Biosimilars Law in Flux:An Update on U.S. Biosimilars

Brian Dorn, Ph.D.

What we will cover

• Current landscape: definitions, patent expirations, players, global activity

• Pathways for approval

• Summary of US Biosimilar legislation and FDA regulations

Definitions• Originator molecule: biological molecule developed by

an innovator and approved for use• Biosimilar: biological molecule that is highly similar in

structure and function to a reference originator molecule• Biobetter: biological molecule similar to a reference

biological molecule but has structural change that affects safety, purity, or potency

• Comparability: changes to manufacturing processes of reference originator molecule or clinical studies comparing biosimilar to reference originator molecule

• Interchangeability: biosimilar is interchangeable with reference if the biosimilar can be switched with reference without causing safety, efficacy or immunogenicity

• Exclusivity: market vs. data

US Patent Expirations2007-2018

• Growth factorsNeupogen (2008/2009), Neumega (2011), Aranesp (2014), Epogen (2014), Procrit (2014), Neulasta (2015)

• InsulinHumulin (2008/2009), Novolin (2008/2009), Humalog (2013), Novolog (2014), Lantus (2015)

• InterferonsInfergen (2009), Betaseron (2007), Avonex (2013)

• Coagulation factorsNovoseven (2010), Kogenate (2011)

• AntibodiesAvastin (2018), Remicade (2012), Rituxan (2013), Synagis (2015), Tysrabi (2017), Humira (2016)

• Fusion proteinsEnbrel (2014)

Date of First Approval

• 1980’sHumulin, Epogen, Procrit

• 1990’sNeupogen, Neumega, Novolin, Humalog, Infergen, Betaseron, Remicade, Rituxan, Synagis, Novoseven

• 2000-20102000 - Enbrel, Lantus, Novolog, Kogenate

2002 – Humira

2004 – Avastin, Tysrabi

US Regulatory Pathways

• FDCA, 21 USC § 505: FDA regulates small molecule drugs, hormones, synthetic peptides, LMWHs and approves generic versions thereof

• Biological products regulated through PHSA, 42 USC § 262

US Regulatory Pathway Options

• 505(b)(1) NDA• 505(b)(2), Reliance on innovators

data possible but limited categories of biologicals (hormones and insulin): Omnitrope

• 505(j) ANDA: Lovenox• BLA: Filgastrim, biobetters• New biosimilars pathway - amends

PHSA but FDA developing regs

ANDA: Lovenox

• 505(j) ANDA

• Not a biologic, but a complex macromolecule

• Sandoz gets approved through ANDA process without clinical trials of safety and efficacy (relied on RLD)

505(b)(2): Omnitrope

• Applicant desires to market drug that is modified relative to the Brand product that does not permit an ANDA filing

• Relied on Pfizer’s Genitropin data

• Differences: sequence of plasmid, diluent used to reconstitute product, delivery system, dosing

505(b)(2): Omnitrope

• Sued FDA to get a decision

• FDA did not rely on manufacturing data but did use non-clinical toxicology, clinical trials, pharmacokinetic and pharmacodynamic data

• FDA found Omnitrope “sufficiently similar”

BLA: Teva Filgastrim

• Filing in US in 2009; On sale in Europe since 2008

• 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

• FDA is requiring more information but no new clinical trials

• 12 year exclusivity does not apply and clinical trial data is expected to be comparable

US Biosimilar Law in Limbo

• Passed and signed in 2010• FDA Hearing Nov. 2010• Constitutional Questions• Exclusivity Periods

- 12 Year Market vs. Data- 12 Years vs. 7 Years

• Regulations expected by the end of this year

Regulatory Process has Two Categories with Different

Requirements “Biosimilar” or “Biosimilarity” means(A) highly similar notwithstanding minor differences in

clinically inactive components; and(B) No clinically meaningful differences in terms of safety,

purity, and potency“Interchangeable” or “Interchangeability”• 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

• May be substituted without intervention of the health care provider

First Approved Interchangeable Biosimilar

Gets Market Advantage No determination Second Biosimilar is

interchangeable until Earlier of• 1 year after 1st commercial marketing

after approval as interchangeable;• 18 months after final court decision(s)

or dismissal(s) on all patents in suit; or• 42 months after approval of the 1st FOB

if 1st applicant still has litigation pending; or

• 18 months after approval of 1st FOB if 1st applicant has not been sued.

Biosimilar Application Requirements

• Data to show proposed product biosimilar/interchangeable (analytical, animal, and clinical studies); ***waivable

• Same mechanism as Originator Reference Product

• Labeling has been previously approved for Originator Reference Product

• Same route of administration, dosage form and strength

• Facilities: assure that product is safe, pure, and potent

Studies in Support of Biosimilar Application

• Analytical studies showing product is highly similar

• Animal studies (including toxicity)• Clinical studies showing safety, purity,

and efficacy including immunogenicity as compared to reference originator drug

• 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

Extrapolation

• Will FDA allow extrapolation of administering a biosimilar for 1 indication to multiple indications?

• Case-by-case basis probably necessary based on1) Effects of the molecule (e.g., LMWH vs.

interferons); and

2) Indications to be treated (e.g., RA and cancer vs. 2 different types of cancer)

• Detailed studies to support claims and render further studies unnecessary

Summary of Litigation Scheme

• Very different than Hatch-Waxman

NO Orange book• Access to Applicant’s Confidential

Information, i.e., manufacturing process(es)

• 2 Litigation Tracks• Complicated and tight timelines• Some provisions are ambiguous• Failure to take certain actions can lead to

limitations on remedies

Part 1 LitigationStep 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

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

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

Step 4: Within 60 days RPS rebuts Applicant’s argumentsStep 5: Negotiate patent list to be assertedStep 6: If no agreement after 15 days, Applicant declares how

many patents to be listedStep 7: Within 5 days, exchange list of patents that should be

subject for patent infringementStep 8: Within 30 days RPS must bring suit

Part 2 Litigation

• Applicant must provide RPS with 180 days notice to market biosimilar product

• RPS may seek preliminary injunction on any patent on the 1st exchanged list but not on the 2nd exchanged/negotiated list

FDA Rulemaking

• FDA’s goal is to implement biosimilar rules for FY 2013

• 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.”

FDA Rulemaking

• FDA held hearings on November 2-3, 2010 to hear from stakeholders

• RE: clinical trials, interchangeability, extrapolation, foreign studies, naming, patient safety and pharmacovigilance

• Do inter-batch differences (e.g., different glycoforms, different sialylation rates) constitute biosimilars? Need consistent oversight between originator and biosimilar.

FDA Rulemaking

• Likely to adopt EMA’s case-by-case basis evaluation (Kozlowski et al., NEJM, 2011)

• Evaluate immunogenicity in a risk-based manner

• “Totality of evidence”

Questions?

Feel free to contact me at:

bdorn@merchantgould.com

http://www.linkedin.com/in/briandornphd

http://twitter.com/biotechpatent