Alex Philippidis Senior News Editor Genetic Engineering & Biotechnology News

Agency’s draft guidance should be coupled with HHS’ proposals from last year, which are still being reviewed.

Almost two decades after it first took aim at conflicts of interest among researchers connected to institutions and/or companies, the FDA is looking to clarify what it expects from investigators. It issued a new draft guidance, and the two-month public comment period ends this week.

The agency’s 29-page “Guidance for Clinical Investigators, Industry, and FDA Staff: Financial Disclosure by Clinical Investigators” was developed to update current FDA regulations, which were issued back in 2001. That was before drug companies and research centers, both academic and private, took the topic seriously enough to develop their own policies.

The current proposals, issued in May, are designed to change the thinking of both healthcare providers and industry such that conflict of interest is less a matter of administrative gesture and more an issue of creating a substantive process for evaluating, then addressing, conflicts of interest, Jennifer S. Geetter, a partner in the Washington, D.C., office of the law firm McDermott Will & Emery, told GEN.

“The FDA Guidance and regulations on this topic should be seen as a floor and not a ceiling,” remarked Geetter. “Once upon a time you would see forms that would say to a doctor, ‘Please disclose any conflicts of interest.’ “Now, the best practice would be, ‘These are the types of financial interests that if you have, you’ll have to disclose. We’ll decide if they’re conflicts of interest, and how they can be managed.’ That’s a more robust, more deliberate process.”

Changes from FDA’s 2001 Guidance

One key difference in the new draft guidance is a clarification of the term “clinical investigator.” After a study found that most institutions took the term to mean principal or lead investigator, the FDA added broader language defining a clinical investigator as “an investigator or subinvestigator who is directly involved in the treatment or evaluation of research subjects” and who generally is considered to be “taking responsibility for the study at a given study site.”

The definition also includes the spouse and each dependent child of such an investigator or subinvestigator. “Hospital staff including nurses, residents, fellows, and office staff who provide ancillary or intermittent care but who do not make direct and significant contribution to the data are not meant to be included under the definition of clinical investigator,” the draft guidance stated.

FDA revised what it considers “due diligence” by defining it as collecting information about financial arrangements. “FDA expects that applicants will typically be able to obtain the required information because IND/IDE sponsors are responsible for obtaining financial disclosure information from clinical investigators prior to allowing them to participate in a clinical study.” FDA also adds that applicants must exercise due diligence “whether a covered study is conducted at foreign or domestic sites.”

Another difference from the 2001 guidance: FDA spells out the factors it may consider in mitigating any action against a clinical study involving a researcher found to have a conflict:

  • whether multiple investigators were used (most of whom have no disclosable financial interests)
  •  the total number of investigators and subjects in the study
  • the number and percentage of subjects enrolled by the disclosing investigator
  • information obtained from on-site inspections
  • the method of randomization
  • the design and endpoints of the clinical study
  • whether someone other than the disclosing investigator measured the endpoints
  • the results of the investigator compared to the results of co-investigators.

“Reviewers might also compare results from more than one investigator, re-analyze the data excluding the investigator’s results, analyzing the data in multiple ways and/or determining if results can be replicated over multiple studies,” FDA stated.

Financial Terms Compared to HHS’ Proposal

FDA’s draft guidance comes more than a year after the U.S. Department of Health and Human Services (HHS) proposed its own regulations on managing conflicts of interest for researchers receiving funding from the U.S. Public Health Service (PHS). NIH’s Office of Extramural Research told GEN the new PHS rules remain under consideration by the Office of Management and Budget.

In many cases HHS’ proposed regulations exceed FDA’s current draft guidance and 2001 guidance, and HHS is about to get even tighter. For example, HHS would lower the minimum threshold for disclosure from $10,000 to $5,000 and apply it to “payments and/or equity interests,” instead of “payments or equity interests.” Unlike current rules, any equity interest in a privately held entity would have to be disclosed.

FDA’s draft guidance, by contrast, requires disclosure of:

  • Compensation made to the investigator by any sponsor of the covered clinical study in which the value of compensation could be affected by study outcome.
  • A proprietary interest in the tested product including, but not limited to, a patent, trademark, copyright, or licensing agreement.

