Clinical trials for regulatory approval of biosimilars Shravanti Bhowmik M.D. Clinical Research Sun Pharma Advanced Research Company Clinical trials for regulatory approval of biosimilars 11 Oct 2012

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 11 Oct 2012

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 11 Oct 2012

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. 11 Oct 2012

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Applications (Sep 2012) EU has approved 14 (of 15 ) biosimilar products Filgrastim (7) Epoetin (5) Somatropin (2, one withdrawn) Follitropin alfa Insulin human Infliximab 11 Oct 2012

Worldwide status 91 registered/ launched 42 in phase 3 trials India 43 12 3 1 Brazil 7 4 China 18 2 Japan US 8 5 Ref: Citeline, Oct 2012 11 Oct 2012

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) 11 Oct 2012

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 11 Oct 2012

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 11 Oct 2012

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 than Neupogen 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 of needed 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 11 Oct 2012

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) 11 Oct 2012

Case Study: Alpheon (refusal: 2006, BioPartners GmbH)…….(2) 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. 11 Oct 2012

Case Study: Alpheon (refusal: 2006, BioPartners GmbH)…….(3) 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 11 Oct 2012

Case Study: Alpheon (refusal: 2006, BioPartners GmbH)…….(4) 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 11 Oct 2012

Case Study: Alpheon (refusal: 2006, BioPartners GmbH)…….(5) 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 11 Oct 2012

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 11 Oct 2012

11 Oct 2012