International Collaboration: Options for the
Regulation of Potentially Dangerous Products
October 1992
Table of Contents
- Introduction
- Background
- Improving Efficiency - Preserving Safety
- Changing Trade Conditions Affect Regulation
- Perceptions of Risk
- The Cost of Change
- Talk to Your Legal Counsel
- Some Options
- Glossary of Options
- Be proactive in international harmonization
- Be proactive in mutual recognition
- Be Selective in defining partners
- Work at the scientist-to-scientist level
- Work at government-to-government level
- Agree to testing protocols, accept quantitative test data
- Accept partner's summary data
- Accept conclusions of shared work
- Use post-evaluation surveillance
- Accept foreign submission formats for reporting test data
- Actively communicate with the public
- Take advantage of foreign approvals
- Contribute to the knowledge pool
- Share databases
- Conclusion
Introduction
As a Canadian regulator, you face many competing demands. Trade agreements may
limit your scope for action. You have to strike a fine balance between protecting
consumers and the environment without tying industry up in a web of constraints.
To add to this, you are asked to work with a fraction of the resources available
to many of our major trading partners - resources which appear to be ever on the
decline.
How can one cope? Working closely with evaluators in other nations is a way
that regulators in many agencies have found to be effective, from both the
perspective of serving Canada and their own job satisfaction.
As you know, collaboration isn't easy. Who will your partners be? Will you have
to follow their rules? Will Canada be asked to give up the right to make its own
decisions? The field is full of traps and pitfalls.
This guide is designed to give you a flavour of the innovative approaches
regulators are now pursuing. In it we discuss options for international
collaboration that are all based upon actual cases drawn from around the world.
The options are not prescriptions that can be adopted without thought. The
intention is only to whet your appetite, to provide you with some ideas to think
about, and to identify contacts who can share valuable experiences with you
directly. "Networking" is what this exercise is all about.
If you have ideas to improve the material in this guide, we would like to hear
from you. Sharing ideas, successes and failures is an important part of this process.
In addition, we would welcome discussion with you on ways in which these techniques
can be applied in your own situation. By networking to develop exemplary practices,
we should be able to improve the quality and efficiency of our regulatory programs.
Background
Improving Efficiency - Preserving Safety
International collaboration offers regulators the possibility of improving
efficiency without sacrificing quality of work. In this guide, we discuss
options for the regulation of potentially dangerous products such as food
additives, pesticides, medical devices, toxic chemicals, consumer and
pharmaceutical products. An important goal in this area is to provide timely
clearances of safe and beneficial products, while protecting the public from
unsafe ones.
Changing Trade Conditions Affect Regulation
Globalization of world trade has had an important impact on regulation. Our
participation in GATT and the free trade agreement with the USA puts limits on
the way that we run our domestic affairs. Regulations that create non-tariff
barriers are being steadily eroded. This is not a temporary effect. Regulators
will have to deal with a continuously changing trading environment for the
foreseeable future.
Perceptions of Risk
Public perception of risk affects the scope for international collaboration.
In areas where the perceived risks are low, harmonization and mutual recognition
may be easier to achieve. In situations where the perceived risk is high, public
pressure may favour decision-making in Canada. Perceived risk tends to be high
when exposure to a product is involuntary, e.g. pesticide residues, food
additives. Risk is more readily accepted in voluntary situations, e.g. smoking,
driving a car.
The Cost of Change
International collaboration may entail increased short-term costs to both
industry and regulators. It should, however, lead to savings over the long term
for everyone including consumers. Costs can be mitigated by using the
work-sharing techniques described below. If your regulatory program serves a
well defined group, you should also consider charging user fees. Contact your
Treasury Board analyst about how best to apply user fees in your line of
business.
Talk to Your Legal Counsel
Sharing work with other countries may cause problems under access to
information legislation. Changing or introducing regulation without enforcing it
may also land you in court. Check with your departmental legal counsel before
you act.
