medical research council ethics committee for clinical pharmacology

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Eurecnet - National Information: Hungary

National information: hungary, short description of rec system:.

• - National Ethics Committee for clinical Pharmacology (KFEB) - the only one ethics committee in Hungary which evaluates single- and multi-site clinical trial protocols with medicinal investigational products, with the exception of non-interventional trials. KFEB based in Budapest.
• - National Ethics Committee for Human Reproduction (HRB) - evaluates single- and multi-site clinical trials dealing with interventions for human reproduction, with human genetics and advanced medicinal products (cell and gene therapy).
• - National Scientific and Ethical Committee (TUKEB) - evaluates multi-site clinical trials outside the concern of the other two committees. In the case of trials with medical devices and non-interventional trials also the single-site trials fall in the nationwide competence of TUKEB.
• - Regional Scientific and Ethical Committees (RKEBs) - there are 10 such committees covering the territory of Hungary. They evaluate biomedical research of local or regional coverage, e.g. unicentral research projects or clinical trials (not involving investigational medicinal products), projects of graduate and postgraduate students. RKEBs do not review projects on human reproduction, human genetics, advanced medicinal products, trials or research with medical devices where the principle of single opinion for the country prevails. The RKEBs are supervised by the Presidency of ETT. The list and territorial competence of RKEBs are included in attachment 1 of the Decree Nr. 23/2002 of the minister of Health.
• - Institutional Research Ethics Committees (IKEBs) - in every institution executing clinical trials an IKEB has to operate, otherwise each investigation site has to register in an IKEB within its region. IKEBs are not authorized to evaluate research protocols but to control whether the conditions for the studies running in the institution or registered sites cope with GCP and are sufficient to fulfil the research plan, whether local human and technical resources are adequate for a particular trial. IKEBs are registered with the RKEB of their region. They are in contact with the leader of the institution and with the respective RKEB, and may advice the central ethics committees concerning the eligibility of an investigation site.

All these kinds of ethics committees are defined in the Health Care Act as independent committees. KFEB, TUKEB and HRB members are appointed by the Minister responsible for Health. RKEBs and IKEBs are set up by the respective university or hospital administrator (Decree Nr. 23/2002of the Minister of Health , � 12, section (2)) taking into account the rules laid down in the Health Act, � 159, and the tasks of the committee.

Networking between RECs:

Every research (including clinical trials) conducted on human subjects need to be authorized by a competent authority; the condition for authorization is a supportive opinion of the competent ethics committee. All ethics committees competent to give such a decisive ethical opinion are designated in the Act on Health to belong to the the Medical Research Council (Eg�szs�g�gyi Tudom�nyos Tan�cs, ETT). The disciplinal repartition of the authority of the individual ETT committees is also defined in the Act on Health and in a governmental decree. The authority of the ethics committee defined this way is univocal for the whole country: eo ipso for the three national committees, and by the regional competence of the RKEBs according to the residence of the investigation site in unicentral research projects. By definition, the ETT is the advisory body of the minister responsible for health consisting of the members of its independent committees as well as a board (presidency) headed by the president of ETT. The working facilities of all these bodies (committees and presidency) are assured by the secretariat supported by the Ministry of Human Resources. ETT runs a website keeping up-to-date the information on each of its constituents, the relevant rules of law, the timetables of the meetings of the national ethics committees, of the guidelines and recommendations of the presidency and of the ethics committees. The regional ethics committees (RKEBs) cover the territory of Hungary, are co-ordinated and supervised by the Presidency, and from now are supplied with successive information bulletins. They are convocated yearly for a conference. The control of the realization of the authorized research and clinical trials is performed by institutional ethics committees (IKEBs) under the auspices of the RKEBs. March 2015

Contact: [email protected]

Medical Research Council

Codex of Bioethics

On the concepts and practice of biomedical research.

Download in PDF

Recommendation

A quarter of a century ago the emergence of ethics committees giving expert opinion on clinical biomedical research was one of the major events of the change of regime in Hungary.

Given the fact that ethics committees are composed of not only physicians but of specialists of other fields, as well, that is – among others clergymen and lawyers representing the “laic”, non-medical society –, a system of ethics in compliance with European legislation, also evolved in Hungary.

These ethics committees represent the dual value system, which assess partly in terms of the profession and partly in terms of society, that is in terms of patients’ rights, the professional-ethical aspects of the possibility of initiating a biomedical research.

Within the frames of the Codex of Bioethics, the Medical Research Council operating as a board of the Ministry of Human Capacities combines the experiences of the past 25 years with the widely known international declarations and directives on ethics, the European and Hungarian legislative environment regulating biomedical, clinical research is based on

The Codex addresses both the professionals and the whole society as not only the profession but laymen as well – thus others than physicians – are also concerned by these issues.

The Codex based on the Codex of Ethics of Scientific Knowledge of the Hungarian Academy of Sciences systematizes the ethical aspects not always codifiable by law of a highly important field of science and it provides useful starting points to everybody who wishes to deal with these issues.

29 Feb 2016, Budapest

Dr. Zoltán Ónodi-Szűcs

Table of Contents

Preamble 1. The Conduct of a Biomedical Researcher 2. Protection of the Research Subjects of the Study 2.1. Ethics of Trials Pursued on Healthy Volunteers 2.1.1. Dealing with Random Findings 2.1.2. Aspects of Minimal Risk 2.2. Patients in Biomedical Trials 2.2.1. Placebo 2.3. Participation of People with Limited Ability to Assert their Rights (Vulnerable People) in Biomedical Trials 2.4. Financial Compensation Granted to the Subjects of Trials 2.5. Ethical Aspects of Informing the Subjects of Trials and the Ethics of their Consent 3. Ethical Evaluation of the Trial 3.1. Purpose of the Trial 3.2. Personal and material conditions of the examination 3.3. Ethical Aspects of the Adverse Reactions in the Trial 3.4. Communication of the Trial and that of the Results 3.5. Ethics of Reporting a Trial 4. Research Ethics Committees 4.1. Composition of a Research Ethics Committee 4.2. Tasks of the Research Ethics Committee 4.2.1. Evaluation of Projected Trials 4.2.1.1. The Research Plan Documentation 4.2.1.2. Aspects of the Ethical Endorsement of the Financial Project 4.2.1.3. Ethical Assessment of the Recruitment of Study Subjects 4.2.1.4. Ethical Evaluation of the Procedure of „Informed Consent” 4.2.2. Control of Ongoing Trials by the Ethics Committee 4.2.2.1. Regular Inspections 4.2.2.2. Unscheduled Inspections 4.2.2.3. Notification of the Approving Ethics Committee 4.2.3. Public Reporting on the Work of the Committee 4.3. Obligation of Confidentiality 4.4. Ethical Aspects of the Conflicts of Interest 5. Specific Ethical Aspects of Special Areas 5.1. Human Reproduction 5.1.1. Assisted Reproduction and Genetic Risks 5.1.2. Professional-Ethical Aspects of the Storage of Gametes 5.1.3. General Ethical Considerations of the Evaluation of Human Reproduction 5.2. Genetic Examinations and Research 5.2.1. Special Status of Genetic Data 5.2.2. Prohibition of Discrimination and Stigmatization 5.2.3. Individualization of the Provision of Information and that of Treatment; Genetic Counselling 5.2.4. Consenting to Genetic Examinations 5.2.5. Privacy Policy in Effect in Genetic Examinations 5.2.6. Access to Genetic Data 5.3. Psychiatric Examinations 5.3.1. Person under Guardianship as a Subject of Psychiatric Clinical Trials 5.3.2. Loss of Legal Capacity in the Course of the Clinical Trial 5.3.3. Placebo Controlled Clinical Trials on Psychiatric Patients 6. Time of Validity of the Codex GLOSSARY – TECHNICAL TERMS EXPLAINED

The legal environment for human, biomedical, clinical research is constituted by the following  legislative measures: the Helsinki declaration, the Act 2002/VI ratifying the joining of Hungary to the Oviedo Convention, the documents of the European Union, as well as the documents of the WHO, and additional international directives based on the ethos thereof, and naturally Hungarian legislation. Development in science brought a range of new professional and ethical challenges and problems to the surface, and questions are often arisen, the specific legal regulation of which is unsolvable, and the ethical assessment thereof is also complex. Therefore it is necessary to summarize for both the researchers performing trials and to lay society all those ethical aspects, which might be regularly faced in the everyday practice of research.

The Codex on the Ethics of Science of the Hungarian Academy of Science is valid for all research activities performed in any field of science. In the case of human, biomedical clinical research activities, there may arise numerous special standpoints to be taken into account besides general principles, which anticipate the need for a codex of bioethics resuming the peculiarities of the field.

In our country, the committees of research ethics with a national authority are operated by the Medical Research Council (MRC=ETT). Clinical trials with test preparations fall within the competence of the Ethics Committee for Clinical Pharmacology of MRC , trials on genetics or human reproduction and trials performed with certain, advanced therapeutic methods are the competence of the Committee of Human Reproduction of MRC , and any additional trials fall within the competence of the Scientific and Research Committee of MRC. The approval of these national committees of research ethics on the basis of professional-ethical considerations is required to all biomedical trials, which involve human participants . Besides the MRC ethical committees the system of regional committees (SRC=RKEB) of research ethics has also been established. In cases authorized by law, SRCs may also grant professional-ethical authorization as to the starting and continuation of trials belonging to a specified field. The uniform operation of ethical committees and that of the SRCs are coordinated by the Presidency of the MRC=ETT. Professional-ethical opinions are issued by ethical committees. In these fields profession and ethics are very hard to be divided as the validation of professional criteria has an ethical side as well, to the assessment of which outstanding professionalism is needed. Therefore, the appropriate personal composition of ethical committees and the proportionate representation of professional and ethical considerations are of special importance.

Scientific research activities always constitute the subject of social interest. Society is particularly interested in the results of this field of science once they are also related to healthcare, therefore these researches are constantly under spotlight. Thus transparency is a criterion of extreme importance. In turn ensuring transparency may be conflicting with a great number of other aspects as from the protection of industrial and intellectual property to the interests of individual patients. It is important that ethical aspects and contradictions of this special field should be cognizable to professional circles and to society, as well. It is therefore that the MRC considered the creation of the codex of bioethics of clinical research justified for the benefit of both the researchers and the public.

1. The Conduct of a Biomedical Researcher

General criteria set for the conduct of a researcher dealing with biomedical research related to human subjects, samples taken from human beings and data on humans do not differ from those set for other researchers. There are however such “extra” behavioural considerations and requirements of a special research ethical kind – partly ensuing from related specialities – which exceed generally applicable concepts and rules, and that are to be known, or to be thought of by those acting on this field. The “extra ethical expectations” in biomedical research derive primarily from dealing with people. That is why the knowledge and continuous monitoring of this issue and further training form part of a researcher’s righteous behaviour. The patients’ interest and protection are essential in medicine, and this is the foundation of bioethics too. However traditional medical behaviour and ethics do not prove to be enough. A researcher’s behaviour ensuing from traditional medical ethics is naturally in connection with criterions set for a biomedical researcher’s correct behaviour. Nevertheless an expert dealing with biomedical research might be faced by a lot of questions not dealt with by medical ethics. First of all there is a fundamental aspect that the researchers dealing with biomedical research are restricted in their freedom as researchers independently from their qualification and position. They can only act according to a previously established and approved research project. Assessment of whether the research project is vocationally and ethically correct does not depend on them or on their superiors. They can solely conduct research activities in accordance with projects previously approved by the relevant ethical committee. The professional-ethical judgement of biomedical, clinical research activities have in turn some fundamental aspects that do not arise in other research activities.

2. Protection of the Research Subjects of the Study

The rights, safety and welfare of the people involved in a study have priority over the interests of science and society; therefore the risks faced by the subjects of a research should be minimised as much as possible.

Carrying out a clinical examination or using an investigational medicinal product on a human being may only be performed in possession of an ethical approval and an official authorization. The examination may solely be conducted according to the conditions specified in the authorization, as well as the provisions of the authorized study project. The approved protocol is considered to be a rule for the profession, therefore failure to comply with it has or may have legal consequences.  A deviation from the approved research project is ethically unacceptable unless it has been previously permitted. Hence only those acute cases may be considered to be exceptions, where the physician is forced to abruptly change the protocol by the interest of the patient. Any deviation from the protocol must be documented and reported to the sponsor immediately.

