[Ip-health] WHO’s Reluctance to implement WHA Resolution Affects Access to Affordable Biotherapeutics

Malini Aisola malini.aisola at gmail.com
Thu May 16 04:15:05 PDT 2019


WHO’s Reluctance to implement WHA Resolution Affects Access to Affordable

TWN Info Service on Health Issues (May19/05), 13 May 2019, Third World

By Chetali Rao[1] and K M Gopakumar[2]

The WHO Secretariat is reluctant to implement the World Health Assembly’s
Resolution on “Access to Biotherapeutic Products including Similar
Biotherapeutic Products and Ensuring their Quality, Safety and Efficacy”
(WHA 67.21). This compromises the availability of affordable non-originator
biotherapeutics, also known as ‘biosimilars’ or ‘similar biotherapeutic
products’ (SBPs).

In 2014, the 67th World Health Assembly had adopted Resolution WHA 67.21 to
consider the access challenges emanating from the existing regulatory
pathway for SBPs. Taking cognizance of regulatory implications for SBPs on
affordability and better access to treatments of biotherapeutic drugs
Operational Paragraph 1 (3) requested the Member States: “to work to ensure
that the introduction of new national regulations, where appropriate, does
not constitute a barrier to access to quality, safe, efficacious and
affordable biotherapeutic products, including similar biotherapeutic

Most importantly, Operational Paragraph 2 (4) requested the WHO
Director-General: "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”. From this mandate it can be inferred
that the scientific reasons on which the 2009 Guidelines were based are out
of sync with the current advancements in science and technology.

However, steps taken by the WHO Secretariat since then have not been
consistent with the WHA 67.21 mandate. Instead of updating the existing
Guidelines, the Secretariat has come up with a Question and Answer (Q&A)
document providing further clarifications on the 2009 SBP Guidelines. The
Q&A document is based on selective consultations with some national
regulatory authorities and industry representatives, thereby concluding
that there was no need for the revision of the existing Guidelines.

What are Biotherapeutic drugs?

Biotherapeutic drugs (commonly referred to as ‘biologics’ or
‘biopharmaceuticals’) are drugs produced through biological processes. In
contrast to chemically synthesized small molecule drugs, biologics are
produced in living cells, are relatively large in size and are much more
complex and difficult to characterize. Biologics have several potential
advantages as they can, theoretically, be tailored to hit specific
‘targets' in the human body. Some well-known biotherapeutic products
include human insulin, erythropoietin (EPO) and monoclonal antibodies.

There is a huge market for biotherapeutic products. In 2018,
biotherapeutics accounted for 6 of the 10 top selling branded drugs in
terms of revenues. The 2017 WHO model list of essential medicines also
includes three of the top-selling biotherapeutics – trastuzumab, rituximab
and bevacizumab. The success of biologic drugs reflects their ability to
treat chronic diseases, including cancers and autoimmune disorders, much
better than existing alternatives and with fewer side effects.
Unfortunately, both accessibility and affordability of this new class of
medicines in developing countries is abysmally poor, owing largely due to
their high prices. Unlike small molecules, where generic uptake is high,
the road to uptake of similar biotherapeutic products (SBPs) is paved with
many obstacles, including but not limited to technology, intellectual
property and regulatory requirements.

Barriers to access and affordability; scientific concerns raised

Among the aforementioned obstacles for SBPs uptake, regulatory barriers are
one of the major impediments affecting their accessibility and
affordability. The current regulatory framework for SBP approvals in many
countries is in accordance with WHO’s Guidelines on Evaluation of Similar
Biotherapeutic Products (SBP Guidelines) which was adopted in 2009. Many
WHO Member States including India and South Korea have replaced their
existing SBP regulatory guidelines with new guidelines, in consonance with
the 2009 Guidelines. Regulatory requirements under the current SBP
Guidelines are plagued with many barriers to increasing the availability of
affordable SBPs in the market, the most prominent of them being clinical
trials, interchangeability and extrapolation of indications.

With regard to clinical trials, the 2009 WHO Guidelines insist on:
“Head-to-head comparison of a biotherapeutic product with a licensed
originator product with the goal of establishing similarity in quality,
safety, and efficacy. Products should be compared in the same study using
the same procedures”. Scientists from a range of countries through a
Memorandum to WHO have questioned the head-to-head comparison for SBP
approval. According to them, these clinical trials are not equipped to
detect any meaningful differences in the safety profiles of SBPs.

During the clinical development of SBPs, the interpretation of limited
differences in the product profile is extremely difficult and only a very
large cohort study may provide some meaningful information. Further, the
insistence on clinical trials makes SBP development a highly cost-intensive
and time-consuming process.

During the authors’ discussion with a company involved in SBP development,
it was revealed that the current SBP Guidelines make the development
process a highly time-consuming exercise, requiring an investment of
approximately 7 years till the commercialization stage.  Furthermore,
comparative clinical trials require 50% of the clinical subjects to be put
on the originator product. The sourcing of the originator product, which
constitutes almost 50% of the SBP developmental cost, at times becomes
extremely challenging. The financial implications of clinical trials along
with the time requirement is a major deterrent, if not a barrier, for many
companies, thus representing an obstacle to SBPs adoption and consequently
to the reduction of health care costs and accessibility.