Some Options
Some options for international collaboration are listed below. You may find that
they do not all fit your situation. Nevertheless, you may well be able to gather
useful ideas by talking to colleagues about their own practical experiences.
- Be proactive in international harmonization.
- Be proactive in mutual recognition.
- Be selective in defining partners.
- Work at the scientist-to-scientist level.
- Work at the government-to-government level.
- Agree to testing protocols, accept quantitative test data.
- Accept partner's summary data.
- Accept conclusions of shared work.
- Use post-evaluation surveillance.
- Accept foreign submission formats for reporting test data.
- Actively communicate with the public.
- Take advantage of foreign approvals.
- Contribute to the knowledge pool.
- Share databases.
A brief description of each option is given in the pages that follow.
Glossary of Options
Be proactive in international harmonization
Harmonization means that we will be prepared to accept common test protocols,
formats for submission of test data, packaging, labelling and so on. It may also
mean that we will review conclusions drawn by our partner countries on test data
but that we will always reserve the right to make our own national decisions.
Canada would want to be proactive in this area in order to protect or gain
markets for our export products or to import materials that are important for
the domestic economy. Harmonization tends to reduce non-tariff barriers and
reduces the costs of gathering test data. In addition, experience shows that
active participation in international harmonization has the spin-off effect of
improving the quality and efficiency of domestic regulation.
International negotiations show that harmonization is not easily achieved
unless all interested parties participate from the start. The specific areas to
be harmonized should, ideally, be based on technical matters so that the players
can agree upon quantitative testing procedures. Harmonization is particularly
difficult to achieve when the perceptions of a given risk vary, when current
test protocols are quite different or when public sensitivity to the risk is
high. Often the NIH - "not invented here" - syndrome plays a role
since senior regulators have a tendency to cling to systems that they have
helped to develop.
Example: The EC has established a harmonized system for approval of
medical devices. Each member state will evaluate products based upon common
European standards. If another member states find a product to be unsafe they
may withdraw the product from their domestic market. However, they are bound to
resolve their differences through an arbitration mechanism. Reference:
"On the Approximation of the Laws of the Member States Relating to Active
Implantable Medical Devices", (90/385/EEC). Official Journal of the
European Communities, No. L 189/17.
Example: Canada will be adopting the ISO 9001 standard for quality
assurance as the basis for its regulations on Good Manufacturing Practices (GMPs)
for medical devices. In addition, the USA is developing standards that will be
compatible with ISO 9001. A working group between the two countries will be set
up so as to ensure that both countries develop common interpretations of the
general requirements of ISO 9001. The process aims to simplify compliance
requirements from the perspective of manufacturers. Contact: Director of
Field Operations, Health Protection Branch, Health and Welfare Canada.
Be proactive in mutual recognition
Mutual recognition should encourage better utilization of resources, reducing
duplication of effort. The economic criteria that apply to mutual recognition
are the same as those for international harmonization. This means that we would
generally be proactive when we could gain competitive advantage or when we could
share the costs of approval processes.
Mutual recognition has to be carefully defined. Full mutual recognition of
another nation's regulatory decisions means that we would give up our sovereign
right to make our own judgement. This situation is not likely to apply in the
foreseeable future. However, Canada may well accept mutual recognition of test
data gathered according to strict scientific protocols. Even this more limited
case will only be viable when the actual risks associated with products are low
or when risks are high but the public has confidence in international testing
mechanisms.
Example: Some of the concerns about full mutual recognition are
exemplified by the use of the amino acid L-tryptophan as a drug. In the US, the
material was freely available whereas in Canada it was only obtainable as a
prescription drug. Uncontrolled use of the amino acid caused 1543 cases of
Eosinophilia Myalgia Syndrome in the US resulting in 28 deaths whereas only 17
cases were reported in Canada with no deaths. Some of the 17 had bought their L-tryptophan
in the USA. Contact: Dr. E. Somers - Director General, Drugs Directorate,
Health Protection Branch, Health and Welfare Canada. Reference:
"Drug and Medical Device Regulation: Towards Global Co-operation"; Dr.
