SAHPRA Approach To Biosimilars:Assessment & Approval

Henry M. J. Leng

Outline1. Introduction

Definitions

2. Data Requirements

2.1 New Chemical Entities

2.2 Generics

2.3 Biosimilars

3. Standard Approach to Assessment & Approval

4. Challenges

5. Proposed Approach

2

IntroductionDefinitions

3

Innovator Generic Biosimilar

The first product that contains a specific active pharmaceutical ingredient (or unique combination of APIs) that have been registered by a medicine regulatory authority on the basis of full quality, safety and clinical data, and for which the company has received a patent that protects the medicine from market competition for a defined period of time.

A pharmaceutical product, intended to be interchangeable with the innovator, manufactured without a license from the innovator company and marketed after the expiry date of the patent. Because the active ingredient is identical to that of the innovator the clinical performance of the generic medicine is accepted to be the same as that of the innovator. Consequently, the data required to register a generic are substantially lessthan that for an innovator.

It is a biological medicine that is highly similar to the reference/innovator product in terms of quality (purity and potency), safety and efficacy. Any structural differences have been shown to be clinically inactive.

Comparison of Data Requirements for Registration of NCEs, Generics & Biosimilars

BA/BE

Chemistry,

Manufacturing,

Controls

Non-clinical:•Pharmacokinetics,•Toxicology

•Safety pharmacology•Reproduction toxicology•Mutagenicity•Carcinogenicity

Clinical studies:Clinical efficacy & tolerability for ALL indications

Non-clinical:•Pharmacodynamics•Repeat dose toxicity•Local tolerance

Comparative Physico-chemical & Biological analysis

Clinical studies:Comparative efficacy & Tolerability for

ONE indication

BIOSIMILARS

Medicine registration ProcessReception

O&A

Prescreen

all

contents

Pre-

Screening

O&A

Evaluation

Check

database for

GMP status

New drug

application

-ve

+ve

O&A I&LE

Pre-reg inspection conducted

Evaluation

by P & A

Evaluation

by Clinical

Evaluation

for Naming

and

Scheduling

STOP all other

evaluations

-veGxPP comm

motion for GMP status

+ve

Evaluation

by P & A

Evaluation

by Clinical

Evaluation

for Naming

and

Scheduling

Expert commmotion

Expert commmotion

Expert commmotion

Expert commmotion

Expert commmotion

Expert commmotion

Peer review

Expert comm

Other

directorat

es

Evaluation

by BMC

Evaluation

by BMCExpert comm

motion

Expert comm

motion

Medicine registration Process

O&A I&LE

-veGXPPcommmotion for GMP status

+ve

Evaluation

by P & A

Evaluation

by Clinical

Evaluation

for Naming

and

Scheduling

Expert commmotion

Expert commmotion

Expert commmotion

Peer review comm

Expert comm Peer review resolution

-ve Resolution

on drug

registration

from peer

review for RAC

to approve

Communication

of final –ve

verdict to

applicant on

drug registration

RAC

Final Motion

from expert

comm enter

onto system

(only two

cycles

allowed)

Compilation of B6H

Resolution

on drug

registratio

n from

RAC

Communication of

final verdict to

applicant on drug

registration

Appeal

-ve+ve

Issue all certificates

Other

directorates

Appeal

amendments

Goals of “Stand-Alone” and Biosimilar Development are Different

“Stand-alone” Goal: To establish safety and efficacy

of a new product (incl. quality)

“Biosimilar”Goal: To demonstrate biosimilarity

CMC

Non-clinical

ClinicalSafety and Efficacy

(Phases 1, 2, 3)

Clinical Study for

ONE Indication

Non-clinical

CMC & Comparative Analytical & Bio-assays

The goal is not to independently establish safety and effectiveness of the Biosimilarproduct.

This has already been done with the RBP!!

Biosimilarity

It is the demonstration that a candidate SBP is highly similar to a reference biotherapeutic product (RBP) in terms of structure, function, purity and potency and that any structural or functional differences in the SBP, from that of the reference product, are not clinically meaningful.

This implies that biosimilarity is demonstrated at a physico-chemical level first and is then confirmed with non-clinical and clinical studies.

Any uncertainty of biosimilarity at the physico-chemical level between the SBP and RBP must be thoroughly addressed by clinical studies –the more uncertainty, the greater the amount of clinical data that will be required to confirm biosimilarity .

Totality of Evidence• SAHPRA has now realised that the best approach is to consider ALL the

data – quality, non-clinical and clinical data and especially the comparability data between the SBP and RBP – in the evaluation of biosimilars.

• This means that all of the evidence submitted by an applicant will be considered collectively by ONE Expert Committee in order to determine whether a high degree of biosimilarity exists between the Applicant’s product and the RBP.

• This approach, commonly referred to as the Totality of EvidenceApproach, is also used by other regulatory authorities such as the FDA .

• The current fragmented approach in which the Clinical, Biological and Pharmaceutical & Analytical Committees assess a biosimilar application separately and make recommendations based only on the scope of data packages that each committee reviewed, will cease.

• It is highly likely that one or more biosimilar applications that have been rejected by one committee could have been registered if all the data the applicant submitted were taken into consideration before such a decision was made. Usually when one committee rejects, the other committees stop their evaluation of the dossier.

• With the Totality of Evidence Approach the non-clinical and clinical data packages will now be assessed at the same time as the quality data to determine if they sufficiently address any uncertainties of high similarity at the structural and functional level – before a recommendation is made.

The New Evaluation Model For Biosimilars

Totality of Evidence Approach

PK = pharmacokineticsPD = pharmacodynamicsREMS = Risk Evaluation and Mitigation Strategy

Registration Process For

Biosimilars

11

ScreeningFinal

application

Dispatch to Quality, Biological & Clinical

evaluators

Complies

Reports to Biotherapeutics

Committee

Applicant response

Recommendation to RAC

Register

Yes

No

Accept

Back to BiotherCommittee

Complies Reject

Not accept

Return to applicant

Recommendation to applicant

Thank You