1. AXINN, VELTROP & HARKRIDER LLP © 2007 | www.avhlaw.com AXINN, VELTROP & HARKRIDER LLP Click To Modify Title Name Goes Here FDA Hearings on the BPCI Act Chad A. Landmon 90 State House Square 1330 Connecticut Ave, N.W. cal@avhlaw.comcal@avhlaw.com Hartford, CT 06103Washington, D.C. 20036 February 3, 2011

2. AXINN, VELTROP & HARKRIDER LLP © 2011 | www.avhlaw.com Overview BPCI Act FDA Hearings Issues of Contention Going Forward

3. AXINN, VELTROP & HARKRIDER LLP © 2011 | www.avhlaw.com Biologics Price Competition and Innovation Act Adds Section (K) to the Public Health Services Act Creates an approval pathway for biosimilars products that share the same known mechanisms of action, conditions of use, and means of administration as the reference product Creates a period of exclusivity for the first biosimilar product to establish interchangeability Creates a 12 year period of exclusivity for new reference products In place of an Orange Book listing, creates a process for exchange of information between the biosimilar applicant and reference product sponsor

4. AXINN, VELTROP & HARKRIDER LLP © 2011 | www.avhlaw.com

5. FDA Hearings: Topics for Discussion Biosimilarity Interchangeability Patient Safety and Pharmacovigilance Use of Supportive Data and Information Guidances Exclusivity

6. AXINN, VELTROP & HARKRIDER LLP © 2011 | www.avhlaw.com Basic Lines of Division InnovatorsBiosimilar Proponents FDA should not start approval until specific and general guidelines are in place Cannot extrapolate across indications Full and robust clinical trials are needed for all indications Approval should be on a case by case basis Extrapolation should be allowed for indications with the same mechanism of action Clinical trials can be abbreviated based on the similarities between the products

7. AXINN, VELTROP & HARKRIDER LLP © 2011 | www.avhlaw.com Interchangeability- Innovator View Product is process. Post-market drift and later approved indications means interchangeability can and should be revoked when no longer present. Interchangeability cannot be extrapolated. Interchangeability must be shown for all individuals.

8. AXINN, VELTROP & HARKRIDER LLP © 2011 | www.avhlaw.com Interchangeability- Biosimilar Proponent View Technology exists to detect differences between products. FDA comparability studies allow drift in the reference product. The same studies should allow interchangeability under the same standards.

9. AXINN, VELTROP & HARKRIDER LLP © 2011 | www.avhlaw.com Interchangeability- Other Concerns Patient groups stressed patient knowledge and choice and advocated for no automatic substitution. Some proposed a post-market system for approving interchangeability. FDA stressed the worry that drift would result in separately changing products. There may be difficulties in conducting alternating or switching studies, especially for drugs with long half-lives.

10. AXINN, VELTROP & HARKRIDER LLP © 2011 | www.avhlaw.com Biosimilarity- Innovator View Equivalence rather than noninferiority should be the standard for efficacy. Clinical trials should be conducted across all indications and based on: –complexity of the molecule; –changes introduced during processing and purification; and –immunogenicity risks No surrogate endpoints should be allowed, and no extrapolation across indications.

11. AXINN, VELTROP & HARKRIDER LLP © 2011 | www.avhlaw.com Biosimilarity- Biosimilar Proponent View Drift in innovator product should establish goal posts for biosimilarity. Clinical trials can and should be abbreviated. Studies should use surrogate endpoints such as efficacy for immunogenicity and response rate for survival. Approval should extrapolate across indications with the same mechanisms of action.

12. AXINN, VELTROP & HARKRIDER LLP © 2011 | www.avhlaw.com Clinical Trials- Where to Abbreviate? Studies may focus on PK/PD instead of structural similarity since the goal is same efficacy. Non-toxic reference products may allow simultaneous human and animal studies. Clinical studies may be abbreviated based on differences detected between products. Human trials may be abbreviated based on low immunogenicity and general safety.

13. AXINN, VELTROP & HARKRIDER LLP © 2011 | www.avhlaw.com Pharmacovigilance and Naming Biosimilar proponents argued that tracking can be done through National Drug Codes and lot numbers without unique International Nonproprietary Names. Innovators argued that unique names are required for tracking by patients and doctors. Patient groups stressed that either system needs to deal with patient and doctor confusion. Both sides worried about the effects on insurance reimbursement for their products.

14. AXINN, VELTROP & HARKRIDER LLP © 2011 | www.avhlaw.com Reliance on Foreign Systems The European Medicines Agency has an established system for biologics. The EMA has high standards for biosimilarity. The EMA has no approval for interchangeability approval is made by individual member states and has yet to be approved by any. Innovators advocated adopting similarly high standards in the U.S. The EMA has no unique naming system, but uses a combination of trade names and INN to identify products.

15. AXINN, VELTROP & HARKRIDER LLP © 2011 | www.avhlaw.com Innovators pointed to the EMA as having a de facto unique naming system. Innovators supported looking to the EMA for strict standards for approval. Innovators argued that significant bridging data should be required for any reliance on foreign data, even if the only difference in products is the source. Biosimilar proponents supported looking to foreign data with little bridging. Reliance on Foreign Systems

16. AXINN, VELTROP & HARKRIDER LLP © 2011 | www.avhlaw.com Exclusivity The BPCIA allows approval of a new 12 year exclusivity period for non-related entities for any structural change that results in a difference in purity, safety or potency. Some pointed out that the provision may conflict with Helsinky rules on replication of clinical trials by forcing duplicative human studies. One presenter noted that clarity is needed on whether after- filing acquisition of the applicant or licensing of the product by the original innovator relinquishes the new exclusivity.

17. AXINN, VELTROP & HARKRIDER LLP © 2011 | www.avhlaw.com Innovators argued that this approval should be granted for any change, not just an improvement. Patient groups expressed worry in evergreening and the incentive to make minor improvements rather than new innovations One innovator requested that products that would qualify as biosimilar should not be able to skirt the 12 year exclusivity of the reference product by seeking approval as a new biologic. Exclusivity

18. AXINN, VELTROP & HARKRIDER LLP © 2011 | www.avhlaw.com At the hearings, the representative for BIO asked that FDA interpret Sections (a) and (k) of the act as mutually exclusive, so a product that would qualify under the biosimilarity provisions of (k) not be granted approval under (a). Members of both houses of Congress have recently written FDA to emphasize that the exclusivity is data not marketing exclusivity, as the provision does not prohibit or prevent another manufacturer from developing its own data to justify FDA approval. Biosimilar proponents have since written to FDA to point out that the exclusivity provision has two separate periods of exclusivity a four year period preventing filing of an abbreviated application under Section (k) ( data exclusivity ) and a twelve year period before an application can be approved under Section (k) ( marketing exclusivity ). Exclusivity

19. AXINN, VELTROP & HARKRIDER LLP © 2007 | www.avhlaw.com AXINN, VELTROP & HARKRIDER LLP Click To Modify Title Name Goes Here Any questions? Chad A. Landmon cal@avhlaw.com (860) 275-8100 (202) 721-5415