Voluntary codes of conduct like PhRMA's code frequently become the "standard of practice" against which legal and regulatory authorities measure compliance with legal requirements. Accordingly, it is critical that firms and individuals that participate in clinical trial research become familiar with PhRMA's principles for conducting clinical trials. Such firms and individuals include pharmaceutical manufacturers that sponsor clinical trials, investigative site staff and medical professionals who serve as clinical investigators, hospitals and other institutions where research is conducted, and institutional review boards.
The recent failure of an institutional review board (IRB) to comply with legal requirements imposed on IRBs is illustrative. Based in Colorado Springs, CO, Coast IRB, LLC was caught in an undercover investigation conducted by the U.S. Government Accountability Office (GAO) approving a fake clinical research study for a fake medical device company on a fake medical device. Needless to say, Coast utterly failed to take the steps necessary to protect human subjects and preserve research integrity in clinical trials.
Patient Safety and Research Integrity
The safety of individuals participating in clinical trials has long been of paramount importance. For nearly 50 years, the Food, Drug, and Cosmetic Act (FD&C Act) has provided that the FDA may approve a drug manufacturer's IND application only if the manufacturer promises to "inform any human beings to whom such drugs . . . are being administered . . . that such drugs are being used for investigational purposes" and to "obtain the consent of such human beings." The same "informed consent" requirements apply to medical device manufacturers seeking an investigational device exemption (IDE). FDA regulations provide that the "primary purpose" of IRBs - the committees designated by an institution to review, approve the initiation of, and oversee biomedical research involving patients - is "to assure the protection of the rights and welfare of the human subjects."
Of similar importance is the integrity of clinical trial research. After all, it is the information derived from clinical trials that enables the FDA to determine whether drugs and devices are safe and effective. The FDA itself has stated that its "primary objectives" in reviewing an investigational new drug (IND) are "to assure the safety and rights of subjects" and "to help assure that the quality of the scientific evaluation of drugs is adequate to permit an evaluation of the drug's effectiveness and safety." Unfortunately, the integrity of clinical trial research may be called into question by fraudulent reporting of clinical research or by bias in clinical studies. Whether real or perceived, bias may result from financial arrangements between sponsors and clinical investigators or from other conflicts of interest.
The PhRMA Principles
The newly revised PhRMA code of conduct seeks to address concerns about both the safety of individuals participating in clinical drug trials and the integrity of clinical trial research. Its four principles address the protection of research participants, the conduct of clinical trials, ensuring objectivity in research, and providing information about clinical trials. In summary, the PhRMA code commits the drug industry to:
Protect the Safety of Research Participants
The PhRMA code sets forth the industry's commitment to the "fundamental principle" of protecting the safety of individuals participating in clinical trials, and it provides guidance on patient safety for its member companies who design, conduct, and sponsor clinical trials.
Conduct High-Quality Clinical Research
The PhRMA code urges companies to adhere to applicable laws and regulations, follow locally recognized good clinical practices, and ensure that clinical trial protocols are reviewed by IRBs.
IRBs: Under the code, IRBs are to have "independent decision-making authority" (including the right to disapprove, require changes, or approve the clinical trial before any participants are enrolled) and "the responsibility and authority to protect research participants" (including the responsibility to inform potential participants about the proposed research).
Informed Consent: Clinical investigators are to obtain and document informed consent from individuals participating in clinical trials. Any financial arrangements between the sponsor and the clinical investigator or institution must be disclosed.
Ongoing Safety Monitoring: Safety issues are to be tracked and monitored, and significant new safety information is to be shared promptly with regulatory authorities.
Quality Assurance: Procedures are to be followed that ensure that data from clinical trials is "generated, documented and reported accurately."
Ensure the Objectivity of Clinical Trial Research
The PhRMA code seeks to insulate clinical investigators from improper influence, so they can maintain the independence to protect the safety of individuals participating in clinical trials and "to ensure an objective and balanced interpretation of trial results." To this end, the industry pledges that its "contracts and interactions" with clinical investigators "will not interfere with this independence."
Payments to Clinical Trial Participants: Under the code, drug company payments to research participants must be reviewed and approved by an IRB, constitute reimbursement for time and reasonable expenses, and be consistent with principles of voluntary informed consent.
Payments to Clinical Investigators: Drug company payments to clinical investigators must be pursuant to a written contract, be "reasonable and based on work performed by the investigator," and not be tied to the outcome of the clinical trial. Payments may not be made in company stock or options, and clinical investigators may not have a direct ownership in the specific pharmaceutical product being studied. Resorts are not appropriate venues for company-sponsored clinical trial meetings, nor are recreational or entertainment events. Drug companies may not "pay honoraria or travel or lodging expenses for those who are not involved in the clinical trial." These restrictions conform to PhRMA's Code on Interactions with Healthcare Professionals.
