Protecting Our Health:
New Debates

Women and Health Protection
in collaboration with DES Action Canada

International Harmonisation of the Regulation of New Pharmaceutical Drugs


The public has the right to expect that all new pharmaceutical drugs are fully tested and that the highest possible safety standards are met. Citizens rely on government regulators to set standards for drug approval that are in the public interest. This brochure explains how the push to streamline the drug approval process in the world's three largest pharmaceutical markets is neglecting the special needs of women. It also addresses how this process may be compromising overall drug safety standards and jeopardising access to affordable medicines.

For the last 12 years, a pharmaceutical industry/government organisation called the International Conference on Harmonisation of Technical Requirements (ICH) has been working to blend the approval process for new pharmaceutical drugs from Europe, the United States and Japan into one set of standards.

While not a voting member, Health Canada has participated in the ICH and declared itself "committed to the principle of harmonisation." To date, Health Canada has adopted the vast majority of ICH guidelines through regulatory change1. There was no public debate, in Parliament or more widely, about Canada's adoption of ICH guidelines.

Yet ICH guidelines will have a direct impact on the safety standards used by Health Canada when it approves new medicines and, perhaps, an impact on the availability of less expensive drugs.

Women and ICH
This brochure describes the ICH process, focusing on the changes to drug regulation that are likely to have a negative impact on safety. It will especially examine how changes in drug testing standards can affect women. ICH proposals completely ignore the need for special research guidelines for women. Women use more medicines than men and are vulnerable in different ways. They have been disproportionately affected by some of the major drug disasters in the past that could have been prevented through better regulations, such as DES (diethylstilbestrol) which is described at the end of this brochure. And women are still disproportionately affected: of the ten prescription drugs withdrawn for safety reasons from the US market between 1997 and 2001, eight affected more women than men - half of those drugs because more women took them, half because women were more vulnerable to the drugs' harmful effects2.

ICH membership
The home base for the ICH is in Switzerland at the International Federation of Pharmaceutical Manufacturers' Associations (IFPMA). The key participants in the ICH - the only ones with votes -- are the three brand-name pharmaceutical associations that represent that industry in the United States (US), the European Union (EU) and Japan, and the three government health agencies for these same areas. The US, EU and Japan are the three largest pharmaceutical markets in the world -- together they represent close to 80% of the world market - and they are also home to the world's major multinational pharmaceutical companies. (For detailed information on ICH on the web, you can visit

Soon after the International Conference on Harmonisation was officially formed, in 1990, representatives from the World Health Organisation (WHO), the European Free Trade Area and Health Canada joined as non-voting observers. There is no direct representation from companies or government agencies from developing nations, public health advocacy groups, the broader medical profession, or the generic drug industry, which manufactures prescription drugs after brand name patents have expired.



Why an International Conference on Harmonisation (ICH)?

Trade battles. Trade initiatives played a key role in the formation of the ICH. In the mid and late 1980s, the US and Japan began trade talks that included discussion of opening up the Japanese market for US pharmaceuticals. In response, the European Commission strengthened its resolve to establish a single EU standard for drug approvals in order to be competitive with Japan and the US in international trade negotiations. The International Federation of Pharmaceutical Manufacturers' Associations responded to these competing trade initiatives by organising meetings between the EU, Japan and the US.

Faster approval. The driving force behind ICH is the pharmaceutical industry. Prior to ICH, a multinational company was required to conduct a variety of studies and follow different government regulations in order to get its new product approved for patient use in different countries. The industry was interested in streamlining this process in order to reduce development costs and reduce the time to get drugs to market. These changes would allow trade name pharmaceutical companies to reap greater profits from a drug because a shorter part of the patent protection period is spent in the pre-marketing phase. The patent clock begins ticking from the time that companies file an application for patent, so the quicker the drug can get to market, the longer the exclusive sales period.

ICH is advantageous for the brand-name pharmaceutical companies. To bring drugs to market as quickly and inexpensively as possible, and in as many countries as possible, the pharmaceutical industry needs the ICH to:

All of those measures would help to bring drugs to market more quickly. No one would disagree with doing away with unnecessary and uninformative duplication of research. However, when it comes to cutting corners and shortening timelines, it's another matter. For most of the public, speed of approval is not the major consideration. More important is protection of public health, and new medicines that have been thoroughly tested for safety and that meet real human needs. If the ICH process leads to compromises in safety standards through a rush to "harmonise" to the lowest of existing standards, there is good reason to be concerned.

Canada's Role in the ICH



Concerns about ICH Guidelines

This brochure cannot discuss all ICH recommendations in detail, so the main focus will be on those that raise the greatest concerns for public safety and for women's health.