In the course of the planning and implementation of biomedical research the protection of the safety and rights of persons – either healthy volunteers or patients – involved in the trial is of a top priority. In case of people of increased vulnerability and limited ability to assert their own rights, ensuring the adherence to the requirement is particularly to be taken care of.

2.1. Ethics of Trials Pursued on Healthy Volunteers

Research of any kind may solely be conducted on healthy volunteers if potential risks affecting the subjects of the study do not exceed the potential benefits of the research. In the case of early (Phase I. and II. – see later on) examinations, the basis for the benefit/risk assessment may be primarily formed by the critical judgment of the results of preclinical examinations.

Previous proper notification of the volunteers and obtaining their written consent are required. In lack of these, a study is ethically not to be allowed.

2.1.1. Dealing with Random Findings

In case of an involvement in an examination or in the course of conducting a trial, a health risk previously not known or a potentially existing disease of the volunteer that clinically has not been manifested yet, might be detected by the principal investigator of the study. In such cases, the volunteer must be excluded from the trial. While providing information to persons to be involved (patients or healthy volunteers) particular care is required to be taken to clarify, whether the volunteer wishes to be informed about the content of a potential random finding, which may be not indifferent to him.

2.1.2. Aspects of Minimal Risk

Clinical trials on healthy volunteers may be conducted by complying with extremely stringent, multidisciplinary scientific and technical requirements. In case of research conducted with investigational medicinal products, determination of the dose that can be safely administered is of top priority. In research activities of this type, the exploratory examination should be started by the lowest possible dose calculated on the basis of preclinical data as a dose still not exerting any pharmacological effect, so that the healthy volunteer should not be exposed to the harms of an unknown compound having potentially unfavourable pharmacokinetic attributions. At the same time, the designation of the upper limit of the dose that can be safely administered is of extreme importance as in later stages of development this dose limit may not be exceeded at any time.

In Phase I studies, the number and the volume of blood samples to be taken need to be kept on a minimal level in the interest of the volunteer.

2.2. Patients in Biomedical Trials

Clinical examinations – including those of bioavailability and bioequivalence – have to be planned, implemented and reported according to the concepts of good clinical practice (GCP) in line with the Helsinki declaration on the ethical principles of medical research. Conditions to be met:

(i) from a professional point of view, the examination should be adequately based on preclinical and clinical results in accordance with the phase of the planned clinical examination, as well as the number and health status of research subjects to be included;

(ii) potential risks threatening individual patients must not exceed the potential benefits (at the same time, the notification provided to patients must contain the fact, that it is not sure that the examination would be of any benefit to the involved person).

In the study plan, adequate criterions of inclusion and exclusion are to be determined, that is appropriate parameters are to be defined to make clear, who may take part in the study, and the participation of which patients is contraindicated. It is in the same way that „ stopping rule ” must be specified that is the rule which is related to the stopping of the whole trial or the exclusion thereof of a patient. An independent committee constantly monitoring data and endowed with powers guaranteeing the above mentioned has to be set up.

2.2.1. Placebo

The advantages, risks, burdens and effectiveness of the new intervention must be tested against those of the best proven drug/intervention except for the following cases:

• if there is no proven intervention, the use of the placebo or that of a group without treatment is acceptable;
• if the application of a group left untreated is absolutely necessary for the determination of effectiveness or safety of an intervention;
• if the patients receiving a less efficient treatment than the best possible one, treated with a placebo, or left untreated are not going to be exposed to the risk of any severe or irreversible harm.

The fulfilling of the above conditions should be monitored carefully, and any abuse of this possibility must be avoided.

2.3. Participation of People with Limited Ability to Assert their Rights (Vulnerable People) in Biomedical Trials

Particular care should be taken in order to ensure that the interests of patients belonging to the following groups should prevail, and their privacy should not be hurt: vulnerable persons, pregnant women, their embryos, foetuses, lactating women, infants and young children, persons performing their military service, persons living in care homes, as well as in residential homes. The participation of persons deprived of liberty in clinical trials is ethically unacceptable.

Children may be involved in clinical trials only if the following conditions are met:

• it is justified by the occurrence of the pathology to be treated at underage persons and by the positive risk-benefit ratio expected;
• if the disease to be treated is not restricted to children, the examination carried out on children was preceded by a successful trial on adults with the same indication and with the same investigational medicinal product;
• the examination requiring the involvement of younger children was preceded by a successful trial on older children with the same indication and with the same investigational medicinal product (but the involvement of different age-groups might potentially take place within the frames of the same examination);
• The children to be involved in the examination are informed by means according to their age and mental capacities, and the children give their consent to the examination. The patient information for various age groups is in its substantial part naturally the same, but it ought to be different in terms of its manner.
• The parents are provided with comprehensive information, and thereafter their written consent is obtained.

In case of vulnerable patients with limited ability of asserting their rights, patient information is substituted by the information of the person entitled to give consent, and the consent form is also to be signed by the person entitled to give consent. It is not allowed to involve the vulnerable patient in a trial or in a part of the trial (e.g. genetic test) in the participation of which he refused to get involved in a previous statement. If later on the patient regains his ability to act, he must be informed about the examination without delay, and his further participation should depend on his consent.

2.4. Financial Compensation Granted to the Subjects of Trials

Persons – healthy or ill – participating in the phase I trial may be granted a uniformly defined financial compensation for inconveniences incurred in the course of the examination, as well as for the loss of time and revenue. Those involved in a study on pharmacokinetics and pharmacodynamics of a non-therapeutic purpose may similarly be granted financial allowance.

The amount of compensation is also essential ethically: it should not be disproportionately low or high considering strain. In the latter case it may be feared that the participant gives his consent to take a health risk in return to a financial compensation

At later phase trials, the expenses of the patient supported by invoices (travel, accommodation, catering) may be reimbursed. Donation of smaller objects, medical devices may also occur – it is again the extent of donation that is essential from the point of view of ethics. Financial compensation for the participation in a study must not be offered to minors or incapacitated persons.

2.5. Ethical Aspects of Informing the Subjects of Trials and the Ethics of their Consent

Informed consent is a generally accepted legal, ethical and regulatory requirement at every intervention related to health – in everyday health care routine just as in medical research. It is clearly stated by the latest version (2013, Fortaleza, Brasilia) of the Helsinki Declaration, as well as by the Belmont Report universally accepted in the United States  that a health intervention may only be carried out by fully respecting the autonomy of the concerned persons (should they be patients or healthy volunteers). The information should include the method, purpose, potential benefits and risks of the intervention. The person involved should be given the opportunity to have a free choice between the acceptance and the refusal of interventions.

In leaflets informing patients and healthy volunteers, cultural diversity of participants should be paid regard to. These may exert an influence on moral values, which determine the consenting to the intervention. The information provided to patients must be clear, and no intervention should be started, except for those occurring in special circumstances (emergency, lifesaving), until the patient concerned is not in a state to give a valid consent. Within the provided information it should be clearly stated whether a directly therapeutical intervention or a scientific research is being referred to. It should be made clear too if the current research is targeted primarily to the testing of a new pharmaceutical, which later on could serve the benefit of other patients, and possibly also of the patient involved in the study. In case the involvement of minors is justified in the trial, it is also necessary to supply information adequate for the age and for the supposed mental maturity level of those to be involved, and to supply special information to the parents too.

Health literacy of diseased persons or those of the volunteers are often limited, and it should by any means be taken into account when preparing the information leaflet. Increasing the extent of the text is only justified if it makes the information leaflet more clear and comprehensible, otherwise it would only put the reading and understanding skills of the average non-expert population to the test. It should be kept in view that it is not the main purpose and aim of patient information to disclaim the responsibility of the institution carrying out the trial.

The patient information leaflet should be prepared for every trial according to a precisely defined pattern. This is the documentation that is signed by the patient or the volunteer (either ill or healthy) taking part in the examination. The physician leading the examination must have appropriate skills to meet the challenge of clearly explaining the point of participation to the volunteer. To provide information needs skills to acquire, and their teaching needs to be incorporated in the material of the GCP or in the courses for medical specialists. In today’s health care, directly therapeutic interventions and scientific research aiming to improve the effectiveness of therapies keep converging, and they cannot always be easily distinguished. This difference must be made obvious in the information leaflet given to patients or to healthy volunteers. If the purpose of a particular study is the introduction of a new pharmaceutical, and the examination is initiated and financed by the producing pharmaceutical company, this should be clearly put in writing for the volunteer. Information must also be given about the potentially non-commercial nature of the trial.

As long as the test material (e.g. blood or tissue sample) is intended to be used later on in a previously not determined trial, the consent to this may only be requested from the participant of the trial in case it is definitely guaranteed that the test material originating from him is anonymized, and thus the origin thereof cannot be revealed. If the need for an additional re-examination rises, it is possible to contact the subjects concerned and to obtain their specific permission through the original examination centre where the code of the specimen is confidentially stored according to legal requirements.

The autonomous decision of those taking part in the trial might be influenced by the socio-demographic situation originating from the increase in the average age span of the population. Members of the population aged 65 and over need generally more medical interventions, and it is just because of demographic changes that their participation in certain researches proves to be necessary. As a condition it must be appreciated that some difficulties might come up in the understanding of the essence of trials by the volunteers.

3. Ethical Evaluation of the Trial

3.1. purpose of the trial.

The ethical and scientific assessment of clinical trials is inseparable. The purpose of a trial may be that of clinical pharmacology (studies on pharmacokinetics, pharmacodynamics, bioequivalence, biosimilarity and tolerability), or the examination of the effectiveness of the preparation. The examination of the effectiveness of the preparation may also be explorative („proof of concept”), that is an efficacy study confirming previous expectations. The professional logical and chronological order of the phases of clinical development is determined, so the phase classification of the examination is objective.

Examination of the pharmacodynamic or pharmacokinetic properties or of the tolerability of the experimental drug to be tested, and studies on special population kinetics and interactions should be carried out in the early phase (Phase I), too, i.e. when the active substance is used “first in man”. The ethical condition for the starting of such examinations is that the trial on humans, or its purposes should be duly justified and convincingly supported by the results of the non-clinical in vitro and in vivo pharmacological and toxicological researches previously performed with the substance under development.

In this phase, examinations are performed on a limited number (6-10) of research subjects, most often healthy volunteers. In such trials, people unable to cooperate – e.g. drug-addicts, soldiers under dependency, convicts, etc.) are not allowed to participate either from a professional, or from an ethical point of view. Study subjects should generally be persons aged between 18-40 years, selected from both genders if possible. In case of women’s participation, reproductive activity should particularly be taken into consideration. Health status surveys should be performed by careful screening tests. The phase I trial may only be carried out as laid down in regulation, and only in institutions designated as suitable by the drug regulatory authority. It may occur, that the pharmacological, toxicological properties of the substance contraindicate the testing on healthy volunteers, or its efficiency and pharmacokinetic conditions are to be tested but in a specified disease. In such cases the clinical examination may be performed only on a defined group of diseased persons.

The purpose of phase II (explorative) trials is to verify results gained by that time in phase I studies in a patient group selected according to the effect and mechanism of action of the active substance. Such a trial is ethically acceptable in case the results being already at disposal provide sufficient reasons and grounds to the testing of investigational medicinal product in those suffering of a selected disease, and the target is realizable by the examination performed in the given indication with the methods planned. In addition to this, it is set as a professional-ethical condition that the projected dose-range should be considered safe on the basis of the results of the completed phase I trials.

The purpose of phase III (confirmative) trials is to verify the therapeutic effect perceived in phase II trials by involving a higher number of patients, furthermore to test the investigational medicinal product on particular patient groups (e.g.  elderly patients, children, patients with impaired kidney and liver function, patients with the coexistence of various diseases). Examination of the possibility and risks of drug-interactions also belongs here. It can be assessed on the basis of the previously obtained results whether the proposed aim (or further examination of the product in general) is ethically acceptable.

