the protection of patients’ rights in clinical trials

Science and Engineering Ethics (2006) 12, 131-138

Science and Engineering Ethics, Volume 12, Issue 1, 2006 131

Keywords: protection of patients’ rights, clinical trials, ethic committees ABSTRACT: The Helsinki Declaration is a very important document regarding the protection of patients’ rights in clinical trials and one of the fundamental sources of operational principles for every ethics committee. Although they have been updated, the international guidelines for ethics committees continually fail to address certain issues pertaining to the protection of patients’ rights in clinical trials. These issues include, most significantly, the method of electing ethics committees (a free, secret ballot should be preferred to direct appointment), the avoidance of conflict of interest during the election of ethics committee members, and the necessary insurance coverage for the participants of clinical trials. Polish law should, on the other hand, be developed in such way as to not limit the effectiveness of ethics committees in protecting patients’ rights in clinical trials. The ideal solution would be to draft a uniform law concerning not only clinical trials, but all medical experiments. The opinions of experts who have been reviewing medical research projects for several years may prove to be especially valuable in this setting. The past few decades have brought about significant advances in the protection of patients’ rights in clinical trials. The publishing of several international guidelines and recommendations, most notably the Helsinki Declaration,1 has been beneficial to this field. The Helsinki Declaration was drafted in June 1964 by the World Medical Association and subsequently updated several times. The most recent amendments led to the addition of commentary to articles 29 (Washington 2002) and 30 (Tokyo 2004).

The Protection of Patients’ Rights in Clinical Trials Marek Czarkowski Medical University of Warsaw, Poland

This paper was presented at the 6th International Bioethics Conference on the subject of ‘TheResponsible Conduct of Basic and Clinical Research’, held in Warsaw, Poland, 3-4 June 2005. Address for correspondence: Marek Czarkowski, MD, Department of Internal Medicine andEndocrinology, Medical University of Warsaw, ul. Banacha 1A, 02-097 Warsaw, Poland: email:[email protected]. The author is Chairman, Bioethics Committee of the Warsaw Regional Chamber of Physicians andDentists. 1353-3452 © 2006 Opragen Publications, POB 54, Guildford GU1 2YF, UK. http://www.opragen.co.uk

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132 Science and Engineering Ethics, Volume 12, Issue 1, 2006

The guidelines regarding the use of placebo, detailed in art. 29,a were the subject of intense criticism from circles representing the interests of pharmaceutical companies. This was undoubtedly the result of a conflict between the will to ensure the best possible protection for the participants of clinical trials (trial subjects) and the economic interests of the pharmaceutical companies. Placebo-controlled trials of new medications are more likely to lead to market success than trials in which the effectiveness and safety of a new drug are compared to a widely-known, and usually cheaper, reference drug. Demonstrating the efficacy of a new drug, compared to placebo, allows for its registration as an effective treatment for a given condition. Requiring that the new drug be compared to an older one always creates the risk that the studied drug may prove to be less effective. Thus, from the study sponsor’s point of view, a placebo-controlled trial of a new drug creates a greater probability of economic success than a trial in which it is compared to other existing, effective, and usually cheaper drugs. Pressure from circles representing the interests of pharmaceutical companies has led to the addition of commentaryb to art. 29 which, instead of clarifying art. 29 and stating it more precisely, created a series of ambiguities and is, in my opinion, insufficient in protecting the rights of the participants of clinical trials.

Art. 30 of the Helsinki Declaration,c on the other hand, and the commentary added in Tokyo in 2004,d are examples of well-written guidelines regarding the protection of patients’ rights in clinical trials. Art. 30 and the commentary concern the protection of study participants from the scenario in which an effective treatment is ceased at the end of the trial. It is worth noting that some clinical trials, especially those designed in accordance with the rules of Evidence-Based Medicine, deal with potentially fatal conditions, in which withdrawal of effective treatment may pose a direct hazard to not only the patients’ health, but also their lives. Thus, if patients are offered participation in a clinical trial, it is the study designers’ responsibility to foresee the possible

a. “The benefits, risks, burdens and effectiveness of a new method should be tested against those of

the best current prophylactic, diagnostic, and therapeutic methods. This does not exclude the use of placebo, or no treatment, in studies where no proven prophylactic, diagnostic, or therapeutic method exists.”

