Subsequent Entry Biologics

A payers perspective

Dr. Micheal GuirguisAlberta Blue Cross

Disclaimer

• The views and opinions expressed are those of the presenter and not of his employer ABC Benefits Corporation (Alberta Blue Cross). Alberta Blue Cross neither endorses nor supports the presenters views or opinions.

Main Perspective

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Main Perspective

• Lower drug costs ---- but is it at all costs?

Generics - Clear Path

Small Molecule Generics

• Payers have driven the switch to generics

• In addition they have tried to force generic drug prices down, in line with the global market

• On this is based on a single assumption ….

Small Molecule Generics

• Bioequivalence --- Interchangeability with the higher cost brand

• In most cases we can ensure that small molecule generics are therapeutically equivalent to the brand product.

Subsequent Entry Biologics - Not So Clear

Rewards

• In 2004, sales of over US$20 billion for biopharmaceuticals represented by:

Insulin

Epoetin

GH

Colony stimulating factors

Interferon α/β

ROGER ET AL JOURNAL OF CLINICAL PHARMACY AND THERAPEUTICS 2008 33:459-464

Market Place

n engl j med 358;8 www.nejm.org february 21, 2008 845

to rely on results from the original new-drug applications.27 The process for abbreviated new-drug applications applies if the products are bio-equivalent, and the 505(b)(2) process might apply, for example, for slight differences in dose or formulation, changes in route of administration, or combination products.28,29 However, the Hatch–Waxman Act explicitly amended only the FFDCA — not the PHSA. Congress probably did not in-tend to include the PHSA because, by 1984, Hu-mulin was the only approved recombinant pro-tein and the modern biotechnology industry did not yet exist.1 As a result, there is no stream-lined process to approve a follow-on version of a protein product under the PHSA.

pas t experience with follow- on proteins

Follow-on recombinant proteins may arise from separate manufacturing processes and differ in master cell line, processing and purification, inert ingredients, and packaging. Opponents of accel-erated approval mechanisms for follow-on pro-tein products believe, regardless of rigorous phys-icochemical characterization of the protein, that the “process is the product,” because even small and seemingly insignificant manufacturing chang-es could theoretically contribute to differences in protein folding, aggregates, and glycosylation, which might manifest clinically as decreased ef-ficacy, altered pharmacokinetics, or increased immunogenicity.22,30

Nevertheless, in a few cases, follow-on protein products have been reviewed and approved under the Hatch–Waxman Act. In July 2003, Sandoz sought approval under section 505(b)(2) for Om-nitrope, a recombinant human growth hormone (somatropin) that is structurally identical to Pfi-zer’s Genotropin, which itself was approved un-der a 1995 new-drug application. As part of its application, Sandoz submitted chemical data, bio-assays in hypophysectomized rats, safety studies in rats and rabbits, human pharmacokinetic stud-ies, and results of phase III studies.31 After a year of deliberations, the FDA decided it was unable “to reach a decision on the approvability of the application because of unresolved scientif-ic and legal issues.”32 Sandoz sued, and in 2006, a District Court instructed the FDA to end its “marathon round of keep-away” and make a de-cision about the product.33

The FDA ultimately approved Omnitrope, allow-ing an abbreviated pathway only because human growth hormone had been historically regulated under the FFDCA.34 The FDA also acknowledged that a comparison of “end products of different manufacturing processes” was possible in select cases because of “improvements in the availabili-ty and sophistication of analytical techniques.”31 Specifically, Omnitrope was approvable because it had numerous favorable scientific characteris-tics: for example, it had a well-characterized pro-tein structure (including primary, secondary, and tertiary structures), a known mechanism of ac-tion, a lack of glycosylation, and a “long and well-documented history of clinical use” with a “safety and efficacy profile . . . thoroughly de-scribed in the literature.”31,34

The FDA made clear that its decision applied only to follow-on versions of reference proteins approved under the FFDCA; the agency did not comment on “more complex and less well under-stood” proteins or those approved under the PHSA.31 In 2005, the FDA approved two more follow-on recombinant versions of nonrecombi-nant-protein products that were originally ap-proved under the FFDCA: recombinant salmon calcitonin (Fortical)35,36 and recombinant hyal-

Health Law, Ethics, and Human Rights

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Figure!1.!Total!Spending!by!Nonfederal!Hospitals!and!Percent!Annual!Expen-ditures!for!the!Four!Most!Popular!Classes!of!Protein!Therapeutic!Products,!2002–2005.

The bars represent the aggregated annual hospital pharmaceutical spend-ing on erythropoietins (epoetin alfa [Procrit, Epogen] and darbepoetin alfa [Aranesp]), granulocyte colony-stimulating factors (pegfilgrastim [Neulasta] and filgrastim [Neupogen]), the anti–tumor necrosis factor antibody inflix-imab (Remicade), and the anti-CD20 antibody rituximab (Rituxan). The solid line represents the percent annual hospital pharmaceutical expenditures arising from these four drug classes.8-11

Copyright © 2008 Massachusetts Medical Society. All rights reserved. Downloaded from www.nejm.org at UNIVERSITY OF ALBERTA LIBRARY on March 25, 2009 .

N ENGL J MED 358;843 WWW.NEJM.ORG FEBRUARY 21, 2008

Potential Savings

• European Generics Medication Association estimates the Biosimilars could save over US$ 2 billion for European Health Providers ….

•

ROGER ET AL JOURNAL OF CLINICAL PHARMACY AND THERAPEUTICS 2008 33:459-464

Potential Savings

• European Generics Medication Association estimates the Biosimilars could save over US$ 2 billion for European Health Providers ….

• If there is ....

ROGER ET AL JOURNAL OF CLINICAL PHARMACY AND THERAPEUTICS 2008 33:459-464

Potential Savings

• European Generics Medication Association estimates the Biosimilars could save over US$ 2 billion for European Health Providers ….

• If there is.... Scientific foundation ... for ...

ROGER ET AL JOURNAL OF CLINICAL PHARMACY AND THERAPEUTICS 2008 33:459-464

Subsequent Entry Biologics

• Is there the scientific foundation of therapeutic equivalence?

Subsequent Entry Biologics – Health Canada

• The similarity comparison does not address the issue of therapeutic equivalent.

• Some of the essential data is generate within the submission, but no declaration is provided.

Subsequent Entry Biologics - CDR

• CDR review, provides “advice” to government payers.

• Systematic review does not provide a declaration of therapeutic equivalence.

Subsequent Entry Biologics – Steps forward

• CDR – review needs to examine the therapeutic equivalence to the reference product

• Health Canada – may need to encourage the design of studies that establish therapeutic equivalence

• Manufactures – provide evidence in submission that directly address the question of therapeutic equivalence

• And ...

Follow - on - Proteins

• What does the FDA and Congress do?