Phase IV trials may be conducted in order to verify the safe usage of an already registered pharmaceutical or to confirm its efficiency in everyday practice. The clarification of the purpose is a particularly important issue in the case of these examinations. It is unethical to conduct such studies for promotional purposes primarily or exclusively in the interest of the producers.

The prohibition of discrimination is a fundamental ethical principle in the involvement of participants in the trials.

3.2. Personal and material conditions of the examination

Trials having an acceptable purpose and being reasonably planned may also be professionally and ethically objectionable, if the protection of study subjects or that of their interests, as well as the safety of the obtained results are not guaranteed. The examination must be carried out by persons possessing the required qualifications and professional experience. The projected measurements should be directed at parameters, which are relevant according to current scientific knowledge and suitable to determine actual professional issues. Both interventions and measurements should be carried out with up-to-date and valid methods and tools, and the data are to be subjected to generally recognized statistical analyses. In addition, the preparedness to adequate management of potential risks or complications of the examination is also a key requirement. The professionals prepared to act in such cases, the tools needed and the institutions suitable for providing specialist care in the particular situation should be available, and financial resources for incurring costs must be ensured.

3.3. Ethical Aspects of the Adverse Reactions in the Trial

In case of adverse reactions perceived in the course of the examinations, one should proceed according to professional and administrative rules. In certain cases it may become necessary to stop the study. It is ethically unacceptable to conceal the causes.

3.4. Communication of the Trial and that of the Results

Biomedical research conducted on humans must be made public, and this applies also to the results obtained. Therefore clinical examinations before their starting (launching of the recruitment or performing the first intervention) should be registered in a publicly accessible, searchable database, and the most important data should be made public. In turn, while carrying out the examination the actualization and up-dating of these data must be ensured.

It is ethically unacceptable to take into consideration only a part of the results obtained at the assessment of an examination on humans. In order to avoid this, disclosure of the examination results (not that of the primary data) must also be ensured, regardless whether they are favourable or unfavourable observations from the point of view of parties carrying out, supporting or sponsoring the trial. Main outcome parameters are to be recorded by any means in the open database registering the study, or – if the former is not possible – on an internet platform developed for purpose by the study coordinator or sponsor of the examination. In addition – unless it is prohibited by special circumstances – the publishing of the results in scientific journals is to be sought for even if the findings do not support the expected effects.

3.5. Ethics of Reporting a Trial

The closure of examinations is followed by the compilation of a report. It is unethical toreport the results in an incorrect, distorted way ( misinterpretation ), and to provide an erroneous deduction of consequences. This is particularly dangerous in connection with the assessment of efficacy, or that of indication area. It is unethical if the examination report does not include the data, which do not support the original hypothesis, or are even contrary to the aims specified in the examination plan. It is unethical if the adverse reactions observed during the examination are withheld or blunted. The findings not confirming the original hypothesis should also be made public to the profession.

4. Research Ethics Committees

4.1. composition of a research ethics committee.

Committees contributing to the authorization of biomedical studies conducted on humans, as well as to the monitoring of the implementation of the protocol, give independent professional-ethical board opinion. Besides the representatives of the profession (researchers and physicians), non-professional “laic” members must also participate in the opinion making. As a layman, anybody can participate in the work of an ethical committee, but it is expedient that committee members be primarily involved in health care, thus professionals other than physicians, nurses, bioethicists, or representatives of patient organizations, theologians, as well as health law specialists and jurists dealing with patient rights.

The composition of the ethics committees must be of multidisciplinary and multi sectorial nature. In addition to ensuring of adequate scientific expertise, the well-balanced composition of the committee as to age and gender is a key ethical requirement. In case of examinations directed to rare diseases, wherein the assessment presupposes the existence of a specific knowledge, it may be necessary to request an ad hoc external expert opinion.

Members of the ethics committee receive regular training, and further training courses. The research ethics committee itself has also its own role in the teaching of ethical considerations.

The committee members form independent opinions as the total independence of the committee is a fundamental ethical principle

4.2. Tasks of the Research Ethics Committee

The primary professional-ethical mission of the research ethics committee is to assess the appropriateness of the measures taken for ensuring the protection of people involved in the study. Research activities serve to increase scientific or practical knowledge. However fundamental contradictions may occur between the scientific considerations of researches and the interests of the study subjects.

The ethics committee assesses the benefit-risk ratio of trials conducted with a scientific purpose from the aspect of the protection of participants, and it pays special attention to this viewpoint while judging the inclusion of participants and criticizing the way and quality of the acquisition of their informed consent.

The professional-ethical evaluation is also extended to the questions whether the trial is medically justified, and its execution can give an authentic answer/solution to a relevant issue. These considerations form in fact a part of the protection of study subjects (as well as that of the whole society).

4.2.1. Evaluation of Projected Trials

4.2.1.1. the research plan documentation.

While studying the research plan documentation the committee must assess the professional-ethical appropriateness of the trial. One of the cornerstones of the protection of research subjects is to guarantee that the projected examination is professionally well grounded, and that it serves a meaningful and rational purpose. Furthermore, it is a professional-ethical issue of high importance how much the risk of participating in the trial is proportionate to its benefit, and what measures are taken by the applicant for the sake of the participants’ safety.

So the ethical assessment of research plan cannot be set apart from the professional-scientific evaluation of the soundness of the projected examination and its purposes, of its risk/benefit ratio, and of the conditions to be met.

4.2.1.2. Aspects of the Ethical Endorsement of the Financial Project

While assessing the financial plan of the research, potential, not declared conflicts of interest should be examined. Such an ethical problem rises if the remuneration of researchers is substantially higher than usual, or if the remuneration of the institution hosting the trial is unacceptably low, if the sponsor of the research pays the researcher in a differentiated way according to the number of recruited subjects (above a certain number of subjects, a larger sum is due for the inclusion than under this threshold), if researchers get special incentives for an exceptionally fast recruitment of the subjects. This condition requires a particularly careful consideration in cases, wherein the recruitment for international, multicentre examination is of a “competitive type”, and recruitment is centrally stopped at reaching a previously specified number of recruited subjects.

4.2.1.3. Ethical Assessment of the Recruitment of Study Subjects

The group (age, gender, literacy skills, cultural characteristics, economic status and ethnical characteristics) the study subjects are recruited from, may be influenced by the professional content of the trial. The committee must evaluate the justification of the inclusion and exclusion criteria, and it is by taking into account the characteristics of the target group that it must be considered, whether the way of recruitment and the tools are appropriate for contacting the members of the groups and their representatives, as well as for providing them with comprehensive information.

4.2.1.4. Ethical Evaluation of the Procedure of „Informed Consent”

The consent of study subjects should be based on appropriate information (2.5. point). Information to be provided orally and in writing must be complete and comprehensible from the point of view of study subjects or their legal representatives.

It should be clearly justified, if persons not able of consenting are intended to be involved in the research. In such cases the planned way of acquiring consent or that of the authorization for involvement should be considered particularly carefully.

It should be guaranteed that the subjects of the study be able to obtain new information, which become accessible in the course of the research process if they are relevant for the conduction of the research. If in the course of the research there emerge new pieces of information, which influence the benefit/risk ratio of the research, then a new patient information leaflet and a declaration of consent must be prepared and signed by the participants of the examination. In the course of the research, the receipt and appropriate handling of complaints arriving from study subjects or their representatives is also an ethical requirement.

4.2.2. Control of Ongoing Trials by the Ethics Committee

After having authorized the plan of research, the research ethics committee verifies the process of the research, as well. Besides regular inspections, unscheduled ones might also be necessary, and events may occur that are to be reported to the ethics committee having issued the authorization, and the committee may decide to even suspend the ethical authorization of the ongoing study. The committee receives an account report of the completed or suspended examination and evaluates it.

4.2.2.1. Regular Inspections

The local, regional research ethics committees must control – at least once a year according to ethical viewpoints – the examinations in process falling under their competence. The controlling must cover the process of the informed consent and whether all research activities are performed according to the research plan. It is unethical to deviate from the research plan while conducting a research.

4.2.2.2. Unscheduled Inspections

Unscheduled inspection is ethically justified if:

• some addition or modification of the research plan influences the rights, safety, welfare of the study subjects or the process of the research. In accordance with the provisions issued by the European Medicines Agency (EMA), the approval of the planned changes by the competent Hungarian committee should precede this inspection.
• serious, unexpected side-effects are revealed, with regard to the research or to the product being tested;
• such an event occurs, or such a new piece of information becomes available, which exerts an influence on the assessment of the benefit/risk ratio of the research.

4.2.2.3. Notification of the Approving Ethics Committee

The ethics committee must be immediately notified if:

• an adverse event occurs, which was not indicated in the information form, or in the declaration of consent;
• the appearance of an “anticipated” adverse events is so serious, that it requires additional medical treatment or the prolongation of potential in-patient care;
• an event occurs, which threatens the research subjects’ privacy (e.g. the loss of research documents).

4.2.3. Public Reporting on the Work of the Committee

Ethics committees must inform the public of their activity. Therefore each research ethics committee should report on its work at least once a year, and should make his report available to the public. However the report of the committee must not contain personal information, which refers to the subjects of the trials.

It is considered unethical if the report infringes copyright or violates industrial rights, interests, or it provides undue research advantages. Therefore the report may not contain information connected with these issues.

4.3. Obligation of Confidentiality

In the course of their work, the members of the committee get possession of confidential information. Therefore, the members, i.e. all those who become acquainted with the research documentation must sign – even before concluding a contract – a declaration of confidentiality and must assume an obligation that they will not misuse this knowledge. The obligation of confidentiality is related to the contacting not only with a third party, but also with the leader and the participants of the trials, as well as with the sponsors. Only the regulatory authority is entitled to contact with the sponsor. The violation of the obligation of confidentiality is an ethical and potentially legal offence to be investigated and sanctioned.

4.4. Ethical Aspects of the Conflicts of Interest

Decisions concerning the affairs submitted to the committee should be made by those members who are independent from the given research plan and from persons and institutions involved in its implementation. Committee members should announce the fact of any conflict of interest arising – their involvement directly or indirectly – in advance, and in this case, they cannot take part in the evaluation of the particular research plan.

Members of the ethics committee cannot participate in the evaluation of a given research plan if they or anyone in their close contact are professionally and/or financially interested in the implementation – or even in the cancellation – of the research, take part in the research in any way, have interests at the company submitting the research plan or work at the same department of the host institution.

The adherence to these guidelines is only seemingly simple. Pharmaceutical companies also sponsor – occasionally by way of foundations – numerous, indirect researches that are in connection with their own pharmaceutical products. Research may entail not only financial interest, but it may also mean gain in prestige both for the researcher and the institution. Therefore, interests may almost be confluent, so they do not necessarily clash. The Committee should take this fact also into consideration.

5. Specific Ethical Aspects of Special Areas

5.1. human reproduction, 5.1.1. assisted reproduction and genetic risks.

As a result of the development achieved in the field of biology, cytology and medical technology, reproduction with medical assistance may be realized since the end of the 20 th century.

Assisted reproduction techniques (ART) are primarily applied to the medical treatment of infertility, but the continuous development of reproduction medicine and genetic technology opens a wide range of options for having a child. This is at the same time the application of a “positive right” to reproduction for people unable to beget their own offspring because of an illness. It has numerous scientific and ethical aspects.

The coordinated application of ART and that of genetic laboratory technology (“reprogenetics”) may be realized in various situations. Such a situation may occur, e.g. if in the course of the treatment of infertility  genetic issues emerge, or if the medical examination of the couple that wishes to have a child reveals a genetic trait, which may be transmissible to the offspring, and therefore genetic counselling, genetic risk assessment will be needed in the course of the treatment. In both cases, depending on the outcome of the examination (if carrying genetic alterations leading to a high-risk, serious disease are detected) the application of ART, namely pre-implantation genetic diagnosis (PGDP), gametes donation and adaptation may be professionally substantiated. From an ethical point of view, the designation “serious illness” may cause difficulties; the possibility of healing and that of autonomy, as well as age at the appearance of symptoms must be taken into consideration.

