Download - Shravanti Bhowmik M.D. Clinical Research Sun Pharma Advanced Research Company 1 11 Oct 2012
11 Oct 2012
CLINICAL TRIALS FOR REGULATORY APPROVAL OF BIOSIMILARS
Shravanti Bhowmik M.D.Clinical ResearchSun Pharma Advanced Research Company
1
11 Oct 2012 2
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 3
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 4
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 5
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withdrawn)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 6
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
11 Oct 2012 7
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 8
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 9
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 10
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
11 Oct 2012 11
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 12
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)
11 Oct 2012 13
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)
11 Oct 2012 14
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)
11 Oct 2012 15
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)
11 Oct 2012 16
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 17