b. “The WMA hereby reaffirms its position that extreme care must be taken in making use of a placebo-controlled trial and that in general this methodology should only be used in the absence of existing proven therapy. However, a placebo-controlled trial may be ethically acceptable, even if proven therapy is available, under the following circumstances:

- Where for compelling and scientifically sound methodological reasons its use is necessary to determine the efficacy or safety of a prophylactic, diagnostic or therapeutic method; or

- Where a prophylactic, diagnostic or therapeutic method is being investigated for a minor condition and the patients who receive placebo will not be subject to any additional risk of serious or irreversible harm.

All other provisions of the Helsinki Declaration must be adhered to, especially the need for appropriate ethical and scientific review.”

c. “At the conclusion of the study, every patient entered into the study should be assured of access to the best proven prophylactic, diagnostic and therapeutic methods identified by the study.”

d. “The WMA hereby reaffirms its position that it is necessary during the study planning process to identify post-trial access by study participants to prophylactic, diagnostic and therapeutic procedures identified as beneficial in the study or access to other appropriate care. Post-trial access arrangements or other care must be described in the study protocol so the ethical review committee may consider such arrangements during its review.”

The Protection of Patients’ Rights in Clinical Trials


consequences, as well as to ensure appropriate therapy following the completion of the trial, especially if the studied method proves to be the only effective treatment for a given condition. In such a situation, the continuation of effective treatment may only be possible if the participants are assured of free access to a new, unregistered drug. New products are usually expensive and study participants cannot afford to purchase them. The national health care system cannot, however, refund the cost of such treatment prior to the official registration of the new drug. Assuring the trial participants of access to the studied drug following completion of the trial can significantly increase the cost of such a study. It simultaneously creates the possibility for patients to participate in a long-term open phase of the study, which can yield interesting clinical observations concerning, among other things, the safety of the treatment and how well it is tolerated by the patients. The alternative to the approach outlined in the Helsinki Declaration is the ethically unacceptable scenario in which study participants are placed in a potentially life-threatening situation after the trial is completed and treatment is withdrawn.

Other important international documents, besides the Helsinki Declaration, include the guidelines for ethical committees developed by the World Health Organization2 and European Forum for Good Clinical Practice.3 Certain significant aspects of the protection of patients’ rights in clinical trials were, however, omitted in these documents.

First of all, it was assumed that the elections of ethics committee members by ballot and by direct appointment are equivalent. I disagree with this opinion. Polish bioethics committees (the name given to ethics committees in our country) are elected both by appointment and by free ballot. The first method is used for committees at medical universities and scientific research institutions, the latter for bioethics committees of regional chamber of physicians and dentists. Members of the bioethics committees of regional chamber of physicians and dentists are elected by the doctors of the regional medical council. In the case of the Bioethics Committee of the Warsaw Regional Chamber of Physicians and Dentists, for example, the elections may only commence once at least two candidates have been nominated for each position. The ballot is secret, and members of the committee can only be dismissed if they fail to take part in its activities. The members of the bioethics committees of medical universities and scientific research institutions, on the other hand, are both nominated and elected by arbitrary appointment. Direct appointment is still widely used as a method of electing ethics committee members in the European Union and USA. It does not, however, guarantee the true independence of the committee members, and, furthermore, creates a high probability of conflict of interest. The free and secret ballot method should therefore be preferred to the direct appointment method for the election of members of independent ethics committees in the European Union and USA. The members of ethics committees of medical universities and scientific research institutions should be elected by all the scientific workers of these institutions, while the members of ethics committees of medical boards or local government should be elected by the members of the appropriate board or government.

