|
Introduction
The
concept of “new
chemical entity” has in recent years been the subject of
considerable debate and controversy. In the international legal
context, the definition of “new chemical entity” has the most
relevant bearing with respect to the scope of protection afforded to
clinical data as provided for drug regulatory approval. Data
protection as envisaged under Article 39.3 of TRIPs, extends to the
submitted, undisclosed test or other data, related to pharmaceutical
or of agricultural chemical products which utilise “new chemical
entities” (NCEs); where such origination of data has involved
considerable effort. The protection of data as indicated under TRIPS
is against “unfair commercial use” and “disclosure”, except
where necessary to protect the public. How a country defines new
chemical entities is believed to be to a large extent, a determinant
factor in the scope of protection of new drugs and the availability
of generic alternatives.
Additionally,
in the
context of patent law, there have been growing concerns that the
seeming proliferation of “follow-on” patents on various ancillary
features of existing medicines pose an unnecessary obstacle to
generic production. The question of whether, and to what extent,
countries may take measures to curb the patenting of such “non-NCE”
patents has been intensely debated, particularly in India. Experts
have noted that the concept of “new chemical entity” has been
left undefined, leaving countries with considerable flexibility to
carve out definitions in consonance with policy priorities.
To a
large extent, it has
been acknowledged that Article 39.3 of TRIPs does not mandate “data
exclusivity,” which would prevent national drug regulatory
authorities from registering equivalent generic versions of a drug by
relying on the clinical data submitted by an originator company for a
specified period of time. Despite the strong support for this
position from academia, practitioners, public health organisations
and civil society, some developing countries have nevertheless
introduced a system of data exclusivity, pressured by various
factors, including WTO-accession negotiations, or through bilateral
or regional free trade agreements.
In
view of the
possibility that data exclusivity may increasingly become a reality
for many more countries, recommendations to mitigate its impact on
access to affordable medicines and “real” innovation have been
forthcoming. Prominent among these recommendations has been the
prudence of limiting the scope of the definition of “new chemical
entities.” However, the definitional contours of new chemical
entity remain ambiguous. In
view of the need for greater clarity, the Workshop on Definition of
New Chemical Entities: Implications for Flexibilities in Patent and
Drug Regulatory Laws, organised
by
Centre for Trade & Development (Centad) in collaboration with
WHO
SEARO (World Health Organisation - South-East Asia Regional Office)
was an attempt to explore possible definitions for NCEs. The workshop
initiated discussion over a working paper that attempted to identify
the parameters along which countries may retain flexibilities to
define “new chemical entity” in a manner that is least likely to
create obstacles to the availability of generic competition in both
the drug regulatory and the patent law contexts.
The
working paper
discussed three distinct but fairly interrelated areas in which
conceptualisation of “new chemical entity” could potentially be
of relevance: firstly, in the context of receiving marketing approval
for a new drug, with the submission of clinical data to drug
regulatory authority; secondly, with regard to the conceptually close
yet distinct realm of regulatory threshold at which further clinical
trial data must be submitted to the drug regulatory authority so as
to ensure safety and efficacy; and finally the relevance of “new
chemical entity” in the context of patents on pharmaceutical
products. In exploring the various possible definitions of “new
chemical entity”, the paper attempted to estimate the actual
practical impact of competing definitions by examining drug approval
data from the United States Food and Drug Administration over the
past three years. The workshop opened a way for taking advantage of
credible expertise available on the matter, evoking feedback and
inputs that would help attain clarity on the flexibilities available
and judicious for countries in view of their policy priorities.
Session
I
Setting
the Context –Varied Definitions of New Chemical Entities and Its
Implications
The
Session began with a
clear affirmation of the concern of developing countries such as
India over the impact of data exclusivity on access to affordable
medicines. The objective of the workshop was outlined in terms of
exploring “actual and possible” definitions for new chemical
entities, as an attempt at preventive strategy in case a country
accepts a data exclusivity regime. The Session acknowledged that
India was under no obligation to accept data exclusivity and that the
endeavour to limit the meaning of NCEs may only be considered as a
first line of defense, or a “fall back option” in case of
countries that voluntarily or under pressure are required to embrace
data exclusivity.
The
Session set the
context for the workshop, briefly identifying some of the existing
varied definitions of new chemical entities and its implications. It
was suggested that adoption of a “US-minus” definition of NCE is
likely to drastically reduce the impact of data exclusivity. It was
also argued that determining the safety or efficacy of drugs should
be divorced from the scope of data exclusivity and that a possible
adoption of a US-minus definition should not affect the drug
regulator’s duty to ensure efficacy or safety of drugs. The Session
referred briefly to the relevance of NCEs in the patentability
context. The Session did not directly address the issue of “follow
on” patents, a matter left unresolved by the Mashelkar Committee.
