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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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In the first these two articles (PJ, 14 August, p224) the reasons
why the three major regions in pharmaceutical research and development
(the
EU, the US and Japan) decided to initiate the ICH process (the International
Conference on Harmonisation of the Technical Requirements for Registration
of Pharmaceuticals for Human Use) were explained. The article also described
the participants in the process, the meetings that have taken place,
and recent changes to the way in which guidelines are developed. This
article will explain the selection and production of ICH guidelines.
Initiation of ICH harmonisation action
Proposals for harmonisation action Suggestions for new harmonisation
initiatives may arise in a number of different places, including
ICH regional guideline workshops, other regional and international conferences,
workshops and symposia dealing with research and development and
regulatory
affairs, and recognised associations, federations and societies which
represent scientific and technical professionals concerned with the
development, testing and registration of medicines. Formal proposals
for ICH action must be channelled through one of the six parties
to ICH or one of the observers on the steering committee. Proposals for
action can fall into one of the following categories:
· New types of medicinal product Proposals for guidelines
to cover new products resulting from advances in technology and techniques for producing
medicines (eg, products arising from gene therapy and other developments
in biotechnological and genomic research)
· Lack of harmonisation in current technical requirements Proposals for
further harmonisation of existing requirements (eg, as a result of work
on the Common Technical Document)
· Transition to technically improved testing procedures Proposals for
action to facilitate the replacement of currently established testing
procedures to more efficient and economical methods where these provide
equal or better assurance of the safety and/or quality of new drug products
· Review of an existing ICH guideline Proposals for significant changes
to the technical aspects of an ICH guideline or proposals for a major
addition to the guideline
· Maintenance of an existing guideline Proposals for relatively minor
modification, updating clarification or review of ICH agreements to take
account of either problems with implementation, new information or new
scientific knowledge.
Preparation of a concept paper The ICH party or observer proposing a
new harmonisation action must present the issue in the form of a concept
paper. This provides a short summary of the proposal (maximum two pages)
giving the following information:
· Type of harmonisation action proposed For example, a new tripartite
harmonised guideline/recommendation, or an amendment/update of an existing
guideline
· Statement of the perceived problem Brief description with an indication
of the magnitude of the problems currently caused by a lack of harmonisation
or, in the case of new scientific developments, problems anticipated
if harmonisation action is not taken
· Issues to be resolved A summary of the main technical and scientific
issues which require harmonisation
· Background to the proposal Further relevant information (eg, the origin
of the proposal, references to publications, discussions in other forums)
· Type of expert working group Recommendation
on whether the expert working group, if needed, should be a
six-party group (used for topics related
to the research and development of new drug substances and products)
or an extended expert working group (for topics with implications beyond
new drug research)
Further documentation and reports may be annexed to the concept paper.
Selection of procedure Proposals arising for new types of medicinal
product, lack of harmonisation in current requirements, improved testing
procedures, and review of an existing guideline are automatically subject
to the full ICH process (described below). The proposal and concept paper
is sent to members of the steering committee, observers and ICH co-ordinators;
the copy sent to the ICH secretariat should ask for the item to be included
on the agenda for the next steering committee meeting.
Proposals for maintenance of existing guidelines, in which the sponsor
believes that an abbreviated process is appropriate, should be sent to
the ICH secretariat with a request that the maintenance process, rather
than the full process, be initiated.
Full harmonisation process
Topic selection The steering committee agenda routinely includes an
item on “proposals for new topics”. The sponsoring party or
observer must have circulated the concept paper to co-ordinators and
the secretariat in advance, and the concept paper and any comments
will be submitted to the steering committee. A preliminary determination
is then made on whether the topic is of sufficient interest to all
parties and can be accommodated within the ICH work programme.
The concept paper must indicate the type of EWG that is appropriate
for the topic (ie, six-party membership only, or with membership extended
to other interested parties). If it is considered worthwhile, and interested
parties beyond the six ICH sponsors and three observers are identified
as appropriate, the steering committee then invites, as appropriate,
those additional parties to discussions on the topic, just before its
acceptance by the steering committee as an ICH topic.
Steering committee action When a topic is adopted for harmonisation
action, the steering committee:
· Confirms the objectives and expected outcome of the harmonisation action
· Confirms the composition of the EWG appointed to discuss the technical
issues
· Sets a timetable and action plan for the EWG
The concept paper is then revised and updated to reflect these decisions.
Expert working groups Each of the six ICH parties (see first article,
PJ, 13 August, p224) are asked to designate a leader for the new topic.
The topic leaders participate in the EWG meetings and are the point of
contact for any consultations carried out between meetings. A deputy
topic leader can also be designated.
Observers to ICH are also invited to nominate an expert to the EWG. In
the case of EWGs with extended membership, the secretariat invites the
designated organisations to nominate an expert to participate in the
EWG and act as the contact point for receipt of documents on technical
issues. Other interested parties and their experts may be present and
can express their views to the steering committee when topics in which
they have a particular interest are discussed. The agenda for the steering
committee will be arranged accordingly. In order to manage the likely
numbers of attendees from interested parties during the discussion of
these topics, attendance is limited to one representative in addition
to their expert.