Another major drawback of the method of electing members of bioethics committees at medical universities and scientific research institutions currently used in

M. Czarkowski


Poland is the fact that the majority of doctors who are members of the bioethics committees are salaried employees of these institutions. There are no meritoricale

reasons why candidates for these positions could not be recruited from outside these organizations. A similar situation exists in the other European Union nations and the USA, where members of university ethics committees are usually also employees of the university. The level of protection of patients’ rights in clinical trials would be higher if the members of a given ethics committee were not simultaneously employees of the institution to which the committee is attached. It is in the university’s interest to perform as many sponsored clinical trials as possible, since they constitute an additional source of income. The issue of the true independence of the committee members should also be considered with respect to the possibility of reviewing the protocol of a study designed by a colleague from the same institution, possibly even the direct superior of an ethics committee member.

The protection of patients’ rights in clinical trials will not be adequately ensured as long as the issue of conflict of interest continues to be only partially addressed in international guidelines. Limiting the concept of conflict of interest to situations in which “a member of the Ethics Committee has financial, material, institutional, or social ties to the research,” instead of to a given pharmaceutical company, is more a result of the context in which conflict of interest is described in international guidelines2 than the real-life situations in which it may exist. The assumption that an ethics committee member who is linked with a given pharmaceutical company (e.g. by taking part in another clinical trial sponsored by the company or lecturing at a symposium or training sponsored by the company) is entirely free of conflict of interest is unconvincing. It is thus extremely important that clear regulations be outlined for candidates for positions on ethics committees, with the goal of limiting the role of doctors with extensive and significant material ties to pharmaceutical companies.

The international guidelines2,3 do not specify that all candidates for positions in ethics committees should be required to present a written declaration, stating whether or not they are currently taking part or planning on taking part in sponsored clinical trials, if they are receiving any sort of sponsorship from pharmaceutical companies and, if so, in what form, and whether or not they or members of their family are employed by or otherwise linked to pharmaceutical companies. It is obvious that a potential conflict of interest during the election of ethics committees is a real possibility. As far as the protection of patients’ rights in clinical trials is concerned, it is safer to prevent this scenario from occurring than to attempt to deal with it once the committee has already begun its work. In the case of the Bioethics Committee of the Warsaw Regional Chamber of Physicians and Dentists, every candidate is obliged to present a written declaration, disclosing how many sponsored clinical trials he is taking part in, if he plans to take part in such trials in the future, and whether or not he or members of his immediate family are in any way connected with pharmaceutical companies. This information is communicated during the presentation of candidates prior to the election.

Another issue which has a significant effect on the protection of patients’ rights in a clinical trial is the study’s insurance coverage. In Poland, participants of clinical trials e. Meritorical – pertaining to the content or subject matter.



are covered by civil liability insurance.4,5 This specific type of insurance policy requires that, for compensation to be paid, the insured party must be proven liable for any damages caused. In reality, however, damage occurring during a clinical trial is not always caused by somebody’s error – it can simply be the result of an unexpected adverse effect of the medication. The insurance policy should therefore specify that the insured party assumes responsibility for all damages related to the patient’s participation in the clinical trial, regardless of whether or not they were the result of an error or negligence by the insured party.

The international guidelines fail to note the importance of the meritorical review of insurance policies and detailed terms of insurance, which are presented to ethics committees. Unfortunately, even lawyers, who may be members of ethics committees, often lack the knowledge required to adequately assess these documents. At the Bioethics Committee of the Warsaw Regional Chamber of Physicians and Dentists, we have, for several years, enlisted the services of an insurance broker, who is responsible for the analysis of all insurance policies, in order to guarantee the best possible coverage for participants of clinical trials. The general requirements for the trial’s insurance policy are, of course, outlined by the members of the Bioethics Committee; the insurance broker simply verifies whether or not the policy fulfils all these requirements. In order to ensure adequate protection of patients’ rights in clinical trials, regarding compensation for any damages caused, all aspects of the insurance coverage must be thoroughly analyzed, including a professional review of the quality of the insurance policy. This analysis should be performed by a specialist in the field – the insurance broker. It would be worthwhile to address the issue of guaranteeing adequate insurance coverage for patients participating in clinical trials more extensively in the international and European guidelines.

