Biosimilars Law in Flux

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An update on U.S. biosimilars in presentation to Life Science Association of Manitoba on October 13, 2011

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Biosimilars Law in Flux

  1. 1. Biosimilars Law in Flux: An Update on U.S. Biosimilars Brian Dorn, Ph.D.
  2. 2. What we will cover <ul><li>Current landscape: definitions, patent expirations, players, global activity </li></ul><ul><li>Pathways for approval </li></ul><ul><li>Summary of US Biosimilar legislation and FDA regulations </li></ul>
  3. 3. Definitions <ul><li>Originator molecule: biological molecule developed by an innovator and approved for use </li></ul><ul><li>Biosimilar: biological molecule that is highly similar in structure and function to a reference originator molecule </li></ul><ul><li>Biobetter: biological molecule similar to a reference biological molecule but has structural change that affects safety, purity, or potency </li></ul><ul><li>Comparability: changes to manufacturing processes of reference originator molecule or clinical studies comparing biosimilar to reference originator molecule </li></ul><ul><li>Interchangeability: biosimilar is interchangeable with reference if the biosimilar can be switched with reference without causing safety, efficacy or immunogenicity </li></ul><ul><li>Exclusivity: market vs. data </li></ul>
  4. 4. US Patent Expirations 2007-2018 <ul><li>Growth factors Neupogen (2008/2009), Neumega (2011), Aranesp (2014), Epogen (2014), Procrit (2014), Neulasta (2015) </li></ul><ul><li>Insulin Humulin (2008/2009), Novolin (2008/2009), Humalog (2013), Novolog (2014), Lantus (2015) </li></ul><ul><li>Interferons Infergen (2009), Betaseron (2007), Avonex (2013) </li></ul><ul><li>Coagulation factors Novoseven (2010), Kogenate (2011) </li></ul><ul><li>Antibodies Avastin (2018), Remicade (2012), Rituxan (2013), Synagis (2015), Tysrabi (2017), Humira (2016) </li></ul><ul><li>Fusion proteins Enbrel (2014) </li></ul>
  5. 5. Date of First Approval <ul><li>1980’s </li></ul><ul><ul><li>Humulin, Epogen, Procrit </li></ul></ul><ul><li>1990’s </li></ul><ul><ul><li>Neupogen, Neumega, Novolin, Humalog, Infergen, Betaseron, Remicade, Rituxan, Synagis, Novoseven </li></ul></ul><ul><li>2000-2010 </li></ul><ul><ul><li>2000 - Enbrel, Lantus, Novolog, Kogenate </li></ul></ul><ul><ul><li>2002 – Humira </li></ul></ul><ul><ul><li>2004 – Avastin, Tysrabi </li></ul></ul>
  6. 6. US Regulatory Pathways <ul><li>FDCA, 21 USC § 505: FDA regulates small molecule drugs, hormones, synthetic peptides, LMWHs and approves generic versions thereof </li></ul><ul><li>Biological products regulated through PHSA, 42 USC § 262 </li></ul>
  7. 7. US Regulatory Pathway Options <ul><li>505(b)(1) NDA </li></ul><ul><li>505(b)(2), Reliance on innovators data possible but limited categories of biologicals (hormones and insulin): Omnitrope </li></ul><ul><li>505(j) ANDA: Lovenox </li></ul><ul><li>BLA: Filgastrim, biobetters </li></ul><ul><li>New biosimilars pathway - amends PHSA but FDA developing regs </li></ul>
  8. 8. ANDA: Lovenox <ul><li>505(j) ANDA </li></ul><ul><li>Not a biologic, but a complex macromolecule </li></ul><ul><li>Sandoz gets approved through ANDA process without clinical trials of safety and efficacy (relied on RLD) </li></ul>
  9. 9. 505(b)(2): Omnitrope <ul><li>Applicant desires to market drug that is modified relative to the Brand product that does not permit an ANDA filing </li></ul><ul><li>Relied on Pfizer’s Genitropin data </li></ul><ul><li>Differences: sequence of plasmid, diluent used to reconstitute product, delivery system, dosing </li></ul>
  10. 10. 505(b)(2): Omnitrope <ul><li>Sued FDA to get a decision </li></ul><ul><li>FDA did not rely on manufacturing data but did use non-clinical toxicology, clinical trials, pharmacokinetic and pharmacodynamic data </li></ul><ul><li>FDA found Omnitrope “sufficiently similar” </li></ul>
  11. 11. BLA: Teva Filgastrim <ul><li>Filing in US in 2009; On sale in Europe since 2008 </li></ul><ul><li>Clinical trial comparing safety and efficacy to Neupogen in breast cancer patients, clinical trials comparing safety and efficacy in lung cancer and non hodgkins lymphoma </li></ul><ul><li>FDA is requiring more information but no new clinical trials </li></ul><ul><li>12 year exclusivity does not apply and clinical trial data is expected to be comparable </li></ul>
  12. 13. US Biosimilar Law in Limbo <ul><li>Passed and signed in 2010 </li></ul><ul><li>FDA Hearing Nov. 2010 </li></ul><ul><li>Constitutional Questions </li></ul><ul><li>Exclusivity Periods </li></ul><ul><li>- 12 Year Market vs. Data </li></ul><ul><li>- 12 Years vs. 7 Years </li></ul><ul><li>Regulations expected by the end of this year </li></ul>
  13. 14. Regulatory Process has Two Categories with Different Requirements <ul><li>“ Biosimilar” or “Biosimilarity” means </li></ul><ul><li>(A) highly similar notwithstanding minor differences in clinically inactive components; and </li></ul><ul><li>(B) No clinically meaningful differences in terms of safety , purity, and potency </li></ul><ul><li>“ Interchangeable” or “Interchangeability” </li></ul><ul><li>Expected to produce the same clinical result in any given patient and the risk in terms of safety or diminished efficacy of is not > the risk of using the reference product without a switch </li></ul><ul><li>May be substituted without intervention of the health care provider </li></ul>
