1. Summary: Biological Therapeutics for Rare Plasma Protein Disorders Workshop July 21, 2005 Mark Weinstein, Ph.D. Office of Blood Research and Review CBER, FDA

2. Meeting Objectives To facilitate the development of products to treat U.S. patients with very rare plasma protein disorders - on the order of 10’s or 100’s Learn about current availability and need for these products Identify challenges to product development Review current product development procedures and experience from the perspectives of regulators and sponsors Identify opportunities to facilitate clinical trials Suggest new ideas for product development

3. Product Development Need and Challenges Patient Perspective: –some products available in Europe but not US –Personal importation very expensive, no insurance coverage International Perspective:  Autosomally recessive rare bleeding disorders have prevalences of approx. 1:500,000 to 1:2,000,000 in the general population. Examples: Fibrinogen, FV, FVII, FV+FVIII, FX, FXI, FXIII  Actual number of patients is highly uncertain because of poor data collection. Few long term prospective studies of large cohorts of patients; reliable information about clinical management is often scarce  Recessive disorders are more prevalent in developing countries because of higher frequency of consanguineous marriages  Current treatment: Replacement therapy, Non-transfusional treatment. Single donor fresh frozen plasma is mainstay; some concentrates available in Europe but not the US

4. Product Development: Need and Challenges Physician perspective –Lack available efficacious product –Lack knowledge of appropriate replacement strategies Difficult or unable to obtain insurance coverage for therapy –Imported for personal use –Used off-label Importation and off-label use not adequate long-term solution Challenges with IND –Time required of investigator –Manufacturer must have updated BLA at the FDA (biologics license application) Cost considerations –No funds available to reimburse for time spent –Manufacturer decides financially not feasible to update data at FDA when potential market for drug does not exist

5. Product Development: Need and Challenges Industry perspective: Investment Analysis Techniques are used when deciding to bring new biotherapeutics to market. Decision making factors: –The number of patients that require the treatment –In-market issues such as expected reimbursement and product pricing, and competition between therapy providers –Cost of manufacturing – this is often technically constrained by the manufacturing of other plasma biotherapies –Relative cost of CMC preparation –Relative cost of Clinical Trials –The time taken to launch and then reach peak distribution –Anticipated life-cycle of the therapy (relative to new technologies that may cause redundancy) Non-financial factors are also considered and companies practice benevolence in providing some biotherapies to patients

6. Clinical Trial Challenges –Limited numbers of patients –Chronic replacement treatment –Willingness to switch ? –Increased visits to hospital –More venipunctures / paperwork –Interruption with life / work –Competition for willing patients –Duration of follow-up –No personal incentive –Comparator ? –High cost of clinical trials What information is needed to convince health care purchasers to agree to buy the product for these patients? Product Development: Need and Challenges

7. Current Opportunities: What are the current regulatory pathways and incentives to develop biological products for very small populations? International : European Medicinal Authority (EMEA) Regulatory mechanisms to license with limited clinical data Exceptional circumstances: marketing authorization granted in cases where comprehensive data cannot be provided. Authorization reviewed annually to reassess the risk-benefit balance, but will not normally lead to completion of the dossier Conditional marketing authorization: authorization granted before all data are available but it is expected that the remaining data will be provided in order to have a complete dossier at a certain point in time

8. Current Opportunities: FDA perspective on clinical trial design for very small populations Discussion of the FDA accelerated approval process Statistical considerations for very small clinical trials Orphan Drug provisions and incentives Research support from the NHLBI for rare plasma protein disorders Example of NHLBI support through the Small Business Innovative Research Support grant Review of Medicare payment program

9. Case Studies of product development: –Protein C –Factor XIII –Antithrombin III –Treatment of Glanzmann’s Thrombasthenia –Treatment for Fabry’s disease Future opportunities: Enhanced Data Collection –FDA and EMEA experience with post marketing data collection –Experience of sponsors in collecting post-marketing surveillance data through third parties –Consumer group-initiated post marketing surveillance –Opportunities for data collection through registries and the CDC

10. Potential Opportunities Develop and improve patient registries and data bases –Identify patients for future clinical trials –Obtain data on the natural history of the diseases –Harmonize format of data collection; link data bases to improve accessibility –Forum needed to discuss the different data needs of regulators, industry, physicians, consumer organizations –Need to distinguish routine voluntary post marketing surveillance from a post marketing patient monitoring commitment by sponsor to assure accuracy of reports Consider developing alternate and/or harmonized regulatory pathways –Examine potential for international market authorization based on similar clinical trial criteria –Establish forum for discussion of harmonization

11. Potential Opportunities Improve investment analysis for industry –Establish small indication grants similar to small business grants –Take advantage of Orphan drug financial incentives Determine regulatory options –FDA one to one meetings with sponsors to discuss product development for rare plasma protein disorders Slides from meeting are available for 6 months on: http://www.fda.gov/cber/summaries.htm#biother