PHM-Exch> TWN Info: WHO Biosimilar Guidelines Are a Tepid Attempt to Improve Access and Affordability

[Gargeya Telakapalli]

Third World Network Information Service
TWN Info Service on Health Issues
15 November 2022
Third World Network, www.twn.my


*WHO Biosimilar Guidelines Are a Tepid Attempt to Improve Access and
Affordability12/11/2022 • KM Gopakumar & Chetali Rao*
https://healthpolicy-watch.news/who-biosimilar-guidelines-are-a-tepid-attempt-to-improve-access-and-affordability/

Biotherapeutic products represent a new therapeutic revolution in disease
treatment and are by far the fastest-growing segment of the pharmaceutical
industry – yet the recent biosimilar guidelines issued by the World Health
Organization (WHO) are myopic, inconsistent or vague about some
well-established scientific issues.

Biosimilar products include recombinant proteins and hormones, monoclonal
antibodies (mAbs), cytokines, growth factors, gene therapy products,
vaccines, cell-based products, gene-silencing or gene-editing therapies,
tissue-engineered products, and stem cell therapies among others.

Biotherapeutic products in the form of targeted therapies have transformed
the landscape of how diseases will be cured and alleviated in future.
Biotherapeutic products are large, complex molecules that are manufactured
through biotechnology in living systems such as microorganisms, plant or
animal cells, which results in an inherent variability amongst them. This
differentiates them from conventional small molecules which are synthesized
chemically and have the same active ingredients.


*Alarming lack of access*Monoclonal antibodies (mABs) constitute one of the
most transformative treatment regimens and have an increased dominance in
the biotherapeutic landscape. In 2021 among the top 10 selling medicine
brands, four were mABs.

However, it is alarming that looking from an access perspective, 80% of the
market for these mABs is concentrated in just three geographical areas, the
USA, Canada and Europe.

The arrival of biosimilars (non-originator’s products, like generics in the
case of small molecules) has significantly driven cost savings, improved
patient access and significant budget impact on health systems. But even
after the entry of biosimilars, the competition in the biotherapeutics
space is limited because of the heavy costs associated with setting up a
manufacturing facility, the presence of patent thickets and regulatory
barriers.

While recent developments in modular facilities have drastically reduced
the cost of establishing facilities, patent thickets and regulatory
requirements still constitute a major impediment to the successful entry of
biosimilar products.

The recently issued WHO Guidelines on Evaluation of Biosimilars, which
replace guidelines issued in 2010, focus on removing some of the regulatory
barriers affecting the cost of production of biosimilars, such as the
waiver for comparative efficacy trials.

Despite the WHO’s revisions, the biosimilar guidelines remain myopic,
inconsistent or vague about certain other well-established scientific
issues. These, if not addressed, will continue to impede access to
biosimilars, particularly among low and middle-income countries.

*Four key concerns are as follows:*

*Market Exclusivity*
The guidelines suggest that the chosen reference product – the originator’s
product – must be marketed for a “suitable period of time with proven
quality, safety and efficacy”. This requirement provides a de-facto
monopoly to the manufacturer of a reference product.This also means that a
biosimilar manufacturer will have to wait for a suitable period of time, to
develop a biosimilar version of a newly introduced biotherapeutic in the
absence of patent protection or under a compulsory license.Through the use
of these terms WHO is indirectly trying to import market exclusivity which
goes beyond the data exclusivity requirements currently existing in EU and
US. The absence of a definition of a suitable period of time provides a lot
of latitude to national governments to decide what would constitute a
suitable time period, which is not only illogical but highly improper.By
adopting this new definition, the elbow room provided by the removal of
comparative efficacy trials has been partially neutralized. There was no
requirement of a suitable time period in the previous WHO Guidelines or the
new UK Biosimilar Guidelines.

*Overemphasis on PD markers*
The guidelines mandate the use of PD markers in pharmacokinetic (PK) and
pharmacodynamic (PD) studies – but maintain a stoic silence on alternatives
in the absence of PD biomarkers.A PD biomarker is “a defined characteristic
that is measured as an indicator of normal biological processes, pathogenic
processes or responses to an exposure or intervention”.The objective of PK
and PD studies in biosimilar development is to evaluate the similarities
and differences between the proposed biosimilar and the reference
product.PK, and PD studies help to establish the similarity of the
biosimilar product with the reference product.However, in some cases, PD
biomarkers are not available and identification of such PD biomarkers is a
lengthy and resource-intensive process. In the absence of PD biomarkers,
robust structural and functional characterization and clinical PK studies
should be sufficient to establish meaningful differences between the two
products.Rather than insisting on the use of PD biomarkers, WHO should
follow a progressive approach and focus on the totality of evidence for
meaningful assessment of biosimilarity.

