ClinicalTrials.gov Requirements Continue To Baffle Firms And Feds Alike
Full article reprinted from "The Gray Sheet" - June 23, 2008
Device companies are not the only ones tripped up by the new ClinicalTrials.gov trial registration requirements, as FDA, NIH and others struggle to define what is and is not subject to the law.
The source of the confusion: Title VIII of the FDA Amendments Act, enacted last September. This section of the 2007 law requires that certain drug and device trials be registered with the National Institutes of Health's ClinicalTrials.gov, include certain data elements in the listing and eventually include trial outcomes in a results database (1"The Gray Sheet" Nov. 19, 2007, p. 8).
Registration of trials for some drug treatments has been required on the public database since 1997. Since 2004, trials were required to register in the public database in order to be published in an International Committee of Medical Journal Editors journal.
But implementing Title VIII and expanding the database is proving harder than expected, according to Theresa Toigo, director of FDA's office of special health issues. Toigo's office helps develop and evaluate FDA policies related to patients and health care professionals.
Congress "sort of" specified in the law which trials should be registered, but "the devil is in the details with these definitions," Toigo said during a June 17 webinar hosted by the Food and Drug Law Institute.
What's Applicable, Who's Responsible?
All "applicable" drug and device trials must be registered on the NIH clinical trials portal by the trial sponsor or another designated "responsible party" - the principle investigator, for example. Broadly, applicable trials include prospective, controlled clinical trials involving FDA approved or cleared devices, pivotal trials conducted to gain FDA approval or clearance, and pediatric post-market surveillance studies, the law states.
NIH may not make medical device trial information public until the product is approved or cleared.
Months after the regulation went into effect, FDA is fielding questions from industry, academia, and regulatory and legal professionals about whether specific trials are applicable, who qualifies as the responsible party and how to handle trials for devices that are never approved (2"The Gray Sheet" Dec. 3, 2007, p. 16).
"We are in the process of developing interpretations of those [terms and questions] to provide more guidance to the affected communities," Jerry Sheehan, assistant director for policy development at NIH's National Library of Medicine, said during the FDLI meeting.
For example, FDA needs "to further define who the 'responsible party' is in the context of a trial being conducted under an IND [investigational new drug application] or IDE [investigational device exemption] and for those not being conducted under an IND or IDE," Toigo says.
"The law is complicated. It's an evolutionary process," she said. "We don't have all the answers."
Specific questions can be emailed to 3[email protected], Toigo noted.
The registration requirement went into effect Dec. 26 for studies of serious or life-threatening conditions, and kicks in for the other ongoing applicable trials by Sept. 27, 2008.
Clinical trial registrations jumped from 250 per week to 440 per week from Dec. 13 to Jan. 12, 2008, and they have steadily risen since then, according to NIH. Universities and other research centers are the largest data provider, while 30% of submissions come from industry.
About 18% of new entries are missing information about clinical study arms and 13% are missing responsible party information, which is understandable given the confusion over who is the responsible party, Sheehan said.
Certification Form Confusion
The law also says a certification form must accompany PMA, 510(k) and humanitarian device exemption applications and submissions, as well as amendments, supplements or resubmissions.
Over the winter, FDA quickly created a form to accommodate this. Applicants are supposed to indicate on the form whether the ClinicalTrials.gov requirements apply to their submission. If so, they must certify that the requirements have been met and provide National Clinical Trial numbers for every applicable clinical trial that is "included, relied upon, or otherwise referred to, in the application/submission."
Besides helping to assure that the applicant complies with the law, FDA says these forms help FDA and NIH link information regarding regulatory actions to specific trials at ClinicalTrials.gov. Eventually, the ClinicalTrials.gov listings will also be able to link to reports, medical reviews, advisories, health alerts and other materials.
Initially, device trade group AdvaMed and member Johnson & Johnson questioned the need for the certification form (Form 3674) at all. AdvaMed said completing the new form would be more time-consuming than FDA anticipates.
"FDA could accomplish the same objectives ... by using CDRH cover sheet Form 3514 for PMA, HDE, PDP and 510(k) submissions," AdvaMed's Tara Federici wrote in May 5 comments to FDA.
The firms sought more guidance on what types of trials are applicable under the law, and what documents would require the certification form, which FDA attempted to address in draft guidance issued April 17 (4"The Gray Sheet" April 21, 2008, In Brief).
Certification is not necessary for investigational device exemption applications; meeting requests; 510(k)s that contain no clinical data; HDE and PMA 30-day notices; or adverse event and medical device reports, to name a few, the guidance states.
Industry, however, wants a more complete list.
Health care firm Baxter suggests FDA publish guidance explaining what documents do require a form, while AdvaMed suggests adding several items to the certification-exempt list, including IDE annual and supplemental reports, PMAs and PMA amendments with no clinical data, PMA annual reports with no clinical data beyond adverse events and CLIA-waived in vitro diagnostic petitions.
The trade group identifies specific trials that should not require certification, such as registry and single-arm studies, post-market consumer preference or usability studies, or observational IVD studies.
Comments on the draft guidance were due June 17, but FDA is urging stakeholders to continue submitting questions, concerns and suggestions to help them craft the final guidance - the sooner, the better.
The agency does not intend to change the certificate form, but hopes the final guidance will clarify things further, Toigo says. She could not give a timeline for issuing the final guidance, which is tied to final Office of Management and Budget approval of the certification form, but said it is definitely "getting attention."
Countdown To Results Database
Also by Sept. 27, NIH and FDA must set up a basic results database, in which responsible parties will be required to report trial results. Initially the database will include demographic and baseline characteristics, primary and secondary outcomes, a point of contact and certain agreements, such as restrictions on principle investigators to discuss or publish results after trial completion date.
Results must be entered within 12 months of the earlier of the estimated or actual trial completion date. For not-yet-approved devices, results are due within 30 days of initial approval or clearance.
"We're not at the point of having access to full datasets," Sheehan said. "We're looking for ways to summarize the results in a way that we can communicate them to a broad set of users, in the public, in the medical community and the research community."
Penalties for failing to register a trial or submit required data elements, submitting false or misleading information or failing to submit the certification form are strict, including civil money penalties of up to $10,000 per day.
FDA plans to devote its resources in the early stages of implementation to making sure stakeholders "achieve compliance," Toigo says. A public meeting will be held in March 2009 to review the status of the registry and database, and to discuss what should be included in new regulations expanding the registry and results database in September 2010, three years after FDAAA.
Additional information on the progress of the ClinicalTrials.gov initiative, including a mock-up of a results data entry system, is available at 5http://prsinfo.clinicaltrials.gov/fdaaa.html.
- Jessica Bylander
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