E. Somers, Regulatory Affairs, Vol. 3, pp 346-356, 1991.
Example: Environment Canada participated in an evaluation of high
volume production chemicals with a number of other countries. The results of the
test procedures would be mutually recognized. The exercise is characterized by
uncertainty in the public's perception of risk, a degree of urgency, and fairly
quantitative testing procedures. The approach supports the generally held view
that properly trained scientists in industrialized nations can be trusted to
report quantitative test data accurately and honestly. In economic terms, the
collaboration was extremely beneficial since only 6 of the 150 chemicals
reviewed had to be tested in Canada. Domestic firms sponsored the 6 tests at a
cost of roughly $250,000 each. However, Canada will have access to the test data
for all 150 chemicals. Contact: John Buccini - Director Commercial
Chemicals Branch, Conservation and Protection, Environment Canada
Example: The European Community is moving towards a system of
mutual recognition in drug approvals in which any state will have a limited time
to reject or approve a product approved by another member state. The European
Commission will be the final arbiter in disputes. Some commentators do not
regard this mechanism as being mutual recognition between sovereign states.
Rather, they view it as an arbitration mechanism between states that are moving
rapidly towards a federal system. Reference: "Free Movement of
Medicinal Products in the European Community", Background Report (ISEC/B1/91),
published by Commission of the European Communities, January 1991.
Be Selective in defining partners
Partners need to be deliberately selected in areas where subjective
judgements are made or where sophisticated test procedures are required. Those
chosen would normally maintain standards equal to or higher than those that
apply in Canada. They may also be chosen on the basis of local conditions. For
example, in the approval of a pesticide a partner may be selected because its
climatic and growing conditions are similar to our own.
Example: The United States is the natural partner for Canada. The US
is our largest trading partner and maintains high regulatory standards. However,
it is a very unstable regulatory environment because Congress frequently enacts
legislation in response to pressure from special interest groups.1 In addition,
litigation in the US courts can lead to huge penalties2 so that regulators are
less likely to share decision making with other nations. References: (1)
Final Report of the Advisory Committee on the Food and Drug Administration,
Charles C. Edwards, May 1991. (2) "The Effect of the American Judicial
System upon the Development of New Treatments for AIDS", J.J Dannenberg,
Symposium on Science, Culture and the Health of the World, published by the
International Institute for Human Rights Studies, Padova, Italy, 1990.
Example: The Baume report on the regulation of drugs in Australia
is very specific about the selection of partners. It recommends that Australia
select certain "trigger" countries that can be relied upon as
suppliers of satisfactory evaluation summaries as a starting point for
evaluation review. Moreover, Baume suggests that full review of all clinical
data may not be required under these conditions. The report recommends that
Canada, Sweden and the USA be selected as partners for harmonization of formats.
In addition, if Canada or the USA reject a drug, Australian authorities are
encouraged to determine the basis for their rejection as a key indicator in
determining the acceptability of a drug in Australia. Reference: "A
Question of Balance - The Future of Drug Regulation in Australia", P. Baume,
July 1991.
Work at the scientist-to-scientist level
This pragmatic and direct working level can be used to facilitate sharing
information and workloads. It is of greatest value in areas of high product risk
- real or perceived. Scientists can pool information and resources and share
conclusions but can make final approval decisions on their own. This approach
spreads the workload and preserves the sovereign right to decide. It is the
work-reduction mechanism that can be implemented most rapidly. This kind of
networking may be constrained by the need to respect the confidentiality of
proprietary information. However, the constraint may be overcome through
agreement with the applicant or by making an evaluator in one country an unpaid
employee of the regulating agency of another.
Example: The AIDS drug didanosine (ddI) was reviewed jointly by the U.S. Food
and Drug Administration and the Drugs Directorate of Health and Welfare Canada.