Timetable and action plan The steering committee agrees a target timetable
for development of scientific consensus in the EWG for each new harmonisation
topic. This does not normally exceed two years.
One of the six ICH parties is designated to nominate the rapporteur and
all involved parties are asked to nominate their respective experts within
a fixed time limit.
Steps in the ICH process The five-step process which proved successful
for the first phase of ICH activities will be maintained with appropriate
modifications to accommodate the extended EWGs. The five-step process
is described in Panel 1.
Panel 1: The five-step process in developing ICH guidelines
Step 1: Consensus building
The rapporteur prepares an initial draft of a guideline or recommendation,
based on the objectives set out in the concept paper, and in consultation
with experts designated to the EWG. The initial draft and successive
revisions are circulated for comment, giving fixed deadlines for
receipt of those comments.
To the extent possible, consultation is carried out by correspondence,
using fax and e-mail. Meetings of the EWG normally only take place
at the time and venue of the biannual steering committee meetings.
Additional formal meetings of the ICH EWG must be agreed in advance
by the steering committee.
Interim reports are made to each meeting of the steering committee.
If
consensus is reached within the agreed timetable, the consensus text
with EWG signatures (see below) is submitted to the steering committee
for adoption as Step 2 of the ICH process.
Where complete consensus has not been achieved within the agreed
timetable, a report will be made to the steering committee indicating
the extent of agreement reached and highlighting the points on which
there are differences between the parties. Experts from all parties
represented on the EWG then have the opportunity to explain their
position to the steering committee. The steering committee may then:
· Allow an extension of the timetable, on the basis
that the EWG can give
assurances that consensus could be reached within a short, specified
period
· Decide to suspend or abandon the harmonisation project
· Decide to proceed to Step 2 on the basis of the
current draft, notwithstanding absence of complete consensus in the EWG
Step 2, Phase 1: Sign-off by EWG members
When consensus is reached on the technical issues, all parties represented
on an EWG are invited to sign the document to indicate their agreement
to the consensus text which is submitted to the steering committee.
Circumstances could be envisaged, however, when not all other parties
are present or able to sign the consensus text. It would then be
for the steering committee to decide whether to proceed to Step
2.
Step 2, Phase 2: Start of regulatory action
Step 2 is reached when the steering committee agrees, on the basis
of the report from the EWG, that there is sufficient scientific
consensus on the technical issues, for the draft guideline or recommendation
to proceed to the next stage of regulatory consultation. This agreement
is confirmed by steering committee members for each of the six
ICH parties signing their assent.
Step 3: Regulatory consultation
At this stage, the guideline or recommendation embodying the scientific
consensus leaves the ICH process and becomes the subject of normal
wide-ranging regulatory consultation in each of the three regions.
In the EU it is published as a draft Committee for Proprietary
Medicinal Products guideline; in the US, it is published as a
draft guidance
in the Federal Register; and in Japan it is translated and issued
by Ministry of Health, Labour and Welfare, for internal and external
consultation.
The difference from standard national/EU procedures for consultations
on guidelines is that the regulatory parties exchange information
on the comments they have received in order to arrive at a single
harmonised text. In addition, there is an opportunity for industry
associations and regulatory authorities in non-ICH regions to comment
on the draft consultation documents which are
distributed using contact lists from the International Federation
of Pharmaceutical Manufacturers’ Associations or the World
Health Organization.
A regulatory rapporteur is designated to draw up the final document
and
obtain agreement, in the form of a “sign-off” from the
experts representing the other regulatory parties. Step 4: Adoption of a tripartite harmonised text
At Step 4, the topic returns to the ICH forum where the steering
committee receives a report from the regulatory rapporteur. If
both regulatory and industry parties are satisfied that the consensus
achieved at Step 2 is not substantially altered as a result of
the consultation, the text is adopted by the steering committee.
This adoption takes place on the signatures from the three regulatory
parties to ICH, affirming that the guideline is recommended for
adoption by the regulatory bodies in the three regions.
In the event that one or more parties representing industry have
strong
objections to the adoption of the guideline, on the grounds that
the revised draft departs substantially from the original consensus
or introduces new issues, the regulatory parties may agree that the
revised text should be submitted to further consultation.
Step 5: Implementation
Having reached Step 4, the tripartite harmonised text moves immediately
into the final step of the process: regulatory implementation.
This is carried out according to the same national/regional procedures
that apply to other regulatory guidelines and requirements in the
EU, Japan and the US.
Information on the regulatory action taken and implementation dates
are
reported back to the steering committee and published by the secretariat. |
Abbreviated maintenance process
The maintenance process is intended to provide a rapid, flexible way
of making minor changes and revisions to existing ICH guidelines.
The procedure is intended to provide results quickly and efficiently
using
the minimum amount of resources consistent with the achievement of
a scientifically valid result. As far as possible, maintenance work
should be completed via a written procedure with recourse to meetings
only in exceptional cases.
