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Robin J. Harman, PhD, MRPharmS, is a pharmaceutical
and regulatory consultant based in Farnham, Surrey
(e-mail robin.harman@virgin.net)
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The registration of medicinal products has undergone many changes in
scope and rationale over the past 50 years. In trying to ensure that
all medicinal products conform to the three basic criteria of quality,
safety and efficacy, it is not surprising that the ways in which individual
countries have tried to achieve this has differed, often significantly.
As a consequence, the already lengthy and expensive process for bringing
a new medicinal product to the market became even more so if a manufacturer
wished to market its products in as many countries as possible.
 It became
apparent in different countries at different times that it was important
to have independent evaluation of medicinal products before
they were marketed. Authorisations became a requirement in the US in
the 1930s with the systems established by the Food and Drug Administration.
In Japan, government regulations requiring all medicinal products to
be registered started in the 1950s. In Europe, the trigger was the thalidomide
tragedy of the 1960s.
In many countries globally, there was a considerable increase in the
1960s and 1970s in the laws, regulations and guidelines for reporting
and evaluating the data on quality, safety and efficacy of new medicinal
products. However, as the industry became more international and sought
global markets, the registration of medicines remained a national responsibility.
Although almost all countries based their approvals on quality, safety
and efficacy, the detailed technical requirements had diverged over time.
As a consequence, it became necessary for industry to duplicate many
time-consuming and expensive test procedures.
The urgent need to rationalise and harmonise regulation was impelled
by concerns over rising costs of health care, escalation of the cost
of research and development and the need to meet the public expectation
that there should be a minimum of delay in bringing new treatments to
those patients that needed them.
It is now estimated to cost £350m to bring a new product to market.
Equally, governments have continuously exerted downward pressure on the
costs borne by regulatory authorities in ensuring that medicinal products
are of a high standard but become available to the public at the earliest
opportunity.
Initiation of ICH
The objective of creating a single market in the (then) European Community
in 1981 was a major incentive towards harmonisation of regulatory requirements
and the initial successes within Europe showed that harmonisation was
possible. The impetus was further increased by trilateral discussions
between Europe, Japan and the US. It was in Paris in 1989, at the World
Health Organization Conference of Drug Regulatory Authorities (ICDRA),
that specific plans for action were developed. The regulatory authorities
then approached the International Federation of Pharmaceutical Manufacturers
Associations, in Geneva, to discuss a joint regulatory–industry
initiative on international harmonisation.
Thus was the ICH process (the International Conference on Harmonisation
of the Technical Requirements for Registration of Pharmaceuticals for
Human Use) conceived.
In April 1990, the seeds of ICH were planted at a meeting hosted by the
European Federation of Pharmaceutical Industries Associations in Brussels.
Representatives of the regulatory agencies and industry associations
of Europe, Japan and the US met initially to plan an international conference,
but the meeting also discussed the wider implications and terms of reference
of ICH. An ICH steering committee was established which has subsequently
met at least twice a year, with the location rotating between the three
regions.
At the first ICH steering committee meeting, the terms of reference were
agreed. It was decided that the topics selected for harmonisation would
be divided into quality, safety and efficacy to reflect the three basic
approval criteria. It was also agreed that expert working groups (EWGs)
comprising membership from each of the six main parties should be set
up to discuss scientific and technical aspects of each
harmonisation topic. Eleven such topics were selected for discussion
at the first International Conference on Harmonisa-tion (ICH1).
The basic principles guiding the ICH process have been summarised as:
· Development of scientific consensus through discussions between regulatory
and industry experts
· Wide consultation of the draft consensus documents, through normal
regulatory channels, before a harmonised text is adopted
· Commitment by regulatory parties to implement the ICH harmonised texts
The modus operandi for ICH work was established at this early stage:
the EWGs meet in the same week as the steering committee and report on
their progress to that committee.
The commitment of all parties to ICH was set out in a steering committee
statement issued in Tokyo in October 1990 (Panel 1).
Panel 1: Statement issued by the ICH Steering Committee in Tokyo,
October 1990
· The parties co-sponsoring this conference,
represented at the second steering committee meeting in Tokyo,
23–24 October
1990, reaffirmed their commitment to increased international harmonisation,
aimed
at ensuring that good quality, safe and effective medicines are
developed and registered in the most efficient and cost-effective
manner. These
activities are pursued in the interest of the consumer and public
health, to prevent unnecessary duplication of clinical trials in
humans and to minimise the use of animal testing without compromising
the regulatory obligations of safety and effectiveness.
· This conference will provide a unique opportunity for regulators
and industry to reach consensus on the steps needed to achieve
this objective through greater harmonisation of technical requirements
and to set out practical and realistic targets for harmonising
requirements where significant obstacles to drug development and
the regulatory process have been identified.
