FDA: Guidance for Acceptance of Foreign Clinical Studies Not Conducted Under an IND
On April 28, 2008, the Food and Drug Administration (FDA) amended its regulations on the 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 a new drug application (NDA), abbreviated new drug application (ANDA), or a biologics license application (BLA) (collectively known as “marketing applications” or “applications for marketing approval”).
The final rule requires that such studies be conducted in accordance with good clinical practice (GCP), including review and approval by an independent ethics committee (IEC) and informed consent from subjects. The GCP requirements in the final rule encompass both ethical and data integrity standards for clinical studies. This final rule, which took effect on October 27, 2008, is codified at 21 CFR 312.120. It is intended to help ensure the protection of human subjects enrolled in non-IND foreign clinical studies as well as the quality and integrity of the resulting data.
To address the changes from this final rule, FDA recently released a Guidance for Acceptance of Foreign Clinical Studies Not Conducted Under an IND is intended to clarify for sponsors and applicants how they can demonstrate compliance with these requirements. The guidance is part of FDA’s efforts to encourage sponsors and applicants to standardize information relating to foreign clinical trials in their INDs and applications for marketing approval.
The guidance provides recommendations for the submission of information, whether in an IND or application for marketing approval for a drug or biological drug product, to demonstrate that a non-IND foreign clinical study was conducted in accordance with GCP. The guidance is applicable to all applications submitted under section 505 of the Federal Food, Drug, and Cosmetic Act (FD& C Act) (21 U.S.C. 355) or section 351 of the Public Health Service Act (the PHS Act) (42 U.S.C. 262).
Background
FDA recognized that clinical research is becoming increasingly global, as detailed in reports by the Office of Inspector General (OIG) of the Department of Health and Human Services (HHS) (“OIG Reports”). FDA recognizes that sponsors may choose to conduct multinational clinical studies under a variety of scenarios. Multinational studies may include domestic sites conducted under an IND, foreign sites conducted under an IND, and/or foreign sites not conducted under an IND.
Sponsors may decide to use the data that is obtained from non-IND foreign sites to support clinical investigations and/or marketing approval(s) in the United States. Some sponsors may even seek to rely solely on foreign clinical data as support for an IND or application marketing approval in the U.S. Indeed, the number of INDs and applications for marketing approval supported by foreign clinical trials has increased in recent years and will likely continue to increase in the future.
This increasing globalization of clinical trials presents challenges to both U.S. and foreign regulators, many of which are detailed in the OIG reports. Among other challenges, resource constraints limit the number of foreign clinical site inspections that can be conducted. To address these challenges, FDA has sought to leverage its resources more efficiently by:
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Encouraging sponsors to utilize data standardization in their INDs and applications for marketing approval, in order to improve review and analysis of data and facilitate implementation of a site selection model to prioritize sites for inspection;
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Engaging in collaboration and outreach with international regulatory authorities; and
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Considering alternative mechanisms of clinical trial oversight both by sponsors and FDA, such as a quality management system approach which emphasizes building quality into the research process.
Much of the information in this guidance comes from the preamble to the final rule, 73 Fed. Reg. 22800 (April 28, 2008). It is organized in a question and answer format that tracks the regulatory provisions. In addition to addressing the substantive requirements of the final rule, the guidance addresses organization and submission procedures. When sponsors or applicants submit information about a non-IND foreign clinical study, they should clearly identify in the cover letter (a) that the material is being submitted in accordance with 21 CFR 312.120, and (b) where in the submission the information required by 21 CFR 312.120(b) can be located.
Although FDA will not accept as support for an IND or application for marketing approval any study that does not meet the conditions of 21 CFR 312.120, FDA will examine the data from such a study because the data may have a bearing on the safe use of the product. Sponsors and applicants are reminded that they must submit all studies and other information as required under the applicable regulations for drugs, including studies that do not comply with the requirements of 21 CFR 312.120.
