The Act
The Act expands the current clinical trial registry database and creates a new clinical trial results database. (President Bush signed the Food and Drug Administration Amendments Act of 2007 (P.L. 110-85) into law on Sept. 27, 2007. The law was effective on Oct. 1, 2007.) The FDA now has the authority to require holders of approved new drug applications to conduct post-approval clinical studies, modify labeling, and develop Risk Evaluation and Mitigation Strategies if the agency becomes aware of new safety issues. The Act requires that information regarding clinical trials, adverse drug experiences, and the drug review process be easily accessible to the public through the Internet.
FDAAA Provisions That Expand Information Availability
This article describes some of the FDAAA provisions related to the expansion of information disclosure and discusses the potential effect of the provisions on product liability exposure. Although the article focuses on the Act's provisions and implications related to drug products, it also describes the requirements for the posting of information related to certain clinical trials involving devices.
Clinical Trial Information
Under '801(a) of the FDAAA, study sponsors are required to register almost all clinical trials involving drugs, biologics, and devices at www.clinicaltrials.gov. The Act also requires the publication of clinical trial results for approved products.
An applicable drug or biologic clinical trial is one that meets the definition of clinical investigation under 21 C.F.R. '312.3(b) (any experiment in which a drug or biologic is administered or dispensed to one or more human subjects). An applicable device clinical trial is a prospective clinical study of health outcomes comparing an intervention with a device against a control in human subjects (other than studies designed to determine the feasibility of a device and not health outcomes). An applicable clinical trial does not include Phase I clinical investigations. (Before the enactment of the new law, sponsors were only required to register drug or biologic clinical trials conducted under the FDA's investigational new drug application regulations for products intended to treat serious or life-threatening diseases or conditions.)
The clinical trial registry requirements provide that the 'responsible party' for each applicable clinical trial must submit information on the trial to the National Institutes of Health ('NIH'). The responsible party is either the study's sponsor or the principal investigator, depending on who has control over the study. The responsible party must submit information describing the study, the recruitment requirements and the study's location and contacts. The NIH must ensure that the clinical data registry is available on the Internet and searchable by keywords (e.g., the disease, the product's name, the study's location, the age group under investigation, and the sponsor). Section 801(a) also requires the implementation of a new 'registry and results data bank.' No later than one year from a covered study's completion, the responsible party must submit to the NIH a non-technical summary of the study and its results. The summary must include the patient demographics, a point of contact for scientific information regarding the study, and whether there exists any agreement restricting the ability of the principal investigator to discuss or publish the study's results. The summary of the study's results must include: the primary and secondary outcomes, any information that the FDA has posted from any advisory committee meeting which discussed the study, FDA public health advisories regarding the product and Medline citations to any publications regarding the study's results.
If a company conducts a clinical trial to evaluate a potential new use of an approved or cleared product, it must submit to the NIH information regarding the clinical trial within 30 days of the FDA's decision on the proposed new use. A company that seeks to withdraw its application before the FDA's final decision must also submit information on the clinical trial to the NIH within 30 days of withdrawing the marketing application for the new use.
In addition to the expansion of the clinical trial databases, the FDA must promulgate, by March 27, 2009, regulations requiring sponsors to submit information regarding serious adverse events and frequent adverse events encountered during clinical trials. The adverse event information will be included in the clinical trial database. If rules are not promulgated by Sept. 27, 2009, defining these requirements, the Act requires the clinical trial database to include tables showing serious adverse events and adverse events occurring in more than 5% of any arm in the trial (each treatment approach in a clinical trial is referred to as an “arm”).
Web Site for Drug Safety Information
Section 915 of the Act requires the FDA to develop, by Oct. 1, 2008, a Web site that will provide drug safety information. The site must contain the following information regarding approved drug products: 1) labeling and package inserts; 2) links to any medication guide; 3) any safety alerts or other safety information issued by the FDA; 4) links to clinical trial registry and clinical trial results; and 5) information related to any risk minimization and action plans associated with the drug. Within 18 months of a drug's approval or its use by 10,000 people, whichever is later, the Web site must also contain a summary of the adverse drug event reports received for the drug, any new risks not previously identified for the drug, and any known risks reported in an unusual number. (A risk minimization and action plan ('RiskMAP') is required by the FDA for drug products with defined substantial risks, such as some forms of opiates with a significant risk of overdose, abuse, and addiction. A RiskMAP is a strategic safety program designed to meet specific goals and objectives to minimize known risks of a product while preserving its benefits.)
