[Ip-health] Revise Biosimilar Guidelines, Scientists Demand; WHO Says Not Now

K.M. Gopakumar kumargopakm at gmail.com
Sat Apr 27 12:28:51 PDT 2019


Revise Biosimilar Guidelines, Scientists Demand; WHO Says Not Now
25/04/2019 by William New

Scientists from a range of countries are calling for an update to World
Health Organization guidelines on biosimilar products in order to help
national authorities better implement policies to make biosimilars less
costly. Current guidelines are outdated and are being misused, they say.
But a WHO official told *Health Policy Watch* the guidelines document
should not be made “over-prescriptive”, and that a thorough assessment by
an expert group last year found a revision unnecessary but will keep
considering it.

“A revision of the WHO’s Guidelines on Evaluation of Similar Biotherapeutic
Products (SBPs), in place of a Q&A, is urgently needed to enhance the
knowledge and effectiveness of regulatory agencies based on scientific
evidence,” the scientists said in a memo
arguing that a WHO Q&A on the topic from 2018 is not equivalent to an
update of the guidelines. A WHO expert committee went through a process to
develop a Q&A on the issue, adopted last October. The process included
taking views like the scientists’ into account, according to sources.

The WHO issued Guidelines on biosimilars
in 2009. The Q&A document, available here
is seen as complementing and serving to clarify guiding principles as well
as principles on biosimilar monoclonal antibodies
(a 2016 document).

The WHO webpage on biotherapeutics, with links to the relevant documents, is

The issue is not formally on the agenda of the upcoming 72nd World Health
Assembly, which takes place from 20-28 May at the WHO. But it is expected
to come up during the discussion of a roadmap on access to medicines and
vaccines for 2019-2023
a proponent for revision said.

According to sources, some countries at the January WHO Executive Board
meeting repeated the request to update the 2009 guidelines. The scientists’
memo was sent to two top WHO officials in recent weeks.

The memo recommends the update of the guidelines be based on the following
scientific principles:

   1. “Demonstration of biosimilarity in quality is sufficient to assure
   safety and efficacy of most products
   2. Emphasis on quality testing should focus on impurity profiles and
   3. Well-designed pharmacokinetic/pharmacodynamic (PK/PD) studies will be
   sufficient, if clinical studies are needed
   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.”

Signatories to the memo include scientists from Colombia, India, Italy, the
Netherlands, Spain, and the United States.

At the January Executive Board meeting, Mexico, Colombia, Peru, Sudan, and
Dominican Republic mentioned “biosimilars” and the WHO assistant director
general talked about the “pre-qualification of two cancer biosimilars and
how three biosimilars for an RA drug had a massive influence on price,”
according to Universities Allied for Essential Medicines. Also at least 8
countries in the accelerating cervical cancer debate said that they find
the HPV vaccine to be too expensive or not available in large enough
quantities, UAEM said, noting that a search showed
<https://academic.oup.com/jnci/article/98/7/433/2522050> the original
vaccine was developed by three universities and one public research
institution but two pharma companies cross-licensed their patents.

*‘Gross Misuse’ and Other Concerns*

Among the concerns raised by the memo is that a revision would be better
than a Q&A for educating the national regulatory authorities, and that the
absence of an update has led to “gross misuse” of the original guidelines
by pharmaceutical companies. By using their own interpretation of the
“unclear and outdated” guidelines, pharmaceutical companies are “protecting
their market power in lower middle income countries by putting pressure on
governments to refuse marketing authorization of biosimilars,” it charged.

As examples of misuse, it pointed in a footnote to a lawsuit brought by
“big pharma” against the health ministry of Colombia aimed at getting the
Supreme Court to invalidate a presidential decree containing requirements
for marketing authorization for biologics, including biogenerics. It also
cited a preliminary injunction issued by a judge against the regulatory
authority of Ecuador after it approved a generic version of a drug
(bevacizumab). In suing the governments, the companies are citing failure
to follow the WHO guidelines, the memo said.