Instead, the need for adoption of a robust understanding of
patentability criteria was emphasised.
Session
II
Analysis
of US
plus Definitions of NCEs
This
Session delved in
greater depth into the existing definitions for NCEs. The Chair
emphasised the need to define NCEs so as to help circumscribe the
scope of protection for data and possibly the implications of data
exclusivity, where existing. The Session drew attention to the US
definition of “new chemical entity” as “a drug that contains no
active moiety that has been approved by FDA in any other application
submitted under Section 505(b) of the [Food, Drug and Cosmetic] Act.
Under the US definition, a new ester, salt, or other non-covalent
derivative of an already-approved drug would not qualify as a new
chemical entity and would thus be ineligible for the five-year
exclusivity period available under the US law. However, it was also
shown that under the US law even where the substance does not fall
under the definition of new chemical entity, a supplemental
three-year exclusivity period is available. Illustrative examples
from US FDA approvals such as in the case of Ammonia N-13, were used
to prove that definition of NCEs is not dependent upon the quantum of
data that an applicant must generate and provide to a drug regulatory
agency for approval.
The
Session also referred
to the broad definitions for NCEs being proposed by the US in its
free trade agreements. These FTAs have tended to make data
exclusivity imperative, with the definition of “newness” of
chemical entity being determined locally and also providing
protection to “new uses” as seen in the US-Jordan FTA. On the
matter of bilateral free trade agreements, the discussant raised a
question as to how these agreements were to be reconciled within the
multilateral framework of TRIPS. Certain participants in response
were quick to point out that bilateral agreements must be considered
as binding as multilateral ones and the scope of TRIPS-plus standards
being advocated within these bilateral agreements was left for
countries to accept on individual terms. It was also pointed out that
a TRIPS-plus regime had in practice been ushered in through the
signing of few. The floor also issued a note of caution to
distinguish between countries like India that refused to accept data
exclusivity as an obligation under international law and those who
were voluntarily accepting such a regime. A participant also urged
the importance of not conflating the search for a definition of NCE
with data exclusivity.
The
Session also helped
shed some light on the industry perspective on the implications of
data exclusivity. The mounting pressure from the US on large generic
manufacturers was said to be of concern not only for a leading
generic manufacturer like India but also for other generic
stakeholders. The data exclusivity period that is available upon
marketing approval in the US was argued as having graver implications
outside the US. It was highlighted that certain drug manufacturers
choose to delay obtaining marketing approval outside the US,
especially in developing countries. This practice is believed to
stave off the problems of differential pricing that may occur in
these circumstances, such as those related to insurance cover. The
period of exclusivity enjoyed by drug manufacturers was thus shown to
be an incentive to companies not to make new drugs or therapies.
The
Session emphasised
the importance of considering the issue of data exclusivity in the
light of safety aspects of drug regulation wherein public domain data
may be used for proving bioequivalence. The floor also clarified that
references to the Mashelkar Committee in the context of India should
not be confused with the debate on data exclusivity. The Indian
Parliament was concerned, according to a participant, with the need
for a limit on drug monopoly and wasteful frittering away of research
and development resources. In this regard, it was suggested that
since the definition for NCE is flexible, delay in its definite
contours was advisable for the purpose of obtaining access to maximum
possible data.
The
floor drew support
for viewing NCEs within the context of patentability rather than data
exclusivity owing to the scope for judicial scrutiny and affirmation
of “real” innovation. It was emphasised that certain countries in
recent times had been forced to relent on data exclusivity in the
course of bilateral FTA negotiation, with the hope of trade-offs. To
avert similar experiences, a participant underscored the need for
civil society groups to coalesce with government and industry
representatives and draft a “model” intellectual property rights
legislation.
Session
III
Implications
of US
plus Definitions if NCEs
The
Session quickly
reviewed existing definitions on NCEs, including the USFDA’s, EC
definition of “new active substances” and the inclusion of “new
uses” of old drugs in the US-Jordan FTA and sought to explore the
implications of a US-plus definition. In the EC, as in the US, the
“newness” of a drug eligible for data exclusivity is determined
in reference to whether the drug has been approved in the Community
or in any other Member States. However, the EC regulations do not
utilise the term “new chemical entity” but make the primary
distinction between a “reference medicinal product” and a
“generic medicinal product.”
