11 Oct 2012

CLINICAL TRIALS FOR REGULATORY APPROVAL OF BIOSIMILARS

Shravanti Bhowmik M.D.Clinical ResearchSun Pharma Advanced Research Company

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Agenda

Clinical trials for regulatory approval of biosimilars (guidelines)

Challenges in trial endpoints Effects of trial population composition on

outcomes Acceptance of data generated in emerging

markets for registrations in developed markets Optimizing resources and time utilized

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Guidelines

EMA: 2005 WHO: 2009 USA: Feb 2012 (draft) India: May 2012 Brazil,: dual pathway for approval

of biosimilar products, permitting product approval with abbreviated non-clinical and clinical data

Korea ,Singapore, Australia: follow EMA

Cuba, Canada , Japan : guidelines similar to EMA & WHO.

Malaysia , Thailand: guidelines based on the WHO

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What guidelines generally require…

Clinical comparability studies should use the most sensitive model to detect differences between SBPs and RBPs, and clinical trials should be powered adequately to demonstrate equivalence (ideally) or non-inferiority.

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EU

Approvals till date…Applications (Sep 2012)

EU has approved 14 (of 15 ) biosimilar products

Filgrastim (7) Epoetin (5) Somatropin (2, one

withdrawn)

Follitropin alfa Insulin human Infliximab

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Worldwide status

91 registered/ launched 42 in phase 3 trials 13 in phase 2 trials 30 in phase 1 trials

registered/ launched

phase 3 Phase 2 Phase 1

India 43 12 3 1

Brazil 7 4 0 3

China 18 7 2 2

Japan 2 1 0 1

US 4 8 5 7

Ref: Citeline, Oct 2012

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Case Study: Nivestim (approval: 2010, Hospira UK)…….(1)

RLD: Neupogen (Filgrastim, recombinant human G-CSF)

Indication: reduction in the duration of neutropenia and the incidence of febrile neutropenia in patients treated with established cytotoxic chemotherapy

MAA: Feb 2009; approval: Mar 2010 Took scientific advice from CHMP: 2005/2006

(CHMP released guidance for rG-CSF in 2005)

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Case Study: Nivestim (approval: 2010, Hospira UK)…….(2)

In vitro in vitro cell based bioassay receptor-binding assay

In vivo PD (ANC counts), PK, immunogenicity

(antibody assessment ), toxicity in neutropenic rodents- repeat dose toxicity (1 study)

Local tolerance in rabbits

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Case Study: Nivestim (approval: 2010, Hospira UK)…….(3) Clinical

Two phase 1 studies (healthy volunteer, PK, PD, safety) Single dose (N=44) x iv or sc Multiple dose (N=48) x 5 days x sc injection Primary endpoint : AUC (0- t last) Secondary endpoints: Cmax and others, ANC BE limits: 0. 80-1.25

One phase 3 study for therapeutic equivalence, immunogenicity of Nivestim and Neupogen in the prophylaxis of neutropenia in patients undergoing a myelosuppressive chemotherapy regimen (N=250) Ca Breast receiving Doxorubicin + Docetaxel 6 cycles, 3 weekly Primary endpoint: duration of severe neutropenia (DSN) in cycle

1 2:1 randomization, DB

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Case Study: Nivestim (approval: 2010, Hospira UK)…….(4)

Major Objections Response

Assay sensitivity not demonstrated.

Provided literature references: combination chemo induced severe neutropenia ; Gave historical evidence of sensitivity of the drug effect in the form of a comparison with the results of a similar conducted trial (Ratiograstim EPAR) - same study population, concomitant therapy, endpoints

Greater proportion of patients with severe neutropenia thanNeupogen group in Cycle 1 (77.6 % vs 68.2%) & cycle 2; DSN lasted longer

Justified with clinical relevance per severity of clinical condition of patients: incidence of febrile neutropenia, the number of infections, number ofneeded injections were similar in both groups.

• RMP submitted: CHMP had concerns over the determination of antibody formation ; presence of NAbs in patients treated with Nivestim, Routine PV accepted• Post-authorization commitments to obtain more safety data

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Case Study: Alpheon (refusal: 2006, BioPartners GmbH)…….(1)

RLD: Roferon-A (interferon alfa-2a, recombinant DNA technology)

Indication: chronic (long-term) hepatitis C in patients with e/o liver damage; to be taken with anti-viral (ribavirin)

MAA: Dec 2003; refusal: Jun 2006 Took scientific advice from CHMP: 1999 (CHMP

released guidance for interferon alfa-2a in 2009)

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CMC Multidose vial (Test) Vs pen injector (Ref) for sc use New information on the related substances/ impurities in

Alpheon emerged at a very late stage in the assessment process, thus putting into question the previous data provided and the conclusions drawn from it.

proposed shelf-life for the drug substance was not supported by adequate data

Drug product production process was not considered to be fully validated

Impurity profile different and impurities not fully characterized

Lack of comparability of the clinical trial material with product produced by intended commercial process.

Case Study: Alpheon (refusal: 2006, BioPartners GmbH)…….(2)

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Pre-Clinical In vitro study comparing the activity of Alpheon and Roferon-A in

terms of antiviral activity and induction of interferon-sensitive genes

4- week sc repeated-dose toxicity study (monkey) with PK, PD, TK, immunogenicity, local tolerance

Signals of differences between Alpheon and Roferon-A Adverse event profile Labs PK levels Highly variable data (3F/group)

Had conducted more tox studies in early 1990’s in Korea- limited importance

Case Study: Alpheon (refusal: 2006, BioPartners GmbH)…….(3)

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Clinical: 2 studies for PK (included one with PD)

PK/ PD acceptable from 2nd DB study 1 study for efficacy/safety

Included PK component, however data were highly variable

Included PD, outcome considered ‘similar’ but not ‘equivalent’

Open-label, N=360 Primary endpoint: rate of treatment

responders (patients with undetectable HCV-RNA) after 12 weeks t/t

Case Study: Alpheon (refusal: 2006, BioPartners GmbH)…….(4)

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Clinical Results Primary endpoint met However, a sub-type ‘genotype-1’ population

enrolled was 30%, compared with avg 60% infection rate in genotype-1 in EU (robustness and external validity doubts)

At end-of-observation period (72 weeks), low response compared with Ref in genotype-1

Relatively ‘young’ patients Higher AE rate (though not statistically

significant) Immunogenicity assessment method not

‘fully’ validated

Case Study: Alpheon (refusal: 2006, BioPartners GmbH)…….(5)

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Product/ Design considerations Biosimilar or ‘Biobetter’: Payer willingness for

reimbursement? May require to add outcomes that attract inclusion viz. cancer pathways

Commercial attractiveness Vs regulatory requirements…filing in EM/ EU/ US?

Biomarker endpoints ? Most approvals may require post-marketing

studies for safety/ immunogenicity

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