Other technical points in the memo detail concerns about differences and
interchangeability between the similar biotherapeutic products (the
biogeneric product) and the reference biotherapeutic product (the
originator product), plus the issue of immunogenicity (a negative response
in some humans to the product), and issues around clinical trials.

The memo states: “The methods to analyze proteins have improved
dramatically in the last decade reducing the possibility that a difference
between SBP and Reference Biotherapeutic Product (RBP) is missed, which has
possible clinical consequences. These methods allow full characterization
of proteins, in detail, regardless of their size and complexity. …The
technology and also the experience of scientists involved in the production
of biotherapeutics have matured in the last 20 years. The overall quality
of these products has improved, and the number of safety issues associated
incidents has been extremely low. These evolutions have greatly reduced the
likelihood of a difference between SBP and RBP with a clinical impact.”

On immunogenicity, it states: “In any case, if the SBP and RBP have
comparable purity and levels of impurity and especially aggregates, there
is no reason to suspect differences in immunogenicity and to ask for
immunogenicity studies.”

The insistence on the comparative clinical trial was that SBP may induce a
different immune response, which the memo says this is not true, the
proponent said.

Current regulations are seen as increasing the cost and time due to
clinical trials, the source added, and the memo suggests following the
principles it sets out for revision in order to make development faster and
less costly.

*WHO Expert Committee: All Okay for Now*

At its annual meeting in October 2018, the WHO Expert Committee on
Biological Standardization (ECBS) adopted the Q&A document, which went
through months of public comments, and confirmed that the 2009 guidelines
remained valid and did not require revision at that point. The next meeting
of the ECBS will be October 2019. It was unclear at press time who the
committee members are or how they were chosen.

François-Xavier Lery, Coordinator for Technologies Standards and Norms
[TSN] at WHO, explained to *Health Policy Watch*:

“In 2014 the World Health Assembly requested that the WHO Expert Committee
for Biological Standardization (ECBS) update its 2009 Guidelines on Similar
Biotherapeutic Products (SBPs, also called biosimilars) to take into
account technological advances in the characterization of rDNA-derived
products. In response, WHO organized informal consultations to evaluate the
need for review of biosimilars evaluation considering scientific
developments. In particular, it was agreed in a 2017 consultation that
developing a Q&A document to accompany the 2009 Guidelines would be an
appropriate way to further clarify and complement some of the issues and
points covered in the Guidelines. At its meeting in Oct 2018, the WHO ECBS
adopted the Q&A document and confirmed that the 2009 Guidelines remained
valid and did not therefore require revision at this point.”

“The Q&A document complements and serves to clarify guiding principles
included in the WHO Guidelines on biosimilars (2009) and on biosimilar
monoclonal antibodies (2016),” he continued. “Taken together, these three
documents provide up-to-date guidance on evaluation of biosimilars. As more
experience is gained and with technological advances, the Expert Committee
will keep considering the opportunities for streamlining the WHO
recommendations for promoting access while maintaining high quality, safety
and efficacy standards for biosimilars. The intention is to update the Q&A
document periodically to reflect new developments and issues that arise.”

“It should be noted that the 2009 guidelines document and the complementary
Q&A document do not address issues relating to intellectual property,
interchangeability, switching, substitution, naming, labelling and
prescribing information, or product shortages,” Lery clarified.

“Interpreting the WHO guidance and implementing it at national level for a
better access and use of biosimilars require therefore elaboration of
further national requirements,” he said, “and it would be inappropriate to
ask the WHO guidelines document, the Q&A document or any future updated
versions of the guidelines to address questions out of scope or to be
over-prescriptive towards national regulatory authorities, making difficult
the implementation and in the end creating barriers to access.”

