CLINICAL DEVELOPMENT OF BIOSIMILARS IN INDIA

Dr. Bhaswat S. Chakraborty Sr. VP & Chair, R&D Core

CommitteeCadila Pharmaceuticals Ltd.

Presented at the “Regulatory Requirements for Biopharmaceuticals – From Science to

Commercialization’’, C-CAMP, Bengaluru, Oct. 15, 2015

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CONTENTS Understanding the latest clinical trials regulatory

guidelines as per DCGI and ICMR (IND Committee)

Clinical requirements to demonstrate Safety, Efficacy and immunogenicity  parameters of Biosimilars

Clinical trial documentation standards for Biosimilars

The Pharmacovigilance (PV) requirements2

REGULATORY MECHANISM IN INDIA Legal:

Drugs and Cosmetics Act 1940 and Rules 1945 Patent Act of India 2005 Amendment

Regulatory: Schedule Y of the Drugs and Cosmetics Act Indian regulation for Clinical Studies by DCGI (CDSCO)

Guidelines: CDSCO Guidelines Indian GCP Guidelines ICMR Guidelines DBT Guidelines

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CURRENT D&C ACT: AMENDED UP TO 2005 Chapter I: Introductory – scope, definitions etc. Chapter II: The Drugs Technical Advisory Board, The Central

Drugs Laboratory & The Drugs Consultative Committee Chapter III: Import of Drugs & Cosmetics Chapter IV: Manufacture, Sale and Distribution of Drugs and

Cosmetics Chapter IVA: Provisions Relating to Ayurvedic, Siddha &

Unani Drugs Chapter V: Miscellaneous Schedules including Schedule M (2001) and Schedule Y

(2005) 4

MAJOR AMENDMENTS IN 2013 BILL Insertion of 3 subchapters

Chapter 1A – Constitution of Central Drugs Authority (expanded multi-level authority)

Chapter 1B – Clinical Trials (permission & penalties) Chapter IIA – Import, Manufacture, Sale, Distribution and

Export of Medical Devices The proposed changes in this bill and a few other

changes are still being publicly debated as D&C Amendment 2015; likely to be passed this year

Industry has already started following the directives

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OVERSEEING AUTHORITIES OF CTS IN INDIA Apex Committee (Chaired by Secretary, Ministry of Health and

Family Welfare) for supervising and monitoring the CTs in India Assisted by the Technical Committee for evaluation and input related

to clinical trials to the Apex Committee For clinical trials allowed by the DCG(I)

The NDACs evaluate non-clinical (including pharmacological toxicological data & clinical trial data (Phase I, II, III, and IV) etc. for approval of NCEs or NBEs to be introduced in the country for the first time including vaccines and r-DNA products Assessment of Risk vs. Benefit to the patient Innovation vis-à-vis existing therapeutic option Unmet medical need in India

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APPLICABLE REGULATIONS & GUIDELINES FOR BIOSIMILARS Recombinant DNA Safety Guidelines, 1990 Guidelines for generating preclinical and clinical data for rDNA

vaccines, diagnostics and other biologicals, 1999 CDSCO guidance for industry, 2008:

Submission of Clinical Trial Application for Evaluating Safety and Efficacy Requirements for permission of New Drugs Approval Post approval changes in biological products: Quality, Safety and Efficacy

Documents Preparation of the Quality Information for Drug Submission for New Drug

Approval: Biotechnological/Biological Products Guidelines and Handbook for Institutional Biosafety

Committees (IBSCs), 201113

PRINCIPLES OF DEVELOPING BIOSIMILARS

Biosimilars are developed through sequential characterization studies revealing the molecular and quality attributes comparable with reference biologic

Although the extent of testing of the biosimilar is less than that for the reference, but be sufficient to ensure acceptable levels of safety, efficacy and quality

A reduction in data requirements is possible for preclinical & clinical development program Demonstration of comparability with reference & onsistency in production

process Any significant differences in safety, efficacy and quality studies

would require a more extensive preclinical & clinical evaluation The product will not qualify as a similar biologic