  14. 15. First Approved Interchangeable Biosimilar Gets Market Advantage <ul><li>No determination Second Biosimilar is interchangeable until Earlier of </li></ul><ul><li>1 year after 1st commercial marketing after approval as interchangeable; </li></ul><ul><li>18 months after final court decision(s) or dismissal(s) on all patents in suit; or </li></ul><ul><li>42 months after approval of the 1st FOB if 1st applicant still has litigation pending; or </li></ul><ul><li>18 months after approval of 1st FOB if 1st applicant has not been sued. </li></ul>
  15. 16. Biosimilar Application Requirements <ul><li>Data to show proposed product biosimilar/interchangeable (analytical, animal, and clinical studies); ***waivable </li></ul><ul><li>Same mechanism as Originator Reference Product </li></ul><ul><li>Labeling has been previously approved for Originator Reference Product </li></ul><ul><li>Same route of administration, dosage form and strength </li></ul><ul><li>Facilities: assure that product is safe, pure, and potent </li></ul>
  16. 17. Studies in Support of Biosimilar Application <ul><li>Analytical studies showing product is highly similar </li></ul><ul><li>Animal studies (including toxicity) </li></ul><ul><li>Clinical studies showing safety, purity, and efficacy including immunogenicity as compared to reference originator drug </li></ul><ul><li>If given more than once the risk of switching from the originator reference product is not greater than the originator reference product without switching for interchangeability </li></ul>
  17. 18. Extrapolation <ul><li>Will FDA allow extrapolation of administering a biosimilar for 1 indication to multiple indications? </li></ul><ul><li>Case-by-case basis probably necessary based on </li></ul><ul><ul><li>1) Effects of the molecule (e.g., LMWH vs. interferons); and </li></ul></ul><ul><ul><li>2) Indications to be treated (e.g., RA and cancer vs. 2 different types of cancer) </li></ul></ul><ul><li>Detailed studies to support claims and render further studies unnecessary </li></ul>
  18. 19. Summary of Litigation Scheme <ul><li>Very different than Hatch-Waxman </li></ul><ul><li>NO Orange book </li></ul><ul><li>Access to Applicant’s Confidential Information, i.e., manufacturing process(es) </li></ul><ul><li>2 Litigation Tracks </li></ul><ul><li>Complicated and tight timelines </li></ul><ul><li>Some provisions are ambiguous </li></ul><ul><li>Failure to take certain actions can lead to limitations on remedies </li></ul>
  19. 20. Part 1 Litigation <ul><li>Step 1: Within 20 day of biosimilar approval, Applicant must provide biosimilar application and process of manufacture to Originator Reference Product Sponsor (RPS) so RPS can assess patent infringement </li></ul><ul><li>Step 2: Within 60 days RPS sends list of patents that can reasonably be asserted (1st patent list) and list of patents available for licensing </li></ul><ul><li>Step 3: Within 60 days Applicant identifies patents that are likely to be infringed and provide reason why invalid, unenforceable, or not infringed or state will not market until expired </li></ul><ul><li>Step 4: Within 60 days RPS rebuts Applicant’s arguments </li></ul><ul><li>Step 5: Negotiate patent list to be asserted </li></ul><ul><li>Step 6: If no agreement after 15 days , Applicant declares how many patents to be listed </li></ul><ul><li>Step 7: Within 5 days , exchange list of patents that should be subject for patent infringement </li></ul><ul><li>Step 8: Within 30 days RPS must bring suit </li></ul>
  20. 21. Part 2 Litigation <ul><li>Applicant must provide RPS with 180 days notice to market biosimilar product </li></ul><ul><li>RPS may seek preliminary injunction on any patent on the 1st exchanged list but not on the 2nd exchanged/negotiated list </li></ul>
  21. 22. FDA Rulemaking <ul><li>FDA’s goal is to implement biosimilar rules for FY 2013 </li></ul><ul><li>FDA wants to “strik[e] the appropriate balance in setting a sufficiently high bar to ensure patient safety, but not so high that the biosimilar pathway will be rendered unusable.” </li></ul>
  22. 23. FDA Rulemaking <ul><li>FDA held hearings on November 2-3, 2010 to hear from stakeholders </li></ul><ul><li>RE: clinical trials, interchangeability, extrapolation, foreign studies, naming, patient safety and pharmacovigilance </li></ul><ul><li>Do inter-batch differences (e.g., different glycoforms, different sialylation rates) constitute biosimilars? Need consistent oversight between originator and biosimilar. </li></ul>
  23. 24. FDA Rulemaking <ul><li>Likely to adopt EMA’s case-by-case basis evaluation (Kozlowski et al., NEJM , 2011) </li></ul><ul><li>Evaluate immunogenicity in a risk-based manner </li></ul><ul><li>“ Totality of evidence” </li></ul>
  24. 25. <ul><li>Questions? </li></ul><ul><li>Feel free to contact me at: </li></ul><ul><ul><li>[email_address] </li></ul></ul><ul><ul><li>http://www.linkedin.com/in/briandornphd </li></ul></ul><ul><ul><li>http://twitter.com/biotechpatent </li></ul></ul>

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