The amendments made to Polish law in order to comply with Art. 7 of European Union Directive 2001/20/EC f,6 had a negative effect on the level of protection of patients’ rights in multi-centre clinical trials. First of all, the legal amendments in both Poland and several other European Union nations have led to a situation in which the study sponsor (i.e. the pharmaceutical company) selects the bioethics committee which will review the multi-centre clinical trial’s protocol – see Art. 37s of the Polish Pharmaceutical Act.g,7 According to Polish law, the study sponsor is responsible for

f. “For multi-centre clinical trials limited to the territory of a single Member State, Member States

shall establish a procedure providing, notwithstanding the number of Ethics Committees, for the adoption of a single opinion for that Member State.

In the case of multi-centre clinical trials carried out in more than one Member State simultaneously, a single opinion shall be given for each Member State concerned by clinical trial.”

g. “Art. 37s 1. If a clinical trial based on the same protocol is carried out by different researchers in

multiple research centers in the territory of the Republic of Poland or other nations (a multi-centre clinical trial), the sponsor selects, among all researchers taking part in the trial in the Republic of Poland, a study coordinator.

2. In the case of clinical trials described in pt. 1, conducted in the territory of the Republic of Poland, the sponsor or study coordinator files the necessary documents with the bioethics committee of the region in which the study coordinator is based.”

M. Czarkowski


selecting a national coordinator for a multi-centre clinical trial. The study protocol must be reviewed by the bioethics committee of the region in which the coordinator is based. Thus, by selecting a given researcher (investigator) as study coordinator, the sponsor automatically selects the bioethics committee which will review the protocol. Every bioethics committee should, of course, review clinical trial protocols with equal care and impartiality. The same rule, however, applies to common courts, and yet the law does not allow for the defendant to choose the members of the jury. It would therefore be preferential, in the setting of multi-centre clinical trials, if the sponsor’s decision to select a national coordinator did not affect the choice of the bioethics committee which reviews the study protocol.

Furthermore, the requirement that a single review be presented for each multi-centre clinical trial has created the need for the bioethics committee of the study coordinator’s region to acquire partial reviews from other bioethics committees which supervise the other researchers and centres taking part in the trial. A 14-day deadline has been imposed for the completion of this procedure; if a given regional committee does not file any objections with the study coordinator’s committee within this period, its consent is assumed,h,7 During this 14-day period, the regional bioethics committee must first be notified of the study, then appoint an expert to evaluate the researcher or centre in question, draft a review, invite the researcher to a committee session, vote on any objections that may arise, and inform the national coordinator’s committee of its decision. Polish regional bioethics committees are often unable to complete the entire procedure in such a short time. The rule of assumed acceptance often reflects not so much true acceptance as the lack of a completed review from the regional committee, which did not manage to prepare the necessary documentation on time. In this situation, a new danger has arisen to the safety of participants of clinical trials. Prior to the amendments to Polish law in accordance with Art. 7 of European Union Directive 2001/20/EC,6 every researcher was reviewed by his regional bioethics committee, and there were thus no researchers or centres who had not been reviewed prior to taking part in clinical trials. The current situation is not, of course, a result of Art. 7 of European Union Directive 2001/20/EC6 itself, but of a poorly performed amendment of Polish law to comply with this directive. A more adequate revision of Polish law could eliminate this negative situation.

The proper oversight of clinical trials is vital to the protection of patients’ rights. It is required that all clinical trials in Poland must be monitored.7 The committees must review additional materials concerning the progress of the study, amendments to the protocol, the information given to patients, the informed consent and insurance forms, and any suspected, unexpected serious adverse reactions.7 Aside from the bioethics committees, all clinical trials involving the use of medicinal products must also be

h. “Art. 37s

4. The bioethics committee described in pt. 2 is required to inform all bioethics committees in the Republic of Poland in whose regions the study will be performed of the planned participation of a given centre. These committees may, within 14 days, file objections as to the participation of a given researcher or centre in the study; failure to file objections within the aforementioned period is equivalent to acceptation of the participation of a given researcher or centre in the study.”