In
order to get a sense
of the implications of various definitions of NCEs on the scope of
data protection, the impact of the US, EC and US-Jordan FTA
definitions were compared in the light of US FDA approvals since
January 2005 to April 2008. These existing definitions were
characterised as “mere points” on a spectrum of possible
definitions, with the broadest definition (the US-Jordan FTA
definition inclusive of “new uses”) offering protection to the
largest number of NCEs and the narrower definition, as in the case of
the US, restricting the scope of protection. The Session opened for
discussion the possibility of further limitations to US definition.
According to a participant, the Indian position vis-à-vis
product patents for pharmaceuticals only post-1995 could be
replicated in the case of data protection for drugs which have
likewise filed marketing approval applications after January 1, 1995.
Section 111 of the Indian Patent Act was also identified as an
instructive legislative measure to consider. It was however iterated
that issues relating to data exclusivity were a slippery slope and
debate beyond the parameters of Article 39.3 of TRIPS were best
avoided.
In
this Session, the
Chair emphasised the need to consider discussions in a more holistic
manner. Two factors were identified as crucial in the debate.
Firstly, the development of a movement towards harmonisation of
clinical standards and; secondly, the need to focus attention on the
impact of this debate on the access to affordable medicine. The
discussant agreed that though TRIPs does not mandate data
exclusivity, developing countries are increasingly considering the
issue, thus requiring a deeper understanding of the issues involved
as also exercise of caution. At this point, the discussant raised a
question as to whether patent publication may be considered for
ascertaining “newness” claims. Such a possibility was considered
unlikely by some. However the question remained openended. The
discussant also highlighted that though there are flexibilities
available in defining NCEs, the work of examiners in regulatory
offices are burdensome when considering “newness” claims and
ascertaining technical issues such as close structural analogues. The
discussant approved the approach adopted by Chile in 2005, whereby a
drug that has received marketing approval in any country in the world
for more than 12 months is made ineligible for data exclusivity.
At
the Session, a
participant also raised concern over the possible hurdles that a
generic manufacturer would face in challenging a wrongful NCE grant
in a developed country such as the US. It was however suggested by
the Chair that this concern fell more in the realm of export-oriented
generic manufacturers and may not have a direct impact on the
campaign for access to affordable medicines in the developing world.
Another participant however added that the concern could adequately
be addressed by ensuring that developing countries do not give up
possibilities of judicial review in the course of finalising FTAs.
The
Session also opened
up a debate on safeguards that must be built into a possible data
exclusivity regime. A participant drew attention to the experience of
an Indian generic in a patent challenged in the UK, wherein though
the patent was invalidated, the generic company was unable to launch
its product owing to data exclusivity. Thus, it was shown that unlike
patents which are subject to pre and post-grant opposition as well as
compulsory licensing, the same is not possible in the case of data
exclusivity. It was therefore recommended that developing countries
ensure safeguards in the form of pre and post-grant opposition, as
well as compulsory licensing in the case of data exclusivity.
The
Session also
addressed the concern over the imminent possibility of duplication of
clinical trials owing to data exclusivity. In this regard,
encouragement was drawn from the work done by intergovernmental
agencies in denouncing unnecessarily duplicative trials as ethically
unacceptable. The Session also revealed the perspective of the
generic industry in India, favouring Section 3(d) of the Indian
Patent Act for definition of NCEs, alongside safeguards of pre and
post-grant opposition, as well as compulsory licensing.
The
Session was concluded
with the Chair emphasising the importance of not getting carried away
while suggesting definitional parameters for NCEs. It was pointed out
that the goal should be to emerge with a legal and not a scientific
definition, which would not place an unnecessary burden on the
regulator, ensure efficiency and make use of scarce resources for the
benefit of the maximum number of people.
Session
IV
Exploring
US
minus
definitions of NCEs
This
Session attempted to
tighten the possible definition of NCEs and posed the question about
the possible “unintended consequences” of a stringent definition.
The relevance of determining “newness” was emphasised in this
regard. It was pointed out that while countries like the US and EU
determine “newness” on the basis of marketing approval obtained
within jurisdiction, others such as Chile use broader means in terms
of marketing approvals received for over 12 months anywhere in the
world. India, on its part, has tentatively considered in the Reddy
Report (2007) to refer to NCEs as those “not previously known to
commerce”, within or outside jurisdiction. The IUPAC in turn
further restricts the scope of NCEs, by broadening the search in
terms of those entities not previously described in literature. It
was argued that though the IUPAC definition significantly reduces the
scope of NCEs, many of the current approvals in the US FDA would fail
IUPAC compliance. It was however suggested that a US-minus definition
would be advisable so as to reduce the scope of data protection, as
also the incentive to produce “me too” drugs which show no
clinical superiority to extant drugs in the same category. The
concern over the proliferation of “me too” drugs was shared by
the floor. Although the exclusion of “me too” drugs from NCE
status was considered favourably, the Session highlighted the
practical impediment of determining the threshold at which exclusion
could be considered reasonable, since determining the clinical
superiority of a “me too” drug is measured against a placebo. It
was instead suggested that an exclusion of covalent derivatives from
NCEs would be far easier.