III. Outline
A sponsor may choose, but is not required, to conduct a foreign clinical study under an IND. When a foreign clinical study is conducted under an IND, all FDA IND requirements must be met unless waived.11 When the foreign clinical study is not conducted under an IND, the sponsor must ensure that the study complies with the requirements in 21 CFR 312.120 in order to use the study as support for an IND or application for marketing approval. Under 21 CFR 312.120, FDA will accept a well-designed, well-conducted, non-IND foreign study as support for an IND or application for marketing approval if the study was conducted in accordance with GCP and if FDA is able to validate the data from the study through an onsite inspection, if necessary.12 Note that marketing approval of a new drug based solely on foreign clinical data is governed by 21 CFR 314.106.
The GCP requirements at 21 CFR 312.120 help protect human subjects and enhance the quality and integrity of the resulting clinical data.13 They further help ensure that non-IND foreign studies are conducted in a manner comparable to that required for IND studies.14 Many of the requirements at 21 CFR 312.120 are already incorporated into the IND regulations at 21 CFR part 312, as well as 21 CFR parts 50 and 56,15 and are consistent with certain international ethical and policy standards for clinical trials (e.g., International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) “Good Clinical Practice: Consolidated Guideline” (ICH E6), which FDA adopted for use as guidance for industry in 1997).
FDA regulations 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 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 independent ethics committee (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 “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.” FDA believes an “adequately constituted” IEC is one that consists of a reasonable number of members who collectively have the qualifications and experience to review and evaluate the science, medical aspects and ethics of the proposed trial. One type of IEC is an institutional review board (IRB). Prior to the beginning of the trial, the investigator should obtain the IEC’s written approval of the informed consent form and any additional written information that will be provided to study subjects.
As provided in ICH E6, section 3.2, an IEC includes at least five members, including at least one member whose primary area is in a nonscientific area and at least one member who is independent of the institution where the research will be conducted (i.e., not otherwise affiliated with the institution and not part of the immediate family of a person who is affiliated with the institution). FDA recommends that every nondiscriminatory effort be made to ensure that the IEC composition is not limited to only one gender and that it reflects the social and cultural diversity of the community(ies) from which research participants are most likely to be drawn. It is further advised that only those members who are independent of the investigator and the sponsor of the trial vote on trial-related matters.
FDA recognizes that the organization and membership of IECs may differ among countries because of local needs of the host country. Such variation is acceptable as long as the IEC can assure the protection of the rights, safety, and well-being of human subjects involved in the clinical investigation.
A sponsor or applicant submitting non-IND foreign data in support of an IND or an application for marketing approval for a drug must include a description of the actions the sponsor or applicant took to ensure that the research conformed to GCP. FDA recommends that the sponsor or applicant clearly indicate the following:
1. whether each clinical study was conducted at both foreign and domestic sites or only foreign sites;
2. whether each foreign site was under an IND or was subject to the requirements of 21 CFR 312.120; and
3. for each clinical study subject to 21 CFR 312.120, where in the submission or in previously submitted materials specified information can be found:
Investigator Qualifications (Section 312.120(b)(1))
FDA requires documentation to show that the investigator is qualified to serve as a study investigator based on their training and experience specifically related to the proposed clinical investigation. Such documentation generally includes a curriculum vitae or summary of training. For research involving novel technologies and/or the potential for increased risk of morbidity and/or mortality, the sponsor or applicant may wish to include additional documentation identifying the clinical investigator’s specific experience in this field (e.g., as demonstrated by recent presentations or publications) and with the test article.
Description of the Research Facilities (Section 312.120(b)(2))
The name and address of the research facility is generally not a sufficient description to meet the requirement in 21 CFR 312.120(b)(2). Because FDA is generally less likely to be familiar with the research facilities in which foreign non-IND studies are conducted, greater detail is usually needed. For example, it would generally be adequate to identify and briefly describe the academic medical center, hospital, physician’s office, clinical research unit or other type of facility at which the research is being conducted. The description should include enough information to enable FDA to determine the adequacy of the facilities to execute the protocol requirements (e.g., whether the site is appropriately staffed and equipped to conduct the proposed research and is able to provide the appropriate emergent or specialized care, if required).