The two countries, working together, reviewed the identical submission and made
independent regulatory decisions based on their findings. Approval for ddI was
granted in both countries on October 9, 1991. A second shared review is planned
for dideoxycytidine (ddC) another drug for the treatment of AIDS. Contact: Dr.
E. Somers, Director General Drugs Directorate, Health and Welfare Canada. Reference:
"Towards an Improved Drug Regulatory System: Progress Since Stein",
published by Health and Welfare Canada, 1991.
Work at government-to-government level
Formal government-to-government arrangements would primarily occur in regard to
harmonization and mutual recognition of testing protocols and scientific data.
They are likely to develop slowly and in small increments. Agreements will be
most easily made where quantitative testing applies but will be more difficult
to apply in areas where subjective judgements are required. Nations can be expected
to protect their self-interest in negotiations and may develop or defend non-tariff
trade barriers.
Example: In November 1991, an international meeting was held in
Brussels on harmonization in the pharmaceutical area. Progress was difficult
because of technical complexity and because of a reluctance by some nations to
move from established regulatory mechanisms since the risks perceived by the
public are high. By contrast, Environment Canada spearheaded the international
agreement on the reduction of atmospheric CFCs, the "Montreal
Protocol". International agreement on the rapid phasing-out of CFCs was
possible because of public support for environmentally beneficial regulation. Contact:
John Buccini - Director Commercial Chemicals Branch, Conservation and Protection
- Environment Canada. Reference: Montreal Protocol on Substances that
Deplete the Ozone Layer - 1987,published by the United Nations Environment
Program.
Example: Bilateral exchange agreements relating to good manufacturing practice
(GMP) inspections have been established between Canada and six other countries
- Australia, France, Sweden, Switzerland, the United Kingdom and the United States.
Contact: Dr. E. Somers, Director General Drugs Directorate, Health and Welfare
Canada. Reference: "Towards an Improved Drug Regulatory System: Progress
Since Stein", published by Health and Welfare Canada, 1991.
Agree to testing protocols, accept quantitative test data
Agreements on standard methods for testing pave the way for harmonization and
mutual recognition. Such protocols are most readily applied where tests are strictly
quantitative. The approach is based on the principle that scientists can be relied
upon to report their test data accurately and honestly, especially when standard
protocols allow others to rigorously check their findings. The international sharing
of data is greatly facilitated if procedures are standardized.
Example: Variations on this theme are often encountered. For
instance, testing foods for specific toxins may lead to quantitative test data
that are accepted in many countries. However,
the translation of the test results into regulation will depend upon the
amount of that particular food that is consumed in a normal diet. Thus, while
test data may be standard, the regulatory application of the findings may vary
from country to country because of variations in daily intakes of food.Contact:
Elizabeth Nielsen, Policy Planning and Information, Consumer and Corporate
Affairs Canada.
Example: Canada, the USA and the United Kingdom have established
common biocompatibility requirements for medical devices. In particular, the
requirements establish guidelines for the biocompatibility of polymers. The
recommendations are sufficiently general that they will be able to embrace
yet-unknown methods and materials. While the published findings are not legally
binding, they are likely to form a common foundation for regulation in the three
countries concerned. Contact: Dr. E.G. Létourneau, Director, Bureau of
Radiation and Medical Devices, Health and Welfare Canada. Reference:
Information Letter, no. 737, February 15, 1988, Dr. A. J. Liston, Health and
Welfare Canada.
Accept partner's summary data
When partners have agreed to work at the departmental or national levels, it
may be possible to focus on a reviewers' summary data alone rather than a
company's complete submission. A high level of mutual respect and trust,
however, is a clear prerequisite for this strategy to be adopted. In most cases,
sharing summary data can at least serve as an aid to the reviewers.
Capturing the thinking of regulators in other jurisdictions makes it easier to
identify problem areas and to quickly grasp the key issues under investigation.