· Recognising the substantial progress which has already been
made in achieving harmonisation within Europe and through bilateral
contacts between Europe, Japan, US and other regions, the conference
will seek to make further progress through a trilateral approach,
with clearly defined priorities, methods of work and recommendations
to both industry and regulatory authorities.
· While the conference will be an important step forward, it
is not seen as an end in itself, but as a stage in a developing
process, at a high level, between regulators and industry.
· The conference, its preparations and follow-up activities will
be conducted in an open and transparent manner and the presence
of observers from other regulatory authorities and WHO is welcomed
as a means of ensuring that the benefits of progress towards harmonisation
can be utilised world-wide.
· The conference will not only look at existing issues but will,
based on past experience, seek to minimise future divergence of
new registration requirements, as a consequence of technical progress. |
The process The ICH process was first drawn up at the steering committee
meeting in Washington in March 1992 and amended in Tokyo in September
1992. The process incorporates “decision points” at Step
2 and Step 4, and has enabled the steering committee to monitor the progress
of the topics selected for harmonisation.
The topics selected for discussion in the three EWG workshops at ICH1,
particularly those for quality and safety, were broad in their scope.
Although ICH1 was a successful conference, it was clear that the topics
selected for harmonisation would need to be more focused, with a clearly
defined and realistic objective. Thus most of the 11 ICH1 topics (which
were identified as “Quality T1–T3”, “Safety T1–T4” and “Efficacy
T1–T4”) were subsequently subdivided and given different
codes.
At least one topic has come “full circle” since ICH1. The
quality topic on “Specifications” was divided into topics
on analytical validation (Q2) and impurities (Q3). These were further
subdivided and developed into harmonised guidelines. Once this process
had been completed, it was agreed at ICH3 that work should recommence
on consolidated guidance for setting specifications for new drugs and
products (Q6).
The broad safety topic from ICH1, “toxicity testing programme”,
was also broken down into more manageable elements which have generated
harmonised guidelines. Other topics (eg, safety testing for biotechnology
products and the timing of toxicity studies in relation to clinical trials)
were put on hold, but have since been reconsidered.
Participants in the ICH process
The six founder members of ICH that are directly involved in the decision-making
process represent the regulatory bodies and the research-based industry
in the EU, Japan and the US. They are the European Commission of
the EU, the European Federation of Pharmaceutical Industries Associations,
the Ministry of Health, Labour and Welfare of Japan, the Japan Pharmaceutical
Manufacturers Association, the US Food and Drug Administration and
Pharmaceutical and Research Manufacturers of America (see Panel 2).
Panel 2: The six founder
members of the ICH
The European Commission of the EU The European Medicines Evaluation
Agency (EMEA) was established in 1995 by the European Commission.
Technical and scientific support for ICH activities is provided
by the Committee for Human Medicinal Products (CHMP) (formerly
the Committee
for Proprietary Medicinal Products, CPMP) of the EMEA.
European Federation of Pharmaceutical Industries
Associations EFPIA is based in Brussels and its members are member
associations
in 16 countries in western Europe. A wide network of experts and
country co-ordinators has been established through member associations
to ensure that the federation’s views within ICH are representative
of the European industry.
Ministry of Health, Labour and Welfare, Japan Those affiliated to the MHLW include the National Institute of
Health Sciences and
academia, which carries out research and testing on drugs, vaccines
and biologicals. Technical advice on ICH matters is obtained through
MHLW’s regulatory expert groups, with members from NIHS.
Japan Pharmaceutical Manufacturers Association The JPMA represents
90 member companies. Membership includes all the major research-based
pharmaceutical manufacturers in Japan. ICH work is co-ordinated
through specialised committees of industry experts who also participate
in the Expert Working Groups.
Food and Drug Administration The US FDA has
a wide range of responsibilities for drugs, biologicals, medical
devices, cosmetics and radiological
products. The largest of the world’s drug regulatory agencies,
the FDA is responsible for the approval of all drug products used
in the US. The FDA consists of administrative, scientific and regulatory
staff organised under the Office of the Commissioner and has several
centres with responsibility for the various products which are
regulated. Technical advice and experts for ICH work are drawn
from the Centre for Drug Evaluation and Research and the Centre
for Biologics Evaluation and Research.
Pharmaceutical Research and Manufacturers
of America The PhRMA represents the
research-based industry in the US. The association has 67 companies
in membership which are involved in the discovery, development
and manufacture of prescription medicines. There are also 24 research
affiliates which conduct biological research related to the development
of drugs and vaccines. PhRMA (previously known as the US Pharmaceutical
Manufacturers Association, PMA) co-ordinates its technical
input to ICH through its scientific and regulatory section. Special
committees have been set up, of experts from PhRMA companies, to
deal with ICH topics. |
Other participants in the decision-making process include:
Observers Observers act as a link with non-ICH countries and regions.