reported to the Minister of Health and are subject to inspection by the Office for Medical Products, Medical Devices and Biocides.7 Detailed regulations concerning the nature and extent of clinical trial inspections were published by the Minister of Health in 2005.8 The reviewing and monitoring of clinical trials is thus, as in many other countries, performed dually – by the bioethics committees on one hand, and by the Minister of Health and subordinate departments on the other. Polish bioethics committees cannot, however, withdraw their consent for a given clinical trial to be performed. Should circumstances arise which, in the opinion of the members of the bioethics committee, warrant the termination of a clinical trial, the only action the committee can take is to alert the Minister of Health. The Minister may then, in accordance with Art. 37ac of the Pharmaceutical Act,7 decide to suspend the clinical trial, withdraw his consent for the trial, or indicate measures which must be taken in order to allow for the continuation of the trial. There are no meritorical reasons why the bioethics committees should be limited in their ability to stop clinical trials once they are underway. Polish law should thus be amended, so that not only the Minister of Health, but also the bioethics committees would have the power to suspend a clinical trial or withdraw their consent. Such action would have a positive effect on the protection of patients’ rights in clinical trials, especially in situations in which the participants’ safety is dependent on the speed with which decisions are made.

Another significant issue affecting the protection of patients’ rights in clinical trials is the analysis of the safety of the studied medicinal product, and how well it is tolerated by study participants. Ethics committees currently receive reports from special scientific committees which are responsible for monitoring the patients’ safety. These committees are set up and funded by the study sponsor. Ethics committees are largely reliant on data reported by these committees. It seems that it would be beneficial to the participants of clinical trials if the members of these committees were selected by a party independent of the sponsor, i.e. the ethics committee. The scientific committee members should, of course, be qualified professionals, free of conflict of interest; funding should remain the responsibility of the sponsor. The members of such a committee should assume responsibility for the safety of the given medicine, periodically issue a safety certificate, and regularly report on the safety of the study.

In conclusion, it is worth noting that the Helsinki Declaration1 is undoubtedly the document which should form the foundation for the operational principles of every ethics committee. Although they have been updated, the international guidelines for ethics committees2,3 continually fail to address certain issues pertaining to the protection of patients’ rights in clinical trials. These issues include, most significantly, the method of electing ethics committees, the avoidance of conflict of interest during the election of ethics committee members, and the necessary insurance coverage for the participants of clinical trials. Polish law should, on the other hand, be developed in such way as to not limit the effectiveness of bioethics committees in protecting patients’ rights in clinical trials. The ideal solution would be to draft a uniform law concerning not only clinical trials, but all medical experiments. The opinions of experts who have been reviewing medical research projects for several years may prove to be especially valuable in this setting.

M. Czarkowski


REFERENCES 1. World Medical Association Declaration of Helsinki Ethical Principles for Medical Research

Involving Human Subjects http://www.wma.net/e/policy/b3.htm. 2. Operational Guidelines for Ethics Committees That Review Biomedical Research. (2000) World

Health Organization Geneva. 3. Guidelines and Recommendations for European Ethics Committees. (1997) European Forum for

Good Clinical Practice. Revised Edition EFGCP. 4. April 30, 2004 Order of the Minister of Finance concerning the mandatory civil liability

insurance of researchers and sponsors. (2004) Legislation Journal of the Republic of Poland 101: Pos. 1034

5. May 18, 2005 Order of the Minister of Finance amending the regulation concerning the mandatory civil liability insurance of researchers and sponsors. (2005) Legislation Journal of the Republic of Poland 101: Pos. 845

6. Directive 2001/20/EC of the European Parliament and of the Council of 4 April 2001 on the approximation of the laws, regulations and administrative provisions of the Member States relating to the implementation of good clinical practice in the conduct of clinical trials on medicinal products for human use (2001) Official Journal of the European Communities 44: 34-44.

7. March 13, 2004 Proclamation by the Speaker of the Sejm (Polish Lower House of Parliament) announcing the passing of a uniform Pharmaceutical Act. (2004) Legislation Journal of the Republic of Poland 53: Pos. 533.

8. April 7, 2005 Order of the Minister of Health concerning the nature and extent of inspection of clinical trials. (2005) Legislation Journal of the Republic of Poland 69: pos. 623.

the protection of patients’ rights in clinical trials

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