Docket Management
Docket: 02N-0528 - Risk Management; Public Workshop
Comment Number: EC -8

Accepted - Volume 3

Comment Record
Commentor Mr. James Knox Date/Time 2003-04-30 19:14:07
Organization Orphan Medical Inc.
Category Company

Comments for FDA General
1. General Comments April 30, 2003 Dockets Management Branch (HFA-305) Food and Drug Administration 5630 Fishers Lane, Rm. 1061 Rockville, MD 20852 RE: Concept Paper: Risk Management Programs Docket number 02N-0528 To Whom It May Concern: Orphan Medical Inc is pleased to provide the following comments on the FDA’s three Concept Papers on Pre-Marketing Risk Assessment, Risk Management Programs and Risk Assessment of Observational Data. Our comments primarily focus on the Risk Management Program (RMP) concept paper. These comments are provided from practical experience gained in the development and implementation of the Xyrem® risk management program. Issuance of Three Concept Papers The issuance of the three separate concept papers on Pre-Marketing Risk Assessment, Risk Management programs and Risk Assessment of Observational Data artificially separates activities that form the usual continuum of risk assessment. We propose that the 3 topics would be better addressed in an integrated “risk management” document thereby facilitating consistent definitions and approach. For example the 3rd concept paper on Pharmacovigilance makes no reference to the need for post-marketing adverse event data to be integrated into the ongoing RMP assessment. In addition such an approach would clearly distinguish the use of RMPs as a specific tool within the broader risk management / assessment process. Distinguishing between Risk Management (RM) ands Risk Management Programs (RMPs) We feel it is important to clearly distinguish that risk management (RM) is an ongoing process that applies to all products, whereas a minority of products require additional interventions to reduce risk. These interventions are currently termed Risk Management Programs (RMPs). To avoid confusion between the general process of Risk Management and the use of specific Risk Management Programs we would like to suggest alternative terminology for Risk Management Programs (RMPs) for example: • Safety Enhancement Programs • Targeted Risk Reduction Program Use of alternative terminology clearly distinguishes that Risk Management Programs are a specific and selective component of the broader risk management process. Section D: Categorization of RMPs We do not agree with the proposed categorization of RMPs consisting of Levels 1 through 4. In particular we believe that the term “RMP” should be reserved solely for those levels currently described as level 2-4. This comment is based on the FDA’s definition of risk management (lines 31-35) which states that RMP involve active implementation of interventions. We do not believe that a product whose only risk management “activity” is the package insert (level 1) can be described as an active intervention, and thereby a RMP. Therefore we would propose to assess all drug products for risk and classify drug products into two categories: • Standard Risk Product – RMP not required. • Non-standard Risk Product – RMP required. Appropriate levels (consistent with the currently proposed levels) could then be applied to the products in the RMP required category. Again this classification would clearly distinguish that RMPs are only required for products where the risk / benefit ratio is clearly increased on the risk side. Administration To facilitate implementation of, and ensure consistency between, RMPs we propose that the FDA considers establishing a cross-divisional function to oversee the RMP process and provide Industry liaison and guidance. Such a function would be particularly useful in ensuring a generally consistent design of RMPs between the various reviewing divisions, as requested by several of the interest groups at the April 9, 10, 11 recent FDA RM workshop in Washington. Assessment of Need and Criteria for RMP In our view the RMP concept paper needs to provide greater guidance on the criteria by which a Sponsor establishes the need for a RMP beyond the currently proposed level 1 i.e. levels 2-4. Additional guidance in this area is extremely important as the risk: benefit profile of all products could always be enhanced through application of a RMP, and the tendency with most Sponsors is to adopt the most conservative interpretation of any guidance document. In contrast, the FDA stressed that the intent is to be judicious in the introduction and implementation of RMPs levels 2 – 4. Use of examples could be an appropriate way of illustrating the Agency’s intent in this area. Ongoing Assessment The concept paper discusses the introduction of RMPs but does not address how these may be updated, changed, enhanced, or removed if no longer necessary. The draft guidance paper should establish a framework by which a sponsor could propose changes to their RMP for example: • Changes to RM materials • Changes to level of RMP: request for increase or decrease in level Such a framework is particularly essential for Orphan Drugs where a risk management program may be appropriate in consideration of a relatively small database at approval. Additional safety data collected post-approval would allow further risk assessment and may subsequently support removal of 1 or more elements of the Risk Management program. Integration of Risk Management Into Clinical Overview The Clinical Overview Document within the Common Technical Document format includes a formal assessment of risk: benefit. Accordingly it would be appropriate for each “Clinical Expert” to assess and comment on the appropriateness of a Risk Management Program for each product. Such an approach would ensure that RMPs are viewed as a component of the usual risk: benefit assessment Section V: REMP Evaluation Use of RM tools: A review of currently implemented US RMPs indicates certain common elements including educational materials, prescription stickers etc. We encourage the Agency to include a list of accepted RM tools which would not require pre-validation e.g. leaflets, videos. We also feel it is important to distinguish between the RM tool and the message(s) contained within these tools. Thus it may be more important to validate that the message (rather than the tool) is effective and appropriate. Orphan Medical Inc. is currently one of the companies who is actively implementing a risk management program which could be classified as a level 4. We thank you for the opportunity to provide our comments. We look forward to further collaboration with the FDA for the purpose of ensuing that medications are available to patients that require them. We would welcome the opportunity to discuss / comment on this further, and we would welcome a chance to work with you on developing the guidances. Sincerely, ORPHAN MEDICAL INC. James W. Knox Director, Regulatory Affairs

EC -8