[Ip-health] Access to Biotherapeutics undermined by WHO Expert Committee

K.M. Gopakumar kumargopakm at gmail.com
Fri Dec 13 02:46:22 PST 2019


*Access to Biotherapeutics undermined by WHO Expert Committee
*By K M Gopakumar[1]
<https://twn.my/title2/health.info/2019/hi191201.htm#_ftn1> and Chetali Rao
[2] <https://twn.my/title2/health.info/2019/hi191201.htm#_ftn2>

The WHO’s Expert Committee on Biological Standardisation (ECBS)
<https://www.who.int/biologicals/WHO_ECBS/en/> has declined a request to
revise its 2009 Guidelines for the Evaluation of Similar Biotherapeutic
(WHO Guidelines), which set the requirements for the generic version of
biotherapeutics known as “biosimilars”.

The WHO Secretariat then decided to evaluate the scientific evidence to
support the revision of WHO Guidelines.  From this review the Secretariat
found procedural holes in the ECBS decision.

During its 70th meeting on 21-25 October 2019 the ECBS – which includes a
panel of experts with proficiency in developing norms and standards related
to vaccines, blood products, and biotherapeutics – considered a request
initiated by a group of scientists
<https://twn.my/title2/health.info/2019/hi191004.htm> and civil society
organisations <https://twn.my/title2/health.info/2019/hi191005.htm> (CSO)
to revise the WHO Guidelines on biosimilars.

[Therapeutic proteins from recombinant DNA technology are popularly
known as biotherapeutics, which are larger in molecular size compared to
the traditional chemical molecules.]

The executive summary
of the 70th ECBS meeting states: “Chair of the Committee communicated the
conclusions of the Committee to the WHO Assistant Director-General MVP
(Access to Medicines, Vaccines and Pharmaceuticals) who said that WHO will
evaluate current scientific evidence to support the updating of the 2009

The request was made for the WHO Guidelines to keep up with the latest
scientific evidence in order to simplify the marketing authorisation of
biosimilars as mandated under Resolution WHA 67.21 adopted by the 67th
meeting of the World Health Assembly in 2014. The Resolution called for
consideration of the access challenges emanating from the existing
regulatory pathway for similar biotherapeutic products (SBP) and requested
the Director-General of WHO “*to convene the WHO Expert Committee on
Biological Standardization to update the 2009 guidelines, taking into
account the technological advances for the characterization of
biotherapeutic products and considering national regulatory needs and
capacities and to report on the update to the Executive Board*”.

Since the adoption of the WHA resolution, efforts to revise the 2009 SBP
Guidelines were dismissed by the ECBS without citing any scientific
reasons. Following open letters from scientists and CSOs calling for a
revision, the ECBS considered this issue in its October meeting.

As in the past, the ECBS rejected the request without citing any reasons
for its decision. The Executive Summary of the ECBS meeting states: “*Following
discussion, a second letter was addressed to the ECBS Chair proposing that
the current section 10 of these WHO Guidelines, on the clinical evaluation
of SBPs, be reviewed and an independent expert consultation organized to
discuss in depth the major issues raised, particularly the requirement for
clinical trials. The Committee considered that the hypothesis that quality
data alone would be sufficient to ensure the safety and efficacy of these
products was not supported by the information provided”.*

The past two decades have seen major advancements in the development of
therapeutic proteins popularly known as biotherapeutics – both in the
market as well as in the development pipeline. Biotherapeutics are an
important class of medicines since they serve patients suffering not only
from diseases like cancer but also for those in need of novel therapies.
The latest edition
of the WHO Essential Medicines List (EML) contains 6 biotherapeutics.  In
2018, biotherapeutics accounted for 5 of the 10 top selling branded drugs
in terms of revenue.

