FDA Evaluation Of Risk Management Plans And “Tools” Needed, PhRMA Says

FDA should undertake a review of all current and past risk management plans and "tools" to document their effectiveness, PhRMA says.

In comments on FDA's draft guidance on risk minimization action plans, the Pharmaceutical Research and Manufacturers of America requested that the agency publish a "complete review of all current and past" risk management plans "to demonstrate the value of these overall programs as well as the individual tools used to achieve the objectives."

The draft guidance on ¹ 'Development and Use of Risk Minimization Action Plans' would establish three descriptive categories of risk minimization tools: targeted education and outreach, reminder systems, and performance-linked access systems.

PhRMA "would like to see an analysis by the FDA of previous plans and the tools used, including overall feasibility assessments, as well as the known advantages, disadvantages, and limitations associated with a given tool," ² PhRMA's RiskMAP comments state.

"There are very few examples in the public literature of successes for any tools," PhRMA noted.

Comments from the Biotechnology Industry Organization echoed the argument that developing effective risk minimization tools remains a challenge.

"The literature does not suggest that exposing practitioners to additional education, or that the use of prompts and reminder systems provides long-term and sustained changes in the behavior of healthcare professionals that is necessary to achieve the goals and objectives as outlined in the draft guidance," ³ BIO's RiskMAP comments state.

In a preliminary concept paper on risk management released in March 2003, FDA had included an additional category of tools: programs consisting of changes to the package insert (⁴ (Also see "FDA Risk Management Plan: Four Levels, From Labeling To Restricted Access" - Pink Sheet, 10 Mar, 2003.)).

The agency removed the category in the draft guidance due to industry concerns that a four-level ranking system would stigmatize certain drugs (⁵ ).

PhRMA said FDA should eliminate the "targeted education and outreach" tool category as well, because "many products" utilize such tools as part of "routine risk management."

The group also commented on FDA's process for determining when a RiskMAP should be considered.

"PhRMA believes this section is unduly vague and overly broad," comments state. "As currently written, virtually any product on the market could be determined to need a RiskMAP of one form or another."

"We suggest that FDA re-write the section to: (1) reiterate that a RiskMAP should be considered for only a limited number of products; and (2) define more specifically based upon existing examples, when a RiskMAP should be considered."

Both PhRMA and BIO advocated greater transparency and consistency among review divisions concerning decisions on risk plans.

"There must be sufficient oversight to ensure that decisions to request additional studies or a RiskMAP and the selection of tools to be employed are made consistently between centers and across review divisions," PhRMA said.

FDA plans to develop a RiskMAP website to assist sponsors in designing them. PhRMA suggested "the web site could also provide annual statistics regarding the number of products requiring a RiskMAP."

The guidance should also include information on circumstances under which a RiskMAP could be ended, PhRMA said.

"It is critical for FDA to discuss in the guidance the circumstances and mechanisms by which it would be appropriate for a sponsor to scale back or discontinue elements of a RiskMAP (e.g., goal achieved, prescribing habits established, etc.)," PhRMA's comments state.

As part of its comments, PhRMA also submitted a statement asserting that Congressional statute limits FDA's legal authority concerning risk minimization plan requirements.

Under the Federal Food, Drug, and Cosmetic Act, PhRMA said FDA's ability to refuse approval of a drug is limited, including suggestions on physician use but not including restrictions on distribution.

"The development of RiskMAPs and the use of the kinds of tools described in the risk management draft guidances must be voluntarily developed and adopted by prescription drug companies. They may not be required by FDA," PhRMA said.

PhRMA and BIO also submitted comments about two related draft guidances on ⁶ 'Good Pharmacovigilance Practices and Pharmacoepidemiologic Assessment' and ⁷ 'Premarketing Risk Assessment'.

The three risk management guidances were mandated by the user fee program reauthorization in 2002. FDA said it is working quickly on finalizing the guidelines but does not expect to meet the legislative goal date of Sept. 30. The 60-day comment period for the drafts closed July 4.

Overall, the associations expressed concern that FDA's approaches to handling risk and safety issues could impede drug development, including provisions on the use of large simple safety studies and active comparator trials in drug development.

"A pre-approval requirement of a large simple safety study is a significant burden that should be reserved for only those cases when a signal suggests a possible serious adverse event that if substantiated would result in a significant public health risk and prevent product approval," ⁸ PhRMA's premarketing risk comments state.

"A pre-approval requirement for an LSSS is not a trivial requirement as it represents a de facto fourth phase to development."

PhRMA suggested FDA revise the guidance to limit the LSSS requirement to "'when there are early signals (i.e. pre-clinical or clinical) of serious toxicities or other unique or special considerations (e.g. regarding the safety of the use of the product with a concomitant medication where the previous clinical data have not address the issue sufficiently) that are not likely to be sufficiently resolved by the available data addressed by the remaining ongoing studies."

Similarly, PhRMA is seeking more limited language on comparative trials.

"As a general matter, PhRMA objects to FDA's statement that comparative safety data would be desirable in a variety of situations."

The association is "concerned that the general discussion could encourage FDA to request comparative trials on a more routine basis." That would "represent a new standard for approving drug products that goes beyond the statutory requirements. We thus suggest removing this section," PhRMA said.

If FDA wishes to ask sponsors for such trial data, PhRMA said the agency should "develop a specific guidance applicable to the disease and/or therapeutic class."

BIO and PhRMA shared concerns about FDA's recommended use of data mining in pharmacovigilance as a means of identifying safety signals.

"PhRMA recommends that the agency take care with regard to describing data mining activities in the guidance document, so that it is clear that use of data mining techniques is not a mandatory or expected part of signal identification/evaluation," ⁹ PhRMA's pharmacovigilance comments state.

PhRMA added, "it is still debatable whether data mining is worth considering, due to false positive, false negative, limitations of the data, and lack of gold standard."

BIO "disagrees that data mining, particularly of unstructured data, can be used to further characterize safety signals to determine if they represent risks," ¹⁰ BIO's pharmacovigilance comments state.

Both industry organizations agreed that calculations of reporting rates versus incidence rates should include global databases, not only U.S. data.

"We strongly suggest that FDA allow for inclusion of global data in the calculation of reporting rates for purposes of signaling," BIO said.

In general, the associations also said FDA should better harmonize its risk approach with the International Conference on Harmonization. "It would be useful for FDA to highlight in the guidance documents the important differences from ICH and EU guidance documents, the rationale for these differences, and the steps being taken to harmonize the differences," PhRMA said.