Disclosure of financial arrangements between a clinical investigator and study sponsor will lead to a more stringent product review at FDA, Office of Drug Evaluation I Associate Director-Regulatory Affairs Linda Carter told the Food & Drug Law Institute.

If a reviewer notes that an investigator has a financial interest in a sponsoring company or the product under study, "the reviewer is to first of all address the financial information in his review," Carter said June 5.

The reviewer will take the information into account by examining "the number of subjects the investigator is studying [and] whether or not there were any outliers as far as reporting of adverse reactions," Carter said. "If they note anything like that, they would initiate audits of the data by communicating with the Division of Scientific Investigations."

DSI "might request that the data be analyzed further," Carter said. "They may request additional independent studies to confirm the results of the questioned study, or refuse to treat the covered clinical study as pivotal."

Reviewers and project managers have attended training sessions on FDA's financial disclosure policies. Additional training will be offered on the agency's intranet.

FDA published a draft guidance on financial disclosure in October, which elaborated on a February 1998 final rule (¹ Also see "Investigator/CRO Financial Disclosure Required By FDA; Feb. Rule Expanded" - Pink Sheet, 1 November, 1999.).

The final guidance is due out shortly. FDA also has a financial disclosure Manual for Policy and Procedures drafted, but does not plan to issue it until the guidance is finalized. The MaPP will give direction to reviewers on how to take financial information into account.

For outstanding questions on financial disclosure, FDA's Office of Medical Policy and the Office of Drug Evaluation I will "handle consult requests from reviewers and project managers, and also queries from industry," Carter said.

FDA's financial disclosure final rule, which became effective Feb. 2, 1999, requires sponsors to provide information on investigator compensation, equity interest and other payments. The October 1999 draft guidance added that investigators also have to disclose financial arrangements with contract research organizations that are acting as primary or joint sponsors of the study.

Since the rule went into effect in February 1999, DSI has been alerted to an investigator's financial interest prior to the division's scheduled inspection of several trials. FDA has not yet refused to accept a study as pivotal due to a financial tie.

Although the financial disclosure rule requires investigators to provide information on financial interests throughout the course of the study and for one year after the study is completed, FDA has not specified when it considers a study "completed."

The agency plans to clarify the definition of study completion in its final guidance, FDA Office of International and Constituent Relations Senior Policy Analyst Mary Gross told FDLI. FDA will consider a study "completed" when "all study subjects have been enrolled and followup with primary endpoint data on all subjects has been completed."

If a company does not provide the required financial disclosure information, FDA can refuse to file the application. "We haven't refused to file anything yet," Carter noted. "We've really tried to work with sponsors to help them get their information in."

Carter said that in a recent review of 129 applications received between Feb. 2, 1999 and April 30, 2000, 33 applications included financial disclosure information on one or more investigators.

Four of the applications did not include any reference to the financial disclosure regulations, and the remaining applications addressed financial disclosure in a variety of other ways, such as asserting that the studies included in the application were not "covered" studies so reporting was not required.

The agency has been flexible in situations where companies have not been able to collect information despite their best efforts, Carter said.

Some "firms have had some problems" collecting the information from investigators, but have made an effort to "show due diligence," Carter said. "Some firms have sent out [a request] three times [by] registered mail," but were not able to obtain the information. "But if they tell us what they did and show us that they tried with due diligence to get it, well, that's OK."

The Pharmaceutical Research & Manufacturers of America recommended in June 1999 that FDA should consider a sponsor to have made a reasonable effort if the sponsor can demonstrate that a request was sent and received by the investigator and the sponsor received no response after three months (² Also see "Clinical Investigator Financial Interest Inquiries May Be Costly For Industry" - Pink Sheet, 5 July, 1999.).

PhRMA also suggested, in comments on the draft guidance, that publicly funded studies be exempt from financial disclosure requirements. Although companies lending modest support to public studies do have a commercial interest, the firms' lack of control over trial operations obviate the need for disclosure, PhRMA maintained (³ Also see "Financial Disclosure Reg Should Exempt Publicly-Sponsored Studies - PhRMA" - Pink Sheet, 31 January, 2000.).

Gross pointed to "the definition of sponsor of a covered study and how that definition impacts on publicly funded studies" as a major issue to look for in the final guidance.

The collection of financial interest information between investigators and "multilayered conglomerate drug companies" was also highlighted by Gross as an area that will be addressed in the final guidance.

"Financial information about investigator financial interests in CROs" will be another area of particular interest in the final guidance, Gross said.

Although the draft guidance specifies that investigators have to disclose financial arrangements with CROs that are acting as primary or joint sponsors of the study, it does not require investigators to disclose financial ties with CROs in cases where the CRO is not a sponsor but still has a financial interest in the study. FDA plans to address this issue in the final guidance.

The May 18 issue of the New England Journal of Medicine examined the increasing trend of investigator/sponsor financial ties and potential conflicts of interests (⁴ Also see "CRO Role In Clinical Trial Research Questioned By NEJM Article" - Pink Sheet, 29 May, 2000.).

Industry use of CROs to conduct trials was highlighted as a matter of particular concern because the CROs have an interest their clients being successful.

In a separate presentation at FDLI, CDER Director Janet Woodcock, MD, said there was increasing public concern about the "biomedical-industrial complex," and noted increasing public perception of conflicts of interest that may affect public health (⁵ [A#00620240006]).

Investigator/Firm Financial Ties May Trigger Heavier Scrutiny Of Data By FDA

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