The death of embryos implanted may be caused not only by a genetic defect being present in one of the members of the couple, but also by a random deviation emerging in the course of in vitro fertilization (IVF), mainly aneuploidy.

The idea of carrying out pre-implantation genetic screening (PGS) in order to assess the suitability of pre-embryos to be implanted arises rightly, as it justifies the application of more and more methods and ethical considerations in line with the development of science. In this case there is no need for genetic counselling, as it is not the prevention of any genetic disease appearing with high risk in the foetus that is set as a target, but the increased success of the IVF treatment. However based on past experience, the success of PGS is contested, as it is considered by influential professional organizations to be a procedure in the research phase. However it falls ethically under special assessment that the genetic technics applied in the course of the procedure may enable apart from the screening for aneuploidy, the screening for any other genetic characteristics („ sex selection”, „designer baby”, see below), that is from the point of view of ethics, the method applied to carry out the examination, has also got a relevance. Therefore a special organization – the International Committee for Monitoring Assisted Reproductive Technology (ICMART) – was established for monitoring the new technics and evaluating the results.

Given the genetic disease of one of the members of the couple that wishes to have a child, the risk may be increased that the child to be born will inherit the disorder. In this case, it is from the beginning of the procedure that the involvement of a genetics specialist and a genetic counselling are needed.

In case the termination of pregnancy is not acceptable for the pregnant woman from conscientious or any other reason, the joint application of ART and PGD and thorough information related to parental decision-making are justified. In the offspring to be born the manifestation of the genetic deviation may be prevented by gamete donation. Special ethical considerations (man or woman, age, kinship, etc.) are justified by the procedure (see later on). Mitochondrial transplantation is a specified case for the avoidance of genetic anomaly by ART.

5.1.2. Professional-Ethical Aspects of the Storage of Gametes

The storage of gametes is justified in numerous cases, e.g. in various illnesses. Due to their physiological properties, the extraction of sperms and their storage in a frozen state (cryopreservation) is relatively easily accomplished. As it is only following a lengthy pre-treatment that oocytes may be obtained, and their freezing and long-term storage in a deep-frozen state (vitrification) became possible only recently, the ethical evaluation of the procedures dealing with the gametes of the two genders differs in several respects.

While storing gametes, a special care should be taken to safety including identification, ruling out the exchange of samples as well as ensuring adequate technical conditions.

Male gametes

• Parenting by the use of gametes stored in a sperm bank is ethically acceptable – in case of fruitless relationships of couples being sterile because of the infertility of the husband/male life partner – for single women and lesbian couples.
• Ethical aspects are to be considered in professional procedural guidelines, which determine the medical, genetic screening of the donors before obtaining the sperms.

Female gametes

• The heterologous donation of the oocyte is to be individually organized by the coordination of the processes of the extraction and that of the acute implantation, which renders the anonymity more difficult. It is expedient to carry it out the procedure within the family, in the frame of an agreement, recorded in writing, as well. Consideration should be given to the age of the donor and that of the recipient and to the risks due to diseases of the individuals born from the oocyte.
• Freezing of an oocyte (or ovarian incision and freezing) may be carried out for the purpose of an autologous use, when a woman of a reproductive age faces a treatment bearing a risk of mutation because of a malignant tumour.

5.1.3. General Ethical Considerations of the Evaluation of Human Reproduction

Being motivated to reproduction, which stems from the intrinsic feature of the living world, is determined by biological processes, but assuming the tasks of childbearing depends on autonomous decisions. In the decision regarding reproduction beside the natural instinct resulting from the fact that humans are biological beings, social, economic, traditional and short-term, fashion-generated factors also play a role. Responsibility for childbearing is equally shared by both genders in the natural form of reproduction . In their decision related to reproduction, a man and a woman cannot ignore the interests of the child. However the continuous development of technologies related to reproduction and genetics justifies the consideration of special ethical aspects, which occur when assisted reproduction procedures are applied. While applying ART procedures , the participation of men and women in the processes differs, but efforts should be made that the two genders equally take part in assuming responsibility for childbearing. As it is the case of the natural way of accepting tasks with childbearing, one of the basic aspects of the application of ART is that the interests of the child to be born should be taken into special consideration. In order to promote this, the long term follow up of children who have already been given birth to, should also be rendered possible. It is an important guiding principle, that a treatment of assisted reproduction should only take place, if the conditions guaranteeing the coming fore of the interests of the child to be born are given („ reasonable welfare standard” ).

The process of the assisted reproduction is carried out with the participation of physicians, so the protection and follow up of the health of the child to be born needs increased medical care. As a consequence, in the ART applications, wherein genetic interventions also occur, the individual right to autonomous (non-directive) decision – which is of utmost importance in genetics otherwise – appears in a different way: professional guidance resulting from the professional responsibility and duty of the physician may come into conflict with the autonomous decision right of the individual. The physician should seek a way to inform the individual as thoroughly as possible. In the course of a reproduction treatment, patients are entitled to detailed, individualized information, especially on the nature, sequence, short and long term risks, benefits, as well as the health impacts of the intervention.

Besides promoting the assuming of responsibility for childbearing, the attending physician should take care of health, dignity and privacy rights of patients, especially of women particularly exposed to the procedure.

Respecting the patients’ human dignity is a top priority aspect of care. A clinic providing reproduction treatments should give emotional, mental and professional assistance – even in cases of failure – to couples, as well as to single women requesting reproduction interventions.

It is ethically not acceptable to manipulate gametes or the genetic pool of embryos for the creation of any health, physical-mental traits deemed beneficial („ designer baby ”). It is ethically not acceptable either to choose the gender of the off-spring by the application of ART and/or PGD („ sex selection ”), unless the aim is to prevent the occurrence of sex-linked, serious, untreatable diseases. In this case, the legal order ruling genetic procedures shall prevail.

Though the procedure is by all means artificial, the impacts of “medicalization” should be minimized as far as possible. In the course of the treatment, it is not only the success of the reproduction procedure that is the target, but care should also be taken of the reproductive and general health status of the participants in the intervention.

It is subject to specific assessment, when an in vitro intervention takes place on a non-infertile couple in order to provide help to an already born sick child with the utilization of the umbilical cord blood of a new born baby with compatible properties (a lifesaving sibling). Organ procurement from an underage living individual is ethically impermissible.

In the field of the donation of gametes, as well as that of embryos, the prohibition of profit making should be strictly observed.

5.2. Genetic Examinations and Research

The application of genetic examination methods continuously growing in number –including the human genome analysis – raises a large number of new ethical-professional questions affecting or addressing not only individuals but communities too and regarding even the informed consent. This is why the specific aspects of this field are discussed separately. It is a special ethical problem to decide in what conditions may the results of such an examination, which are in principle anonymized, be brought to the attention of participants. The issue is further complicated by the fact that the volunteers, once interested, can reveal genetic features even by using conventional methods.

5.2.1. Special Status of Genetic Data

Human genetic data are to be treated as sensitive personal data of the individuals, as they are connate, do not change through the life span, and the information obtained from the sample taken from the individual is projected to several persons, i.e. the family members.

The special status of human genetic data is due to the fact that they can predict the genetic predispositions of individuals, they can exert a significant impact on the family, the off-springs included, on the following generations, and in certain cases on the whole group the concerned individual belongs to.

Genetic data are peculiar as they may include information, the relevance of which was unknown at taking the biological sample, but which have medical and cultural significance for the individual and his family in the future.

Each individual possesses specific genetic features. Nevertheless the individual’s identity cannot be merely reduced to his genetic characteristics, as it includes complex educational, environmental and personal factors, emotional, social, mental and cultural ties to others, as well as the dimension of freedom.

5.2.2. Prohibition of Discrimination and Stigmatization

When it is justified to compare genetic samples originating from different populations or to study genetic characteristics of individuals in certain patient groups, it must be done so that it should not incur any stigmatization disadvantage either for the individuals, or for the groups, as it is ethically unacceptable. All efforts should be made to avoid the use of human genetic data for purposes that are discriminative or that lead to stigmatization of either the individual, or the family or the group in any way.

5.2.3. Individualization of the Provision of Information and that of Treatment; Genetic Counselling

Before genetic sample taking, the individual should be given detailed information on the purpose of the procedure (of the research), and the result of the examination should be communicated in an individualized way, including the explanation of the consequences. In case the examination regards predictive or inclining factors, a genetic counselling must be ensured to the patient in a way detailed by law. The provision of information must specify the purpose for which human genetic data are generated from the biological sample, and communicate the fact, that these data will be utilized and stored. The provision of information must notify – if needed – the risks and consequences.

With regard to the specific personal status of genetic information, the provision of information before the sample taking for genetic examination should be ensured in the frame of genetic counselling in a form imposed by a special legislating rule. It is an ethical imperative that when human genetic data are collected for research, serving diagnostics, health care, or medical and scientific purposes, genetic counselling of an adequate way should be ensured in every phase of genetic testing and screening. Genetic testing should not be enforced; it should be culturally adapted and consistent with the best interests of the person concerned.

5.2.4. Consenting to Genetic Examinations

As to the collection of human genetic and biological data, as to their subsequent processing, utilization and storage, a free, informed, unambiguous and uninfluenced previous consenting of the participants should be requested, irrespectively to whether the procedure takes place in a public or in a private institution. The consent should also regard the way the sample will be stored. When the participants are being informed, the attention of the individual should be drawn on the peculiarity of the genetic sample, namely that it might reveal important information for the future of the individual and his family, which is yet unknown at the time of sample taking, and that the individual can only access these information, if the link between the sample and the individual has not been destroyed irretrievably (coded vs. anonymised storage).

When human genetic data and biological samples are collected for medical and research purposes, the person concerned may withdraw his consent, except for the case, when these data may not be linked irretrievably to an identifiable person. The withdrawal of the consent may not entail either disadvantage, or retribution as to the person concerned.

Once the consent has been withdrawn, genetic data or biological samples of the individual may only be used further if their linking with the person concerned is irretrievably impossible. If data can still be associated with the person concerned, then the procedure is up to him/her. When the decision of the given person is not available, not realizable or not safe, then the data and the biological samples must be either made irretrievably unconnectable with the person concerned or destroyed.

5.2.5. Privacy Policy in Effect in Genetic Examinations

Through getting to know genetic data, insight may be gained to personal information, which could have been concealed by the individual, or which have been unknown even to him (e.g. a predisposition to diseases occurring later in life). In case of genetic data, the disposal of human rights and personal data are rendered even more difficult by the fact that the interpretation of genetic data is the task of specialists, therefore the interpretation of the result of a predictive genetic test takes place in the frame of the genetic counselling. Personal genetic data should be treated by ensuring adequate informatics and data protection expertise and by taking current legislation into consideration. The persons and competent people responsible for the processing of human genetic data and biological samples must take the necessary measures to ensure the accuracy, reliability, quality and safety of these data and biological samples. In the course of the planning of research protocols, the practical implementation of data protection should also be envisaged.

5.2.6. Access to Genetic Data

Not a single person may be denied the possibility of accessing their own genetic data, except if these data are irretrievably not linked with the person in question as an identifiable source, or if the access is restricted by the legislation of the given country because of interests related to public health, public safety or national security. Human genetic data and biological samples that can be linked to an identifiable person are not allowed to be disclosed or to be made available to third party, especially to employers, insurance companies, educational institutions and to the family, unless it is authorized by law. Human genetic data and biological samples collected for medical and scientific research purposes may remain linkable to an identifiable person only in case it is required by the research, assuming that the right of the individual to secrecy and the confidentiality and also the secrecy of the data and that of the biological samples are ensured according to the provisions of the national legislation.

When human genetic data are collected for medical purposes or for those of scientific research, it is to be notified that as a part of information procedure at the time of consent the person concerned has the right to decide whether or not they wish to be informed on the results. It may not be applied in the case of data irretrievably disconnected from the identifiable person, as well as data, which do not lead to results individually related to the person taking part in the research. The right of not being informed may be extended, where necessary, to the relatives who may be concerned by the results.