*Barriers To interchangeability*
In the case of biotherapeutics, there is some resistance to
interchangeability – the shifting from an originator’s product to a
non-originator’s product – for safety reasons. But after 15 years of
approval of various biosimilars and a flawless record of safety and
efficacy, this is not a valid concernTaking note of the robust evidence
available in favour of biosimilar safety, the European Medicine Agency
(EMA) and the Heads of Medicines Agencies (HMA), on 19 September signed off
on a policy of “interchangeability” of biosimilars.That means a biosimilar
medicine approved in the EU can now be interchanged with its reference
medicine or with an equivalent biosimilar approved in the EU. This will
flatten the path for switching patients from the expensive originator’s
biotherapeutics to biosimilars and will improve access and financial
sustainability. For example, in the case of Roche’s Trastuzumab,
interchangeability allows either a doctor or pharmacist to switch from the
originator’s product to a biosimilar – such as those produced by
Mylan/Biocon, Actavis, Apotex or Samsung Biosepis – or even amongst
biosimilars themselves.The guidelines not only exclude interchangeability
but also create a barrier by insisting that “the biosimilar should be
clearly identifiable by a unique trade name together with the INN”. The
insistence on marketing the biosimilar with a trade name (brand name in the
trademark context) is an added wrinkle for the competition in the market as
it creates product differentiation based on trade names. Prescription using
trade names forces biosimilar manufacturers to invest in promotion and
branding.This would leave the patients worse off as the high costs incurred
on branding and promotion activities will result in higher prices thus
further diminishing the availability of affordable biosimilars. Allowing
the NRAs unrestricted autonomy in the context of prescribing information
would intensify uncompetitive behaviour and ultimately lead to the
unaffordability of biosimilar products.From a public health perspective,
marketing medicines using the INN (International Non-proprietary Name) is
considered a pragmatic way of generating competition as such a move would
prevent doctors from prescribing the medicines by trade name.

*Reluctance to obviate animal studies*
There is a growing consensus for waiving in-vivo animal studies, which
stems from the recent advice by many regulatory bodies including EMA and UK
that it is unnecessary to test new biological therapies in animals.
However, WHO’s usage of language such as “animal studies may represent a
rare scenario” in the guidelines maintains a status quo rather than
providing clear guidance on the removal of animal studies. This creates
uncertainty and often National Regulatory Agencies, especially in
developing countries that are looking for clear guidance from WHO, and tend
not to use their discretion in favour of speedy approval of
biosimilars.Furthermore, the tone and tenor of the guidelines is not
constructive in some places and do not clearly give articulate and cogent
directions for implementation at the National Regulatory Agencies level.
Instead of giving clear guidance, it often uses ambiguous language and
conveys the idea of a case-to-case basis approach.As an example, the
guidelines mention that “A comparative efficacy trial may not be necessary
if sufficient evidence of biosimilarity can be inferred from other parts of
the comparability exercise.”  Rather than underpinning that comparative
efficacy trials are not required, statements like these continue to imply
that comparative efficacy trials may well remain the norm, which is
incorrect and clearly belie the purpose of updating the guidelines.Removal
of comparative efficacy trials will benefit biosimilar industry  One of the
most notable changes brought about by the WHO Guidelines has been the
removal of the requirement for “comparative efficacy trials” to obtain
marketing approval for biosimilars from regulatory agencies.A recent study
estimates the developmental cost of biosimilar manufacture in the US to be
between $100-300 million and takes on an average six to nine years from
analytical characterization to approval, and the clinical trials accounted
for more than half of the budget. Such monumental developmental costs
prevented biosimilar manufacturers from selling their products at an
affordable price in comparison to small molecules drugs (chemical compounds
manufactured through chemical synthesis) which are typically 80-85%
cheaper, once the generics have entered the market. Evidence shows that
biosimilar entry cuts the price of the original biologic product by only
30%.There is no doubt that the removal of this requirement will change how
biosimilars are approved globally and drastically reduce the duration for
marketing approval. This will lower the costs of biosimilars which in turn
will result in cost savings and access to effective treatments for patients
especially those suffering from chronic diseases like
cancer.ConclusionEvidence-based regulatory reforms for the biosimilar
industry have tremendous potential to reduce the cost of treatment,
increase access and improve people’s health.The WHO revisions have come out
clearly as part of a long process since the adoption of the World Health
Assembly (WHA resolution 67.21) in 2014. However, even after deliberating
for eight long years, the guidelines are conspicuous by the absence of an
effort from WHO to promote accessibility.While removing some barriers, it
has created fresh barriers and thus stymied the availability of affordable
biosimilars. In the current form, the guidelines thwart the repetition of
the intense competition that was witnessed in the small molecule space
after the entry of generic manufacturers.Both the content and process of
the guidelines raise serious concerns about WHO’s commitment to access to
medicines. The most appropriate way to address these concerns is to make
changes in the guidelines and not to come up with inadequate solutions like
Frequently Asked Questions (FAQs) or changes in the Implementation
Guidelines.The authors are afraid that a delay in addressing these concerns
effectively and appropriately would lead to a situation wherein the
decision of the WHO could result in the denial of the right to health and
the denial of a human-right based approach to science, thus depriving
inclusive access to benefits of scientific advancement to millions of
people.

*KM Gopakumar is a senior researcher and legal advisor at Third World
Network (TWN) and is based in New Delhi, India.*
*Chetali Rao is a biotechnology patent lawyer and works on pharmaceutical
innovations, access to medicines and global health issues. She is based in
New Delhi, India.*
-------------- next part --------------
An HTML attachment was scrubbed...
URL: <http://phm.phmovement.org/pipermail/phm-exchange-phmovement.org/attachments/20221116/b3fea175/attachment-0001.htm>