Detailed Summary of the Protocol and Study Results and, If Requested, Case Records or Additional Background Data (Section 312.120(b)(3))
Submitting only the Synopsis would not be adequate to provide a sufficiently detailed summary of the protocol and study results as required by 21 CFR 312.120(b)(3). By contrast, submitting an integrated, full CSR in accordance with ICH E3 would meet this requirement, although alternative approaches are also acceptable.
Yes, FDA may need to review source documents such as hospital records to verify data, whether during an on-site inspection or upon request. For example, a review division within FDA may request submission of investigator, hospital, or institutional records outside of an inspectional context. If so, these records must be made available to the Agency for FDA to rely on the data. In addition, FDA believes that informed consent documents should notify subjects that international regulatory authorities may need to have direct access to the subjects’ original medical records for verification of clinical study procedures and data.
If the necessary records are not available, FDA may not accept the study data in support of an IND or application for marketing approval. If the records exist but a sponsor or applicant cannot disclose them to FDA because such disclosure is prohibited by applicable foreign law, the sponsor or applicant may seek a waiver of this requirement. For FDA to rely on such data that cannot be disclosed, the sponsor and FDA would need to agree on an alternative validation procedure.
Description of the Drug Substance and Drug Product, Including the Components, Formulation, Specifications, and, If Available, the Bioavailability of the Drug Product (Section 312.120(b)(4))
In general, the description of the drug required under 21 CFR 312.120(b)(4) would already be included in other sections of the IND or application for marketing approval. This requirement can therefore generally be met through cross-references to other sections of the submission.
Information Showing that the Effectiveness Study is Adequate and Well Controlled Under 21 CFR 314.126 (Section 312.120(b)(5))
As an example, integrated, full CSRs in accordance with ICH E3 generally provide appropriate detail to show that the study is adequate and well-controlled as described in 21 CFR 314.126. Note: the sponsor or applicant should also explain how the foreign data are applicable to the U.S. population and U.S. medical practice.
The sponsor or applicant is required by 21 CFR 312.120(b)(6) to provide only the name and address of the IEC that reviewed the study and a statement that the IEC meets the definition of an IEC in 21 CFR 312.3(b). However, as provided in 21 CFR 312.120(b)(6), the sponsor or applicant must maintain records supporting the statement, including the names and qualifications (e.g., occupation, training, and experience) of all IEC members, and must make these records available for Agency review upon request. If that is not possible because of governing law relating to privacy concerns, FDA recommends that sponsors and applicants clearly document the attempts made to obtain IEC member names along with an explanation as to why the IEC member names cannot be obtained or disclosed. Such information can then be submitted to FDA in a waiver request.
Summary of the IEC’s Decision to Approve or Modify and Approve the Study, or to Provide a Favorable Opinion (Section 312.120(b)(7))
In most cases, a brief summary of the IEC actions to approve or modify and approve the clinical investigation would be sufficient. For example, it may suffice to provide FDA with the name of the IEC and a list of IEC actions and dates (e.g., initial approval date, date of approval of modification, etc.), or alternatively to provide FDA with the approval letters from the IEC (including those for protocol amendments). If FDA determines that additional information is necessary to understand the IEC’s decisions on the clinical investigation, the Agency will request this information from the sponsor or applicant.
After submitting this required documentation in the IND/NDA/BLA, the sponsor is not required to submit IEC actions on continuing review to FDA. However, such continuing review information should be maintained and available to FDA upon request.
Description of How Informed Consent Was Obtained (Section 312.120(b)(8))
Submitting documentation of the informed consent process is one acceptable means of meeting the requirement in 21 CFR 312.120(b)(8) to describe how informed consent was obtained.
Description of What Incentives, If Any, Were Provided to Subjects to Participate (Section 312.120(b)(9))
FDA believes that there should be some flexibility in this requirement. The sponsor or applicant may follow ICH E6 or ICH E3, providing a sample or model informed consent form that describes any incentives provided. Alternatively, a sponsor or applicant may satisfy this requirement by submitting a brief narrative description of any incentives provided to subjects who participate in the study.