Another barrier for the rapid adoption of SBPs and to reduce cost and
increase access of these drugs is the absence of an interchangeability
designation. Interchangeability is the inherent property of a product and a
condition for substitution that allows substituting an originator
biotherapeutic with the SBP, at the pharmacy level, without the consent of
the prescribing physician. Although interchangeability and substitution
bear a close relationship, yet they have different meanings.[3] To receive
the interchangeability designation, the manufacturer must demonstrate not
only that the SBP has a similar efficacy and safety as compared to the
originator biotherapeutic, but also that there is no greater risk in
switching between the SBP and the originator.

To impede the acceptance of SBPs in the market, the originator companies
have allegedly linked switching from an originator product to SBP with the
increased risk of immunogenicity. Immunogenicity is defined as the ability
of a substance to produce an immune response and is one of the key factors
for producing a safe biopharmaceutical drug. Immunogenicity of
biotherapeutics is a widely studied phenomenon and among some 16,000
published papers, there has been no data associating switching with
immunogenicity. No scientific evidence has been established for any
possible biological or clinical adverse effect caused by switching a
patient from an original product to its SBP.[4] In many European countries,
there are rules against substitutions; however some EU national regulatory
authorities (NRAs) have declared SBPs as interchangeable. The WHO
Guidelines do not include a statement on interchangeability of SBPs and
have left the decision to the respective NRAs. In principle, WHO’s
reservation to designate SBPs as interchangeable, has posed a major
hindrance to their rapid adoption.

In addition to interchangeability, extrapolation across indications
represents another major regulatory barrier for SBP adoption. Extrapolation
is the approval of a SBP for use in an indication that is held by the
originator biotherapeutic but not directly studied in a comparative
clinical trial with the SBP. According to the existing regulatory
framework, an SBP may be approved for all indications for which the
originator product is approved without clinical requirements, provided it
demonstrates comparable efficacy with the originator biotherapeutic
product. However, such an approval may also be denied based on scientific
justifications. On the other hand, certain scientific reasonings in the
Memorandum have countered the current regulatory framework on extrapolation
of indications.

According to the concerned scientists, one of the major characteristics of
biotherapeutic drugs is their high degree of specificity. Hence for a SBP
that is comparable in nature to the originator biotherapeutic product,
differences in clinical efficacy for different indications relative to the
originator product would be difficult to contemplate. The purpose of
introduction of SBPs was to reduce the cost of biotherapeutic products and
to make them more affordable and accessible, which was to be achieved by an
abridged procedure for regulatory approval. Such onerous dossier
requirements for regulatory submissions entail significant expenditure for
the SBP manufacturer. If such rigorous demands for extrapolation persist,
the mandate to make lower costs SBPs available to the diseased population
can never be realized.

Mandate of WHA 67.21 not followed

The WHO Secretariat provided the following justification for coming up with
a Question and Answer (Q&A) document instead of revising the 2009 SBP
Guidelines, as mandated by WHA 67.21: "In April 2015, an informal
consultation was organized during which participants from NRAs of both
developing and developed countries, as well as from industry, recognized
and agreed that the evaluation principles described in the Guidelines were
still valid, valuable and applicable in facilitating the harmonization of
SBP regulatory requirements globally. It was therefore concluded that there
was no need to revise the main body of the existing Guidelines.”

This justification itself raises certain legitimate questions. First, the
WHA 67.21 gave a clear mandate to the WHO Director-General “to convene the
WHO Expert Committee on Biological Standardization to update the 2009
Guidelines”. Thus the WHA resolution clearly tasked the WHO Secretariat to
update the SBP Guidelines, and not to have consultations to discuss and
take a decision on whether to update the Guidelines or not. What remains
unanswered is whether the mandate of the WHA can be overruled by such
informal consultations convened by the Secretariat. Legally speaking, the
WHO Secretariat cannot overrule the decision of its highest decision-making

Second, the Secretariat’s explanation is that the decision on non-revision
was taken in consultations with the NRAs and the industry. Thus the
Secretariat assumed that the NRAs are a separate entity above the Member
States and the WHA resolution may be adopted in consultations with the
NRAs. Interestingly, the 2015 informal meeting saw representation from the
industry as well. Furthermore, the manner in which the consultations were
done casts doubts on the entire process for updating the guidelines. The
Q&A goes on to state that: “WHO convened a series of meetings to identify
those parts of the Guidelines which required updating”. There is complete
paucity of public information on these series of meetings and the issues
discussed. Interestingly, the WHO Secretariat has not released any details
of the meetings, especially the 2015 informal meeting mentioned in the Q&A
including verbatim records, list of participants or the agenda of the
informal meetings.