5.3. Psychiatric Examinations

The peculiarities of psychiatric diseases urge the consideration of special aspects in the ethical assessment of biomedical research activities conducted in this field. The issue of legal capacity directly affecting informed consent, as well as the possibilities and risks of the application of placebo are to be highlighted in particular.

5.3.1. Person under Guardianship as a Subject of Psychiatric Clinical Trials

Guardianship partially limiting legal capacity is not an absolute excluding factor in terms of participation in psychiatric clinical trials, i.e. it does not deprive the person under guardianship from his right of taking part in a clinical study and of making independently a statement thereof. Nevertheless, an individual with limited legal capacity can only take a decision without the consent of the guardian appointed for him, in issues of such consequences that do not considerably affect his lifestyle and living conditions. Thus it is essential to consider how his participation in a given examination can be specifically evaluated. Those who have previously, in the possession of their legal capacity, excluded or refused to participate, cannot be included in the trial.

Clinical research conducted on an incapacitated person or on a person with limited legal capacity may solely be carried on in case it does not exceed significantly a minimum level of risk, i.e. if

• the trial may be directly beneficial to the health of the research subjects,
• the scientific knowledge to be acquired may be useful for the person in question or for those suffering of similar diseases,
• the research cannot be carried out with similar efficiency on persons who are in possession of their legal capacity,
• the patients gave their consent according to respective rules.

5.3.2. Loss of Legal Capacity in the Course of the Clinical Trial

In case of certain psychiatric diseases, one must reckon with the fact that the patients involved in the trial might lose their ability to act in the course of the trial. The loss of the ability to act does not give grounds in itself for the exclusion of the patient from the study.

5.3.3. Placebo Controlled Clinical Trials on Psychiatric Patients

General considerations as to the application of placebo (see chapter 2.2.1) in psychiatric examinations are completed by the following professional-ethical rules:

• It is ethically unacceptable to provide placebo only treatment to patients with high risk for auto- and/or hetero-aggressive acts.
• It is forbidden to replace the sustaining treatment of patients suffering from certain psychiatric diseases in a steadily compensated state with placebo.

As to the application of placebo, a continuous revision is justified from a professional-ethical standpoint on the following areas:

• in the prevention of the relapse of schizophrenia,
• in acute maniac episode and in the serious form of major depression,
• in case of obsessive-compulsive disorder and in serious forms of social phobia.

Continuous hospitalization and intense observation are needed for the application of placebo in certain psychiatric diseases, which should be regarded separately in the protocol.

6. Time of Validity of the Codex

The scope of certain parts of the Codex may undergo rapid changes. The permanent renewal of methods and technologies, the occurrence of new diseases, as well as the showing up of new social claims may also entail a constant change in the trends and problems of biomedical research. Therefore, systematic rethinking and review will be predictably required in certain parts of the Codex.

GLOSSARY – TECHNICAL TERMS EXPLAINED

The Codex of Bioethics has been published by the Medical Research Council, Hungary.

Editor : József Mandl

Co-editor : Miklós Csala

Written by : Péter Arányi, György Blaskó, János Borvendég, István Bitter, Miklós Csala, Tamás Fenyvesi, Zsuzsanna Fürst, György Kosztolányi, József Kovács, József Mandl, Judit Sándor, all of them are members of the Medical Research Council.

The material of the Codex of Bioethics has been discussed and adopted as a corporate decision by the Presidency of MRC, as well as its three committees, the Committee of Human Reproduction, the Ethics Committee for Clinical Pharmacology and the Scientific and Research Committee.

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Each and every application,  both initial applications and protocol amendments, are assessed from professional and ethical points of view – our focus is the benefit of the patients.

Zsuzsanna Fürst – President, Ethics Committee for Clinical Pharmacology, Hungary

Dr. Zsuzsanna Fürst, President of the Ethics Committee for Clinical Pharmacology, elaborates on the role and activities of the ethics committee, shares her insights on structural framework of the application process for clinical trials, and the future outlook of clinical research in Hungary.

Can you give insights on the structure of the Ethics Committee for Clinical Pharmacology and how it fits in the bigger framework of the country?

The Ministry of Human Capacity (EMMI) is the overarching governmental body that oversees the activities of the Medical Research Council (ETT). Within the ETT there are four ethical committees for clinical research; the Scientific and Research Ethics (TUKEB), the Ethics Committee for Clinical Pharmacology (KFEB), the Regional Research Ethics Committees (RKEB), and the Human Reproduction Commission (HRB). Furthermore, there are three theoretical committees for basic research; the Committee on Research and Development (KFB), the Clinical Research Committee (FDI), the Board of Forensics Experts in the Field of Health (ISZT). All these bodies operate as advisors to the EMMI which report to the State Secretary of Health – unlike most countries, there is no stand-alone Minster of Health in Hungary.

The Ethics Committee for Clinical Pharmacology (KFEB) is an independent body that has 30 members which are appointed by the Minister of Human Capacity (EMMI) by the recommendation of Semmelweis University, and the Academy of Science. Our members cover 24 different medical professions and include six laypersons: two theologists, lawyers, and nurses. Their expertise is welcomed when dealing with subjects such as General Data Protection Regulation, or when assessing the ethical and practical implications of clinical trials. Within the committee, quorum meetings are organized regularly involving a minimum of five members, among them two laypersons at least, who have the power to assess and pass decisions on bioequivalence, phase IV studies, substantial amendments, and other urgent matters related to the National Competent Authority (NCA). Each and every application,  both initial applications and protocol amendments, are assessed by KFEB from professional and ethical points of view – our focus is the benefit of the patients.

How is the clinical trial regulation structured in Hungary?

The trial applications pass through the NCA and then are forwarded to the KFEB. Once the assessment is completed by the ethics committee, our decision is returned to the NCA. The NCA and KFEB both must accept the whole of the application documentation in order for the trial to get authorized.

The Ethics Committee for Clinical Pharmacology has tri-weekly meetings which are determined in January for the rest of the year. The quorum meets on a weekly basis to evaluate and amend clinical trials that have been submitted. There is a 60-day deadline for the evaluation process to take place – 30 days for initial applications and another 30 days for amendments. This timeframe also includes the time the sponsor needs to answer the deficiencies. However, the NCA has 15 more days for their decision to be taken.

This lengthy process has been a sore point for companies. However, this process is being reviewed and changed in preparation for the upcoming EU Clinical Trial Regulation No 536/2014 which is anticipated to go into effect in the upcoming year. Under the recommendations of the Clinical Trial Facilitation Group (CTFG) and the Voluntary Harmonization Procedure (VHP), the regulation is being implemented in parallel to the existing application process to streamline the assessment of multinational clinical trial applications.

The VHP procedure is a potential model for the clinical trial authorization procedure before the implementation of the EU Clinical Trial Regulation No 536/2014. In most countries, this procedure reduces the time period required for the authorization of multinational studies. Nevertheless, according to the Hungarian regulation, the authorization period for Hungary is 75 days for the national phase compared to the 10 days given in the VHP Guidance document. The reason for this is that the national phase authorization procedure in Hungary includes the ETT and KFEB evaluation as well. In order to decrease this long authorization period and to prepare for the new Clinical Trial Regulation, Hungary offers the possibility for applicants to submit national documentation (patient and site documentation) in parallel to the VHP Plus (VHP+) procedure. This means that Part I and Part II of the evaluation can be done in parallel, reducing the time required for the assessment to 10-15 days.

What are the trends associated with clinical trials?

Over the past decade, clinical trials in Hungary have been relatively stable, ranging between 320 and 390 new trials evaluated every year. However, the number of amendments made have been increasing yearly, which is related to the growing complexity of the active components that are being assessed. In Europe, the number of clinical trials has been decreasing, whereas in the United States, it has been increasing. Hungary on other hand, has remained unaffected by these changes.

Nevertheless, we have noticed an increase in the number of clinical trials in the field of oncology and hematology. This reflects a global trend, where cancer rates are increasing, and it is an area with still substantial groundwork to cover. In our committee, we have three hemato-oncologists which allows us to evaluate these specific trials in depth. Interestingly, cardiovascular is an area that has been decreasing, despite there still being a need in Hungary. On the other hand, we see interesting fields of study like analgesia, inflammatory diseases, autoimmune disease indications, and application of biologicals as drug candidates in any of those fields. However, biological compounds are expensive to produce, and once a trial is completed, treatments may not continue for patients who benefit from the therapy applied; lack of funding enhances this problem.

What are the strengths and weaknesses of the clinical pharma landscape in Hungary?

The strengths of Hungary’s educational and medical institutional network, alongside the practitioners’ competency, make the clinical pharma landscape in the country attractive for pharmaceutical companies. Medical universities like Semmelweis, or organizations like the Institution of Experimental Medicine, are just two examples amongst many that have a historical leadership and strong international ties. The collaboration with international entities permits an exchange of best practices, both in theory and in practice. Hence, the doctors that we have are very knowledgeable and competent, which makes them sought after. Unlike most countries, Hungary has an occupation called clinical pharmacologist who are specialists in the clinical field. They have to be the head of the institution and/or principle investigator (PI) where the trials are conducted. This is very attractive for international clients. Consequently, personnel are sought after from this environment and we are all exasperated by the fact that Hungary suffers from a brain drain.

Although Hungary has such strengths, competition to attract trials remains very high and there is only a limited amount of funding available in the country. Many hospitals, university clinics, small and unknown organization scramble for the finances and medical equipment necessary to conduct their trials. This affects also the talent search, as the best qualified doctors go where the best economic prospects are for them. Infrastructure is also another issue which we have raised with the NCA as they inspect trial facilities. They follow the Good Clinical Practices (GCP) guidelines, but they do not necessarily align with our recommendations as well take into consideration a wider range of factors.

What stages of the clinical trial are Hungary most prolific?

We receive most trials in the third phase, as there are a greater number of patients participating in them. Hungary is ranked first in Europe in terms of accessibility and availability of trials per capita, which is another factor that makes us attractive to the international market. First phase trials are not frequent but are only performed by facilities accredited by the NCA, thus high quality of their performance may be expected. In this case head of the site, as well as the PI have to be qualified as clinical pharmacologist. In further phases PI has to have recent GCP credit and qualified in the clinical profession corresponding to the indication of the trial. Phase two trials are more demanding in terms of clinical science. We have a fair share of those as well, probably owing to the good reputation of the best Hungarian clinicians.

How is the committee collaborating with the government and the industry?

Clinical trials are a very sensitive area and we must exercise caution as to not allow radical ideas to disrupt the system, which is apparently functioning: it is also part of the committee’s role. The committee is not directly involved with government but is through the connections with the NCA, that we collaborate with the state. Nevertheless, there is always collaboration with the industry and the government, as it is in everyone’s interest for a smooth process.

How do you see the clinical trial environment evolve in the next five years?

With a new Pharmacovigilance Hub opened by Roche this year, it might be an indication of a heightened interest in Hungary as a pharmaceutical market. Potentially, this could be a sign of new foreign direct investments to come, which would infuse the pharma landscape with much needed funding and dynamism.

We plan to enhance the influence of our ethics committee, to create a favorable legal framework for clinical trials, to improve the current IT system, to increase the number of Secretariat operative staff, in order to facilitate faster decision-making, and to increase the effectiveness of control, both in terms of facilities of sites and suitability of the investigators. The final purpose is to make Hungary an attractive place to bring in clinical trials in increasing number, and to make Hungary increasingly attractive to applicants as a country for effective and reliable clinical trials.

In Conversation

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Clinical trials with cannabis medicines—guidance for ethics committees, governance officers and researchers to streamline ethics applications and ensuring patient safety: considerations from the Australian experience

• Jennifer H. Martin   ORCID: orcid.org/0000-0002-8614-0199 1 ,
• Courtney Hill 1 ,
• Anna Walsh 2 ,
• Daryl Efron 3 , 4 , 5 ,
• Kaitlyn Taylor 3 ,
• Michael Kennedy 6 ,
• Rachel Galettis 1 ,
• Paul Lightfoot 7 ,
• Julie Hanson 8 ,
• Helen Irving 9 ,
• Meera Agar 10 &
• Judith Lacey 11 , 12 , 13  

Trials volume  21 , Article number:  932 ( 2020 ) Cite this article

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With cannabis medicines now obtaining legal status in many international jurisdictions (generally on the authorisation of a medical professional), a rapid increase in consumer demand for access to cannabis as a therapeutic option in the treatment and management of a range of indications is being noted. Despite this accessibility, knowledge on optimal use is lacking. Further drug development and clinical trials at regulatory standards are necessary both if a better understanding of the efficacy of cannabis medicines, optimal product formulation and indication-specific dosing is needed and to ensure the broader quality and safety of cannabis medicines in the clinical setting.

