Client Alert. FDA Offers New Guidance on Acceptance of Foreign Clinical Trials. Introduction. FDA Regulation of Foreign Clinical Trials 6

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1 Number 1325 April 23, 2012 Client Alert Latham & Watkins Corporate Department FDA Offers New Guidance on Acceptance of Foreign Clinical Trials Introduction With this newly released guidance, the FDA seeks specifically to encourage standardization of foreign clinical trial data in INDs and applications for marketing approval, in hopes of improving the quality and efficiency of data review and analysis. Over the last decade, drug, device, and biotechnology companies have taken their demand for clinical trial work to the global marketplace vastly increasing the number of trials taking place outside of the United States. In 2008, for instance, eighty percent of approved marketing applications for drugs and biologics contained data from foreign clinical trials, and more than half of all clinical trial subjects and sites were located outside the US. 1 While usage of foreign clinical trials to support drug and biologic marketing applications continues to increase, the US Food and Drug Administration s (FDA) ability to inspect foreign sites has stagnated. Despite the tremendous rate of usage in 2008, FDA inspected clinical investigators at less than one percent of foreign sites. 2 Recognizing that its own resource limitations make it difficult to effectively supervise industry s ever-increasing reliance on foreign clinical trials, the FDA recently took steps to strengthen its oversight of clinical trials conducted outside of the U.S. In March 2012, FDA released a new guidance document entitled, FDA Acceptance of Foreign Clinical Studies Not Conducted Under an IND, Frequently Asked Questions 3 in follow-up to the agency s April 2008 regulations that made FDA s acceptance of data from foreign clinical trials contingent on the trials compliance with good clinical practice (GCP) requirements (codified at 21 C.F.R ). 4 With this newly released guidance, the FDA seeks specifically to encourage standardization of foreign clinical trial data in INDs and applications for marketing approval, in hopes of improving the quality and efficiency of data review and analysis. 5 FDA Regulation of Foreign Clinical Trials 6 FDA may accept data from foreign clinical trials in support of domestic applications and submissions if certain requirements are met. Under 21 C.F.R , to be accepted by FDA as support for an IND, a new drug approval (NDA) or an abbreviated new drug approval (ANDA) application, the trial must be conducted in compliance with FDA s Good Clinical Practice (GCP) regulations, and FDA must be permitted to validate data through onsite inspection. 7 Latham & Watkins operates worldwide as a limited liability partnership organized under the laws of the State of Delaware (USA) with affiliated limited liability partnerships conducting the practice in the United Kingdom, France, Italy and Singapore and as affiliated partnerships conducting the practice in Hong Kong and Japan. Latham & Watkins practices in Saudi Arabia in association with the Law Office of Mohammed A. Al-Sheikh. In Qatar, Latham & Watkins LLP is licensed by the Qatar Financial Centre Authority. Under New York s Code of Professional Responsibility, portions of this communication contain attorney advertising. Prior results do not guarantee a similar outcome. Results depend upon a variety of factors unique to each representation. Please direct all inquiries regarding our conduct under New York s Disciplinary Rules to Latham & Watkins LLP, 885 Third Avenue, New York, NY , Phone: Copyright 2012 Latham & Watkins. All Rights Reserved.

2 To comply with GCP, the study must, among other things, provide patient informed consent and investigator statements, and perform adverse event and periodic reporting to FDA. 8 The GCP regulations also require that the study be conducted under the oversight of an independent ethical committee (IEC) 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. 9 IEC oversight must include approval of the study protocol prior to initiation, continuing review of an ongoing study, and approval for obtaining and documenting informed consent. 10 Sponsors must document compliance with GCP and IEC procedures in addition to meeting other GCP data submission requirements. These include providing a description of investigator qualifications, research facilities, drug product, study protocols and results. Sponsors must identify the reviewing IEC and document its decisions relating to the study. They must also describe the methods used to obtain informed consent, any incentives provided to subjects, study monitoring procedures, and the training provided to ensure compliance with GCP and the approved protocol. 11 Records of all the foregoing must be retained for two years after the agency s decision on an application for marketing approval or, if a study is submitted in support of an IND but not an application for marketing approval, for two years after the submission of the IND. 12 This enables FDA onsite inspection, if necessary. New Guidance In seeking to standardize the data submissions regarding foreign clinical trials, the guidance document outlines not only how to present the required information to FDA, but also offers additional direction on how to demonstrate compliance with each of the GCP requirements. At its most basic, FDA recommends that, for each foreign clinical study subject to 21 C.F.R , the location of each of element required under the regulation be clearly delineated, so that information is not duplicated. FDA also notes that, while studies submitted according to International Conference on Harmonization (ICH) Guidelines E3 (Structure and Content of Clinical Study Reports) or E6 (Guideline for Good Clinical Practice) may meet many of the requirements under Section , additional information may still be necessary to demonstrate compliance. Specifically, the guidance recommends the information necessary to demonstrate compliance with the following supporting information requirements: Investigator Qualifications ( (b)(1)): A CV or summary of training (or reference to one already included) is generally provided, unless additional documentation of specific experience is necessary by virtue of a novel technology or increased risk of morbidity. Description of the Research Facilities ( (b)(2)): The name and address of the facility is not a sufficient description; sponsors must at a minimum provide a brief description of the facilities in order to permit FDA to evaluate their adequacy to execute the protocol requirements. Detailed Summary of the Protocol and Study Results, and If Requested, Case Records or Additional Background Data ( (b)(3)): FDA recommends greater detail here than that which is included in the synopsis from Annex I of ICH E3. While a full CSR in accordance with ICH E3 would be sufficient, FDA accepts alternative approaches as well. FDA also recommends that informed consent 2 Number 1325 April 23, 2012

