Will Your Studies Meet the Standards?

Clinical trials are the lifeblood of new pharmaceuticals in the United States. Investigational new drugs require such studies as proof of the safety and efficiency of the drug. Over the past fifteen years, however, it has become increasingly clear that it is not possible or practicable to have all of the clinical trials take place in the United States. Increasingly, more trials are being done in Eastern Europe, South America, and Asia.¹ These studies take place outside the United States for a variety of reasons:

• There are not enough competent clinical investigators in the United States to conduct all the new studies for the increasing number of new drugs and devices being tested.
• Cost of the trials is often less overseas — especially in Eastern Europe, Asia, and South America.
• There is increasing concern in the United States over doctors who conduct studies and who are also paid consultants by pharmaceutical companies, which may mean even fewer available clinical investigators.
• In Eastern Europe, South America, or Asia, the study subjects are less likely to already be on drug therapy.
• Tests can be done out of season. For example, tests of an allergy drug can be done in South America in January.

Over the last decade, however, this trend has also caused some concern and some criticism. As early as 2001, the Office of Inspector General (OIG) of the Department of Health and Human Services authored The Globalization of Clinical Trials: A Growing Challenge in Protecting Human Subjects.² This report found that foreign clinical investigators conducting drug research under an Investigational New Drug Application (IND) had increased sixteen-fold over the past decade.³ The Office of Inspector General recommended that the Food and Drug Administration obtain more information about the performance of foreign institutional review boards and encourage sponsors to obtain attestations from investigators that they would adhere to ethically sound principles of research. The OIG also urged the FDA to take a leadership role in ensuring that there were adequate human safety protections in all non-U.S. clinical trials.

Since the release of this report, the use of foreign clinical trials in support of FDA- approved pharmaceuticals has increased dramatically. A study in the New England Journal of Medicine looked at the ClinicalTrials.gov registry to find the countries in which studies were taking place. It found that, as of November 2007, for the twenty largest U.S.-based pharmaceutical companies, approximately one-third of the Phase 3 trials were being conducted solely in foreign countries and that a majority of study sites were outside of the United States.⁴ In recognition of this trend, in April 2008, the FDA amended its regulations on the acceptance of foreign studies not conducted under an Investigational New Drug as support for the approval of the drug being studied.⁵ These amendments were made to ensure that all such studies were conducted in accordance with good clinical practices. This final rule is codified at 21 CFR § 312.120.⁶

In March 2012, the FDA issued the Guidance for Industry and FDA Staff: FDA Acceptance of Foreign Clinical Studies Not Conducted under an IND Frequently Asked Questions (“Guidance”).⁷ The Guidance notes that a sponsor may choose, but is not required, to conduct a foreign clinical study under an IND, and in such a case, all the requirements of an IND must be met unless waived. But if the foreign clinical study is not conducted under an IND, it must comply with the requirements of 21 CFR Section 312.20. This Guidance seeks to answer questions as to how sponsors of a new drug can demonstrate compliance with these regulations regarding foreign clinical studies, in particular that such studies be conducted with good clinical practice (GCP). Good clinical practice is defined by regulation 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 the rights, safety, and well-being of trial subjects are protected.”⁸ Additionally, the Guidance notes there are certain international ethical and policy standards for clinical trials, such as the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) “Good clinical Practice: Consolidated Guideline” (“ICH E6”), which the FDA has adopted for use as further guidance.

The Guidance states that GCP requires review and approval of a foreign study by an independent ethics committee (“IEC”) before the study is started to ensure that the rights and safety of the participants in the study are being protected. It indicates, however, that the FDA is flexible about the requirements of an adequate IEC because the membership and organization of the committee may vary from country to country based on local needs and customs.⁹ The FDA considers an independent ethics committee to be adequate if it has “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.”¹⁰ The Guidance also refers the sponsor to ICH E6, section 3.2, which requires there be at least five members of an IEC and at least one member to be someone who is not affiliated with the institution where the research will be conducted. The Guidance notes that the sponsor only has to provide to the FDA the name and address of the IEC that reviewed the study along with a statement that the IEC meets the applicable requirements for an IEC, but the sponsor must maintain records supporting this submission, including qualifications of members of the committee.¹¹ The IEC has to approve the study and any modifications to it, and must continually review the study. Documentation of such actions, however, need not be submitted to the FDA. Such documentation should be kept and provided to the FDA upon request.¹²

The IEC must also approve the informed consent. ICH E6 defines informed consent as “a process by which a subject voluntarily confirms his or her willingness to participate in a particular trial, after having been informed of all aspects of the trial that are relevant to the subject’s decision to participate.”¹³ The Guidance notes that under 21 CFR section 312.120 (b) (8), a description of how the informed consent was obtained must be provided. It also states that the FDA believes that the informed consent documents should notify the subjects that international regulatory authorities may need to have direct access to their medical records for verification of study procedures and data.¹⁴ Additionally, the informed consent would normally contain a brief statement of any type of incentives that were given study participants. If it does not contain such a statement, the FDA should be given a brief narrative description of such incentives.¹⁵

