Over the last several months, the U.S. Food and Drug Administration (FDA) has taken additional steps to increase federal oversight over clinical research. Though not all of these measures are final, the regulatory effort to more closely monitor the accuracy and scientific validity of clinical research data is noteworthy.
ClinicalTrials Conducted Outside of the United States
On June 6, 2004, the FDA announced proposed rules for submission of data from clinical trials not operating under an Investigational New Drug Application (IND) conducted outside of the United States (see, "Human Subject Protection; Foreign Clinical Studies Not Conducted Under an Investigational New Drug Application," 69 FR 32467 and see, 21 C.F.R. 312.120 for the current rule for non-IND studies.) Though the FDA has significant oversight over certain foreign-conducted IND clinical trials (an IND application based solely on foreign clinical data must meet a series of suitability requirements, see, 21 C.F.R. 314.106 and foreign clinical trials conducted under an IND must meet the same IND requirements that control U.S. conducted IND studies, see, 21 C.F.R. 312), it has not previously chosen to monitor non-IND foreign trials as closely. The FDA, however, is increasingly wary of relying on data collected in clinical trials conducted outside the United States for two reasons. First, the agency cannot currently verify the scientific validity of the research design and the accuracy of the data collected. Second, the agency does not want investigators interested in conducting research to use foreign trials as a means of escaping the vigorous human subject protections that apply to domestic research.
Previously, the FDA required assurances that any foreign clinical trial not operating under an IND be conducted in accordance with the principles espoused in the Helsinki Declaration. The proposed rule would require, instead, that investigators conduct such foreign studies in accordance with good clinical practices (GCP). A GCP is a "standard for the design, conduct, performance, monitoring, auditing, recording, analyses and reporting of clinical trials that provides assurance that the data and reported results are credible and accurate, and that rights, integrity and confidentiality of trial subjects are protected." Compliance with GCP would include GCP review and approval by an Independent Ethics Committee (IEC). The FDA proposes to define an IEC 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."
The FDA believes that the GCP should supplant the Helsinki Declaration as the controlling authority for non-IND trials for two reasons. First, ethical guidelines for the conducting of human subjects research have evolved since the declaration was originally published. For example, the International Conference on Harmonization for Registration of Pharmaceuticals for Human Use (ICH) has issued a number of guidances announcing industry best practices incorporating the GCP. Second, the FDA believes that additional controls are required to protect the integrity of the scientific data developed in foreign clinical studies. The declaration does not contain specific safeguards to ensure quality scientific data, although it generally espouses the principle that research should be properly designed and only conducted when it will provide valuable information.
Though the rule does not set forth an exhaustive list of requirements for a foreign study to be acceptable to the FDA, the proposed rule identifies issues that should be considered when conducting a study outside of the United States, which include the involvement of a neutral, properly constituted review body (similar to an IRB) to review the research proposal and monitor the research; fully informed voluntary consent; reporting of adverse events; sponsorship of monitoring of the clinical trial and assurances of the scientific validity of the data; and availability of onsite inspections by the FDA to ensure the implementation of GCP.
Any sponsor who wishes to rely on data from a clinical trial conducted outside of the United States would need to meet the existing requirements and would also need to provide a description of the sponsor’s plan to ensure that the research conformed to GCP. Currently, a sponsor must submit to the FDA the following information: a) a description of the investigator’s qualifications; b) a description of the research facilities; c) a detailed summary of the protocol and results of the study, and if FDA requests, case records maintained by the investigator or additional background such as hospital or other institutional records; d) a description of the drug substance and drug product used in the study, including a description of components, formulation, specifications, and bioavailability of the specific drug product used in the clinical study, if available; and e) if the study is intended to support the effectiveness of a drug product, information showing that the study is adequate and well controlled (see, 29 C.F.R. 312.120(b)(1)-(b)(5)). Such a description would include, at minimum, the following information:
- Names and qualifications of the members of the IEC that reviewed the study;
- Summary of the IEC’s decision to approve or modify and approve the study, or to provide a favorable opinion;
- Description of how informed consent was obtained;
- Description of what incentives, if any, were provided to subjects to participate in the study;
- Description of how the sponsor(s) monitored the study and ensured that the study was carried out consistent with the study protocol; and
- Description of how investigators were trained to comply with GCP and to conduct the study in accordance with the study protocol, and copies of written commitments if any, by investigators to comply with GCP and the protocol.
Though under certain situations the proposed rule indicates that a sponsor could apply to the FDA to waive these requirements, entities participating in research should be prepared for increasing FDA oversight of trials conducted outside the United States and may want to consider developing GCP policies in anticipation of the final rule.
Clinical Trial Registration
Recently, there has been increasing concern that pharmaceutical companies conduct clinical trials, but then choose not to publish the data if the study results are not favorable to the company’s strategic objectives. Critics charge that selective publishing makes it difficult for physicians to make treatment decisions and for future investigators to reasonably assess the risks and benefits of drug or device under investigation. Though there may be a variety of reasons why a company chooses to publish clinical data or not, the FDA is also concerned that the public and medical community’s ability to evaluate the clinical safety and effectiveness of a drug is compromised when conflicting results are not definitively known.