Contact network for maintenance of guidelines Each of the six ICH parties
has established a network of experts for dealing with maintenance issues
and has identified one “maintenance contact” for each Step
5 ICH guideline or implemented agreement. These maintenance contacts,
in close liaison with their respective ICH co-ordinators, are empowered
to deal with all maintenance issues concerning their respective guidelines.
Co-ordinators have provided the ICH secretariat with details of the maintenance
contacts for each guideline. However, the first point of contact on all
maintenance issues is through the ICH co-ordinators.
Procedure: maintenance network Once a maintenance issue has been identified
a concept paper is prepared (see above under full guideline process).
Any issues to be resolved are stated as clearly as possible, for example,
giving details of wording to be changed and the proposed new wording.
The concept paper is sent to the ICH secretariat and co-ordinators. If
the co-ordinators agree that the proposal constitutes a “minor” change,
the maintenance process is initiated.
The review and sign-off procedure is as follows:
· The secretariat registers the maintenance proposal, designates a code
number, and prepares a draft sign-off sheet identifying the proposed
changes to the guideline. This is attached to the concept paper and sent
to the maintenance network via the ICH co-ordinators.
· The steering committee members and observers are informed about the
proposal.
· The maintenance contact from the sponsoring party (ie, the party proving
the concept paper) acts as topic co-ordinator and is responsible for
circulating comments and further proposals as necessary.
· After regional or internal consultation, each of the maintenance contacts
indicates whether there can be agreement with the proposal made. Minor
changes to the wording may be proposed.
· If agreement cannot be reached, the matter is referred to the next
steering committee for a decision on establishing an expert working group
and initiating the full ICH process (as described above).
· If there is agreement by all experts, the completed sign off sheet
is returned to the ICH secretariat. The secretariat then circulates the
signed-off proposal to the steering committee, with a request to respond
within a month.
Procedure: steering committee When the steering committee receives notification
that a proposal for an amendment to an ICH guideline has been agreed
by the maintenance network, each party is asked to give their opinion
on whether the proposal is accepted and can be implemented immediately,
without further consultation. If it can, the secretariat updates and
circulates the text of the ICH guideline to the steering committee and
maintenance contacts. The revised text is announced and published.
Alternatively, the proposal may be accepted but with the proviso that
it requires wider consultation. In such a case, it is treated as a “step
2” document (see Panel 1) for formal regulatory consultation, in
accordance with the procedures set out under the full guideline process
(see above). The secretariat has to obtain signatures for all six parties
on the “step 2” consultation document, after which the consultation
will be announced following normal procedures.
Finally, it may be decided that there are further issues to be resolved
and the matter is then sent for discussion at the next steering committee.
To achieve this, the secretariat informs the maintenance contacts, and
the item is included on the steering committee agenda.
ICH guidelines
ICH topics are divided into four major categories (quality, safety,
efficacy and multidisciplinary), and ICH topic codes are assigned according
to these categories.
Quality Quality (“Q”) topics are those relating to chemical
and pharmaceutical quality assurance. These include Q1 — stability
testing, Q3 — impurity testing, Q5 — quality of biotechnological
products, and Q7 — good manufacturing practices.
Safety Safety topics (“S”) are those relating to in vitro
and in vivo pre-clinical studies. Examples include S1 — carcinogenicity
testing, S2 —genotoxicity testing, S5 — reproductive toxicology,
and S7 — pharmacology studies.
Efficacy Efficacy topics (“E”) are those relating to clinical
studies in human subjects. Examples include E4 — dose response
studies, carcinogenicity testing, E5 — ethnic factors, E6 — good
clinical practices, and E7 — clinical trials.
Multidisciplinary Multidisciplinary topics (“M”) are those
that do not fit uniquely into one of the above categories. The multidisciplinary
topics considered by ICH are M1 — medical terminology, M2 — electronic
standards for transmission of regulatory information (ESTRI), M3 — timing
of pre-clinical studies in relation to clinical trials, and M4 — the
common technical document.
The ESTRI project includes the verification of procedures for consistent,
accurate transfer of information; the evaluation of encryption technologies
and key certification procedures for the transfer of regulatory information.
The working group has undertaken test projects to define logical electronic
communication standards to ensure the integrity of information and data
exchange between pharmaceutical companies and authorities. Tests have
also been conducted which involve transferring encrypted and non-encrypted
files between a limited number of international centres.
Recommendations have been made on the implementation for electronic standards
for the transfer of regulatory information and data (ESTRI), the core
standard set, physical media (floppy disks and CD-ROM), network messaging,
secure EDI transmission over the internet and electronic document and
message formats.
Conclusion
The harmonisation process has been ongoing for some 15 years and has
enabled companies and regulatory authorities to both produce largely
one set of data for a marketing authorisation application and to
give greater confidence to all regulatory authorities that the data submitted
would be acceptable to all parties to the agreement. The logistical
issues solved by the introduction of the common technical document
have also enhanced this process.
By inference, it has also ensured that any authority outside the
original tripartite agreement can have confidence in the same data
that it, too,
has to evaluate in order to bring novel and innovative products to
its citizens. Overall the ability to bring new products to the market
on
a global basis has been greatly enhanced by the ICH process. |
The
Pharmaceutical Journal