Risk Management Guidance Suggests Advisory Cmte Review For RiskMAPs

FDA recommends that advisory committees weigh in on whether a risk minimization action plan is appropriate for a particular drug.

In the final guidance "Development & Use of Risk Minimization Action Plans," FDA suggested that the advisory committee process will allow parties "who will later have roles implementing the RiskMAP" to help develop the program.

"Involving all stakeholders during the initial phases of considering whether a RiskMAP is appropriate allows input and buy-in by all parties," the guidance states. "If a RiskMAP is appropriate, stakeholders can help shape the RiskMAP to foster its success in the health care delivery environment."

"Therefore, we recommend public discussion about the appropriateness of a RiskMAP through the FDA advisory committee process," the ¹ RiskMAP guidance states.

The guidance adds the advisory committee process can address whether a RiskMAP is appropriate, as well as its objectives and circumstances under which the program should be revised or terminated.

"The FDA advisory committee structure and processes are well suited to foster such discussions as they arise on a case-by-case basis," the agency said.

FDA released a trio of risk management final guidances March 24. In addition to risk minimization action plans, the guidances address "Premarketing Risk Assessment" and "Good Pharmacovigilance Practices & Pharmacoepidemiologic Assessment."

The publication of the guidances completes a requirement under the prescription drug user fee act reauthorization from 2002.

The guidances also fulfill part of FDA's drug safety initiative announced Nov. 5. Acting FDA Commissioner Lester Crawford included completion of the risk management guidances as a component of the initiative (² (Also see "IoM Drug Safety Study May Buy Time For FDA; Report Will Play In PDUFA IV" - Pink Sheet, 15 Nov, 2004.), p. 8).

The documents were in development since March 2003, when three concept papers on risk management were issued. They were subsequently discussed during a public workshop, then reissued as draft guidances in May 2004.

The RiskMAP draft guidance moved away from the initial concept paper's four levels of risk management programs, instead coining the term RiskMAP to encompass risk management tools (³ , p. 18).

"The term RiskMAP means a strategic safety program designed to meet specific goals and objectives in minimizing known risks of a product while preserving its benefits," the guidance states.

The guidance expounds on three systems used in RiskMAPs: targeted education and outreach, reminder systems to foster reduced-risk prescribing and use, and performance-linked access systems that guide use of the product to target populations and conditions of use most likely to confer benefits and minimize risks.

In comments on the draft version, the Pharmaceutical Research & Manufacturers of America suggested FDA stress that RiskMAPs should be utilized for only a limited number of products (⁴ (Also see "FDA Evaluation Of Risk Management Plans And “Tools” Needed, PhRMA Says" - Pink Sheet, 2 Aug, 2004.), p. 39).

"Only a few products are likely to merit consideration for additional risk minimization efforts," the guidance states. "FDA recommends that RiskMAPs be used judiciously to minimize risks without encumbering drug availability or otherwise interfering with the delivery of product benefits to patients."

A decision to implement a RiskMAP, the guidance explains, should be based on the nature and rate of known risks versus benefits, preventability of adverse effects and the probability of benefit.

FDA plans to develop a RiskMAP website to provide descriptions of risk management tools.

Development of the RiskMAP website likely will follow development of another website related to drug safety; a broader drug safety initiative announced in February includes the creation of a website that will list drugs with emerging safety signals before FDA has taken regulatory action on them (⁵ (Also see "FDA Unveils Rx Safety Board, Website; Postmarket Surveillance Overhaul Next" - Pink Sheet, 21 Feb, 2005.), p. 4).

The good pharmacovigilance practices guidance suggests utilizing existing claims databases, such as those kept by HMOs or Medicaid, when evaluating safety signals using pharmacoepidemiologic studies.

"Depending on the type of pharmacoepidemiologic study planned, there are a variety of data sources that may be used, ranging from the prospective collection of data to the use of existing data, such as data from previously conducted clinical trials or large databases," the ⁶ pharmacovigilance guidance states.

"In recent years, a number of pharmacoepidemiologic studies have been conducted in automated claims databases (e.g., HMO, Medicaid) that allow retrieval of records on product exposure and patient outcomes. In addition, recently, comprehensive electronic medical record databases have also been used for studying drug safety issues," the guidance notes.

HHS Secretary Leavitt told PhRMA's annual meeting March 17 that the Medicare Rx drug benefit could also provide a good source of post-marketing data.

Use of claims databases in assessing safety signals has recently garnered attention through some high-profile examples.

One month prior to Merck's withdrawal of the COX-2 inhibitor Vioxx , a retrospective study using Kaiser Permanente's patient database observed an increase in cardiovascular risk for Vioxx patients compared to those taking regular NSAIDs (⁷ (Also see "COX-2 Retrospective Study Prompts Review By FDA, Kaiser On Merck’s Vioxx" - Pink Sheet, 30 Aug, 2004.), p. 6).

The study's lead author, FDA Drug Safety Officer David Graham, testified before a Senate Finance Committee hearing on the Vioxx withdrawal (⁸ (Also see "Crestor, Serevent Safety Issues Push Vioxx Out Of Spotlight In Senate Hearing" - Pink Sheet, 22 Nov, 2004.), p. 4).

In addition, Public Citizen has requested that FDA withdraw Abbott's Cylert based in part on a claims database analysis.

The pharmacovigilance guidance describes different tools sponsors can use to evaluate suspected safety signals. In addition to pharmacoepidemiological studies, the guidance discusses the use of registries and surveys in following up safety signals.

"FDA recommends that the most aggressive follow-up efforts be directed towards serious adverse event reports, especially of adverse events not known to occur with the drug," the guidance states.

The guidance lists features that sponsors should consider in assessing case reports to determine a causal relationship between a product and an adverse event, including: occurrence of the adverse event in expected time; absence of symptoms prior to drug exposure; evidence of positive dechallenge or positive rechallenge; and consistency of the event with the pharmacological/toxicological effects of the product.

In addition, sponsors should consider: consistency of the event with known effects of drugs in the class; existence of supporting evidence from earlier studies; and absence of alternative explanations for the event.

The pharmacovigilance guidance also recommends methods for assessing reporting rates versus incidence rates (⁹ (Also see "Post-Marketing Safety Surveillance Should Include Data Mining, FDA Says" - Pink Sheet, 10 May, 2004.), p. 17).

The ¹⁰ premarketing risk assessment guidance focuses largely on safety assessment during Phase III studies.

The size of a premarketing safety database should be decided on a case-by-case basis, FDA suggested, depending on the following factors: the molecule's novelty, availability of alternative therapies, the intended population and intended duration of use.

For products intended for short-term or acute use (less than six months), "FDA believes it is difficult to offer general guidance on the appropriate target size of the clinical safety database," the guidance states.

"Sponsors are therefore encouraged to discuss with the relevant review division the appropriate size of the safety database for such products."

For products that are not used for life-threatening conditions and have an expected duration of use exceeding six months, FDA has "generally recommended that 1,500 subjects be exposed to the investigation product (with 300 to 600 exposed for six months, and 100 exposed for one year)."

However, because study design should be created on a product-by-product basis, "FDA recommends that this issue be discussed with the relevant review division at the end-of-Phase II meeting, if not earlier."

During a March 24 media call, FDA Office of Pharmacoepidemiology & Statistical Science Director Paul Seligman expressed hope that the release of the guidances would facilitate "closer and earlier discussions and collaborations between FDA and the industry on safety issues."