Clinical Trial Disclosure Legislation Likely To Await PhRMA, AMA Discussions

The next step in the push to create a national database of clinical trial results is likely to be discussion among stakeholders rather than legislation.

During a Sept. 9 House Energy & Commerce/Oversight Subcommittee hearing on disclosure of pediatric antidepressant data, representatives from the American Medical Association, the American Academy of Pediatrics, and the pharmaceutical industry all agreed that the issues surrounding data disclosure and trial registries require further discussions.

At the hearing, Reps. Henry Waxman (D-Calif.) and Edward Markey (D-Mass.) announced plans to introduce legislation expanding ClinicalTrials.gov into a registry of all clinical trials and results.

The Republican leadership of the committee, however, signaled a clear interest in focusing on FDA's conduct as the next step in the committee's investigation without offering any opinions on legislation to mandate trial registration.

Committee Chair Joe Barton (R-Texas) opened the hearing by introducing the topic, declaring his interest in learning why 12 of the 15 pediatric studies of antidepressants were never published.

However, the rest of his opening statement focused on criticism of FDA for its "lack of cooperation with the committee in obtaining relevant and responsive information."

"Unfortunately, over the last several months, the committee has been met mostly with stonewalling, slow-rolling and plain incompetency from the FDA," Barton asserted.

That theme is likely to be picked up during the committee's next hearing, on Sept. 23, which is entitled "FDA's Role in Protecting the Public Health: Examining FDA's Review of Safety & Efficacy Concerns in Anti-Depressant Use by Children."

[Editor's Note: Further coverage of the FDA regulatory issues discussed during the hearing appears in ¹ "The Pink Sheet" DAILY . Visit our website, www.ThePinkSheetDAILY.com, to sign up for a free trial, or call customer service at 800-332-2181.]

From the point of view of the Pharmaceutical Research & Manufacturers of America, the tone of the hearing can be interpreted as a sign that industry's movement on clinical trial registration is paying off.

The Sept. 9 hearing was planned for July 20, but it was postponed when former Oversight Subcommittee Chair Jim Greenwood (R-Penn.) decided to accept an offer to serve as the next head of the Biotechnology Industry Organization (² (Also see "Antidepressant Investigations Continue; GAO Studying FDA Process" - Pink Sheet, 26 Jul, 2004.), p. 5).

The pharmaceutical industry appears to have made strides in taking the edge off of criticisms of trial disclosure practices in the time since the hearing was originally scheduled.

The industry's position appears to have been helped by unilateral decisions by companies to create registries, and PhRMA announced plans for an industry-initiated clinical trials results registry Sept. 7.

In addition, GlaxoSmithKline and Forest have resolved formal investigations initiated by New York Attorney General Eliot Spitzer by committing to clinical trial posting.

The industry also appears to be improving its compliance with the requirement to post trials on the federal ClinicalTrials.gov website. FDA Acting Deputy Commissioner for Operations Janet Woodcock noted that non-federal sponsors listed 80 new trials in August, twice the average monthly listing for 2003.

Perhaps most importantly, PhRMA appears to have initiated a productive dialogue with AMA on the topic.

The current push for a standard clinical trial registry grew out of AMA's formal call for HHS to establish a comprehensive national registry of all clinical trials during its annual meeting in June (³ (Also see "HHS Registry Of Clinical Trials Proposed By AMA To Limit Publication Bias" - Pink Sheet, 21 Jun, 2004.), p. 6).

During the Sept. 9 hearing, AMA fleshed out its proposal, but repeatedly emphasized the need for further discussion before requirements are finalized.

AMA recommends that a comprehensive registry should include Phase II, III, and IV trials "conducted in support of new drug, biologic, or device applications," along with investigator-initiated and federally funded randomized controlled trials, and "pharmacoepidemiologic studies designed to test a hypothesis."

The registry should include a unique trial identifier, contact information for the principal investigator and the name of the trial sponsor and any funding sources. Trial details should describe the trial type, purpose, methodology, location, dates, disease, eligibility criteria, and title.

AMA would enforce the registry by making listing of trials a requirement for IRB approval.

However, AMA agrees with manufacturers that there is a need for further discussions about the best way to balance "access to information to more effectively translate clinical research into medical practice" and "the need to protect pharmaceutical manufacturers' proprietary information."

A group of journal editors (including the Journal of the American Medical Association) intends to make trial registration a pre-condition of publication; the editors explicitly rejected industry's concerns about protecting trade secrets (see ⁴ ).

Another area for further discussion, AMA said, is how to validate data that has not been peer-reviewed.

"We recognize that there are inherent risks in publishing data that has not been validated or peer-reviewed in one way or another," AMA said.

"The question of what would comprise validated results (other than the raw data) for studies that have not been published in the peer-reviewed literature or as part of an NDA needs broader discussion."

The American Academy of Pediatrics also believes it is vital to discuss issues involved in posting non-published studies.

"There are considerable concerns that non-published studies which have not undergone peer review (or for that matter, any review) may be included in a database that will be easily accessible by the general population and will contain insufficient information by which to judge a study's validity," AAP said.

"There is little to prevent a company or individual from posting 'results' of their independent research that demonstrates the benefit of a completely non-efficacious or potentially harmful intervention (with claims based on seriously flawed research)."

AAP also stressed the importance of considering disclosure issues beyond the narrow focus of pediatric antidepressant data, and even beyond the scope of all pharmaceutical research. "The same concerns apply to clinical trials focused on other non-pharmacological therapies."

However, AAP added, "for practical reasons" it makes sense to focus on pharmaceutical trials first.

"We anticipate that the effort required to develop a safe and effective clinical drug trial registry will be extensive and therefore recommend that the focus, at least initially, be on clinical drug trials."

"The success (and challenges) of this registry can inform the later development of comparable efforts to promote broader access to clinical trails of non-pharmacological interventions."

Although Reps. Waxman and Markey are ready to move forward with legislation, another Democrat on the committee, Rep. Bart Stupak (D-Mich.), focused on ensuring that consumer advocates are included in the stakeholder discussions.

After Pfizer VP Cathryn Clary said that the company supports a broad discussion among stakeholders on clinical trial disclosure issues, Stupak asked if the public would "have a chance to come to your meetings."

"We would welcome that," Clary responded. "We would welcome the organizations that deal with people who have depression and other mental health problems."

"How about Public Citizen?" Stupak asked. "I certainly think that they are a voice in this debate," Clary replied.

As a practical matter, the deadline for discussions among stakeholders is likely to be the reauthorization cycle for the pediatric exclusivity program, which coincide with the user fee reauthorization cycle in 2007.

Waxman argued that the experience with antidepressant data suggests that the standards for six-month pediatric exclusivity extensions should be higher.