3 documents notify subjects of the possibility that FDA may request their hospital or medical records to verify data and procedures (during on-site inspection or upon request). 13 These records must be made available unless foreign law prohibits it, in which case the sponsor or applicant would seek a waiver and collaborate with FDA on an alternate validation procedure. Failure to make these records available may result in FDA not accepting the study data. Description of the Drug Substance and Drug Product, Including the Components, Formulation, Specifications, and, If Available, the Bioavailability of the Drug Product ( (b)(4)): This requirement can generally be met by merely crossreferencing other parts of the submission where the description is provided. Information Showing that the Effectiveness Study is Adequate and Well Controlled Under 21 CFR ( (b)(5)): To comply with this requirement, information equivalent to an integrated, full CSR in accordance with ICH E3 is necessary. The sponsor should also include an explanation of the application of foreign data to the U.S. population and medical practice. The Name and Address of the IEC that Reviewed the Study and a Statement that the IEC Meets the Definition in 21 CFR 312.3(b) ( (b)(6)): The guidance explains that an adequately constituted IEC is one that consists of at least five members, one of whom is independent of the research institution (only members independent of the investigator and sponsor may vote on trial-related matters). Collectively, the IEC must have the qualifications and experience to review and evaluate the science, medical aspects, and ethics of the proposed trial. Furthermore, FDA recommends that every non-discriminatory effort be made to ensure that IEC composition is diverse (not limited to one gender) and reflects the host community s social and cultural diversity. While the regulation only requires a sponsor or applicant to provide the name and address of the IEC that reviewed the study, the guidance notes that supporting records must be maintained and made available upon request, including member names and qualifications. If foreign law makes this impossible, the sponsor or applicant must seek a waiver after documenting attempts to obtain IEC member names. Summary of the IEC s Decision to Approve or Modify and Approve the Study, or to Provide a Favorable Opinion ( (b)(7)): Approval letters from the IEC, the name of the IEC and a list of actions and dates, or a brief summary of the IEC actions is sufficient to satisfy this requirement. While continuing review by the IEC is required, submission of continuing review documentation is not (but should be maintained). Description of How Informed Consent Was Obtained ( (b)(8)): FDA points to ICH E6, section 4.8 and/or relevant sections of ICH E3 as acceptable means of meeting this requirement. Description of What Incentives, If Any, Were Provided to Subjects to Participate ( (b)(9)): FDA indicates that the sponsor or applicant may provide a sample or model informed consent form describing any incentives provided (as under ICH E6 or ICH E3), or a brief narrative description. Description of How the Sponsor Monitored the Study and Ensured that the Study was Carried Out Consistently with the Study Protocol (312.12(b)(10)): This requirement should include a description of the methods used to oversee conduct of and reporting of data. FDA points to ICH E3, section 9.6 as an acceptable means of meeting this requirement. FDA also recommends crossreferencing audit-related information. 3 Number 1325 April 23, 2012