However, not many patients have been able to access this class of drugs. In
comparison to the small molecule segment, which witnessed very steep price
erosion after the entry of generic versions, the price erosion for
biotherapeutics after the entry of their generic versions popularly has not
been steep. This is due to low generic competition in this segment due to
rigid entry barriers relating to their manufacturing and marketing

One of the most important documents that is believed to be a harbinger for
the introduction of biosimilars in the market is the WHO’s 2009 Guidelines.
This instrument was supposed to aid the entry of biosimilars in the market;
however, contrary to expectations, the Guidelines’ onerous requirements in
fact stymied their entry. The Guidelines have been adopted by many
developing countries to formulate their own regulatory pathways for
biosimilars. In compliance with the Guidelines, many developing countries,
including India, have made it mandatory to conduct clinical trials for
obtaining the relevant marketing approval.

As a consequence, a non-originator seeking marketing approval has to carry
out a Comparative Clinical Trial (CCT) consisting of 200 to 400 people to
establish the efficacy and safety of the product. Since these trials are
comparative in nature, it means that to seek marketing approval, 50% of the
clinical trial subjects are administered the originator’s product and the
remaining 50% are administered with the non-originator product. The
sourcing of the originator product, which is extremely challenging,
constitutes almost 50% of the biosimilar developmental cost, thus making it
unaffordable for most of the needy patients, especially in the developing

The current WHO Guidelines are based on a high degree of precautionary
assumptions that do not hold true after 10 years of experience in the
biosimilar area. For instance, at one place the Guidelines state: “*Even
minor differences in the manufacturing process may affect the
pharmacokinetics, pharmacodynamics, efficacy and/or safety of
biotherapeutics product”*.  Such assumptions hold little value in 2019 in
light of substantive and verifiable scientific evidence that is available
to refute the assumption.

The WHO Guidelines prescribe stepwise development of biosimilars starting
with a comparative characterisation of the molecule to prove the structural
similarity with the originator molecule. This is followed by pre-clinical
and clinical studies. According to some scientists working on biosimilar
development, scientifically speaking structural similarity translates into
functional similarity. Using the latest analytical techniques, the
characterisation exercise can establish a very close similarity with the
originator’s molecule structure.

Unlike small molecules, because of their inherent nature, protein-based
molecules cannot exhibit a 100% structural similarity. This applies equally
to both originator and biosimilar molecules. The variations are such that
even different batches of the originator may not be 100% similar to each
other.  Surprisingly, the WHO Guidelines do not accept this scientific fact
and insist on the clinical evaluation through CCTs.  They further state
that though “clinical trials are required to demonstrate similar efficacy
between the SBP and the RBP, yet in certain cases, comparative PK/PD
studies may be appropriate, provided that 1) the PK (pharmacokinetics) and
PD (pharmacodynamics) 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." In many cases, PD markers for efficacy do not exist and
hence biosimilar manufacturers are forced to carry out CCTs.

Since the adoption of the WHA 67.21 the Secretariat has shown a great
degree of resistance to amend the WHO Guidelines.  Instead of updating the
guidelines, WHO reinforced its 2009 Guidelines framework through three more
guidelines viz. Guidelines on evaluation of monoclonal antibodies as
similar biotherapeutic products (SBPs),
Assessment of Approved rDNA-derived biotherapeutics
and the WHO Questions and Answers on Biosimilar

The document “Regulatory assessment of approved rDNA-derived
biotherapeutics” is a clear example of the resistance to revise the 2009
SBP Guidelines as it states: "Products already approved under the
pre-existing regulations will need to be reassessed to ensure that they
meet the new requirements". This means that all the products that were in
the market before the adoption of the 2009 SBP Guidelines should be

The Secretariat further defended its stand by stating that the term
“update” does not mean a revision of the 2009 Guideline, arguing that the
adoption of the three documents fulfilled the obligation under the WHA
resolution. The Secretariat’s explanation compels us to state the
dictionary meaning of the term update i.e. “to change (something) by
including the most recent information”.

Following the Scientists’ Memorandum and CSO letter, the WHO
Director-General agreed to set up a process to revise the WHO Guidelines in
a letter dated 29th July 2019. First, the ECBS would review scientific
evidence related to the set of WHO recommendations for the evaluation of
SBPs regarding pharmacodynamic and pharmacokinetic studies. Second, the
Expert Committee on Selection and use of Essential Medicines (EML) would
review the evidence. Third, there would be a systematic review of all the
scientific evidence on biosimilars.