In the pesticides area, manufacturers are encouraged to summarize toxicology
data in their submissions. Accessing summaries provides a means of increasing
efficiency by reducing the "learning-curve" of evaluators. It has not
lead to a wholesale reduction of the review work in the cases where used.
Examples: Canada has joined the European Free Trade Association
scheme for the Mutual Recognition of Evaluation Reports on Pharmaceutical
Products. As a result of this initiative, over 20 evaluation reports from other
countries have been used by Canadian reviewers. Contact: Dr. E. Somers,
Director General Drugs Directorate, Health and Welfare Canada. Reference:
"Towards an Improved Drug Regulatory System: Progress Since Stein",
published by Health and Welfare Canada, 1991.
Accept conclusions of shared work
Relying completely on others' work will only be acceptable where full mutual
recognition has been achieved. At present, accords of this type have been made
only in very limited areas that are perceived to be of low risk.
Example: Several OECD countries are sharing reviews of hazardous chemicals that
have been on the market for a long time, but which now should meet more stringent
regulatory criteria. Because of the very large number of evaluations required,
countries found the only way they could do this was work-sharing. Environment
Canada is a participant in this exercise which entails OECD countries splitting
up the list of some 150 common high volume chemicals to be evaluated. Participating
countries have agreed to review procedures and will be accepting the evaluations
of other countries.
Use post-evaluation surveillance
Post-evaluation surveillance is an excellent method of international work-sharing
since most regulating agencies appear to be willing to share information on safety
and efficacy once products have been approved. Effective systems of post-market
surveillance allow products to be released in a more timely manner. Post-evaluation
surveillance fundamentally extends the scope and size of trials in a systems that
are based on risk-management.
Example: The Health Protection Branch has a risk-based system of
this kind planned for the near future for monitoring pharmaceutical products. Contact:
Dr. E. Somers, Director General, Drugs Directorate, Health and Welfare Canada. Reference:
CIOMS (Council for International Organization of Medical Sciences) Working Group
I on international reporting of adverse drug reactions.
Accept foreign submission formats for reporting test data
Submission formats provide a mechanism for easing or deterring entry to our
domestic market. In general, harmonizing formats for the submission of test data
with other countries is the best route that Canada can follow since it allows us
to have input into the international process. Harmonization is not always
possible in instances where another country has a dominant position in a
specific market. Under these circumstances, accepting a foreign format may
reduce effort and costs to applicants. It can also facilitate dialogue and
work-sharing amongst regulators. Wherever possible, formats should be harmonized
with our major trading partners to minimize direct submission costs and costs
due to time lost in preparing special documentation.
Examples: Many countries use regulatory devices to protect their
domestic markets. One country's famous refusal to accept European standards for
skis because their snow was "different" is an excellent example of a
non-tariff barrier to trade. Given that Canada's economy depends vitally on
world trade, it is important to encourage, and to be seen to encourage, a
reasonably free movement of products. By creating formats for submission of test
data that are specifically Canadian we can inadvertently deter entrants to our
domestic market. In many cases it is possible to harmonize formats with one or
more of the following: USA, EEC, EFTA or international organizations such as the
OECD or WHO.
Example: The Baume report on drug evaluation in Australia
recommended that efforts be made to achieve a common electronic format for new
drug applications with Sweden and Canada. It now appears that Australian
authorities will go further than this by also accepting submissions in US or EC
formats.
Actively communicate with the public
Active communications about the regulatory program and the use of international
collaboration would normally be required under most conditions. They are particularly
important when the perceived and real risks are high. Failure to communicate
could ultimately undermine public trust and make regulation more difficult.
Serious problems are ideally addressed through informed debate in an open forum.
Example: The debate over breast implants is of interest in this
context. Some of the companies involved are being criticized as much for their
failure to publicize potential risks involved as for practical problems
associated with the devices themselves.
Take advantage of foreign approvals
In cases where foreign approvals have been made, investigators can attempt to
gain access to relevant reports and summary data. This would allow them to learn
from the experience of others and thus expedite the evaluation process.
