The US Food and Drug Administration needs to step up its efforts to ensure that clinical trial sponsors are properly disclosing investigators’ financial interests and minimise any potential conflicts of interest, says a report from the Department of Health and Human Services’ Office of Inspector General (OIG).
As the OIG noted in its report on The Food and Drug Administration’s Oversight of Clinical Investigators’ Financial Information, sponsors have to collect financial information from investigators before clinical trials get underway. However, the sponsors file this information with the FDA only when they submit a marketing application at the end of the trial programme.
A financial form is included for each clinical investigator used, either certifying that the investigator has no financial interest in the trial or disclosing the financial interest. For each disclosed financial interest, sponsors must attach details of the interest and a record of the actions taken to minimise potential bias in the study results. Federal regulations also allow sponsors to indicate that they have acted with due diligence but were unable to obtain financial information from a clinical investigator, the OIG observed.
The FDA then assigns the marketing application to a multidisciplinary team of reviewers, part of whose job is to evaluate financial information as well as the measures taken by sponsors to minimise any potential bias. If reviewers suspect that any disclosed financial interests have compromised data integrity, the OIG report pointed out, “they are required to take action to ensure the reliability of the data”.
OIG researchers reviewed financial forms, attachments and accompanying FDA review notes for all 118 marketing applications approved by the agency in fiscal year 2007. They found that only 1% of the clinical investigators listed in financial forms (206 of 29,691 investigators listed) disclosed at least one financial interest, with almost all of these investigators disclosing only one interest.
The report also concluded that the FDA could not determine whether sponsors had submitted complete financial information for all clinical investigators, since the agency did not have a complete list of clinical investigators. Nor did the agency use on-site inspections to confirm that submitted financial information was complete.
In addition, the OIG discovered that 42% of the FDA-approved marketing applications were missing financial information. More specifically, 23% of the applications lacked a certification or disclosure form or the required attachments. In 28% of cases, sponsors had used the due diligence exemption to indicate they were unable to provide complete financial information. With some marketing applications, there were attachments missing and the due diligence exemption was marked.
Moreover, the FDA did not document a review of any financial information for
31% of the approved marketing applications. Agency teams were more likely to document a review of financial information when they used a review template, the OIG noted.
With 20% of marketing applications where there were disclosed financial interests, FDA reviewers did not take any action and sponsors did not indicate that they had minimised potential bias during the clinical trials, the OIG reported. For over half of these marketing applications, reviewers did not document a review of financial information. And when the FDA did take action, these actions were inconsistent, the OIG said.
OIG recommendations
In response these findings, the OIG made three core recommendations:
– The FDA should ensure that all sponsors submit complete financial information for all clinical investigators – for example, by checking that sponsors include all of the required attachments with financial forms, and by updating guidance to sponsors on the due diligence exemption.
– The agency should ensure that reviewers assess financial information consistently and take action in response to disclosed financial interests – for example, by requiring that all FDA centres consistently use a template with a prompt to document a review of financial information.
– The FDA should require sponsors to submit financial information on clinical investigators as part of the pre-trial application process.
The agency agreed with all but the last recommendation, the OIG said. The FDA stressed that collecting financial information before a clinical trial started was the responsibility of the sponsor – even, though, as the OIG pointed out, “FDA has no mechanism in place to ensure that sponsors are in fact collecting financial information before beginning clinical trials”.
The agency also argued that collecting and reviewing financial information during the pre-trial application process would entail substantial additional effort on the part of both industry and the FDA. However, the OIG report added, “pursuant to regulation, FDA already requires sponsors to collect financial information before the start of clinical trials. In addition, basic information on clinical investigators is submitted to FDA as they are added to clinical trials”.
The agency further asserted that the additional effort involved “would not be worthwhile because financial interests are only one form of potential bias and not all clinical trials are presented in the marketing application”, the OIG reported. Yet gathering financial information during the pretrial application process “would allow FDA to have information on all potential sources of financial bias. FDA could then work effectively with sponsors to identify potential bias”.
Not only that, the OIG commented, but “receiving financial information related to ongoing clinical trials is in keeping with FDA’s stated intention to improve its oversight of ongoing clinical trials”.