*Scientists and CSOs make formal request and presentation*

Upon request of the ECBS secretariat a formal request along with supporting
evidence was submitted to the ECBS requesting the review of the Guidelines
as mandated under WHA 67.21.  This formal submission was followed by a
teleconference on 10th October 2019. From the WHO side experts who were
part of the development of the WHO Guidelines participated in the
teleconference. However, nobody raised any question on the evidence. One of
the proposals agreed during the teleconference was to highlight the part of
the Guidelines which hampers access.

The presentation of Prof. Hubb Schellekens before the ECBS on 21st October
focused on Section 10 of the Guidelines which requires CCT for the
marketing approval of a biosimilar. The presentation was accompanied by a
written submission, which made the following proposals complementing the
Scientists’ Memorandum:

   - 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.

   - 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

   - 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.

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

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

The submission also made the following proposals:

   - 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 the 2009 SBP Guidelines, especially the requirement of comparative
   clinical trial, interchangeability and extrapolation etc.

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

During the discussions no one raised concerns on the proposal that
evaluation of comparative potency in cellular-molecular analyses *in vitro*
is enough to satisfy the efficacy requirements for the regulatory purposes.
All the questions were focused on whether CCT is required to address the
safety concerns.

[It was unfortunate that the ECBS Chair and the Secretariat denied
permission to circulate the printed version of the submission and the
supporting documents to ECBS Members at the 21st October meeting.]

Scientists from across the globe are questioning the rationale behind CCTs.
According to them, CCTs do not provide any valuable information on
efficacy, safety, and immunogenicity – the three most cited reasons for
conducting CCTs. One of the scientists from among the growing scientific
community, Francois-Xavier  Frapaise, in his paper
states that: “Clinical trials are not powered to detect meaningful
differences in the safety profiles of biosimilars, and when numerical
imbalances in adverse events are observed during clinical development of a
biosimilar, the interpretation of limited differences is very difficult,
only large cohort studies may detect differences, if there are any, in
safety parameters." Questioning the utility of clinical trials for cancer
treatment in which biotherapeutic drugs are often administered in
combination with other drugs, another scientist
Christopher J Webster explains that clinical trials are nothing more than a

Regarding efficacy aspects, the Scientists’ Memo states that the clinical
trials are of little use. Instead of clinical trials they proposed:
are of the opinion that if appropriately designed and performed such PK/PD
studies are often more sensitive to detect potential differences in
efficacy than trials using clinical endpoints. They also demand that the
efficacy should be studied in conditions providing the highest sensitivity
to detect differences. They argue for making well-designed PK/PD studies
the norm rather than the exception*”. Webster et all
writes in a recent article that “*no biosimilar  that has been found to be
highly similar to the reference by both analytical and human PK studies has
been failed to be approved  because it was found not be clinically
equivalent to its reference in a powered study”.*

Though the CSO Letter and the submission to the ECBS requested for reasons
with verifiable evidence for its decision, the executive summary does not
provide any reason or evidence for its decision.

It fact the WHO staff who is Group Lead for Norms and Standards for
Biologicals was one of authors of the 2009 WHO Guidelines. Therefore, the
consideration of the request for review by ECBS also involves procedural
lapses. Apart from the above mentioned WHO staff, at least two more persons
involved in the drafting of the WHO Guidelines attended the 70th ECBS
Meeting which considered the request for review. This  could have resulted
in the decision to maintain the status quo .

The refusal of the ECBS to provide any verifiable reason/evidence for its
conclusion and the refusal to hold an open consultation of experts shows
the non-transparent way in which it functions. The ECBS’s defence of its
indefensible position and the non-transparent way of working raises serious
questions on the accountability of WHO and ECBS. The lack of accountability
in the functioning of expert committees like ECBS gives way to a few people
holding the health of millions of people at ransom without any verifiable
evidence to support their views.+

[1] <https://twn.my/title2/health.info/2019/hi191201.htm#_ftnref1> K M
Gopakumar, legal advisor with TWN, was part of the delegation that made the
presentation before the ECBS on 21st October 2019.

[2] <https://twn.my/title2/health.info/2019/hi191201.htm#_ftnref2> Chetali
Rao is an independent researcher based in Delhi, India.

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