On February 9, 2009, the National Library of Medicine Board of Regents Working Group on Clinical Trials met to discuss and evaluate the progress made to date in implementing the clinical trial registration and results requirements imposed by the Food and Drug Administration Amendments Act (FDAAA).1 This meeting was primarily intended to allow those at the National Institutes of Health (NIH) charged with the day-to-day task of managing the federal database at ClinicalTrials.gov to report on their successes and various challenges, and begin brainstorming with the Working Group as to how best to proceed with their legal mandate.
At last week’s meeting, NIH representatives also announced that they have scheduled the public meeting required by FDAAA to gather input from interested parties regarding the expansion of the ClinicalTrials.gov results database through new regulations. This stakeholder meeting will take place on April 20, 2009, at the Lister Hill National Center for Biomedical Communications in Bethesda, MD. NIH will soon publish a notice in the Federal Register confirming the date, as well as the proposed agenda. Updated information is also likely to be posted on ClinicalTrials.gov’s FDAAA Web site.
Because there are a number significant details about the expanded results database that are under consideration at this time, the upcoming stakeholder meeting will provide an excellent opportunity for pharmaceutical and biotechnology companies to provide feedback to NIH as it engages in the task of drafting the required regulations. Interested parties are invited to provide oral comments at the meeting, but because both time and space will be limited, companies should also consider submission of written comments.
Although FDAAA’s “basic results” requirements became effective in September 2008,2 the law also directs NIH to expand the results database by rulemaking mandated to occur not later than September 2010.3 At a minimum, this expansion will require that sponsors (or other responsible parties) submit lay and technical summaries of their trials and results, if they can be included on ClinicalTrials.gov without being misleading or promotional, as well as the full trial protocol and other information that NIH deems appropriate.
NIH is also directed to determine whether to mandate results disclosure for unapproved products (which is not currently required under the law’s basic results provisions), whether to lengthen results submission deadlines from one year following trial completion to a period not to exceed 18 months, and how the expanded results requirements will apply to trials that have already complied with the basic results elements, among other things.
Key Issues Regarding Expanded Results Requirements
Although NIH is directed to consider an extensive list of topics when promulgating the required regulations, comments during the February 9 Working Group meeting suggest that NIH may be inclined to focus significant attention on the following:
- Enhancement of Patient Access to and Understanding of Clinical Trial Results. On several occasions, the Working Group came back to the question of who ClinicalTrials.gov is for – who is the intended audience? Recognizing that the database should have some utility for the lay public, as opposed to medical professionals and scientists alone, the Working Group expressed concern that the average patient may have difficulty understanding the posted results information and its relevance, particularly with regard to adverse events. Accordingly, NIH is considering the inclusion of explanatory background information in order to provide some context for individual trials, such as basic user guides on statistics and scientific terminology. NIH is also considering the possibility of going further, potentially offering users a systematic review of trial information. It is unclear, however, whether this would take the form of simple links to related postings on ClinicalTrials.gov, or whether it would involve some sort of narrative analysis integrating those postings. If the latter, it is also unclear who would be responsible for that analysis, as well as its accuracy and balance.
- Quality Control of ClinicalTrials.Gov Submissions. Although NIH expressed some relief that submissions to the federal database have improved as responsible parties have gained experience with the system and NIH expectations, another major source of concern at the Working Group meeting was the extent to which the responsibility for Quality Control should rest with NIH or with trial sponsors. At this time, NIH often engages in several rounds of review and interactions with sponsors to ensure that the information submitted is complete, logical, and understandable before it is posted for public viewing.4 This approach may result in better information on ClinicalTrials.gov, but the Working Group recognized the enormous resource strain of this model. It therefore discussed the possibility of migrating towards a system in which sponsors are given fewer chances to get things right, and are instead held responsible for noncompliance when they submit incomplete or incomprehensible information. Regardless of any quality review by NIH, it is important to remember that FDAAA made it a prohibited act for a responsible party to submit clinical trial information that is false or misleading. Similarly, Maine regulations hold manufacturers responsible for posting information that is reliable, accurate, and true.
- Other Issues. NIH also explained that although users can currently view how trial entries have changed over time, the interface for accessing archived information on ClinicalTrials.gov is somewhat cumbersome. The Working Group discussed possible opportunities for resolving that issue, but sponsors should realize that the information submitted to the federal database can only be modified – not deleted – once posted. Finally, NIH addressed the ambiguity regarding the types of circumstances that could be eligible for good cause extension of applicable results submissions deadlines. One example that it has already expressed a willingness to accept is a scenario in which a trial has reached its completion date based on primary endpoints, but remains ongoing and blinded for purposes of secondary endpoints. NIH will not accept delay of results submission for purposes of publication in a medical journal, but seeks input regarding delay caused by the need for additional data analysis and other possible grounds for good cause extensions.
NIH has accomplished a great deal since the first round of expansion of ClinicalTrials.gov was mandated by FDAAA, and it continues to make strong progress towards fully implementing the law. However, there are many open issues to be resolved in the upcoming rulemaking that may have a serious impact on trial sponsors and other responsible parties. NIH has been extremely receptive to concerns raised by the affected industry thus far, and has expressed significant interest in obtaining additional feedback at the April 20, 2009, public meeting.