[Ip-health] Submission to WHO to Facilitate Access to Biosimilars

K.M. Gopakumar kumargopakm at gmail.com
Wed Oct 23 22:07:52 PDT 2019


*TWN Info Service on Health Issues (Oct19/04)23 October 2019Third World

*Submission To The WHO Expert Committee on Biological Standardization for
Updating of the 2009 Similar Biotherapeutic Products (SBP) Guidelines
(October 2019)*

We the undersigned thank the Expert Committee on Biological Standardization
(ECBS) for their willingness to start a discussion that will hopefully lead
to the review and update of 2009 Guidelines on the Evaluation of Similar
Biotherapeutic Products (SBPs), in line with WHA67.21 Resolution.

We acknowledge the work of the ECBS after the adoption of WHA 67.21
Resolution regarding the issuance of the supplementary guidelines and
documents on SBPs namely:

   - Guidelines on evaluation of monoclonal antibodies as similar
   biotherapeutic products (SBPs)
   - Regulatory Assessment of Approved rDNA-derived biotherapeutics
   - WHO Questions and Answers on Biosimilar products

These documents still reinforce the SBP Guideline approach requiring phase
III clinical trials for the approval of SBPs. A huge amount of evidence has
been produced since 2009 highlighting the scientific improvements on the
characterization of proteins. The technology has matured, the consensus
around best practices has increased and the methods used for the production
of different biopharmaceuticals have become highly comparable. Besides, the
hardware and ingredients used in the production are similar and sourced
from the same limited number of suppliers. Hence, any remaining
uncertainties about safety and efficacy are marginal and can be evaluated
throughout PK/PD studies, which will provide sufficient clinical evidence.
PK/PD studies should be the only clinical assays required for the marketing
authorization of SBPs. This should be clearly stated in all WHO SBP

The 2009 SBP Guidelines are based on some of the below mentioned
assumptions have become scientifically obsolete:

1.      Relatively large and complex proteins, such as biotherapeutics, are
difficult to characterize.

2.      Because of the former assumption, clinical studies are always
required to support safety and efficacy, as the clinical performance of
biotherapeutic is highly influenced by the manufacturing process.

3.      SBPs are manufactured and controlled according to their
development, and the manufacturer of an SBP normally does not have access
to all the necessary manufacturing information on the originator product.

4.      Even minor differences in the manufacturing process may affect the
pharmacokinetics, pharmacodynamics, efficacy and/or safety of
biotherapeutic products.

In this regard, we would like to make the following requests before the

*Proposal 1*

We respectfully request the ECBS to start discussing and focus on the
entire Part 10 of the 2009 SBPs Guideline, which deals with clinical
evaluation of SBPs. We suggest that it be replaced with a language clearly
explaining the circumstances that demand in-vitro surrogate efficacy
analyses, further comparability analyses for demonstration of
non-inferiority and the details of Phase I trial to address safety concerns
with an inbuilt PK /PD study.

The most frequent side effects of biotherapeutics are local reactions at
the injection site. These side effects are in most cases caused by the
formulation and not by the active molecules. Biotherapeutics have lower
toxicity because they act by binding ligands either on the surface of cells
or ligands that are free-floating in extracellular fluids, including the
blood and lymph. Unlike small molecules, biotherapeutic proteins are
degraded into amino acids (and sometimes sugars) that are normal
constituents of body metabolism. The side effects of biotherapeutics are
often the result of the pharmacodynamic effect. Hence, if the SBP has the
same potency as the RBP, their side effect profiles will be the same.

The most important development, which justifies the revision of the 2009
SBP Guideline, is the improvement in analytical methods. The methods to
analyze proteins have improved dramatically in the last decade reducing the
possibility that a difference in the clinical consequences between SBP and
RBP is missed. These methods allow full characterization of proteins, in
detail, regardless of their size and complexity. For instance, we have seen
a ten-fold increase in the sensitivity to identify different glycoforms of
glycoproteins such as those shown for epoetins and monoclonal antibodies.
This makes it possible to asses the quality and efficacy based on the
similarity of the structure without any clinical studies. (1)

However, the 2009 SBP Guideline insists on clinical studies to prove the
efficacy of the biosimilar product. The development of SBP is considered a
step-wise process. The basis of its development involves an extensive
analysis of the different batches of the RBP. Based on the physical,
chemical and biological characteristics of the RBP, a manufacturer designs
its own process aiming to have a product that is similar to the RBP.
Current WHO guidelines demand the confirmation of this similarity via
preclinical and clinical studies. However, the logic should be the
opposite; preclinical and clinical phases should not be used to confirm
findings made during the analytical phase, but to discard any major
residual uncertainties remaining from comparative characterization about
safety and efficacy. The approach by the regulatory authorities should be
that the comprehensive characterization and comparison at the quality level
are the basis for waivers or data reduction of the non-clinical and
clinical development. In other words, the more similar the product in
physical-chemical and in-vitro biological characterizations, the less is
the need for a clinical trial. In most cases, those trials are not needed
and comparative analytical characterization is enough.

