Download EMEA Comments on the project: “Priority Medicines for Europe and

EMEA Comments on the project: “Priority Medicines for Europe and the world”
The EMEA supports the objective and methodological approach taken to delineate those
areas of drug development that are currently overlooked by the pharmaceutical industry.
This report can be useful for setting priorities in the 6th framework programme and
particularly on topics related to LSH-2004-1.2.1-1: “New approaches for accelerated
development of new, safe and more effective medicines.” The focuses of this topic are the
identification of bottlenecks/barriers in the current drug development process and also
finding solutions to overcome these barriers.
Concerns over availability of treatments to patients in need is increasingly linked to the
discussion on “regulatory barriers” that are said to drive cost of drug development.
Regulatory requirements have allegedly become more difficult to meet, rendering
particularly clinical) drug development exceedingly costly to the extent that only
“blockbusters” with annual revenues of at least 500 million dollars seem worthwhile for
taking to the market. The relative importance of regulatory hurdles to stifle drug
development is perhaps better judged by others but it suffices to say that no comprehensive
analyses of the dynamics behind industry’s choices and the real costs of drug development
seem to exist. Further independent studies into these issues appear warranted The fact
remains that we are left with growing white spots of unmet medical need (like for example
Tuberculosis and infections caused by multiresistant bacteria) and under such circumstances
also alleged barriers to drug development associated with regulatory requirements should
be scrutinised.
The need to provide, in general, randomized controlled clinical trials for demonstration of
efficacy is laid down in EU legislation1. However, the level of evidence required establishing
efficacy of new drugs sometimes remain controversial between regulators and
pharmaceutical industry, particularly for conditions where systematic uncertainty is present,
due to the rarity of the disease. Indeed some applications for marketing have been approved
based on other designs such as open, uncontrolled studies with historical controls or case
series. This is particularly true for certain rare conditions, where standard requirements
cannot be applied due to the small number of patients. Also surrogate markers have
frequently been used for regulatory approvals, especially in the case of anti-HIV and
anticancer products. Such approvals that are based on limited information are generally
subject to post authorisation commitments where additional data on efficacy and safety are
provided in phase IV. Medical need is an intrinsic part of benefit/risk assessment of new
drugs, as concerns over uncertainties are balanced against the demonstrated patient benefits.
Although deviating from the standard requirements for randomized controlled trials is
sometimes possible, the obvious risks with this approach require careful consideration. To
illustrate this, it is sufficient to mention that almost one third of drug applications in the EU
centralised procedure between 1997 and 2000 had failed to reach a marketing authorisation,
. Annex I of Council Directive 2001/83/EC states that “in general clinical trials shall be done as “controlled clinical trials if
possible, randomised and as appropriate versus placebo and versus an established medicinal product of proven therapeutic
value; any other design shall be justified. The treatment of the control group will vary from case to case and also will depend on
ethical considerations and therapeutic area; thus it may, in some instances, be more pertinent to compare the efficacy of a new
medicinal product with that of an established medicinal product of proven therapeutic value rather than with the effect of a
placebo”.
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and that the most important reason for rejection was failure to establish clinical efficacy due
to the lack of adequate randomized controlled trials (Eur J Clin Pharmacology (2002) 58: 573580). Clearly, the provision of scientific and regulatory advice to drug developers is a top
priority of the EMEA. The early dialogue with applicants is expected to contribute to a more
successful drug development, ensuring optimal regulatory and scientific standards, and
maximising the chances of regulatory approval. Whilst it is expected that randomized
controlled trials remain essential for proving efficacy, where these are not technically
feasible, new approaches should aim to optimise methods to minimise bias and enable the
coherent use of prior information.
It could be said that currently applied trial designs and methods of analysis are often very
simple models of the true state of the nature. Other approaches could resemble the clinical
situation more closely. However, this may well increase the complexity of the design, the
analysis and the assessment of medicinal products and research would need to prove that
new designs are acceptable in terms of methodological rigor.
The future plans are outlined in the EMEA Road Map to 2010 (http://www.emea.eu.int). The
EMEA is committed to provide advice on drug development strategy and methodology
early on in the process. A specific effort will be made to support small and medium sized
enterprises and to further build on protocol assistance for orphan medicinal products. The
EMEA will continue to be actively involved in the development of scientifically based
guidelines that complement the EU legal requirements and specifically address different
disease areas and methodological considerations. Many of these guidelines have been
developed jointly with industry within the framework of the ICH (International Conference
of Harmonization), facilitating a more global drug development. With the implementation of
the new regulation, conditional approvals will be possible and the agency will work out the
detailed prerequisites for such authorisations. Also accelerated review and a harmonised EU
view on the access to compassionate use programs will be implemented with the new
regulation. The time to market will also be shorter with shorter decision-making time.
November 2004
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