The key focus of ICH is on getting drugs to market more quickly. From a public health perspective, this drive does not benefit the consumer unless the drugs brought to market more quickly are new drugs that meet significant unmet health needs, such as providing treatment for previously untreated or inadequately treated life-threatening illnesses. Otherwise, there are strong safety disadvantages to rushing to market with drugs that duplicate those already on the market ("me-too" drugs) or novel drugs that represent only minor advances (such as new flu drugs with marginal effectiveness against symptoms). Rushing such drugs to market can lead to confusion and over-prescribing, as companies compete fiercely for a limited market or push to create a demand. Rushing such drugs to market can compromise safety (because the safety profile of new drugs is incomplete), lead to increased costs (since new drugs are almost always more expensive than older drugs) and undermine the use of older drugs with established safety profiles.

Speed of approval is not our only area of concern:

  1. Public accountability is missing in the ICH process.
  2. ICH has not addressed the problems women currently face with drug regulation.
  3. Some ICH changes are reducing the safety tests during clinical trials, and thus potentially weakening public health protection.
  4. ICH is not concerned enough with drug safety once the product reaches the market. Stricter, mandated regulation is needed for post marketing safety.
  5. Changes in manufacturing quality standards as a result of ICH may limit competition, raise the costs of medicine and threaten the production of inexpensive generic drugs.
  6. The ICH will streamline the process to get a new drug approved, but will these new medicines meet real health needs?

Measuring Drug Efficacy in Different Populations - including women!
A key requirement of any new medication is that it must be effective and safe in treating the condition for which it was designed and for all of the populations that will be using it. Even before ICH, drug testing had fallen short in ensuring fair representation of all populations. Pharmaceutical companies rarely include enough women, elderly people or ethnic minorities in trials so that effectiveness and safety can be assessed separately for each of these groups. With the advent of ICH, companies can now get approval with even fewer test subjects.

To address this concern relating to fair representation of multiple populations, the ICH created detailed guidelines for companies on ensuring ethnic representation, geriatric representation and pediatric standards.4 There is, however, a complete absence of ICH guidelines on women in clinical trials. And this is despite the fact that both the US and Canada have for many years had well-respected policies and guidelines on inclusion of women in clinical trials.5

A drug should be tested on the range of types of people who are likely to use it. If especially vulnerable people are among the potential users, trials in these groups are necessary.

A 'Special' Population
Women have historically been under-represented in drug research trials for fear that if they are, or become pregnant, the drug could cause birth defects in the child to be born. Enough women should be involved in all stages of drug development so that safety and efficacy can be analysed separately for them. Results from male-only studies cannot be generalised for many reasons, including the following:



Safety Guidelines during Clinical Trials

The ICH has challenged the necessity of particular safety checks on new drugs.

Testing for Cancer Risks and Adverse Drug Events
Animal testing is carried out to make sure a new drug is safe for eventual human use. The ICH wants to minimise the number of such tests because of financial concerns (reducing pre-market testing requirements helps speed the process of getting drugs to market) and controversy over the use of animals. However, without a suitable replacement, reducing animal testing could expose Canadians to significant cancer risks or toxic side effects:

Despite the above,

Health Canada should not adopt any ICH guidelines that reduce long-term testing, or testing of two rodent species, unless there is reliable scientific evidence that another model is equally valid.

Testing for Repeat Dose Problems
In another phase of testing, animals (non-rodents) are exposed to large or repeat doses of an experimental medication to ensure that the drug does not become toxic above certain levels. Before the ICH, the US required 12 months of such testing, while in European countries only 6-month toxicity testing has been required prior to marketing approval. When it set out to harmonise these two systems, the ICH concluded that it was not advisable to reduce the repeat dose testing to 6 months because the US Food and Drug Administration proved that some cases of toxicity only showed up by 12 months. To protect the consumer, the ICH should have adopted a 12-month standard. Instead, an ICH Expert Working Group concluded that a study of 9 months duration should be long enough to detect toxicity. Equally problematic was that it didn't even impose nine months as a minimum standard, but rather as a maximum one.

An industry representative acknowledged that science was heavily influenced by political considerations in reaching this guideline:

"It isn't pure science. There you are in the US where drugs have always been tested with a year's toxicity and suddenly because of some negotiating with Europe, you're now reducing the safety margin on drugs being tested [to 9 months]… I think the EU had to be very careful about the public reaction which says 'hey wait a minute, all these years we've had drugs on the market which were only tested for 6 months and now you're telling us they should have been tested for 9 months… "

(interview by John Abraham with a representative of the IFPMA ).

Patient safety must be rigorously protected. The ICH, and Health Canada, should ensure that a standard of 12 months toxicity testing be required.



After a New Drug Reaches Market: Protecting the Consumer

Post-Marketing Safety Data
Once new drugs are approved for use, governments must still monitor their safety. Sometimes side effects don't show up in a research group of 3,000 volunteers, but become obvious when drugs are used in larger populations. Interactions with other medicines are not uncommon and can't always be assessed in a pre-marketing research trial because patients taking other medications are excluded from these trials. Similarly, a drug can have adverse effects in particular populations who were excluded from pre-marketing trials. This is why it is crucial to follow a new drug after it has been approved for use.

There are some areas of concern about the ICH deliberations in this area.

The ICH's guidelines on PSURs cover how and when companies report to regulatory agencies. But such requirements have limited impact unless government regulatory agencies require:



Brand Name Protectionism?

ICH guidelines have set new manufacturing standards for pharmaceuticals. The ICH argues these new standards will benefit the public, but others, such as the World Health Organisation, are concerned that these new 'gold standards' for manufacturing may provide little true therapeutic benefit and may additionally have other effects:

Health Canada should press ICH for evidence of public health benefits from the quality standards, rather than blindly adopting the latter.

Generic Drugs and the ICH
After a trade-name company's 20 years of patent protection has expired, a generic company can manufacture an equivalent drug and sell it, usually at a significantly lower price. Health Canada is recommending that the new ICH drug manufacturing standards be applied to the production of generic drugs. This is despite the fact that the ICH was not designed to discuss generics - indeed, the subject was supposed to be the regulation of new drugs -- and the generic industry is not formally represented on the organisation. After a trade-name company's 20 years of patent protection has expired, a generic company can manufacture an equivalent drug and sell it, usually at a significantly lower price. Recently, at the insistence of US regulators, the international generic industry has been invited to have observer status on a limited number of issues selected by the ICH. A generic industry spokesperson says that while some aspects of the manufacturing standards make sense for the generic industry, others simply don't.

Health Canada should only implement new manufacturing standards for generic drugs in agreement with the Canadian Generic Pharmaceutical Association.



New Medicines - Do They Meet Real Needs?
The Promise of Innovation

Industry and government participants have justified the ICH process on the basis that money saved as a result of harmonised regulations could be used for innovative research, creating necessary new drugs. But fewer than 9% of new medicines approved in Canada between 1991 and 1997 were determined to be breakthrough drugs by the criteria used by the Patented Medicines Review Board. Most were developed for commercial reasons but were not necessarily safer or more effective than existing drugs.

Companies are not required to direct a percentage of their research and development dollars to address identified but unmet patient needs.



Opening the Doors to Public Consultation

The work of the ICH involves decisions that directly affect public health. While some proposed changes are positive, others - as this brochure has outlined - jeopardise public health and safety. To address these concerns, the ICH process should be much more accountable.

The ICH Steering Committee and working groups should have representatives from public health advocacy groups, developing nations, the generic drug industry, and the broader medical profession.

Health Canada must make more efforts towards inclusion. ICH guidelines should not be adopted until after they have been reviewed and approved by a Canadian committee that includes members of all the relevant stakeholder groups.




Harmonisation of pharmaceutical regulation has important implications for public health, not just for the pharmaceutical marketplace. If public health were the priority, an International Conference on Harmonisation would differ substantially from the current ICH process. For a start, national governments and the WHO would be voting members, and the international and regional industry associations would be observers. Currently ICH operates in the opposite manner - it is chaired by the international brand-name industry association (IFPMA). The harmonisation should be reformulated into an open, accountable and democratic process.

Canada could play a truly visionary role by encouraging the WHO to set up a genuine democratic process relating to harmonisation and by demonstrating a willingness to help finance it.

Canada can additionally play a leadership role by ensuring that any discussions henceforth on harmonisation consider the specific implications for women's health as noted in this document. Canada has specific policies relating to a gender-based analysis of health policy (Women's Health Strategy, 1999) and guidelines for the inclusion of women in clinical trials (Inclusion of Women in Clinical Trials, 1997) which could be shared in the international arena.

With these basic tenets in mind, we further recommend that:

  1. The House of Commons Standing Committee on Health as well as the Canadian Senate should conduct open, broad-based hearings on the effects on Canadians and Canadian health systems of international harmonisation of regulations relating to drugs and devices
  2. Women should be enrolled in clinical trials in all stages of drug development in Canada and elsewhere in numbers sufficient to be able to separately assess drug effectiveness, safety, side effects and dosage levels for women vs. men; results from male-only studies cannot be generalised to women. Government regulators, such as Health Canada, should ensure that adequate monitoring and enforcement of these guidelines takes place.
  3. Only government regulators should be able to make exemptions in the exclusion of any populations in drug trials. This should not be left to the discretion of drug companies.
  4. Health Canada should not adopt any ICH guidelines which reduce long term testing, or testing of two rodent species, unless there is unbiased and reliable scientific evidence that another model is equally valid.
  5. Patient safety should be rigorously protected. Health Canada should ensure that a standard of 12 months toxicity testing in non-rodents is required prior to human testing and marketing approval, and should argue for the same standard in the international arena.
  6. With respect to "Periodic Safety Update Reports" for new drugs, Health Canada should urge the ICH to harmonise these requirements upwards to the US standard of quarterly reporting to protect public health. Canada should follow the US model of standards for PSURs, and must additionally set up and fund an ongoing active post-market monitoring system that is at least as comprehensive as airline safety systems.
  7. Determining what must be reported as "new information" of adverse drug reactions should not be left to the discretion of drug companies. Companies should report any patterns of Adverse Drug Events (any events that occur while a person is taking a drug whether or not they are thought to be associated with the product) and any other unexpected patterns to government regulators as quickly as possible.
  8. Health Canada must have a policy and an effective warning system in place to let health professionals and the public know if a problem with safety or effectiveness of a drug is suspected or if a drug has been banned or restricted for safety reasons in other countries.
  9. Health Canada should approach ICH, ICDRA and the WHO on how to address the neglect of standards for labelling and patient information, so that standards of best practice are adopted internationally (recognising that best practice standards may vary according to national cultures.) Priority needs to be given to clear labelling and informative patient inserts that take varying literacy levels into account. Labelling and inserts should insure that patients understand what they are taking, why, what side effects might occur and what to do if they are affected.
  10. Health Canada should defend generic drug policies that protect consumers from rising prescription costs. Generic manufacturers should not be forced to adopt ICH standards that are inappropriate for them.
  11. To ensure accountability, Health Canada should urge the Steering Committee and working groups of the ICH to have representatives from public health advocacy groups, developing nations, the generic drug industry, and the broader medical profession.
  12. Before adopting ICH guidelines, members of all the relevant stakeholder groups noted above should be added to any Canadian committee which reviews these guidelines.




DES (diethylstilbestrol) was one of Canada's worst drug disasters. Between 200,000 and 400,000 pregnant women and their children were unnecessarily exposed to a harmful medicine.

DES was the first synthetic estrogen. The drug was prescribed to prevent miscarriage between 1941 and 1971 in North America (longer in Europe), but proved ineffective. Although good evidence from animal studies indicated that DES might cause cancer, the drug



Written by members of Women and Health Protection, based on an original paper by John Abraham

The original idea for the series -- Protecting Our Health-- was conceived by Rosanna Baraldi, DES Action Canada.

Other titles in this series include:

For more information about Women and Health Protection, visit the website at .

This project was made possible by funding from the Centres of Excellence for Women's Health Program in the Women's Health Bureau of Health Canada. The views expressed herein do not necessarily represent the official policy of Health Canada.




1 For a complete list of documents from TPD on the adoption of ICH guidelines, go to:

2 Heinrich J. Director Health Care-Public Health Issues. US General Accounting Office. Drug Safety: Most Drugs Withdrawn in Recent Years Had Greater Health Risks for Women. GAO-01-286R Drugs Withdrawn from Market. Letter to: To Harkin, OJ Snowe, US Senate and HA Waxman, House of Representatives. January 19, 2001

3 See

4 Ethnic Factors in the Acceptability of Foreign Clinical Data", ICH, 1998; Studies in Support of Special Populations: Geriatrics, ICH, 1993; and Clinical Investigation of Medicinal Products in the Pediatric Population, ICH, 2000. For further information see ICH website,

5 US guidelines: Guideline for the Study and Evaluation of Gender Differences in the Clinical Evaluation of Drugs (FDA, 1993, and Guidelines for the Inclusion of Women and Minorities in Clinical Research(NIH, 2001,;
Health Canada Guidelines: November 1997

6 Heinrich J. Director Health Care-Public Health Issues. US General Accounting Office. Drug Safety: Most Drugs Withdrawn in Recent Years Had Greater Health Risks for Women. GAO-01-286R Drugs Withdrawn from Market. Letter to: To Harkin, OJ Snowe, US Senate and HA Waxman, House of Representatives. January 19, 2001

7 Reporting can be encouraged by making it clear to physicians that this is a valid and important activity (using Health Canada's usual vehicles for information communication) and by giving doctor's rapid and useful feedback about reports that they have filed.

8 For more on these topics, please see our brochures in this series: How Safe are our Medicines (2000), and Direct-to-Consumer Prescription Drug Advertising (2001).


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