In the light of the above-mentioned advancement in the science around
analytical techniques as well as the knowledge gained through the
biosimilar development, we propose the following changes in the efficacy
data requirements in 2009 SBP Guidelines:

1.      Biomolecular structure analyses have now, both technically and
empirically, established rigorously that the structural comparability
information is sufficient for regulatory purposes. Therefore, all efficacy
examination requirements should be removed from regulatory guidelines.
Detailed structural characterization requirements should be a part of the
guidelines. The demonstration of similarity in quality is sufficient to
assure the safety and efficacy of most products. The emphasis on quality
testing should focus on impurity profiles and potency.

2.      While biomolecules are indeed structurally distinct from small
molecules sufficient to cause regulatory uncertainties about structure,
their pathways of efficacy are known with certainty at the
molecular-cellular levels. Therefore, in-vitro tests examining the
triggering of molecular-cellular pathways involved in efficacy are more
than sufficient as efficacy analyses for regulatory purposes. Efficacy for
biomolecules should be evaluated in-vitro, not in-vivo, for biosimilar
macromolecules. All efficacy-directed examinations in-vivo should be
removed from the guidelines and be replaced by in-vitro test requirements.

3.      Given the demonstration of structural similarity and in-vitro
surrogate efficacy analyses, further comparability analyses for
demonstration for non-inferiority should not ordinarily be required.
However, if and where necessary, evaluation of comparative potency in
cellular-molecular analyses in vitro would be deemed sufficient for
regulatory guidelines.

4.      Immunogenicity studies are only needed if SBP does not match the
critical quality attributes related to manufacturing.

5.      Interchangeability and extrapolation to all indications should be
the default unless there are scientific reasons to deny extrapolation.

*Proposal 2*

We propose the the revision/revamping Section 10 of the 2009 SBP Guideline,
which deals with the clinical evaluation of SBP. Since the SBP Guideline
states: “Usually, clinical trials are required to demonstrate similar
efficacy between the SBP and the RBP. In certain cases, however,
comparative PK/PD studies may be appropriate, provided that 1) the PK and
PD properties of the RBP are well characterized, 2) at least one PD marker
is a marker linked to efficacy (e.g. an accepted surrogate marker for
efficacy), and 3) the relationship between dose/exposure, the relevant PD
marker(s) and response/efficacy of the RBP is established.”. This usual
requirement of clinical studies requires time and resources and effectively
compromises access to affordable biotherapeutics. Therefore our proposal in
the submission focuses on the revamping of clinical study requirements for
efficacy studies through comparative clinical trials.

Once revision /revamping of Section 10 of the 2009 SBP Guidelines is
amended, a revision of the whole text will be needed, because the dated
underlying reasoning concerning the need for confirmatory clinical trials
exists throughout the guidelines.

In the teleconference held on October 11th 2019 between the WHO staff, some
members of the ECBS and the Chair asked us to:
1) Highlight the problematic paragraphs.
2) Propose alternative language.

In the following weeks, we will provide a document that details the
problematic provisions of the 2009 SBP Guidelines and the reasons for the
proposed changes from a scientific and access perspective.

We respectfully request the ECBS to examine the document in light of the
scientific memo and the scientific evidence we already submitted, and that
the committee takes a serious consideration to review the 2009 SBP

*Proposal 3*

In the spirit of informed discussion, we request:

1.      To organize an expert consultation of experts free of conflict of
interest to be coordinated or in coordination with the Committee on
Essential Medicines and Science Division. The purpose of this expert
consultation is to have an in depth discussion on the major issues related
to 2009 SBP Guidelines especially the requirement of comparative clinical
trial, interchangeability and extrapolation etc.

2.      To make public the ECBS responses to our above-mentioned proposals
as well as those in the memo with supporting verifiable evidence.


1.      Prof. dr. H. Schellekens MD,
Ph Department of Pharmaceutical Sciences,
Utrecht University Universiteitsweg, 99
Utrecht The Netherlands

2.      Claudia Patricia Vaca González
Associate professor Medication,
Information and Power Think Tank Faculty of Sciences / Department of
Pharmacy, National University of Colombia,

3.      Dr,Satyajit Rath
Adjunct Faculty
Indian Institute of Science Education and Research (IISER)
Pune, India

4.      Carolina Gomez,
Medication, Information and Power Think Tank
Faculty of Sciences / Department of Pharmacy,
National University of Colombia,

5.      Chetali Rao, Independent Researcher, New Delhi, India

6.      K M Gopakumar, Legal Advisor, Third World Network

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