*Original WHA Resolution*

The original mandate to update the guidelines came from the 2014 World
Health Assembly resolution, WHA67.21
<http://apps.who.int/medicinedocs/documents/s21459en/s21459en.pdf> – Access
to Biotherapeutic Products Including Similar Biotherapeutic Products and
Ensuring Their Quality, Safety and Efficacy, which:

REQUESTS the Director-General:

   1. to support Member States in strengthening their capacity in the area
   of the health regulation of biotherapeutic products, including similar
   biotherapeutic products;
   2. to support, as appropriate, the development of national regulatory
   frameworks that promote access to quality, safe, efficacious and affordable
   biotherapeutic products, including similar biotherapeutic products;
   3. to encourage and promote cooperation and exchange of information, as
   appropriate, among Member States in relation to biotherapeutic products,
   including similar biotherapeutic products;
   4. 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;
   5. to report to the Sixty-ninth World Health Assembly on progress in the
   implementation of this resolution.

The scientists’ memo bases the rationale for the urgent request on the 2014
resolution, saying, “The leading principles on which the WHO guidelines are
based are ‘the guidelines will serve as living document that will be
developed further in the line with the progress in scientific knowledge and
experience’.” It also noted the resolution said, “it is expected that a
guideline on the scientific principles for evaluation of SBPs will help
harmonize the requirements worldwide and will lead to greater ease and
speed of approval and assurance of the quality, safety and efficacy of
these products.”

The 2009 resolution called for the committee “to update the 2009
guidelines, taking into account the technological advances for the
characterization of biotherapeutic products and considering national
regulatory needs and capacities’.”

*Is a Q&A Enough? *

The final Q&A was adopted by the expert committee in October 2018. The
final version did not make many changes from the draft version, sources

The draft Q&A stated that in response to the resolution, WHO convened
meetings “to identify the needs and text which should specifically be
updated.” In April 2015, an informal consultation on the possible amendment
of the guidelines was organized.

In the consultation, WHO said, “All participants from national regulatory
authorities (NRAs) from both developing and developed countries, as well as
industry recognized and agreed that the evaluation principles described in
the WHO Guidelines were still valid, valuable and applicable in
facilitating the harmonization of SBP requirements globally.”

“It was therefore concluded,” the Q&A said, “that there was no need to
revise the main body of the existing WHO Guidelines on SBPs.”

“However,” it explained, “it was also agreed that there was a need for
additional guidance on the evaluation of monoclonal antibody products as
biosimilars which was then developed and adopted by the ECBS 2016. In May
2017, WHO held another meeting entitled ‘WHO consultation on improving
access to and use of similar biotherapeutic products’. From the outcome of
this meeting, WHO noted that developing questions and answers (Q&As) is
more appropriate than revising the Guidelines in order to further clarify
and complement some areas and points written in the Guidelines. The Q&As
would be produced for guidance only and should be read in conjunction with
relevant WHO guidelines. The Q&As are intended to provide clarity by
addressing questions that may arise in the use of WHO Guidelines.”

*More on the Memo*

In the introduction to their memo, the scientists shorthand the goal of the
mandated update to be “to increase access and affordability of biosimilar
products across the globe.” The WHA resolution is less direct, stating the
goal: “*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 products*.”

The memo was sent to Soumya Swaminathan, who recently moved from deputy
director general to chief scientist at WHO, and Mariângela Batista Galvão
Simão, who recently shifted to assistant director general for
prequalification and technology assessment from assistant director general
for drug access, vaccines and pharmaceuticals. Simão still has
responsibility for the issue, a source said.

The signatories to the memo are:

Prof. H. Schellekens, Utrecht University (Netherlands); Prof. Sarfaraz K.
Niazi, University of Illinois and University of Houston (US); Satyajit
Rath, Indian Institute of Science Education and Research; Amit Misra,
CSIR-Central Drug Research Institute (India); Paola Minghetti, University
of Milan (Italy); Susan Milan, Mabxience (Spain); Claudia Patricia Vaca
González, National University of Colombia; and Jan Hendriks, Utrecht Centre
for Affordable Biotherapeutics (Netherlands).

The scientists work independently on biosimilars and are not part of a
group, the proponent said. Schellekens is the founder of a center for
affordable biosimilars and founder of Gabi journal (http://gabi-journal.net/).
Niazi also is advocating for affordable biosimilars in the United States.
And González was active in changing Colombia’s biosimilar guidelines to
make it possible to get speedy approval in certain cases, the source said.

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