The
Session evoked deep
discussion on the scientific aspects of defining NCEs. A note of
caution was however expressed by a participant that an attempt to
create a definition of NCE was to create a “legal fiction” and
not a scientific determination. It was therefore suggested that the
search for a definition could well end in Section 3(d) of the Indian
Patent Act, minus the “significant efficacy” criterion.
Session
V
Implications
of US
minus
Definitions
The
Session though
dedicated to a debate on the implications of a US-minus definition of
NCEs, was steered by the discussant to consider NCEs from a patent
perspective. The Session revealed that though in patent law there can
be no distinction on the grant of patents on the basis of technology,
nevertheless countries have done so as in the case of selection of
patents in Azo dyes. It was recommended by the discussant that though
patent law grants patents upon the fulfillment of the criteria of
novelty, inventive step and industrial application, there could be
exceptions to the rule in the case of prodrugs, metabolites and
entities described in literature. The discussant argued that
metabolites need not be put through the regulatory system and that a
patent grant on metabolites could be challenged even when not
previously described in literature, owing to its evolution in
vivo
and lack of inventive step.
The
suggestion of drawing
upon Section 3(d) of the Indian Patent Act for determining the scope
of NCEs was not believed to be foolproof. It was stated by the
discussant that the introduction of the “new animal” of
“efficacy” into patent law was a deviation from what is
considered to be traditionally a regulatory requirement. It was
emphasised that efficacy arguments in terms of “novelty of effect”
was a dangerous slippery slope that would soon lead to “novelty of
use” which has been excluded in the latter part of Section 3(d) of
the Indian Patent Act. It was also suggested from the floor that if
data exclusivity were to be considered, then a requirement for
submission of all clinical data must be made mandatory, along with an
indication of data which is in public domain. A participant believed
such a measure was necessary to act as a deterrent to frivolous
claims. At this point, it was stressed that though there is
conceptual bleeding between data exclusivity and patentability, they
should not be conflated.
The
Session also
addressed concerns relating to the possibility of patentability of
naturally occurring substances and the inclusion of “new uses” in
data exclusivity regime. The Session affirmed that from a drug
regulatory perspective, there is a need to restrict the meaning of
NCEs for the purpose of data protection. The Session also clarified
that data exclusivity concerns were not merely running coterminous
with patent term and that data exclusivity could also apply to
non-patentable entities, thus maintaining market exclusivity even in
the absence of patent protection.
Session
VI
Definition
of NCEs in the Context of Patents
The
Session continued the
thread of discussion that had emerged in previous session, namely
concerning the definition of NCEs in the context of patents. The
Session revealed divergent opinions. Some believed that a definition
of NCEs could be considered as the “bright line” which helped
exclude everything else from patentability while others argued that
the three-fold patentability criteria was sufficient in itself. In
this regard, the need for a robust understanding of patentability
criteria and basic concepts, on a case-by-case basis was suggested as
useful in restricting the scope of NCEs.
A
participant commented
that the workshop not only serves public health but also encourages
the innovation industry to focus R&D on “real” innovation.
The Session also raised the question as to how far insufficient
disclosure of data for establishing safety and efficacy could affect
patentability. Such an eventuality was considered unlikely in the
international scenario. It was recommended that similar definitional
parameters for NCEs in the drug regulatory and patent context should
be avoided. To avert the confusion in defining NCEs, one of the
participants also mooted the possibility of using other terms for the
purpose, such as “therapeutically beneficial substance” (TBS).
The
Session and the
workshop ended on a positive note, with most participants feeling
that the workshop had revealed a set of possibilities for
definitions, such as would help determine the scope of data
protection. The workshop highlighted the importance of defining
“newness” to make a breakthrough in the debate. As a follow-up to
the workshop, some also suggested that another workshop be organised
to explore the meaning of “unfair commercial use” in cases
relating to use of clinical data submitted to a drug regulatory
authority.
Prepared
by Tina
Kuriakose-Jacob, Ph.D. Research Scholar, JNU
|