To enable this, clinical, academic and public calls for the undertaking of rigorous clinical trials to establish an evidence base for the therapeutic use of cannabis medicines have been made internationally. While this commitment to undertake human studies with cannabis medicines is welcomed, it has highlighted unique challenges, notably in the review stages of ethics and governance. This often results in lengthy delays to approval by Human Research Ethics Committees (herein ‘HREC’, Australia’s nomenclature for Institutional Review Boards) and trial commencement. A principal concern in these cases is that in contrast to clinical trials using other more conventional pharmaceutical products, trials of cannabis medicines in humans often involve the use of an investigational product prior to some (or any) of the preclinical and pharmaceutical safety issues being established. This paucity of data around product safety, potential drug interactions, continuity of supply, shelf life and product storage results in apprehension by HRECs and governance bodies to endorse trials using cannabis medicines.

This manuscript draws from the experiences of Australian researchers and staff involved in clinical trials of cannabis medicines to describe some of the common difficulties that may be faced in the HREC approval process. It also presents practical advice aimed to assist researchers, HRECs and governance officers navigate this complex terrain. While the authors’ experiences are situated within the Australian setting, many of the barriers described are applicable within the international context and thus, the solutions that have been proposed are typically adaptive for use within other jurisdictions.

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Introduction

Like many countries, Australia has legalised the use of cannabis when used as a pharmaceutical-grade product prescribed by a medical professional for the therapeutic treatment of management of specific indications [ 1 ]. Unlike the standard pathway followed for other pharmaceutical products, a strong and public argument has been made by consumers and researchers for clinical trials to occur using cannabis medicines as investigational products in human studies prior to the preclinical and pharmaceutical safety issues being fully elucidated. Given this atypical approach, real-world ‘effectiveness’ clinical trials, including randomised controlled trials, are a means through which the risks of widespread use of off-label therapeutics and the collection of rigorous data to inform clinical practice can be balanced. However, understandably, this approach often raises seemingly complex issues for ethics and governance committees during the review and approval process.

A key concern of HRECs is that many of the studies of cannabis medicines are undertaken in the outpatient setting, involving self-medicating. Thus, issues such as potential use of a concomitant illicit product, adequacy of storage and dosing, measurement of toxicity, concomitant medication use and adequacy of follow-up are commonly raised. Further, the use of an unregistered product, such as cannabis medicines, in this relatively unsupervised setting introduces a novel set of additional issues for ethics and governance committees to overcome.

In 2019, a group consisting of Australian lead investigators of large investigator-initiated, Government or institutionally-funded studies; clinical trials officers; and regulatory staff came together to discuss common barriers and the lack of clear information available to guide the process of designing and undertaking clinical trials using cannabis medicines. Drawing on the current Australian Research Standards (such as the Australian National Guidelines, the National Statement on Ethical Conduct in Human Research ) and the authors’ practical experience navigating these barriers this manuscript offers guidance as to how some of the key issues that arise when using cannabis medicines as investigational products can be remedied [ 2 ].

Through a series of discussions, six (6) common challenges were identified as the main barriers/issues faced when submitting clinical trials involving cannabis medicines to Human Research Ethics Committees (HREC) and regulatory authorities (such as Research Governance Offices (RGO) in Australia) for review and approval. These include (1) considerations when selecting cannabis medicines products, (2) accurate dosing and administration, (3) adverse events, (4) drug-drug interactions, (5) consent and (6) post-trial access to cannabis medicine products.

Considerations when selecting cannabis medicines products in the trial setting

Sourcing a supply of cannabis medicines for use in clinical studies takes time, and the following should be considered and discussed in the ethics application when choosing a product for use:

Does the product meet Good Manufacturing Practice (GMP) and current Federal and State regulations (such as the Therapeutic Goods (Standard for Medicinal Cannabis) (TGO 93) in Australia [ 3 , 4 ])?

Is there a guaranteed consistent supply available for the duration of the trial?

Does the supplier of the product have knowledge of, and experience in the pharmaceutical environment (e.g. ability to provide an investigator’s brochure)?

Cannabis medicines are available in a variety of preparations with different concentrations of Cannabidiol (CBD), Delta-9-tetrahydrocannabinol (THC), other cannabinoids, varying terpene combinations, and maybe a whole plant product or a highly purified extract. Researchers and ethics committees both should be aware that one cannabis medicine product, even if available in the same dose, formulation or concentration, may have vastly different potency or purity to another. Cannabis medicine products may also have different absorption rates and pharmacokinetic profiles due to the variety of carrier oils, extraction methods and delivery systems available (such as vaporised, nanotechnology, oral vs. sublingual). The selection and formulation of the cannabis medicines product should, therefore, be clearly defined and explained in the research/study protocol.

Researchers need to be aware that cannabis medicines used in clinical trials, as with other registered products, must align with the existing framework for the use of unregistered/unapproved medications in clinical trials. This is done by Australia’s federal regulator, the Therapeutic Goods Administration (TGA) through their Clinical Trial Notification (CTN) scheme [ 5 ]. This scheme has the required elements to support the documented use of cannabis medicine products within a clinical trial in Australia [ 6 ]. Additionally, it is recommended that early consideration should be given to the classification or scheduling Footnote 1 of the medicine and other prescribing regulations around such products, as this will have significant impacts on the logistics of a trial. In Australia, cannabis medicines are currently classified as either a Schedule 8—Controlled Drug or Schedule 4—Prescription Only Medicine, both requiring different national and state approval schemes for use [ 8 ]. For example, Schedule 8 medicines in the state of New South Wales, which includes cannabis medicine products containing THC, also requires State approval. Additional requirements may include specific features mandated by pharmaceutical regulations, such as the need for child-resistant openings, instructions for storage and use, labelling and movement and transportation of the medicine.

Researchers must confirm local requirements and consider the related implications, especially if planning a multi-site trial across borders. It can be helpful to have a specific section within the trial protocol which outlines these elements (referencing the relevant legislation), including issues around import/export and product transport, as well as the proposed methods of compliance for the clinical trial, to provide clarity for members of the ethics committee.

In the case of outpatient dosing, diversion can be limited by informing patients that reconciliation of their returned product will be performed upon return and encouraging patients to document drug consumption accurately, including any wastage.

An experienced clinical trial coordinator, collaborative research group or an accredited clinical trial pharmaceutical or contract research organisation can provide expertise in the import of products, labelling and packaging requirements and assist with meeting all required regulations. This is particularly important for an unregistered product, particularly when it may also be used with an unregistered device, such as vaporisers, which may also require approval from a regulatory body to be used in a clinical study. Seeking this support is strongly encouraged if the necessary skills are not contained within the supplier or the research team.

Accurate dosing and administration

Cannabis medicines are unique when it comes to dosing and administration; apart from Nabiximols, there is currently no registered product information, which traditionally provides dosing schedules for new products. Dosing is individualised for each patient, with the clinicians and patients relying on titration to reach the optimum dose, if one exists, regardless of the cannabinoid content [ 9 , 10 ]. In Australia, the Federal regulator recommends that starting doses should be low and increased over time until patients respond positively, or the negative effects outweigh the perceived benefits [ 11 ]. Product information dosing guidance has been developed in the interim to help ethics committees with this issue [ 9 , 12 ]. Investigators can utilise a broad range of published data to outline the parameters they have used to inform the dosing schedule, which may include data in other populations, or from other cannabis medicines studies. To support informed ethical review, clarity around these data and decisions that have been made is an important part of the study rationale.

Additional factors that may affect dosing include the underlying condition being investigated, the type of product used, route of administration, dosage regimen, individual patient variation, possible development of tolerance, interaction with other medications and previous exposure to cannabis, either recreationally or medically [ 9 ].

As with all drugs, lower doses are less likely to be associated with adverse effects, possibly limiting therapeutic doses being achievable without toxicity, such as sedation without pain relief. To determine the efficacy of the cannabis medicine product for the patient and their medical condition, clinicians and patients need to work together to determine a personalised dosage escalation regimen, including starting dose and develop a plan for dose increments or decrements where the patient benefit is maximised, and adverse effects are minimised.

When selecting a cannabis medicine product for a clinical trial, the mode of administration is important, depending on whether a large exposure is needed, for example with chronic pain, where constant concentrations above a minimum are needed, or if a high maximum concentration is needed for a short time, e.g. for breakthrough pain. Rapid onset can be achieved by choosing an administration method bypassing metabolism in the liver, i.e. not oral. Examples include the commonly used inhaled (vaporised) route and oral mucosal, but developing routes for rapid absorption include transdermal, intranasal, buccal and sublingual routes. Researchers may also need to consider complexities such as using specific volumes and concentrations for doses and include and actual dose amount, such as milligram per day measured. Storage and administration devices such as droppers, vaporisers and non-pharmaceutical standard storage bottles must be checked for residual medicine and include specifications on the cleaning of delivery devices. Many of the above issues can potentially be eliminated by choosing a simpler, standardised route and a pharmaceutical-grade product and dispenser. One such option is encapsulating the medicine using preloaded vaporised dosing [ 13 ].

Adverse events

Two elements of safety need to be considered in cannabis medicines trials; this is no different to the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) Good Clinical Practice (GCP) E6 (R2) requirements for clinical trials of other interventions. Firstly, the safety data which underpins the study design elements, such as participant population, dosing and expected adverse effects [ 14 ]. The second is to outline a safety monitoring approach, which is based on available data considering the population under study. The interpretation of safety data for cannabis medicines is complicated. While cannabis has been used by humans for millennia, details of the short- and long-term adverse reactions profile remains poorly understood. Overall, the known common adverse effects of cannabis medicines include sedation/somnolence, dizziness, anxiety, cognitive dysfunction, nausea, vomiting, diarrhoea, vertigo, increased or decreased appetite and dry mouth [ 15 ]. The adverse event profile of different formulations varies depending on the ratio of CBD: THC, the presence and amount of other cannabinoids and terpenes and the dose prescribed [ 16 ]. THC, particularly at higher doses, may be associated with treatment-emergent hallucinations, perceptual disturbances or paranoia [ 17 ].

ICH-GCP provides specific guidance on the procedures for assessing, classifying, documenting and reporting adverse events [ 2 ]. There is a lack of a standardised measure for assessing adverse events of cannabis medicines so all adverse events should be recorded and reported. Researchers may choose to use a measure such as the Common Terminology Criteria for Adverse Events version 5 for describing adverse events [ 18 , 19 ].

Blood tests may be conducted to assess for treatment-emergent abnormalities in haematology, biochemistry and liver functioning. Antiepileptic blood concentrations and concentrations of other drugs metabolised by the cytochrome P450 (CYP450) enzyme system may require monitoring depending on the study [ 20 , 21 ].

In addition to routine biochemical and haematological monitoring, any unusual event, including large changes in heart rates and blood pressure, should be recorded both during the trial and for a specified duration after the trial has concluded. Furthermore, it should be noted that safety data from plant-derived cannabis products cannot be applied to synthetic cannabinoids, the safety of which needs to be considered independently.

Drug-drug interactions

Currently, cannabis medicines used in clinical trials utilise either a single cannabinoid extract (THC or CBD) or a combination of these two cannabinoids in varying ratios, and as part of a whole plant product or as combined extracts, with or without added minor cannabinoids or terpene extracts. The pharmacokinetics and pharmacodynamics of most analogue cannabinoids are not known and little work has been undertaken on the stereoisomeric forms of the cannabinoids or pharmacogenomic studies on their metabolism [ 22 ].