Information Related to the FDA's Review of a Drug Application
Section 916 of the Act requires the FDA to make available on the Internet an 'action package' regarding the approval of a drug product. The Act defines an 'action package' to include the following: 1) documents generated by the agency related to its review of the application; 2) a summary of the conclusions reached by each reviewing discipline; 3) a description of any disagreements with the applicant and within the review team; 4) a description of how the disagreements were resolved; 5) an explanation of any nonconcurrence with review conclusions; and 6) documents related to the FDA Office Director's review of the application. Within 48 hours of approval, the FDA is required to post information related to the summary review conclusions and a description of any disagreements within the review team or with the applicant.
Adverse Event Information
Section 921 of the Act requires the FDA to conduct a bi-weekly screening of the adverse event reporting system database and post a quarterly report of any new safety issues or the potential signal of a serious risk identified in the database. The FDA must also establish a system that allows patients, health care providers, and drug sponsors to submit adverse event reports through the Web site. On an annual basis, the FDA must review post-market commitments for approved drugs and determine which commitments should be revised or eliminated. On an annual basis, the FDA must report these determinations to Congress.
Potential Implications of the FDAAA on Product Liability Exposure
One of the FDAAA's major goals is to provide transparency to the FDA's regulation of medicinal products. As described above, the Act requires the FDA to make accessible information regarding a product's pre- and post-approval history. Doctors and patients will now be able to review and submit adverse event reports through the Internet. Clinical trial results for drug products and devices will be available through the Internet. In addition, any disagreements that arose during the review of a drug product's application will become publicly available. If the FDA has taken any action regarding a safety issue or concluded that the product may present a potential safety issue, the information will also be readily accessible.
The FDA's current Web site contains some of the information required by the Act, but the information is often in a raw form that is difficult to find, read, and understand. When the FDAAA's provisions are implemented completely, anyone should be able to visit the FDA's Web site and access a wealth of information regarding almost any approved product.
Disclosure and accessibility to clinical trial and product information will provide benefits to health care providers and the public. However, the vast expansion of readily available information may increase a company's product liability exposure. Many product liability cases are based on allegations that a company failed to warn users adequately of the risks associated with its product. A manufacturer's duty to warn is limited by the “learned intermediary doctrine,” which applies to prescription products. (See article by Diane Lifton and Michelle Bufano, infra at page 1.) The learned intermediary doctrine states that a manufacturer meets its duty to warn when it adequately informs the prescribing physician of the potential risks associated with the use of its product. (See, e.g., Stone v. Smith, Kline & French Labs., 731 F.2d 1575, 1579-1580 (11th Cir. 1984)).
Another common theory used by plaintiffs in product liability lawsuits is 'negligence per se.' Under this theory, a plaintiff argues that a drug company, at a minimum, must comply with applicable FDA regulations. If a company has not complied with such regulations, it has breached its duty to the plaintiff.
The increased availability of a product's safety profile may increase the likelihood that a product liability lawsuit will be filed. For example, a recent study in the Canadian Medical Association Journal found that the publication of a clinical study concerning adverse events associated with a drug led to a rapid and sustained increase in Internet-based solicitation for litigants for personal injury claims. (See David Juurlink, et al.: The Effect of Publication on Internet-Based Solicitation of Personal-Injury Litigants. Can Med Assn J, 1369-1370 (Nov. 20, 2007)).
A company's failure to comply with the FDAAA's registry and posting requirements may provide the basis of a product liability suit. A user could argue that a company's non-compliance with the law constituted negligence per se by failing to warn adequately of safety issues.
It may sound simple, but for a company to minimize its liability exposure, it must comply with the FDAAA's requirements. However, because the Act requires so much information to be made easily accessible, a company must also be careful that it does not disclose proprietary information or provide misleading information.
A company should establish standard operating procedures (SOP) outlining its monitoring of safety information regarding its products. While an SOP should be company- or product-specific, it should ensure that the following areas are addressed:
- All covered clinical trials are properly registered;
- The results of clinical trials are submitted in the proper format and within the required timeframe (including a summary of adverse events encountered during the study);
- Verification that all information posted by the FDA regarding a product is accurate;
- Verification that any information submitted to the agency and posted by the FDA does not contain confidential information (all submissions and communications made to the agency should be reviewed by appropriate personnel to ensure that confidential/trade secrets are identified); and
- Frequent review of the FDA's Web site that lists adverse experiences to ensure the company is aware of any emerging safety issues.
Conclusion
The FDAAA is likely to create a new paradigm regarding the dissemination of clinical trial and safety information for approved products. Companies should be prepared for this new world where information regarding its product will be readily accessible to anyone with an Internet connection.
Alan G. Minsk, a member of this newsletter's Board of Editors, is a Partner and Chair of the Food and Drug Practice Team at Arnall Golden Gregory LLP, Atlanta. E-mail: [email protected]. David Hoffman is also a member of the Food and Drug Practice Team. E-mail: [email protected].