If the reference has more than one indication, the efficacy and safety of the biosimilar has to be justified and may be demonstrated separately for each indications

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PRINCIPLES OF DEVELOPING BIOSIMILARS

Integration of Information to Biosimilarity15

THE REFERENCE BIOLOGIC The reference biologic should be licensed in India

The innovator product If not marketed in India, it should be licensed and

widely marketed for 4 years post approval in innovator & regulated jurisdiction

The same reference should be used throughout For safety, efficacy and quality studies of biosimilar Same route of administration of biosimilar & reference

The active ingredient of the reference & biosimilar must be shown to be similar

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DATA REQUIREMENTS FOR CLINICAL DEVELOPMENT Pharmacokinetic studies Pharmacodynamic studies Confirmatory safety and efficacy study Safety and immunogenicity data Extrapolation of efficacy and safety data to

other indications

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PHARMACOKINETIC (PK) STUDIES PK studies performed in healthy volunteers or patients to

demonstrate the similarities in PK characteristics between biosimilar & reference

Design: Single dose, comparative, PK studies Parallel arm or Cross over Multiple dose, comparative parallel arm steady state PK studies

Other design of comparative PK takes the following factors into consideration: T1/2 ; Linearity/non-linearity of PK; • Endogenous levels and

diurnal variations of the biosimilar (if applicable); Conditions and diseases to be treated; • Route(s) of administration; & Indications

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SINGLE DOSE COMPARATIVE PK STUDIES Comparative PK Study (Studies)

Dosage studied should be within the therapeutic dose range of reference Appropriate rationale for dose selection RoA: to detect differences with the largest sensitivity Sample size: statistically justified Comparability limits defined and justified a priori

Analytical method: Validated wrt specificity, sensitivity and dynamic with adequate accuracy

and precision Detects and follows the time course of the parent &/or degradation

products) in a complex biological matrix that contains many other proteins Similarity in terms of absorption / bioavailability of B & R

But also differences in elimination kinetics (e.g., CL & T1/2) A parallel arm design is more appropriate for:

Biologics with a long T1/2 ; proteins for which formation of antibodies is likely; or patient PK studies

For short T1/2 biosimilars, justified cross over design may be OK 19

MULTIPLE DOSE COMPARATIVE PK STUDIES Multiple-dose, comparative, parallel arm steady

state PK studies are required For a biosimilar used in a multiple dose regimen Where a markedly different (higher or lower)

concentrations are expected at SS than that expected from SD PK measurements

Where dose- & time-dependence PK may exist Multi-dose comparative PK studies may not be

required with adequate justification

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COMPARATIVE PHARMACODYNAMIC (PD) STUDIES Comparative, parallel arm or cross-over, PD study in patients or healthy

volunteers: For detecting differences between biosimilar & reference If a PD marker is available, study in healthy volunteers can be done Comparative PD studies are recommended when the PD properties of

reference are well characterized with at least one PD marker being linked to the efficacy of the molecule

Dose-Response & marker relationships of the reference should be well established to justify the design

Acceptance ranges for similarity in PD parameters should be predefined & justified.

PD study can also be a part of Phase III clinical trials wherever applicable

PD parameters Clinically relevant Surrogate markers be clinically validated

If PK/PD relationship exists & characterized, Combined PK-PD studies can be done 21

CONFIRMATORY CLINICAL S&E STUDY One or more comparative S&E trial in relevant patient population is

mandatory for all biosimilars Biosimilar will be treated as a “stand-alone product” if not comparable

with reference in preclinical & PK/PD studies (>1 CT may be needed) Exception of requiring both S&E; e.g. recombinant human soluble insulin

products: only clinical safety Efficacy and primary efficacy endpoints:

Design & clinical comparability margins of the primary efficacy endpoints should be carefully chosen