Description of How the Sponsor Monitored the Study and Ensured that the Study Was Carried Out Consistently with the Study Protocol (Section 312.120(b)(10))
Following ICH E3, section 9.6, is one acceptable way to meet this requirement. The sponsor or applicant should describe the methods used to oversee the conduct of and reporting of data from clinical investigations. The sponsor or applicant should also provide a cross-reference to audit-related information for the investigations, as applicable (e.g., audit certificates).
Description of How Investigators were Trained to Comply with GCP and to Conduct the Study in Accordance with the Study Protocol, and Written Commitments by Investigators to Comply with GCP and the Protocol (Section 312.120(b)(11))
Submitting a statement in accordance with ICH E3, section 9.6 (i.e., whether investigator meetings or other steps were taken to prepare investigators and standardize performance), is one acceptable means of compliance, provided that the description includes how investigators were trained to comply with GCP and to conduct the study in accordance with the study protocol.
Although FDA encourages sponsors to obtain written commitments from investigators, such commitments may not be required or may even be prohibited in some countries, and FDA does not want to preclude submission of well-designed and ethically conducted foreign clinical studies solely because a written commitment was not obtained. To meet this requirement, sponsors or applicants must submit a statement indicating whether written commitments by investigators to comply with GCP and the protocol were obtained and, if so, to maintain such commitments on file to be provided upon the Agency’s request.
WAIVERS (21 CFR 312.120(c))
Although rare, sponsors or applicants may ask FDA to waive any applicable requirements by submitting a waiver request. FDA will decide whether to grant or deny waivers on a case-by-case basis, taking into account all appropriate circumstances. Examples for waivers being sought include:
– The non-IND foreign clinical study was conducted before the effective date of the revised 21 CFR 312.120 (April 28, 2008).
– Disclosure of case records or additional background data is prohibited by governing law. In this case, the sponsor or applicant should document this disclosure prohibition by the foreign entity (e.g., the countries that prohibit such disclosure, the nature of the prohibitions, and the extent to which these prohibitions may impede sponsors in carrying out other obligations requiring record access).
If the sponsor or applicant cannot obtain IEC member names because of governing law relating to privacy concerns. In this instance, FDA recommends that the sponsor or applicant clearly document attempts made to obtain the names along with an explanation as to why the names cannot be obtained.
Required Contents and Submission of a Waiver Request (Section 312.120(c)(1))
A waiver request is required to contain at least one of the following: (i) An explanation why the sponsor’s or applicant’s compliance with the requirement is unnecessary or cannot be achieved; (ii) A description of an alternative submission or course of action that satisfies the purpose of the requirement; or (iii) Other information justifying a waiver.
Waiver requests may be submitted as a part of an original IND or application for marketing approval, a supplemental application, or an amendment to an application. The affected application should use the waiver section of Module 1 in eCTD format and/or include a cover letter that clearly states that a waiver is being requested. The waiver section or the cover letter should identify the affected studies and the relevant sections of the application.
FDA may also discuss issues with a sponsor during a pre-IND or pre-NDA/BLA meeting. For example, a sponsor who is considering locating sites in a foreign country where privacy laws would prohibit them from obtaining IEC member names may wish to discuss their concerns during the early stages of planning a study.
FDA will notify the sponsor or applicant in writing as to whether the waiver request is granted or denied. The sponsor or applicant should contact the FDA review division to which the waiver was submitted to inquire about the status of the waiver request. The sponsor or applicant should not assume that no response means that the request for waiver has been granted.
FDA may grant a waiver if it finds that doing so would be in the interest of the public health. The regulation allows the Agency to decide on a case-by-case basis whether to grant or deny a waiver, taking into account all appropriate circumstances.
A sponsor or applicant must retain the required records for a foreign clinical study not conducted under an IND for at least 2 years after an Agency decision on the supporting marketing application or, if the study is submitted in support of an IND but not a marketing application, for 2 years after submission of the IND.