the IEC that it is properly constituted within the applicable laws that they must follow. Another comment suggested that we change the requirement to ``information on the composition (preferably names and qualifications, but at a minimum qualifications) of the IEC that reviewed the study to ensure that the IEC is duly constituted.'' Another comment recommended that we only require a statement from the IEC that it is organized and operates according to ICH E6 and the applicable laws and regulations, which the comment stated was consistent with ICH E6, section 5.11.1(b). Two comments stated that the proposed requirement deviated from ICH E3, which includes a list of IECs or IRBs (plus the name of the committee chair, if required by the regulatory authority). The comments recommended that the requirement be revised to be consistent with ICH E3. (Response) Because oversight by an adequately constituted IEC is an essential component of human subject protection, it is critical that there be adequate documentatio