THC and CBD are metabolised by the CYPP450 system. The CYP system is also a common site for drug-drug interactions, which have been responsible for many deaths in Australia [ 23 ]. Inhibition by drugs such as ketoconazole and clarithromycin significantly increase concentrations of THC and CBD, while inducers such as rifampicin, carbamazepine and St John’s Wort lower THC and CBD concentrations. Other, pharmacodynamic (PD) interactions may occur at the level of the endocannabinoid receptor but are not yet known, including G-protein-coupled receptors (GPCR) interactions and common binding of cannabinoids to mu, dopamine, serotonin and similar receptors [ 24 ].

As per standard clinical trial practice, complete details of any co-administered medications, alcohol intake, tobacco smoking and complementary medications should be recorded, and dosing of a cannabis medicine product altered as medication changes. Adherence to GCP guidelines requires that the mode of delivery, duration of cannabis medicines therapy and previous exposure to cannabis are documented in the evaluation of any therapeutic effect. Similarly, this information needs to be reported in accordance with good pharmacovigilance practice in the recording of adverse drug reactions.

There has been a strong consumer demand for cannabis medicines [ 25 ], particularly in the setting of life-limiting conditions and symptom control. The population is generally comprised of vulnerable people, such as children with epilepsy, patients moving towards the palliative care phase of their illness and people living with mental health issues, or drug and alcohol dependence [ 26 ]. Often, these vulnerable populations are willing to ‘try anything’ to alleviate difficult to manage symptoms.

In line with the Australian National Guidelines, participation in cannabis medicines trials, as with any clinical trial, must be voluntary and based upon enough information, and with the ability to withdraw consent and involvement in research at any time without prejudice [ 2 , 27 ]. An individual’s capacity to consent must be assessed, and it is important to note that a participant’s capacity may fluctuate with time and situation during trials using cannabis medicines due to sedative effects [ 28 ]. While it is not a requirement in Australia that consent is routinely witnessed [ 2 ], we recommend that participant consent should be witnessed in cannabis medicines trials to ensure participant safety and self-determination. Participants must also be advised that they will be unable to drive or operate heavy machinery while taking a cannabis medicine product containing THC.

Post-trial access

Post-trial access is an ethical obligation should the study drug prove safe and effective and must be considered during the development of the protocol. Researchers should confirm ongoing access pathways and communicate this to participants at the time of consent [ 29 ]. Consideration should also be given to the most appropriate alternative cannabis medicine product in the event of supply issues. Due to the botanical nature of the source of the study drug and variation in base excipients between manufacturers, it may be difficult to identify an alternate product to the specific medication used in a researcher’s clinical trial.

To ensure ongoing clinical care and safety monitoring of a participant, open-label extension of a clinical trial is common, with the treatment provided at no cost and the benefit of continued data collection in a managed access programme [ 30 ]. The CARE NSW trial in Australia is an example of such a trial to adopt this mechanism in the advanced cancer population; however, this is uncommon due to cost, sponsor unwillingness and logistical issues, such as coordination of access by research staff, who may be employed only for the period of the trial. Open-label extensions are not an ethical requirement; however, patients must be informed that medication supply will not be available at the end of the study [ 31 ].

The alternative that can be included in a study protocol is to utilise the existing framework for prescribing non-registered medicines. In Australia, approved cannabis medicine products which meet TGO93 may be prescribed post-trial at the direct cost of the patient through Australia’s TGA special access schemes (SAS) or by their doctor obtaining personal authority to be a registered prescriber of cannabis medicines [ 32 ]. It is, however, important to highlight the cost burden of this to participants in advance.

Availability of and access to cannabis medicines for participants post-trial must, therefore, be confirmed during protocol development, and arrangements should be clearly communicated in the Protocol and Patient Information Sheet and Consent Form (PICF).

Notwithstanding the need to adhere to the National, Federal and State guidelines, recently clinicians, public health professionals and academics are concerned about the barriers arising through the ethics review process, often due to the complexity for committees of navigating large clinical trials using (often unregistered) cannabis medicines. While cannabis medicines are a relatively new and promising therapy, clinical trials need to be undertaken to understand how to demonstrate their efficacy and safety in different conditions. Thus, it is likely that ethics and governance committees will receive an increasing number of research protocols involving studies of cannabis medicines for review. However, because cannabis is also an illicit substance when used outside of regulated medical settings, it is imperative to educate staff working in the ethics and governance about the major differences between illicit cannabis and cannabis medicines. Education and discussion for all key stakeholders to address the current perceived risks, including product safety, regulations, storage and supply will ease concerns from ethics committees around such trials.

Availability of data and materials

Not applicable

Under the Australian regulatory system overseen by the Therapeutics Goods Administration (TGA), medicines and poisons are scheduled according to the level of regulatory oversight required to protect public health and safety [ 7 ]. Therapeutic Goods Administration. Scheduling of medicines & poisons [Internet] 2016 [cited 07 August 2020]. Available from: https://www.tga.gov.au/scheduling-medicines-poisons

Abbreviations

Cannabinoids for Symptom Control in Advanced Cancer, an Open-Label Prospective Clinical Trial in New South Wales (NSW)

Cannabidiol

Clinical Trial Notification

Cytochrome P450

G-protein-coupled receptors

Good Manufacturing Practice

Human Research Ethics Committee

International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use Good Clinical Practice

Pharmacodynamic

Patient Information Sheet & Consent Form

Research Governance Office

Special Access Scheme

Australia’s Therapeutic Goods Administration

Therapeutic Goods (Standard for Medicinal Cannabis)

Delta-9-tetrahydrocannabinol

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Acknowledgements

We would like to thank the members of the Australian Centre for Cannabinoid Clinical and Research Excellence (ACRE) Guidance Writing Group for Clinical Trials in Cannabinoids: Guidance for Ethics Committees and Governance Officers for their contribution to the development of this paper. A/Prof Peter Grimison (Chris O’Brien Lifehouse), Dr Kylie O’Brien (Global Health Institute Queensland), Dr Paul Scuffham (Menzies Health Institute Queensland), Prof Nick Linzteris (South Eastern Sydney Local Health District), Dr Jaroslav Boublik (LeafCann Group Pty Ltd) and Courtney Hill (ACRE) for general administrative support including management of meetings and formatting of the document throughout its lifetime.

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Jennifer H. Martin, Courtney Hill & Rachel Galettis

NHMRC Clinical Trials Centre, University of Sydney, Sydney, New South Wales, Australia

Murdoch Children’s Research Institute, Parkville, Victoria, Australia

Daryl Efron & Kaitlyn Taylor

The Royal Children’s Hospital, Parkville, Victoria, Australia

Daryl Efron

Department of Paediatrics, The University of Melbourne, Parkville, Victoria, Australia

St Vincent’s Clinical School, UNSW Medicine, UNSW Sydney and Department of Clinical Pharmacology and Toxicology, St Vincent’s Hospital Sydney, Sydney, New South Wales, Australia

Michael Kennedy

Department of Neurology, Austin Health, Heidelberg, Victoria, Australia

Paul Lightfoot

School of Nursing, Midwifery and Paramedicine, University of the Sunshine Coast, Maroochydore, Queensland, Australia

Julie Hanson

Children’s Health Queensland, Hospital and Health Service, University of Queensland, Brisbane, Queensland, Australia

Helen Irving

IMPACCT, University of Technology Sydney, Sydney, New South Wales, Australia

Chris O’Brien Lifehouse Comprehensive Cancer Hospital, Camperdown, New South Wales, Australia

Judith Lacey

School of Medicine, University of Sydney, Sydney, New South Wales, Australia

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Contributions

All authors were involved in the design of the manuscript and all have read and approved the final manuscript. Specific section contributions include DE and KT—adverse events; MK—drug-drug interactions; JL and AW—considerations when selecting cannabis medicines products in the trial setting and accurate dosing and administration; MA, HI and JH—consent; RG and PL—post-trial access; and JM—abstract, introduction, summary and oversite of all sections.

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Correspondence to Jennifer H. Martin .

Ethics declarations

Ethics approval and consent to participate, consent for publication, competing interests.

JH, AW, PL, KT, MK and HI declare no competing interests.

Professor Meera Agar is chair of the Medical Research Ethics Committee at the University of Technology Sydney, a member of South West Sydney Human Research Ethics Committee. Professor Agar also receives NSW Government funding for clinical trials ‘Evaluation of pharmaceutical cannabinoids and standardized botanical leaf cannabis for anorexia in advanced cancer’.

Professor Jennifer Martin, Dr Rachel Galettis and Courtney Hill are part of the Australian Centre for Cannabinoid Clinical and Research Excellence (ACRE), which is funded through the National Health and Medical Research Council’s Centres of Research Excellence Program. ACRE also receives funding through NSW Health’s Clinical Cannabis Medicines Program, which supports Dr Galettis and Ms Hill’s roles as Clinical Trial Manager and Clinical Trial Coordinator for the CARE NSW Trial.

A/Prof Judith Lacey is an investigator on a “Phase 2 Randomised, Double-Blind Clinical Trial Assessing the Tolerability Of Two Different Ratios Of Cannabis medicines In Patients With Glioblastoma Multiforme (GBM)”. Supported by Bioceuticals pharmaceuticals.

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Martin, J.H., Hill, C., Walsh, A. et al. Clinical trials with cannabis medicines—guidance for ethics committees, governance officers and researchers to streamline ethics applications and ensuring patient safety: considerations from the Australian experience. Trials 21 , 932 (2020). https://doi.org/10.1186/s13063-020-04862-6

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Physicians engaged in clinical research face the ethical question of how to combine the delivery of individual care for the patient with the rigorous demands of science. The first documents in Europe adressing the need of introducing standards in clinical research ethics were the 1900 Regulation of the Prussian ministry of Education and the 1931 Reich Circular “Regulations on New Therapy and Human Experimentation”. These pre-war documents contained already important ethical principles in clinical research such as informed consent, voluntary participation and the concept of vulnerable patient groups. However, they were only national documents. The development of more generally accepted guidelines started not until after World War II as a result of the inhuman Nazi experiments. Thus the “Nuremberg Code” was formulated in 1947, and in 1964 the World Medical Association issued the Declaration of Helsinki, one of the most important documents in the history of research ethics. The Declaration has undergone several revisions, one of paramount importance in 1975 when the concept of oversight by an “independent committee” was introduced, thus giving birth to independent Ethics Committees (IEC) worldwide.

Today the function of IEC is multifaceted. Over the last decades they have grown from small groups of peers voluntarily reviewing protocols to institutions implemented under various laws, performing specialized tasks requiring a high level of professionalism. This development over time along with the various strategies employed to effectively handle the increasing number of tasks is described using the IEC of the Medical University of Vienna as an example.

• Ethics Committee
• Albert Neisser
• Nuremberg Code
• Declaration of Helsinki
• ICH E6 ICH-GCP
• Clinical Trial Directive 2001/20/EC

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Karl Brandt (January 8, 1904–June 2, 1948) headed the administration of the Nazi euthanasia program from 1939 and was selected the personal physician of Hitler in August 1944.

ECS – an open-source software solution satisfying all requirements of an EC office. The Vienna experience.

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Wolzt M, Druml CH, Leitner D, Singer EA (2009) Protocols in expedited review: tackling the workload of ethics committees. Intensive Care Med 35(9):1636–1640, Epub 2009 June 19

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Singer, E., Druml, C. (2016). Ethics in Clinical Research. In: Müller, M. (eds) Clinical Pharmacology: Current Topics and Case Studies. Springer, Cham. https://doi.org/10.1007/978-3-319-27347-1_5

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Clinical trials with cannabis medicines-guidance for ethics committees, governance officers and researchers to streamline ethics applications and ensuring patient safety: considerations from the Australian experience

Affiliations.