Accordingly, on July 6, 2004, the FDA announced a proposed rule that would require every IRB that reviews clinical trials regulated by the FDA to register with a central databank (see, 69 FR 40536). Senators Dodd, Kennedy, Johnson and Wyden have also introduced a bill to amend the Public Health Service Act to expand the existing clinical trials drug data bank (see, S.2933, October 7, 2004). Proposed legislation is entitled the "Fair Access to Clinical Trials Act of 2004" or the "FACT Act" and would create a comprehensive national registry of all publicly and privately funded clinical trials that involve drugs, biological products or devices. The registration would include the number of active protocols involving FDA-regulated test articles reviewed by the registering IRB in the previous calendar year and a description of the types of FDA-regulated test articles involved in the protocols that the IRB reviewed. The FDA states that such a registration requirement will also make it easier for the FDA to inspect IRBs and to monitor trials undertaken (even if the results are not published) since the FDA has never compiled a comprehensive list of all IRBs involved in reviewing research regulated by the FDA. The Office of Human Research Protections (OHRP) maintains a public database of every institution that has entered into an assurance with OHRP to conduct human subjects research in accordance with the requirements of the so-called common rule (see, 42 C.F.R. Part 46). However, this database does not include institutions that do not receive federal funding for research (for example, many private companies) and does not include current information regarding the studies being reviewed by those institutions’ designated IRBs.
The FDA and OHRP are currently developing a joint internet site for IRB registration. The registration system will be required regardless of whether the IRB reviews clinical investigations regulated by the FDA or conducted or supported by the U.S. Department of Health and Human Services (DHHS). In order to ensure the database is comprehensive, OHRP announced a similar proposed rule requiring IRB registration of IRBs that review research that is conducted or supported by DHHS and that are designed under an assurance with DHHS to comply with OHRP’s regulations. The databank would make the name of the institution and of the IRB publicly available. All other information contained in the databank would be accessible pursuant to the Freedom of Information Act regulations.
IRBs affected by the proposed rule include those that review clinical investigations regulated by the FDA because the research involves an IND or an Investigational Device Exemption (IDE), IRBs that review clinical investigations that support applications for research or marketing permits for FDA regulated products and foreign IRBs. IRBs would need to provide significant information, including the following:
- Name and mailing address of the institution operating the IRB and the name, mailing address, and contact information for the senior office of that institution responsible for overseeing IRB activities
- IRB’s name, IRB chairperson’s name and contact person for the IRB
- Number of active protocols involving FDA-regulated products
- Description of the types of FDA regulated products such as human drugs, biological products, devices, etc.
- IRB is accreditation information
- Additional information for IRB’s regulated by OHRP
Under the proposed rule, IRBs would register and then renew their registrations every three years. The initial registration would have to be complete within 30 days of when the IRB begins reviewing any research regulated by the FDA. The IRB would need to update the registry when reportable information changed. Sponsors or investigators will be considered out of compliance with FDA regulations if they use an unregistered IRB, endangering their applications to the FDA and subject to existing regulatory sanctions for non-compliance with FDA rules for the conducting of clinical research. The FDA intends to give covered IRBs 60 days from the publishing of the final rule to register.
IRBs should consider developing policies and procedures to comply with these regulations. In response to high level investigations into pharmaceutical companies’ alleged non-disclosures of clinical trial date, some pharmaceutical companies and professional associations are developing written guidelines for the disclosure of clinical trial data (see, e.g., PhRMA, "Updated Principles for Conduct of Clinical Trials and Communication of Clinical Trial Results," June 30, 2004.)
Computerized Clinical Research Systems
On October 4, 2004, the FDA announced its draft guidance on Computerized Systems Used in Clinical Research (69 FE 59239; guidance available at www.fda.gov/cder/guidance/6032dft.htm). The draft guidance in an extensive document outlining the key features —as identified by the FDA —of appropriate software for the generation and maintenance of clinical trial data. It is designed to assist entities in their efforts to develop policies and procedures addressing clinical research computer programs. Though the guidance is only in draft form, and when final will not be absolutely binding, the document is a useful tool for entities currently constructing policies. In particular, the draft guidance identifies a number of key themes and features, including the following:
- Study protocols should identify the computerized system to be used and how it will be used to manage data.
- Computerized systems should be tailored to record and track data in accordance with protocol specifications.
- Computerized systems must comply with regulatory record retention requirements.
- Security measures should be in place to protect the confidentiality and integrity of the data.
- Computerized systems should have audit trail capabilities.
- Entities should develop standard operating procedures for the use of computerized systems.
In addition, the draft guidance makes clear that though the FDA is currently exercising enforcement discretion with respect to specific FDA requirements related to computer-generated, time-stamped audit trails, entities and investigators must still comply with "predicate rule requirements" and other rules that may trigger certain audit requirements. In other words, regulatory requirements that a study be adequate and accurate make it necessary to track any changes to electronic records. In the FDA August 2003 guidance, "Part II, Electronic Records; Electronic Signatures – Scope and Application," the FDA announced that while Part II is under review, the FDA will exercise enforcement discretion with respect to Part II specifications for validation, audit trails and record management.
Though the focus of the guidance is directed at clinical sites collecting data, the guidance specifically indicates that contract research organizations, data management centers and private sponsors may also use systems subject to this guidance. Therefore, a broad array of private and public entities involved in clinical research may want to consider initiating the development of standard operating procedures for clinical research computerized systems.
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