4 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 ( (b) (11)): A compliant description must include how investigators were trained on GCP and the protocol, regardless of whether the statement is in accordance with ICH E3, section 9.6, which FDA has deemed acceptable. FDA encourages sponsors to obtain signed commitments from investigators (if not prohibited by foreign law), but it is not required. At a minimum, however, a sponsor or applicant must submit a statement indicating whether he/she obtained written commitments by investigators to comply with GCP and the protocol, and must maintain such commitments on file. The guidance also notes that sponsors or applicants who are not able to meet one of the aforementioned requirements may seek a waiver pursuant to 21 C.F.R (c). While rare, waivers may be granted by FDA on a case-by-case basis. As referenced above, waivers may be necessary, for example when disclosure of certain case records or IEC member names, which are required to be kept on-file, is prohibited by foreign law. FDA is also granted some flexibility by the regulations to grant waivers on a case-by-case basis if the agency believes, taking into account all appropriate circumstances, that doing so would be in the interest of public health. 14 Waiver requests should be submitted either as a part of an original IND or application for marketing approval, as a supplemental application, or as an amendment to an application. 15 As clinical research continues to globalize, FDA is also likely to continue its effort to strengthen its oversight of foreign trials potentially offsetting cost and time efficiencies currently achieved by overseas programs. However, by standardizing data submissions and ensuring FDA access to the proper qualifying data, sponsors and applicants may be able to mitigate unnecessary regulatory delays in the approval process. 4 Number 1325 April 23, 2012

5 Endnotes 1 U.S. Dept. of Health and Human Services, Office of Inspector General, Challenges to FDA s Ability to Monitor and Inspect Foreign Clinical Trials (2010), at ii, available at oei pdf. 2 Id. 3 U.S. Dept. of Health and Human Services, Food and Drug Administration, Guidance for Industry and FDA Staff: FDA Acceptance of Foreign Clinical Studies Not Conducted Under an IND, Frequently Asked Questions (2012) (the Guidance ) available at RegulatoryInformation/Guidances/UCM pdf Fed. Reg (Apr. 28, 2008). 5 Guidance, at 2. 6 For additional information on FDA regulation of foreign clinical trials, see Latham & Watkins Client Alert, New FDA Regulation Alters Standards for Foreign Clinical Trials (May 29, 2008), available at lw.com/upload/pubcontent/_pdf/pub2201_1.pdf C.F.R (a)(i). Note that foreign clinical trials performed under an investigational new drug application (IND) or investigational device exemption (IDE) must meet the requirements applying to U.S. Studies under 21 C.F.R. Part 312 or 21 C.F.R. Part 812, respectively, unless waived. Marketing approval of a new drug based solely on foreign clinical data is governed by 21 C.F.R Id. See also 21 C.F.R. pt. 312, see subpt. D C.F.R (b) (2011) C.F.R (a)(1)(i) C.F.R (b) CFR (d). 13 In accordance with another recently released FDA Guidance Document on compliance with informed consent elements, if the foreign clinical involves a drug, biologic, or device that is manufactured in the United States, or is conducted under an Investigational New Drug Application ( IND ) or Investigational Device Exemption ( IDE ), the informed consent documents must also include a specific statement that refers to the trial s description on See U.S. Dept. of Health and Human Services, Food and Drug Administration, Guidance for Industry and FDA Staff: Questions and Answers on Informed Consent Elements, 21 CFR 50.25(c) (Small Entity Compliance Guide) (2012) available at 14 In addition a waiver might be appropriate where the non-ind clinical study was conducted prior to the revision of 21 CFR Guidance, at Amendments are submitted under 21 C.F.R. Parts 314 and 601. In certain circumstances, FDA will also discuss a waiver with a sponsor or applicant prior to submitting a request. Guidance, at Number 1325 April 23, 2012

6 If you have any questions about this Client Alert, please contact one of the authors listed below or the Latham attorney with whom you normally consult: Carolyne R. Hathaway Washington, D.C. Anne L. Hanson Washington, D.C. Client Alert is published by Latham & Watkins as a news reporting service to clients and other friends. The information contained in this publication should not be construed as legal advice. Should further analysis or explanation of the subject matter be required, please contact the attorney with whom you normally consult. A complete list of our Client Alerts can be found on our website at If you wish to update your contact details or customize the information you receive from Latham & Watkins, please visit to subscribe to our global client mailings program. Abu Dhabi Barcelona Beijing Boston Brussels Chicago Doha Dubai Frankfurt Hamburg Hong Kong Houston London Los Angeles Madrid Milan Moscow Munich New Jersey New York Orange County Paris Riyadh* Rome San Diego San Francisco Shanghai Silicon Valley Singapore Tokyo Washington, D.C. * In association with the Law Office of Mohammed A. Al-Sheikh 6 Number 1325 April 23, 2012