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