The reporting obligations would be added to several FDA regulations, including those directing Good Laboratory Practice for Nonclinical Laboratory Studies (21 C.F.R. § 58), Color Additive Petitions (21 C.F.R. § 71), Petitions for Nutrient Content Claims and Petitions for Health Claims (21 C.F.R. § 101), Information in a Premarket Notification for a Food Contact Substance (21 C.F.R. § 170), Food Additive Petitions (21 C.F.R. § 171), Dietary Supplements (21 C.F.R. § 190), Investigational New Drug Applications (21 C.F.R. § 312), New Animal Drugs for Investigational Use (21 C.F.R. § 511), Food Additive Petitions (21 C.F.R. § 571), and Investigational Device Exemptions (21 C.F.R. § 812).
The seeds for the proposed regulation were planted in the 1990's when FDA became aware of several flagrant acts of data falsification by clinical investigators. By way of example, a set of falsified data in one case was cited in 91 applications submitted by 47 different sponsors. FDA subsequently conducted meetings and participated in congressional hearings to investigate why such a widespread practice went unreported to FDA, and reviewed the existing requirements for reporting noncompliant investigators. FDA also obtained the opinion of an industry trade group and established an internal working group to contemplate the issue. The working group identified several areas of ambiguity in the current regulations, which FDA hopes to address with the proposed regulations. The areas of ambiguity included the extent to which possible falsification of data had been reported to FDA, the amount and type of information that sponsors must report when a study or investigator's participation in a study has terminated, whose falsification of data must be reported, and the timing of reporting.
FDA is proposing new regulations to address the identified ambiguities, making it clear that promptly reporting is a sponsor's legally mandated duty. FDA feels the reporting of data falsification is an appropriate burden to place on sponsors, because sponsors are responsible for the integrity of their study data in the first place, and they are in a better position to become aware of possible fraud through their required monitoring, auditing, and reviewing of applicable data. FDA does not envision any other monitoring responsibilities above and beyond those enumerated in the proposed regulations. In addition to allowing the FDA to identify persons who falsify data and effectively address issues in a more timely fashion, the proposed regulations would also allow FDA the opportunity to collect and assess submitted information to identify patterns, potential signals, or other indicators of misconduct that may trigger further investigations. Although other regulations address research misconduct, FDA believes these regulations do not cover the scope of research FDA evaluates satisfactorily, and hence more specific regulations are required.
By way of example, the proposed rule for investigational new drug applications currently provides, "When a sponsor becomes aware of information indicating that any person has, or may have, engaged in the falsification of data in the course of reporting study results, or in the course of proposing, designing, performing, recording, supervising, or reviewing studies conducted by or on behalf of a sponsor or relied on by a sponsor involving studies subject to this part, the sponsor must report this information to the Center for Drug Evaluation and Research (Center). A sponsor must report this information regardless of whether the sponsor has evidence as to the intent of the person who has, or may have, falsified data. The sponsor must report this information to the Center promptly, but no later than 45 calendar days after the sponsor becomes aware of the information."
In the proposed regulations, the term "sponsor" would encompass petitioners submitting food or color additive, nutrient content claims, health claim petitions, manufacturers or distributors submitting new dietary ingredient notifications, and sponsors as defined in the non-clinical laboratory studies, new drug applications, new animal drugs, and investigational devices regulations. A sponsor would be responsible for reporting falsification of data that it became aware of before or after the study, as well as during the review, approval, or authorization of the relevant product or labeling.
For the purposes of the regulations, "data" would include, but not be limited to, "individual facts, tests, specimens, items of information, or statements made by individuals." The fact that the regulations encompass not only data from studies conducted by or on behalf of a sponsor, but also data relied on by a sponsor, means that any data cited in a petition, new dietary ingredient notification, or application to FDA in support of any claim, product marketing, or regulatory action, is covered by the reporting obligation.
"Falsification of data" means the "creating altering, recording, or omitting" of data in a way that the data do not signify what actually occurred during the study. FDA is concerned about data covering clinical investigations, nonclinical laboratory studies, and clinical animal studies. Examples of such falsification include, but are not limited to, creating fake data, altering data, recording data from a source that is not accurately portrayed, or omitting appropriate data. Even though there are several common types of falsification of data that FDA is envisioning being reported, sponsors do not have to categorize the type of falsification they believe is occurring in their report. The person who falsifies the data can be any person responsible for conducting the study, their colleagues, or their subordinates. FDA is specifically excluding errors (such as typographical and transposed numbers) from the reporting requirement because FDA believes that errors are easier to catch and address by FDA, while falsification has a greater negative impact than errors because of its likelihood to be repeated, and FDA does not wish to "overwhelm" itself with information.
Sponsors are encouraged to be aware of possible instances of falsification of data through the monitoring of their studies, reviewing and evaluating the data therein, and receiving complaints. Reports of data from sponsors to the proper FDA center would be required not only for data that is confirmed to be falsified, but also data that is possibly falsified. Evidence of the falsification is not necessary, and there is no specified threshold that will trigger the reporting requirement. The data would be reported to the "appropriate" FDA center. If the investigation involves a combination product, then the information should be reported to the center with primary jurisdiction over premarket review and regulation. The report to FDA should include the name of the person who has, or may have, falsified the data, the last know address(es) and phone number(s) of the person, the specific study which is possibly affected, and the information that suggests or describes falsification. This information may be reported in any fashion, such as phone, mail, e-mail, or fax.
Once FDA is made aware of the falsification or possible falsification of data, it aspires to "identify patterns, potential signals, or other indications of misconduct" so that it can determine whether a further investigation is necessary in light of aggregated reports from any source. FDA encourages, therefore, that sponsors not wait to report to FDA while investigating whether falsification actually occurred, or under what circumstances it happened. FDA requests that falsification be reported "as soon as possible," but within 45 days, to give FDA as much data to cull from as is available when conducting its investigation. Indeed, the failure of a sponsor to report falsification, or possible falsification, of data may violate the Federal Food, Drug, and Cosmetic Act or other Federal rules that address the submission of a false statement to the Federal government. Any investigations into the matter by FDA may lead to administrative or enforcement actions including excluding falsified data from consideration, putting an entire trial on hold, disqualifying investigators, and/or criminal proceedings.
In addition to general feedback and comments, FDA is requesting comments on specific aspects of the proposed rule by May 20, 2010. In particular, FDA is soliciting feedback from industry and the public on: