Position on Commission Proposal for a Clinical Trials Regulation

A European Institute of Women’s Health Position Paper, January 2013.

Our position on the Commission Proposal for a Clinical Trials Regulation:

The EIWH welcomes the Commission’s proposal for a Clinical Trials Regulation to replace the current Clinical Trials Directive 2001/20/EC. We look forward to the legislation’s speedy adoption by the European Parliament and Council.

The Commission’s choice of a Regulation will allow for closer harmonisation and implementation of some common rules in all EU member states. It is our hope that these new legal measures will speed up the approval process of clinical trials, reduce the bureaucratic burden and facilitate the development of robust, innovative collaborative multinational research that best serves patients and society. However, we are concerned that the assessment procedure has been split into two parts: Part I for a single coordinated application file to be submitted electronically to an EU Portal, addressing the non-ethical aspect of the clinical trial, and Part II which leaves ethical issues, such as ethics committees, informed consent, patient participation and information largely up to Member States. In our view it is unacceptable and a step back not to include the ethical dimension in such an important piece of legislation that concerns human life.

Strengthening the ethics dimension

While we understand that the reason for this is that under Treaty rules, ethics are considered a national issue, we wish to assert that science and ethics are an integral part of the quality and robustness of biomedical research and clinical studies. Referring to the European Charter of Fundamental Rights, the Declaration of Helsinki and the ICH–GCP Guidelines, is reassuring. Other internationally agreed ethical standards such as the International Ethical Guidelines for Biomedical Research Involving Human Subjects, prepared by the Council for International Organizations of Medical Sciences (CIOMS) in collaboration with the World Health Organization (WHO) should be referenced as well.1 Point 9 of the Declaration of Helsinki states: “Medical research is subject to ethical standards that promote respect for all human subjects and protect their health and rights.”

  • We insist that the ethical dimension is clearly stated in the legislative proposal to protect trial participants, patients and societal interests.  Irrespective in which country the trial is taking place, in the EU or outside, an ethical review is an overarching principle without which the clinical trial cannot be started.

Women in clinical studies

The European Institute of Women’s Health (EIWH) major focus is on including women in clinical studies in sufficient numbers to make a robust benefit/risk assessment of how the medicine works in both men and women. Historically the research community has been reluctant to include women in clinical trials for safety reasons. Following the Thalidomide tragedy in the late 1950s, women of childbearing age were excluded from clinical trials due to the fear of exposing the unborn child to investigational procedures. Gradually this ban has been relaxed, as women were better able to control their fertility.  Today it is increasingly recognised  that both sex (biological) and gender (socio-behavioural) factors affect health – for women and men. Differences exist in the incidence, treatment response and prognosis of a range of diseases, including heart disease, arthritis, depression, infectious diseases and autoimmune diseases.

Many physiological and pathological functions are influenced by sex-based differences.

“Differences also exist at the basic cellular and molecular levels”.2  A person’s sex may differentially influence genetic predisposition, the impact of both environmental and biological risk and protective factors, time of onset, symptoms and the progression of many diseases. This knowledge has improved our understanding of a range of diseases and consequently enhances our ability to intervene more effectively.  Future innovative research is expected to take place in the field of personalised/stratified medicine, and biological sex differences will become even more important.

Gender may also influence the effectiveness of medication and its duration

The EIWH holds the view that it is important to ensure that men and women are enrolled in clinical trials at all stages of drug development in order to define the risks and benefits associated with drug therapy for both male and female patients.Since for women, physiological changes and hormonal levels during childbearing years and menopause, as well as the use of oral contraceptives or hormone replacement therapy, may affect the efficacy and safety of a drug, the influence of these parameters should be studied during drug development.  For a long time, scientists referred to women as a sub-population when in fact women make up over half of the world’s population.A recent Nature article argues that “gender inequalities in biomedical research are undermining patient care”.  The article calls for the “sex bias in basic research and clinical medicine to end”.3  The current lack of evidence about the effectiveness of medicines  in women may result in withholding treatments from women that could be beneficial or exposing them to treatments that may be harmful.

Guidelines by the International Conference on Harmonisation (ICH) covering the conduct of clinical trials internationally, state that an underlying principle of drug development is that “patients entering clinical trials should be reasonably representative of the population that will be later treated by the drug.”4  In 2006 the European Medicines Agency (EMA) published its own Guidelines entitled ICH – Gender considerations in the conduct of clinical trials which summarises various ICH Guidelines that refer to women.5  The document states that while women appear to be participating in all phases of study development, participation is lower in Phase I and I-II studies. However, these are the studies in which safety, safe dosage range and side effects are determined.

Women, including women’s health advocates, must be included when decisions about what research to do and how to do it are debated. It is not sufficient to include women as research subjects; they must also be included further upstream, helping to inform the design of the clinical study. Furthermore research funded from public money, should follow the US National Institutes of Health example to require as a funding criteria that such research includes women.6

Women take more medicines and have more side-effects

It is well recognised that women experience more side-effects when taking medicines than men. Several studies document that men and women respond differently to medicines and therapies. It appears that women have a higher susceptibility to adverse drug reactions (ADR). According to Rademakers  “Female patients have a 1.5- to 1.7-fold greater risk of developing an ADR, including adverse skin reactions, compared with male patients.”7 However, the reasons for this are not clear. Differences in the complex interaction of pharmacokinetics and pharmacodynamics, pharmacogenetics, immunological and hormonal factors may be responsible.  Another influencing factor may be the greater use of medicines in women and their longer lifespan which often brings with it chronic conditions and disability.“ A 2005 study of 300 new drug applications between 1995 and 2000 found “that even those drugs that showed substantial differences in how they were absorbed, metabolized and excreted by men and women had no sex-specific dosage recommendation on their labels.” 8

We therefore urge that the new Regulation addresses the following points:

  • Ensure sex/gender distribution in clinical studies, which reflects the patient population that are intended to receive the treatment.
  • Make inclusion of women in clinical trials explicit and the numbers included statistically relevant to allow for systematic analysis of sex differences. It is a common misunderstanding that taking sex into account by adjustment in statistical analyses is all that is needed to exclude sex differences. This procedure only eliminates the possibility that sex is a confounding factor.
  • Stratified analyses should be carried out. Clearly state these requirements in the Study Protocol and Assessment Report. Without making such requirements a formal request for the clinical studies, there is no assurance that women will be automatically included in appropriate numbers.

Pregnant women and medicines

Pregnant women are generally excluded from clinical studies. This practice is intended to protect pregnant women, their unborn/future child from avoidable harm by exposing them to experiments. However, in real life women suffering from certain diseases such as epilepsy, diabetes, depression, auto-immune diseases, HIV-AIDS are faced with a dilemma: should they risk pregnancy at all and how would pregnancy affect them, their treatment and the well-being of their child.
Currently, pregnant women and their doctors have to rely on evidence gathered from pharmacovigilance data and pregnancy registries. The EMA adopted Guidelines on the “Exposure to Medicinal Products during pregnancy” in 2005. The Guidelines propose active surveillance for collecting post-authorisation data in pregnancy.9  In addition to pregnancy registries required under the EMA Risk Management Plan for a new drug, a case-control surveillance system is needed to collect safety data of newly registered and already authorised drugs to protect mother and child. Pregnancy registries can detect high or moderate teratogens of newly registered drugs while a case-control surveillance system can detect teratogens of all drugs on the market.

Older women and clinical trials

Between 2010 and 2030, the number of Europeans aged over 65 will rise by nearly 40%, posing challenges for healthy ageing and healthcare budgets. People 65+ will account for 30% of the EU population compared with 17% in 2008. Women make up the largest proportion of the older population and are the heaviest users of medicines. The fastest growing age group is 85+ and is mostly female. Older people are generally excluded from clinical trials; the cut off age is around 65 years. Therefore the evidence base for clinical decision-making in older people is poor, although older people are the biggest users of health services including medicines.
Older people use more than 30% of prescribed medicines and more than 40% of over the counter medicines. Moreover, in some countries, they account for up to 60% of total pharmaceutical expenditure. Additionally, the percentage of older people who take several medicines for various chronic conditions is high and on the increase. Older people also have the highest risk to develop Adverse Drug Reactions (ADRs). In Europe, ADRs cause 20% of physicians’ visits as well as up to 30% of hospital admission. Older people show different pharmacokinetics, the way a medicine moves through the body and pharmacodynamics and may have different ADRs from younger adults. Some conditions, such as Dementia and Alzheimer’s are specific to older people. Despite the above, medicines are not routinely tested for the specific use in older people. Recognising this lack in addressing the needs of an ageing population, the European Medicine Agency (EMA) published its geriatric medicines strategy in February 2011 with the aim to ensure that the medicines used by older people are of high quality and are studied appropriately in the older population, both before and after authorisation;improve the availability of information for older people on the use of medicines10 Many older people place a high value on their quality of life and ability to live autonomously. This means that clinical research in older people may require different endpoints. Older people are usually subject to several diseases at one time and this requires special attention to avoid medicines counter- or interacting with each other, harming the patient. The diseases burden and loss of function increases considerably with advancing age and there are differences in health status between the ‘younger’ older person and the ‘frailer’ older person. Additionally a person can be ‘old’ at age 60 and relatively ‘young’ at 80.
A two-year DG Sanco supported research consortium, called Predict, investigated the reasons for the exclusion of older people and collected data on the barriers they face enrolling in clinical trials. To this end Predict developed a European Charter for Older people in Clinical Trials. The document is available in 10 EU languages.11
We urge that the EMA’s geriatric medicines strategy is supported by a Geriatric Medicines Committee.

Common guidelines for the ethical review process

Since the draft legislation leaves ethical issues largely up to Member States, we fear that this is a step back for clinical trials conducted in the EU and outside. A strong link to the Helsinki Declaration must be ensured for all aspects of the legislation. We are  concerned that the current legal text would allow different standards applied across the EU, resulting in  divergent views of ethics committees, which may not be in the best interest of Europe’s patients nor support public health objectives. The proposed timelines seem very ambitious and require tackling the heterogeneity of ethics committees and their working methods. We need to ensure that ethics committees working methods are fit for examining ethical research questions in the most effective way to protect patients and to enable cutting-edge scientific research, such as research into orphan diseases or personalised/stratified medicines which require much more collaboration not only of the scientific, but also of the ethical aspect as an integral part.

Ethics committees often neglect to consider the gender issue. A recent study investigating research ethics committees (RECs) in five European member states (Austria, Germany, Ireland, the Netherlands and Sweden) found that they “pay limited attention to gender equality in their working methods and, in particular in protocol evaluation. The study recommends that “policy and regulations of EU are needed to strengthen attention to gender equality in the work of RECs.”12

In the European Union, a DG Research-funded report entitled Engendering Health(y) Research, published in 2003  made recommendations for a future instrument of health protocols by research ethics committees in 5 EU countries.13 Additionally, the ethics committee of the University Vienna has issued guidelines regarding the inclusion of women in clinical research.14

In our view there is an urgent need to draw up common guidelines and standards for national, regional, local ethics committee review and about the way they operate.
We urge that these recommendations be included in drawing up a comprehensive set of common guidelines and standards to support national ethics committee’s in their work. This should be financed under the new Health for Growth programme, along the line of the work of EUnetHTA on health technology assessment, which also falls under Member States competency.
We welcome the new Clinical Trials Regulation proposing a patient involved in the assessment procedure. It must be clarified that this also includes Part I and Part II of the assessment. However, we argue that one patient is not enough to cover the complex spectrum of diseases to be reviewed as well as representing both male and female trial subject. We therefore recommend that the patient view be drawn from a group of patient experts or their legal representative both male and female, and of the appropriate age group.  The Commission should be encouraged to set up at database of relevant patient organisations.

The Guidelines should also include standards for the information given to trial participants/patients, meaningful and patient-friendly Informed Consent form, and in the case of women of childbearing age, carefully explain the need for effective contraception. Trial participants/patients have a right to the same information within and outside the EU. Representatives of patient and health organisations, must be involved in drawing up theses guidelines.

Transparency of clinical studies data – EU clinical trial database

We welcome the move towards greater transparency of clinical trial data published one year after the trials is completed in a EU database. Our long-standing concern has been for access to timely information about the trial results including failed trials. Negative results can be just as important as positive ones to improve our scientific understanding and avoid duplication. We feel that such information will support innovation rather than hinder it, reveal more about the sex/gender and age differences in the population studied and prevent duplication of trials which wastes valuable resources without bringing real benefit to patients and society.

However, a summary of results drawn up by the sponsor is not sufficient. To ensure the quality and usefulness of study results which will be published in the EU database one year after the trial is finished, it must contain the number of men and women that were included in the clinical trial, the age groups covered and how bias was minimised or eliminated.  We recommend that standards be developed by regulators in collaboration with researchers, civil society and patient organisations to define clearly what information should be contained in the EU database, the methodology used to reduce bias and to ensure that the data is relevant to all groups information needs.


The revision of the Clinical Trials legislation is an opportunity to streamline clinical studies in Europe.  It is also an opportunity to move towards more personalised medicine, taking account of the differences between men and women at molecular and cellular level, as well as age-specific factors. Incorporating sex, gender and age into clinical research is good science and an imperative in a fair and just society. The integral part of scientific and ethical issues must be ensured across the legislation. Keeping European research on the forefront of innovation is a major goal of the 2020 Strategy. This must be enabled through supportive measures such as the European Clinical Trials legislation.

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