Be justified on clinical grounds Equivalence trials with lower and upper comparability margins are

preferred Non-inferiority trials when required must be clearly justified &

consulted with CDSCO a priori to study initiation Sample sizes should have statistical rationale and power;

comparability limits defined and justified22

CONFIRMATORY CLINICAL S&E STUDY.. Safety:

A separate Ph1 safety study is not required Nature, severity & frequency of AEs should be compared

between B & R Based on safety data from a sufficient number of patients

treated for an acceptable period of time Sufficient number of patients should be treated for

acceptable period of time to allow detection of significant differences in safety between B & R

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WAIVER OF CONFIRMATORY CLINICAL S&E STUDY If structural and functional comparability of B & R can be

characterized by well validated physicochemical and in vitro techniques

The biosimilar is comparable to reference in all preclinical evaluations

PK / PD study has demonstrated comparability and Preferentially done in in-patient setting With safety measurement (including immunogenicity) for

adequate period justified (from efficacy studies) With a comprehensive post-marketing risk management plan

That will gather additional safety data with an emphasis immunogenicity data

The confirmatory clinical S&E study study cannot be waived if there is no reliable and validated PD marker 24

SAFETY AND IMMUNOGENICITY DATA Both pre-approval and post-approval safety assessment for

biosimilars Pre-approval safety assessment:

Comparative pre-approval safety & immunogenicity data is required for biosimilars for which confirmatory CT waiver given

Pre-approval safety data: absence of any unexpected safety concerns.

Proposed non-comparative post-marketing study And comparative pre-approval data (adequate patients and time)

and published data on the reference provide a comprehensive evaluation of safety of the biosimilar

For immunogenicity & reactogenicity Assay using the same platform technology, the same reagents under

the same assay conditions is best25

EXTRAPOLATION OF EFFICACY AND SAFETY DATA TO OTHER INDICATIONS Extrapolation of S&E data of an indication for which clinical

studies done of a biosimilar to other clinical indications may be possible if: Similarity wrt quality has been proven to reference Similarity wrt preclinical assessment has been proven to

reference Clinical safety and efficacy is proven in one indication Mechanism of action is same for other clinical indications Involved receptor(s) are same for other clinical indications

New indication not mentioned by innovator will be covered by a separate application.

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REQUIREMENTS FOR APPROVAL: EXAMPLES

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POST-MARKET DATA FOR BIOSIMILARS Risk Management Plan

To monitor and detect both known inherent safety concerns & unknown potential safety signals

Pharmacovigilance Plan PSURs every 6 months for the first 2 years after approval and annually

for subsequent 2 years ADR Reporting

All cases involving serious unexpected ADRs must be reported to the licensing authority within 15 days of initial receipt of information

Post Marketing Studies (PMS) At least one non-comparative post-marketing clinical study with

focus on safety & immunogenicity Designed to confirm that the biosimilar does not have therapeutic

consequences of unwanted immunogenicity If immunogenicity is evaluated in clinical studies, no

additional non-comparative Post-market immunogenicity studies

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PATIENTS WITH NAB CAN DEVELOP PRCA

PRCA = Pure Red Cell Aplasia or Aplastic Anemia

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POST-APPROVAL COMMITMENT [EXAMPLE]

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ARCHIVING OF DATA Applicant should archive all the data up to clinical evaluation

for a period of at least five years after marketing approval in India

Archiving site should be indicated in the study protocols and reports Archived material should also be mentioned They include test substance, vehicle, plasma / serum, tissues,

paraffin blocks, microscope slides, documents, electronic material etc and the individual durations (e.g.test material until date of expiry)

Archivist and their associates should be approachable for inspection or retrieval when required & indicated in the study report

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CONCLUDING REMARKS Recent changes in D&C Regulations & SC directives are

progressive and have made many things transparent CDSCO and DBT guidelines are clear and more or less

harmonized with international standards Differences between Biosimilar & Reference would

affect the Biosimilar’s potency, Clinical & PK characteristics and safety profile

A particular Biosimilar might never be interchangeable with the Reference

Demonstrate clinical biosimilarity through immunogenicity, PK & PD and clinical outcomes

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Thank You