The Guidance also addresses what must be submitted to the FDA about the investigators for the study. Documentation must be submitted to the FDA to show that each investigator has the experience and training “specifically related” to the proposed clinical study.¹⁶ Usually, the Guidance states such information would include the investigator’s CV and, if the study is novel or has increased risks of mortality and morbidity, additional information regarding the investigator’s experience. Such experience might include, for example, recent presentations or publications. A statement should also be submitted describing how the investigators were trained to comply with GCP and to conduct the study in accordance with the study protocol. Sponsors are also encouraged to obtain written commitments that the investigators will comply with GCP and the protocol.¹⁷ The FDA recognizes, however, that such commitments may be prohibited in some countries and does not want to “preclude submission of well-designed and ethically conducted foreign clinical studies solely because a written commitment was not obtained.”¹⁸

The Guidance also addresses requirements for information about the foreign institutions in which the study will take place. It specifically states that the name and address of the research facility is not enough information to meet the requirements of the regulations, pointing out that the FDA is generally less likely to be familiar with foreign facilities. According to the Guidance, a description of the research facility would include enough information, such as the staffing, equipment, and the ability to provide any emergent or supportive care, to enable the FDA to assess the adequacy of the facility. All of this information is needed to demonstrate that the study is adequate and well managed.

The Guidance makes it clear that the FDA may need to review source documents of the study such as hospital records: “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 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.”¹⁹ For such data to be relied upon, the sponsor and the FDA would have to agree on another way to validate the data: “[T]he sponsor or applicant should also explain how the foreign data are applicable to the U.S. population and U.S. medical practice.”²⁰

Under 21 CFR 312.120 (c), requests for waivers from these regulations are allowed, but the Guidance makes it clear that the FDA expects few requests for such waivers. Since the regulations were published, few waivers have been requested.²¹ A waiver request must contain at least one of the following criteria: Why compliance with the regulation is “unnecessary or cannot be achieved,” a description of an alternative action that satisfies the purpose of the requirement, or other information that justifies a waiver from a specific regulation.²² The Guidance gives some examples of the types of situations in which the FDA might expect a waiver request to be made. For example, a waiver would be anticipated if privacy laws in a foreign country prohibit the disclosure of the members of the IEC or of hospital records. In such situations, the sponsor or applicant has to document all attempts to get the information and why the laws prohibit such disclosure. Increasingly, pharmaceutical companies are multinational. Chances are that your pharmaceutical company has been grappling with the issue of foreign clinical trials for years: where the study should take place, who will be the investigators, how good GCP can be assured and documented. The Guidance provides information in an easy-to-use question-and-answer format. It would be prudent to review the Guidance as well as the international agreements regarding clinical studies before sponsoring any foreign clinical studies. Having all the these issues covered before the study even starts will lead to fewer problems and cost savings when the study is later considered as part of the ne

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[i] This trend means that pharmaceutical companies conducting or sponsoring clinical trials abroad must have knowledge of foreign laws that will apply to the trial, including the European Union Directive on Privacy and the European Clinical Trial Directive. They should also comply with the World Medical Association Declaration of Helsinki: Ethical Principles for Medical Research Involving Human Subjects.

[ii] September 2001, OEI-01-00-00190.

[iii] Id. page i.

[iv] Glickman, Seth, M.D., et. al. “Ethical and Scientific Implications of the Globalization of Clinical Research,” New England Journal of Medicine Volume 360, No. 8, February 19, 2009.

[v] 21 CFR § 312.20 requires that a sponsor submit an INDA to the FDA if it wishes to conduct a clinical investigation of a new drug and cannot begin such a trial until it has done so. Under 21 CFR § 312.21, an INDA may be submitted for one of more phases of an investigation. The FDA has to review the application to assure the safety of all the subjects and, in Phases 2 and 3, to determine that the scientific evaluation of the drug is adequate to determine if the drug is safe and effective. 21 CFR § 312.22.

[vi] See also 21 CFR § 314.106.

[vii] This Guidance was issued by the FDA, Center for Drug Evaluation and Research, Center for Biologics Evaluation and Research, Office of Good Clinical Practice. This Guidance is the current thinking of the FDA but is not binding, and alternative approaches can be taken if the approach satisfies the requirements of the applicable regulations.

[viii] 21. CFR § 312.120(a)(1)(i).

[ix] See p.4 of U.S. Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research, Center of Biologics Evaluation and Research, Office of Good Clinical Practice, Guidance for Industry and FDA Staff, March 2012. PDF available at <http://www.fda.gov/downloads/RegulatoryInformation/Guidances/UCM294729.pdf>. Last accessed April 17, 2012.

[x] Id. at 9.

[xi] Id. at 10.

[xii] Id. at 10-11.

[xiii] International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use. Guideline for Good Clinical Practice: E6(R1). 10 June 1996. 1.28. PDF available at <http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E6_R1/Step4/E6_R1__Guideline.pdf>. Last accessed April 17, 2012.

[xiv] Guidance for Industry and FDA Staff at p. 8.

[xv] Id. at 11.

[xvi] Id. at 6.

[xvii] Id. at 12.

[xviii] Id. at 12. For more information on this issue, this Guidance refers the reader to the FDA’s Guidance, Information Sheet Guidance for Sponsors, Clinical Investigators, and IRBs: Frequently Asked Questions – Statement of Investigator (form FDA 1572), available at <http://www.fda.gov/downloads/RegulatoryInformation/Guidances/UCM214282.pdf>. Last accessed April 17, 2012.

[xix] Id. at 8.

[xx] Id. at 9.

[xxi] Id. at 12.

[xxii] Id.

Finis