Using foreign rejections may also be a method of expediting evaluation,
particularly when back-logs of work exist. While each applicant is entitled to a
review of data submitted, foreign rejections allow domestic regulatory to
evaluate problem areas fairly quickly.
Example: In 1990, Canada joined the European Free Trade Association
scheme for sharing evaluation reports on pharmaceutical products. In addition to
the 6 EFTA countries, Italy, the United Kingdom, the Netherlands, Germany,
Australia and Hungary are also members. Sharing the data requires the consent of
applicants. However, firms with an approved drug in one country are, naturally,
fairly willing to have the findings shared with another. Contact: Dr. E.
Somers, Director General Drugs Directorate, Health and Welfare Canada. References:
"Towards an Improved Drug Regulatory System: Progress Since Stein",
published by Health and Welfare Canada, 1991.
Contribute to the knowledge pool
Canada can contribute to the pool of international information on products
under most circumstances; withholding information is an option that leads to
little competitive advantage. By promoting dialogue with fellow regulators, and
being seen as a positive force, one is more likely to gain access to information
held by others. This is a particularly important feature of any post-market
surveillance system since the bulk of experience with any given product will
tend to have been gathered outside Canada because our domestic market is
relatively small.
Example:Environment Canada publishes decisions on the control of
chemicals under the Canadian Environmental Protection Act. Publishing data of
this kind provides interested parties with a means of focusing discussion on
well defined, technical subjects. This has the effect of raising the level of
debate. Support or criticism is directed towards specific issues and away from
departments and individuals. Contact: John Buccini - Director Commercial
Chemicals Branch, Conservation and Protection - Environment Canada. Reference:
See for example, Canadian Environmental Protection Act; Priority Substances List
Assessment Report No 1 - Polychlorinated Dibenzodioxins and Polychlorinated
Dibenzofurans, 1990.
Example: Agriculture Canada regularly publishes "CAPCO
Notes". These are typically one page flyers that advise interested parties
about enforcement decisions on the use of pesticides. In addition, they provide
helpful analyses to users. Contact: J.B, Reid, Pesticides Directorate,
Agriculture Canada. Reference: CAPCO Notes can be obtained through the
National Pesticide Call Line: 1-800-267-6315.
Share databases
Canada should access information from databases as far as is possible.
Accumulating and summarizing knowledge for decision-making is the essence of the
regulatory process. In areas where we have superior database systems, we should
consider selling access to our foreign partners. We should readily provide
information to international systems in instances where harmonization, mutual
recognition and post-market surveillance apply. In addition, we should rapidly
transfer information on domestically produced goods when this will speed access
to other markets.
Example: The Bureau of Medical and Radiation Devices is developing an
artificial intelligence system that will help in the evaluation of new devices
through comparative risk analysis; both the US and the EEC have expressed
considerable interest in this potentially powerful new tool. In an important
preparatory step, the Bureau has developed a standardized nomenclature system
for medical devices with its American counterpart, the Center for Devices and
Radiological Health. Contact: Dr. E.G. Létourneau - Director, Bureau of
Radiation and Medical Devices.
Example: The Canadian postmarketing pharmaceutical surveillance
program is directly linked to the World Health Organization (WHO) Centre for
International Drug Monitoring in Uppsala, Sweden. Canadian case reports are
entered quarterly in the WHO database and signal assessments, alerts and
decisions regarding regulatory actions are communicated via a computerized
network. By this mechanism the program is kept current on drug safety topics
arising in over 30 countries worldwide. Contact: Dr. C. Appel, Bureau of
Pharmaceutical Surveillance, Drugs Directorate, Health and Welfare Canada.
Conclusion
Best practices in international collaboration are not cast in stone but change
with time. They will reflect trading agreements, changes in technology, trends
in industrial competitiveness as well as public and political sensitivities.
Your contribution to the development of these practices would certainly be welcome.
Contact us at Regulatory Affairs, tel: 613-952-3459. We would be glad to hear from
you.
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