Conflicts of Interest: Drug companies are urged to encourage physicians and researchers who submit an article or letter to a medical journal to disclose "all financial and personal relationships that might bias their work" and state explicitly whether potential conflicts do or do not exist. Moreover, they are to "identify individuals who provided writing or other assistance and disclose the funding source for such assistance."
Increase Transparency of Clinical Trials
The PhRMA code recognizes that the "availability of information about clinical trials and their results in a timely manner is often critical to communicate important new information to the medical profession, patients and the public." Accordingly, it makes several commitments on behalf of member companies.
Registration of Clinical Trials: Under the code, drug companies commit to register in a public database summary information about each clinical trial they sponsor, whether for already marketed drugs or for investigational drugs, within 21 days of enrolling the first patient. Summary information includes all of the information mandated in the FDA Amendments Act (FDAAA), even for studies not subject to FDAAA, unless "providing such information could jeopardize the intellectual property protection with respect to the product."
Disclosure of Clinical Trial Results: Companies also commit to publish "timely" summary results of all clinical trials conducted "in patients" (thus excluding most Phase I studies) that involve "the use of our products that are approved for marketing, or that are investigational products whose development programs are discontinued, regardless of outcome." For approved drugs, "timely" means 12 months after the trial ends or 30 days after the drug is approved. For unapproved drugs, "timely" means one year after a company discontinues the drug development program. A drug development program is "discontinued when the company is no longer studying the applicable molecule, does not expect to resume development, and has no plans for the molecule on its own or through collaboration or out-licensing."
Authorship and Research Contributors: Only clinical investigators who provide "substantial contributions" to a study, write or revise the manuscript, and have final approval of the version to be published in a medical journal may be listed as an author. According to the code, the "acquisition of funding, collection of data, or general supervision of the research group, alone, does not justify authorship." These requirements conform to International Committee of Medical Journal Editors (ICMJE) standards. Staff employed by drug companies to help analyze and interpret data must work with the investigator-author and must be identified in resulting publications. Financial and material support from a drug company must also be acknowledged.
Investigator and Patient Access to Data and Study Results: The PhRMA code directs drug companies to provide all investigators with a full summary of the study results, even if an investigator does not contribute to the publication of the study. Investigators in a multi-site clinical trial are provided an opportunity to review data for the entire study. Investi-gators also are encouraged to communicate a summary of the trial results to research participants after the study ends.
Sponsor Review: Under the code, drug companies have a right to review manuscripts, presentations, or abstracts that are based on clinical trial data before they are submitted for publication, but they "commit to respond in a timely manner, and not suppress or veto publications or other appropriate means of communication" of study results.
The principles outlined in the PhRMA code, if adopted as industry practice, likely will enhance the safety of individuals participating in clinical trials and the integrity of clinical trial research.
The Case of Coast IRB, LLC
FDA's recent action against Coast IRB, LLC illustrates the utter failure of a firm involved in clinical trials to protect human subjects and preserve research integrity. Although the Coast case concerned a GAO-created "bogus medical device company" and a "fictitious medical device," not a drug company or an investigational drug, the principles relating to the conduct of clinical trials are the same.
For its undercover investigation, GAO created a fake medical device company and a fake device "with no proven test history and bogus specifications." GAO also created a research protocol with "vague information about certain aspects of our proposed study." Moreover, the "fictitious device was a post-surgical healing device for women that matched multiple examples of 'significant risk' devices provided in publicly available FDA guidance." GAO then launched its sting operation, selecting three independent IRBs and submitting the fictitious protocol to each for its review. Of the three IRBs, Coast was the only one to approve the bogus protocol.
In a Warning Letter to Coast, the FDA identified the following violations of the law:
- "The IRB failed to determine that risks to subjects are minimized."
- "The IRB failed to determine that risks to subjects are reasonable in relation to anticipated benefits, if any, to subjects, and the importance of the knowledge that may be expected to result."
- "The IRB failed to determine the applicability of 21 CFR Part 812 and failed to make a risk determination for the investigational device study."
- "The IRB failed to ensure that basic elements of informed consent are included in the IRB-approved consent form."
- "The IRB failed to demonstrate its ability to ascertain the acceptability of the proposed research in terms of regulations, applicable law, and standards of professional conduct and practice."
Because of the seriousness of the violations and the "risk to the rights and welfare of human research subjects," FDA required Coast to agree to stop reviewing new FDA-regulated studies and halt enrollment of new subjects in ongoing trials. The impact was not insignificant, as Coast's work extended to approximately 300 studies involving 3,000 investigators throughout the U.S. The ultimate consequence for Coast: it was forced to "cease future company operations."
Patient safety and research integrity will continue to form the basis for the ethical and professional conduct of clinical trials - whether for drugs or devices. For firms and individuals involved in clinical trial research for drugs, the new PhRMA code on conducting clinical trials will be the industry standard against which they will be judged. Familiarity with and adherence to the new code will go far to ensuring that the Coast experience is not repeated.