Third, the decision of the WHO to not update the SBP Guidelines was based
not on any scientific reason but on global harmonization of the regulatory
requirements. It states: "NRAs of both developing and developed countries,
as well as from industry, recognized and agreed that the evaluation
principles described in the Guidelines were still valid, valuable and
applicable in facilitating the harmonization of SBP regulatory requirements
globally.” Harmonization has historically aimed at setting uniform
standards globally, often favouring the big companies to pursue their
commercial interests and is oblivious to the needs of the developing
countries. Consequently, it prunes the ability of developing member
countries to address their public health concerns. On the current issue at
hand, it has also faltered to underpin the needs of the developing nations
with respect to affordability and accessibility of SBPs.

In 2017, the WHO Secretariat convened an “Expert Consultation on Improving
Access to and Use of Similar Biotherapeutic Products” with the following
purpose: "WHO's support to the Member States in regard to SBPs has thus far
concentrated on the development and implementation of regulatory
guidelines, reference preparations, and nomenclature standards. Going
forward, additional types of support will be needed which may include (but
not be limited to) the development and dissemination of policy guidance and
treatment guidelines. The purpose of the consultation was to canvas the
opinion of experts to advise WHO on activities that might be prioritized to
facilitate improved access to and use of SBPs”.

The focus of this meeting was mainly on the post-marketing access. One of
the outcomes of the meeting as stated in the report was: "WHO will review
and provide clarification on the SBP 2009 guidelines to reflect
technological and analytical advances". However, the Q&A has completely
overlooked the technological or analytical advancement in the field of SBP
development and has consequently failed to address relevant concerns
regarding clinical trials, interchangeability and extrapolation of
indications, which have a major impact on accessibility and affordability.

It can thus be inferred that the WHO meetings to update the SBP Guidelines
clearly lacked a focussed discussion on their revision based on
technological advancement of characterization of SBPs. The annexed agenda
to the report neglects the analytical characterization studies in the
pre-clinical stages, which could have played a pivotal role in addressing
affordability concerns. Scientists in their memorandum have also questioned
the Q&A document. The memorandum states that: “serious concern remains
among the scientific community that presenting guidelines as a Q&A document
alone does not serve the intended purpose. A revision of the current
guidelines is still needed, as mandated by the WHA 67.21, to expand
availability of safe and effective biosimilars”.

What needs to be done

The memorandum recommends updating the Guidelines based on certain
scientific principles and to help national authorities better implement
policies to make SBPs less costly. Some of the pertinent points, apart from
the ones already incorporated in the aforementioned regulatory barriers
discussion, include the following:

·        A demonstration by an SBP exhibiting comprehensive
characterization and analytical comparison at the quality level should be
sufficient to ensure the safety and efficacy of the products;

·        Emphasis on quality testing should be focused on impurity profiles
and potency;

·        Well-defined pharmacokinetic and pharmacodynamic studies should be
sufficient (in case clinical studies are deemed necessary); immunogenicity
studies should only be conducted where the SBP does not match the critical
quality attributes related to manufacturing; and default interchangeability
and extrapolation to all indications should be permitted unless there are
scientific reasons to deny the same.

These suggestions would drastically drop the financial cost as well as the
time period for commercialisation of biosimilars.

The failure of the Expert Committee on Biological Standardisation and the
WHO Secretariat to update the SBP Guidelines to reflect the current
scientific evidence and technological advancements compromises access to
affordable biotherapeutic products, as the unnecessary requirements of the
SBP Guidelines hinder the prompt availability and accessibility of
affordable SBPs. This has grave consequences for the realization of the
right to health and the right to enjoy scientific progress and its
applications (right to science).

Another important attempt by WHO to reinforce the current regulatory
paradigm is through the pre-qualification (PQ) of SBPs. As of September
2017, 30 national regulatory agencieshave agreed to accept the SBPs PQ. As
a result, WHO prequalified products would automatically gain marketing
approval by the 30 participatory NRAs. PQ is most often used to facilitate
internationally funded procurement programs such as those of Unitaid,
UNICEF, GAVI and the Global Fund.

However, in the case of biotherapeutics, PQ is aimed at not only
facilitating the international donor sponsored tenders but also
facilitating faster regulatory approvals and harmonisation of regulatory
practices among Member States. The WHO’s plan to advance with PQ in
biotherapeutic products, based on its current SBP guidelines will
ultimately benefit the big companies to obtain easy registrations thereby
reinforcing a system which imposes strenuous conditions on SBP

It seems that WHO’s actions since the adoption of WHA 67.21 are not to
implement the resolution in its letter and spirit but to further impede the
availability of affordable SBPs in the market through regulatory barriers.
The key question that remains is whether the WHO Member States will take up
this issue in the upcoming 72nd WHA, which is to take place from 20th to
28th May 2019 in Geneva.

New Delhi, 13 May 2019


[1] Chetali Rao is an independent lawyer working on law and policy related
to biotherapeutics.
[2] K M Gopakumar is Legal Advisor to Third World Network.
[3] Schellekens, H et al. Safety and efficacy of biosimilars in oncology.
The Lancet 2016; 17(11): 502-509
[4] Ibid.

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