Similar But Not InterchangeableHTA for Subsequent-Entry Biologics

Philip Schwab, PhDMay 5, 20132013 CADTH SymposiumSt. John’s Newfoundland

BIOTECanada Position on SEBs

• BIOTECanada supports the development of a transparent, predictable regulatory framework for the approval of Subsequent Entry Biologic (SEB) products. This framework needs to:

• Rigorously ensure patient safety and;

• Preserve incentives for the continued introduction of innovative biologics.

Biologic Basics

Proteins, antibodies, cell therapies, blood products, vaccines, etc.

Produced in living cells – E. coli, CHO, yeast, etc.

Large molecules commonly injected into the body

Primary, secondary and tertiary structural characteristics

Slight changes in structure can affect efficacy and safety

Examples of Biologics•Inflammatory Conditions

– adalimumab (Humira)/infliximab (Remicade) – Rheumatoid Arthritis, AS, Crohn’s Disease, Psoriasis

– etanercept (Enbrel) – Rheumatoid arthritis, AS, Psoriasis– belimumab (Benlysta) – Lupus

•Chronic Diseases– erythropoietin alfa (Eprex) – anemia– insulins (Humulin, Novolin, Lantus, Levemir) – diabetes– interferon alfa-2b (Pegatron) – hepatitis C– natalizumab (Tysabri) – multiple sclerosis

•Oncology– panitumumab (Vectibix) – colon cancer– ipilimumab (Yervoy) - melanoma– filgrastim (Neupogen) – neutropenia

•Rare Diseases– glucocerebrosidase (Cerezyme) – Gaucher Disease– canak inumab (Ilaris) - cryopyrin-associated periodic syndrome – ecolizumab (Soliris) - paroxysmal nocturnal haemoglobinuria– romiplostim (Nplate) –immune thrombocytopenic purpura

Biologics Are Larger and More Complex than Pharmaceuticals

Aspirin

180 daltons

Insulin

51 amino-acids

~6,000 daltons

Somatropin

191 amino-acids

~22,000 daltons

IgG1 antibody

>1000 amino-acids

~150,000 daltons

Typical Protein Therapeutic Production Process

Different manufacturers will have different processes …

gene sequence

START

vector host cell

fermentation/culture

conditions

Formulation and

filling process

EN

D

Will result in distinct

biophysical characteristics

What Is a Subsequent-Entry Biologic?

Health Canada has issued “guidance for sponsors” regarding the approval process for Subsequent-Entry Biologics (SEBs)

A SEB is a biologic drug that would enter the market subsequent to, and ‘similar’ to an innovator product authorized for sale in Canada.

A subsequent entry biologic relies in part on prior information regarding safety and efficacy that is deemed relevant due to the demonstration of similarity to the reference biologic drug. (Health Canada Guidance)

Health Canada considers a SEB as a “new drug” and not bioequivalent to the reference product.

Canada has one approved biosimilar “Omnitrope (somatropin)”

Health Canada SEB Guidance

• SEBs are not “generic” biologics

• High Standard for Similarity – Full CMC + comparability

• Clinical Trials Always Required

• Preference for “Equivalency Trials.”

• Strong Post-Market Surveillance/Risk Management Plan

• SEB is regulated independent of reference product once approved

• No declaration of bioequivalence

CADTH’s Role in SEBs

Before reviewing Omnitrope, the CDR initiated a pilot project for reviewing SEBs, recognizing that SEBs are a new category of Health Canada submissions with different data requirements

Purpose: to determine requirements for submissions, establish review framework, and learn about Health Canada’s approach

Submissions need to include a comparison with similar products currently marketed in Canada

CADTH will evaluate the pilot project after three SEB reviews.

CEDAC Advice for Omnitrope

“CEDAC’s advice is that drug plans consider a similar reimbursement policy

for Omnitrope as for other growth hormone products.”

– Limited Clinical Data: Omnitrope efficacy was compared to Genotropin, a product that is not marketed in Canada, in an 89 patient, 4 arm, open label, 9 month study in children.

– Indication Extrapolation: No clinical data was submitted in support of the adult indication and no references were provided for the meta analysis.

– Safety Differences:

• 57% of the Omnitrope patients developed anti-growth hormone antibodies vs. 2% for Genotropin.

• Hypothyroidism occurred 3.5x as often in the Omnitrope group vs. the Genotropin group.

– Uncertain Cost Advantage: In the treatment of children, Omnitrope is less expensive than other somatropins, although the extent of the cost savings depends on a patient’s weight.

All classes of EU marketed biosimilars have robust sales growth

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A high-level “reset” is probably needed to align broader expectations around the potential value of current biosimilars …

Total healtcare

spend

Total spend on non-

pharma

Total spend on

pharmaceuticalsTotal biologic spend

Biologic off-patent

spend exposed to

biosimilar

competition

Series1 1,212,872,081,463 1,065,125,798,544 147,746,282,919 29,972,671,530 1,039,346,508

0

200

400

600

800

1,000

1,200

1,400

Billio

ns

2010: Composition of health care spend in EU-27

Source: IMS, supplied to EuropaBio in October 2012

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