Also required to be disclosed, both during the study period and up to one year after:

  • Any equity interest in any sponsor of the covered clinical study, i.e., any ownership interest, stock options, or other financial interest whose value cannot be readily determined through reference to public prices.
  • Any equity interest in any sponsor of the study if the sponsor is a public company and the interest exceeds $50,000 in value.
  • “Significant payments of other sorts” with a cumulative monetary value of $25,000 or more made by any sponsor to the investigator or the investigator’s institution. These support activities of the investigator outside the costs of conducting the study or other clinical studies or provide additional reimbursement such as retainers for ongoing consultation or honoraria.

Significantly, FDA’s list of required disclosures under the draft guidance has not changed too much from the 2001 guidance. But the draft makes some changes, for example, the 2001 guidance required disclosure of “any equity interest in a publicly held company that exceeds $50,000 in value” compared with any public companies that sponsor a covered study.

As with current rules, exempt from disclosure are “income from seminars, lectures, or teaching.” HHS’ guidance changes what kind of entities can convene advisory committees or review panels where service is exempt from disclosure from “public or nonprofit entities” to “government agencies or institutions of higher learning.”

HHS’ proposal requires investigators to disclose “significant” financial interests related to their “institutional responsibilities,” with their institutions to determine whether those interests relate to any PHS-funded research. Current rules limit disclosure to significant financial interests related to PHS-funded research only. The new plan would include travel reimbursements within the definition of significant financial interests, a change from current policy.

History of HHS and FDA’s Involvement in Regulating Conflict of Interests

FDA began seeking disclosure of conflicts of interest years after a management advisory report by the inspector general of the U.S. Department of Health and Human Services in 1991 faulted agency’s failure to collect such information from clinical investigators who study products undergoing review. The first conflict rules were proposed in 1994.

Since 1999, FDA has required information on the compensation and financial interests of any clinical investigator conducting studies connected with marketing applications of any drug, biological product, or device. The rule applies to marketing applications and any study where a single investigator “makes a significant contribution to” the demonstration of safety. Soon after, FDA amended its rule to reduce the data required for studies completed before February 2, 1999.

Drawing Final Rules

HHS’ proposed rules have drawn some criticism from a group representing the nation’s medical schools and teaching hospitals and health systems. The Association of Academic Medical Centers (AAMC) last year was one of four groups to sign a joint letter urging HHS to roll back several provisions of its proposed conflict-of-interest rules, including:

  • Effective date: The group wants the new rules phased in through October 1, 2013; the proposal doesn’t address the implementation period.
  • Reporting period: The group supports an annual reporting rule but wants more flexibility for institutions on how they define their year, rather than basing it on PHS grant agency award dates as HHS proposes.
  • Training: The group supports only initial training of investigators in financial conflict of interest management; HHS would also require retraining every two years. No training requirement now exists.
  • Subrecipients: HHS would require PHS grantees to detail via “legally enforceable terms” whose conflict policies apply to researchers from “subrecipients,” defined as a subgrantee, contractor, or collaborator. The groups instead want subrecipients to certify to grantees that their conflict policies conform to federal regulations, unless subs are also main grantees of any PHS agency, in which case they would be exempted.
  • “Low-risk” grant exemption: The groups suggested HHS explore an exemption to the conflict rules for “low-risk” equipment, construction, and training grants.

“There is a paucity of evidence that the disclosure and management of financial conflicts of interest affect objectivity and integrity. In the absence of such evidence, onerous regulations are not only unwarranted but could create a glut of policies that increase activity without adding protections and at the same time erode the trust between the regulators and those being regulated,” according to the letter.

The AAMC was joined by the Association of American Universities, the American Council on Education, and the Association of Public and Land-grant Universities.

As for FDA’s latest draft guidance, AAMC has taken a more supportive stance, noting that the agency hasn’t so much changed its original decade-old rules as it has clarified them. “I don’t know that the new guidance will affect the conduct of research,” Heather H. Pierce, AAMC’s senior director, science policy and regulatory counsel, told GEN.

The presence of separate FDA and HHS conflict rules presents an opportunity. The agencies can, and should, combine both sets of regulations into a single conflict of interest standard that offers even more clarity about what information researchers have to disclose to regulatory agencies and what information they can withhold.

The fewer sets of rules investigators and their institutions and partners must master, the easier it will be for all to deliver the transparency the agencies and the broader community understandably seek.

Alex Philippidis is senior news editor at Genetic Engineering & Biotechnology News.

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