The observers to ICH are:
· The World Health Organization (WHO)
· The European Free Trade Area (EFTA), represented at ICH by Switzerland
· Canada, represented at ICH by Health Canada
International Federation of Pharmaceutical Manufacturers Associations The IFPMA is a federation of associations representing the research-based
pharmaceutical industry and other manufacturers of prescription medicines
in 56 countries throughout the world. The IFPMA has been closely associated
with the ICH since its inception to ensure contact with the research-based
industry outside the ICH regions. IFPMA runs the ICH secretariat.
ICH steering committee The ICH is administered by the ICH steering committee
which is supported by the ICH secretariat. Since the ICH was established,
each of the six co-sponsors has had two seats on the ICH steering committee
which oversees the harmonisation activities. The IFPMA provides the secretariat
and participates as a non-voting member of the steering committee.
The observers nominate non-voting participants to attend the ICH steering
committee meetings.
ICH co-ordinators Fundamental to the smooth running of the ICH has been
the designation, by each of the six co-sponsors, of an ICH co-ordinator
to act as the main contact point with the ICH secretariat and to ensure
that ICH documents are distributed to the appropriate persons within
the area of their responsibility.
Each party has also established a “contact network” of experts
within their own organisation or region in order to ensure that, in the
discussions, they reflect the views and policies of the co-sponsor they
represent. The way in which this network operates differs according to
the administrative structure of the party concerned.
ICH secretariat The ICH secretariat operates from the IFPMA offices
in Geneva, and is primarily concerned with preparations for, and documentation
of, meetings of the steering committee as well as co-ordination of preparations
for expert working group meetings and six-party drafting groups. At the
time of ICH conferences, the secretariat is responsible for the technical
documentation and for liaison with the speakers for the conference. Organisational
aspects of the conferences are handled by the industry and regulatory
parties in the country where the conference takes place.
Recent changes to ICH procedures
After 10 years of ICH activities, and a reasonable degree of success
in achieving the objectives of harmonisation of technical guidelines,
it was decided at ICH5 in San Diego in November 2000 to revisit the
aims and targets likely to be achieved over future years.
Delegates at ICH5 agreed that success had been possible because of
the scientific consensus reached between the experts in both regulatory
authorities
and the pharmaceutical industry. Another important aspect had been
the willingness of all parties to implement the harmonised guidelines
and
recommendations.
One further benefit that has now come to fruition has been the implementation
of harmonisation of the format and content of marketing authorisation
applications using the Common Technical Document format. This has now
been implemented in all regions involved in the ICH process and indeed
in many others outside the primary three regions.
The current large scale of successful harmonisation actions and the
need for all guidelines and recommendations to keep step with an evolving
scientific environment has needed greater effort on the implementation
and monitoring of ICH commitments.
At ICH5, it was also agreed that one area in which increased regulatory
co-operation would help enhance the protection of the health of citizens
on a more international basis was that of postmarketing activities.
The important role for WHO in disseminating information and providing
input beyond the ICH regions was also recognised. Moreover, the steering
committee identified the need to expand its communication and dissemination
of information with non-ICH parties. A more active involvement of WHO
through its regional centres was suggested as one way of achieving
this.
As a consequence of the discussions taking place at this time, a set
of revised terms of reference of the ICH process were developed. These
terms of reference were:
· To maintain a forum for a constructive dialogue between regulatory
authorities and the pharmaceutical industry on the real and perceived
differences in the technical requirements for product registration in
the EU, US and Japan in order to ensure a more timely introduction of
new medicinal products, and their availability to patients
· To contribute to the protection of public health from an international
perspective
· To monitor and update harmonised technical requirements leading to
a greater mutual acceptance of research and development data
· To avoid divergent future requirements through harmonisation of selected
topics needed as a result of therapeutic advances and the development
of new technologies for the production of medicinal products
· To facilitate the adoption of new or improved technical research and
development approaches that update or replace current practices, where
these permit a more economical use of human, animal and material resources,
without compromising safety
· To facilitate the dissemination and communication of information on
harmonised guidelines and their use such as to encourage the implementation
and integration of common standards
Since 2000, harmonisation initiatives are now described as “major” and “minor”.
A major topic includes proposals for new guidelines and changes to existing
guidelines which involve interpretations of statutory or regulatory requirements,
changes in interpretation or policy that are more than a minor nature,
usually involving complex scientific issues. Other changes are considered
minor.
Major topics are handled under the full ICH process. This is based on
the original “five-step” approach, which has proved extremely
successful for the first phase of ICH activities. Proposals for “minor” changes
to existing ICH tripartite harmonised guidelines are handled through
an abbreviated maintenance process.
The full ICH process will be described in a second article. |
The
Pharmaceutical Journal