• 1 Australian Centre for Cannabinoid Clinical and Research Excellence (ACRE), Division of Clinical Pharmacology, School of Medicine and Public Health, University of Newcastle, Newcastle, New South Wales, Australia. [email protected].
• 2 Australian Centre for Cannabinoid Clinical and Research Excellence (ACRE), Division of Clinical Pharmacology, School of Medicine and Public Health, University of Newcastle, Newcastle, New South Wales, Australia.
• 3 NHMRC Clinical Trials Centre, University of Sydney, Sydney, New South Wales, Australia.
• 4 Murdoch Children's Research Institute, Parkville, Victoria, Australia.
• 5 The Royal Children's Hospital, Parkville, Victoria, Australia.
• 6 Department of Paediatrics, The University of Melbourne, Parkville, Victoria, Australia.
• 7 St Vincent's Clinical School, UNSW Medicine, UNSW Sydney and Department of Clinical Pharmacology and Toxicology, St Vincent's Hospital Sydney, Sydney, New South Wales, Australia.
• 8 Department of Neurology, Austin Health, Heidelberg, Victoria, Australia.
• 9 School of Nursing, Midwifery and Paramedicine, University of the Sunshine Coast, Maroochydore, Queensland, Australia.
• 10 Children's Health Queensland, Hospital and Health Service, University of Queensland, Brisbane, Queensland, Australia.
• 11 IMPACCT, University of Technology Sydney, Sydney, New South Wales, Australia.
• 12 Chris O'Brien Lifehouse Comprehensive Cancer Hospital, Camperdown, New South Wales, Australia.
• 13 School of Medicine, University of Sydney, Sydney, New South Wales, Australia.
• 14 NICM Health and Research Institute, Western Sydney University, Penrith, New South Wales, Australia.
• PMID: 33203469
• PMCID: PMC7673085
• DOI: 10.1186/s13063-020-04862-6

With cannabis medicines now obtaining legal status in many international jurisdictions (generally on the authorisation of a medical professional), a rapid increase in consumer demand for access to cannabis as a therapeutic option in the treatment and management of a range of indications is being noted. Despite this accessibility, knowledge on optimal use is lacking. Further drug development and clinical trials at regulatory standards are necessary both if a better understanding of the efficacy of cannabis medicines, optimal product formulation and indication-specific dosing is needed and to ensure the broader quality and safety of cannabis medicines in the clinical setting.To enable this, clinical, academic and public calls for the undertaking of rigorous clinical trials to establish an evidence base for the therapeutic use of cannabis medicines have been made internationally. While this commitment to undertake human studies with cannabis medicines is welcomed, it has highlighted unique challenges, notably in the review stages of ethics and governance. This often results in lengthy delays to approval by Human Research Ethics Committees (herein 'HREC', Australia's nomenclature for Institutional Review Boards) and trial commencement. A principal concern in these cases is that in contrast to clinical trials using other more conventional pharmaceutical products, trials of cannabis medicines in humans often involve the use of an investigational product prior to some (or any) of the preclinical and pharmaceutical safety issues being established. This paucity of data around product safety, potential drug interactions, continuity of supply, shelf life and product storage results in apprehension by HRECs and governance bodies to endorse trials using cannabis medicines.This manuscript draws from the experiences of Australian researchers and staff involved in clinical trials of cannabis medicines to describe some of the common difficulties that may be faced in the HREC approval process. It also presents practical advice aimed to assist researchers, HRECs and governance officers navigate this complex terrain. While the authors' experiences are situated within the Australian setting, many of the barriers described are applicable within the international context and thus, the solutions that have been proposed are typically adaptive for use within other jurisdictions.

Keywords: Cannabinoids; Cannabis medicines; Cannabis medicines research; Clinical trials; Governance; Human research ethics; Investigational medicinal product.

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Ethics in Clinical Research: The Indian Perspective

J. sanmukhani.

Department of Pharmacology, Government Medical College, Bhavnagar-364 001, India

C. B. Tripathi

Ethics in clinical research focuses largely on identifying and implementing the acceptable conditions for exposure of some individuals to risks and burdens for the benefit of society at large. Ethical guidelines for clinical research were formulated only after discovery of inhumane behaviour with participants during research experiments. The Nuremberg Code was the first international code laying ethical principles for clinical research. With increasing research all over, World Health Organization formulated guidelines in the form of Declaration of Helsinki in 1964. The US laid down its guidelines for ethical principles in the Belmont Report after discovery of the Tuskegee's Syphilis study. The Indian Council of Medical Research has laid down the ‘Ethical Guidelines for Biomedical Research on Human Subjects’ in the year 2000 which were revised in 2006. It gives twelve general principles to be followed by all biomedical researchers working in the country. The Ethics Committee stands as the bridge between the researcher and the ethical guidelines of the country. The basic responsibility of the Ethics Committee is to ensure an independent, competent and timely review of all ethical aspects of the project proposals received in order to safeguard the dignity, rights, safety and well-being of all actual or potential research participants. A well-documented informed consent process is the hallmark of any ethical research work. Informed consent respects individual's autonomy, to participate or not to participate in research. Concepts of vulnerable populations, therapeutic misconception and post trial access hold special importance in ethical conduct of research, especially in developing countries like India, where most of the research participants are uneducated and economically backward.

The word ‘ethics’ is derived from the Greek word, ethos , which means custom or character. Ethics is the systematic study of values, so as to decide what is right and what is wrong. In clinical research human beings are involved, as opposed to animals, atoms or asteroids, as the object of study. It focuses on improving human health and well-being, typically by identifying better methods to treat, cure or prevent illnesses. Ethics in clinical research focuses largely on identifying and implementing the acceptable conditions for exposure of some individuals to risks and burdens for the benefit of the society at large.

The ethical guidelines in various parts of the world were formulated only after discovery of inhumane behaviour with participants during research experiments. In the pre World War II era, most of the research experiments were carried on own self or on one's own patients. World War II led the states to take more interest in science and research resulting in initiation of larger, systematic clinical investigations to gain knowledge for better treatment of patients, specially the soldiers. Most of the studies were carried out through defence efforts and used mainly the prisoners without concern of their consent and well being. The experiments by the Nazi doctors in their concentration camps were the cruellest of all of them. In some of the most dreadful of these experiments, they kept the prisoners in compression chambers, freezing water, created gunshot wounds and even transplanted grafts among twins to see the body's response in such adverse situations. Death was the end point in most of the experiments and when it was not so, the doctors did antemortum dissection to study changes in the body. The discovery of these experiments stunned the whole world which led to formulation of Nuremberg code[ 1 ] in Germany to prevent recurrence of such episodes. It was the first international code for ethics in clinical research laying down the guidelines for research on human subjects. It laid down ten clear principles to be followed by researchers and made voluntary consent essential, allowed subjects to withdraw from the experimentation at any time, banned experiments that could result in major injury or death of the subjects and made mandatory to have preclinical data before experimenting on humans.

DEVELOPMENT OF VARIOUS ETHICAL GUIDELINES - CHANGING SCENARIO

The Nuremberg code was not honored by some researchers and there continued to be abuses and exploitations of humans in research. The Willowbrook State Study[ 2 ] to know natural course of infective hepatitis in children and the Jewish Chronic Disease Hospital study[ 3 ] to understand body's ability to reject cancer cells in debilitated subjects were examples of unethical research. This led the World Medical Association (WMA) to develop a set of guidelines to safeguard the rights and well being of participants in clinical research. The set of guidelines was adopted by the 18 th WMA General Assembly and was called the Declaration of Helsinki[ 4 ]. It was revised five times and the latest version was published in 2000 at the 52 nd WMA, Edinburgh, Scotland. It contains 32 principles, which stress on informed consent, confidentiality of data, vulnerable population and requirement of a protocol, including the scientific reasons of the study, to be reviewed by the ethics committee.

In the United States the ethical guidelines were setup after the discovery of the Tuskegee Syphilis Study[ 3 ]. The study was started in 1932 with 399 syphilitic African American men to see the natural course of syphilis and was supposed to last for about six months but as the researchers were getting “good data” they decided to continue it. The participants were misled and deprived of treatment even after the introduction of penicillin in the 1940s. These ethical atrocities were exposed in 1972 resulting in discontinuation of the study, but till then it had already led to 28 deaths and permanent disability in 100 subjects; moreover 40 patients infected their wives resulting in 19 cases of congenital syphilis. To probe into the study the ‘National Commission for the Protection of Human Subjects of Biomedical and Behavioural Research’ was formed which wrote the Belmont Report[ 5 ] in 1979 and laid the foundation for regulations regarding ethics and human subjects’ research in the US. The Belmont report stressed upon three basic ethical principles: respect for person, beneficence and justice. These were applied in the form of informed consent, assessment of risks and benefits by ethics committees and selection of subjects.

With the increasing interest of pharmaceutical industries in carrying out research experiments in the developing and the under developed countries, in 1982, the Council for International Organizations of Medical Sciences (CIOMS)[ 6 ] in association with World Health Organization (WHO) developed ‘International Ethical Guidelines for Biomedical Research Involving Human Subjects’. They especially stressed upon ethical issues in less developed countries like investigator's duties regarding consent, appropriate inducements, special/vulnerable populations, therapeutic misconceptions and post trial access.

THE INDIAN PERSPECTIVE

The Indian Council of Medical Research (ICMR), in February 1980, released a ‘Policy Statement on Ethical Considerations involved in Research on Human Subjects’. This was the first policy statement giving official guidelines for establishment of ethics committees (ECs) in all medical colleges and research centres. But as with other nations of the world, these guidelines were not respected by many researchers and India was not free of controversial research works. In 1970s and 1980s researchers at the Institute for Cytology and Preventive Oncology in New Delhi, carried out a study on 1158 women patients of different stages of cervical dysplasia or precancerous lesions of the cervix[ 7 ]. These patients were left untreated to see how many lesions progressed to cancer and how many regressed. By the end of the study seventy one women had developed malignancies and lesions in nine of them had progressed to invasive cancer. Sixty-two women were treated only after they developed localised cancer. After the controversy about the study became public in 1997, the ICMR started developing ‘Ethical Guidelines for Biomedical Research on Human Subjects’ and finalised them in the year 2000. These are a set of guidelines which every researcher in India should follow while conducting research on human subjects. Although not a law, these guidelines have been put into force through Schedule Y. With the changing scenario in the research field and development of modern techniques, the guidelines were revised in 2006[ 8 ]. These guidelines have elaborated the three basic ethical principles: respect for person, beneficence and justice by inducting twelve general principles as follows:

Principle of essentiality:

The research being carried out should be essential for the advancement of knowledge that benefits patients, doctors and all others in aspects of health care and also for the ecological and environmental well being of the planet.

Principles of voluntariness, informed consent and community agreement:

The research participant should be aware of the nature of research and the probable consequences of the experiments and then should make a independent choice without the influence of the treating doctor, whether to take part in the research or not. When the research treats any community or group of persons as a research participant, these principles of voluntariness and informed consent should apply to the community as a whole and also to each individual member who is the participant of the research or experiment.

Principle of non-exploitation:

Research participants should be remunerated for their involvement in the research or experiment. The participants should be made aware of all the risks involved irrespective of their social and economic condition or educational levels attained. Each research protocol should include provisions of compensation for the human participants either through insurance cover or any other appropriate means to cover all foreseeable and hidden risks.

Principle of privacy and confidentiality:

All the data acquired for research purpose should be kept confidential to prevent disclosure of identity of the involved participant and should not be disclosed without valid legal and/or scientific reasons.

Principle of precaution and risk minimisation:

Due care and caution should be taken at all stages of the research and experiment (from its beginning as a research idea, formulation of research design/ protocol, conduct of the research or experiment and its subsequent applicative use) to prevent research participant from any harm and adverse events. EC has to play an active role in risk minimization.

Principle of professional competence:

Clinical research should be carried out only by competent and qualified persons in their respective fields.

Principle of accountability and transparency:

The researcher should conduct experiments in fair, honest, impartial and transparent manner after full disclosure of his/her interests in research. They should also retain the research data, subject to the principles of privacy and confidentiality, for a minimum period of 5 years, to be scrutinized by the appropriate legal and administrative authority, if necessary.

Principle of the maximisation of the public interest and of distributive justice:

The results of the research should be used for benefit of all humans, especially the research participants themselves and/or the community from which they are drawn and not only to those who are socially better off.

Principle of institutional arrangements:

It is required that all institutional arrangements required to be made in respect of the research and its subsequent use or applications should be duly made in transparent manner.

Principle of public domain:

The results of any research work done should be made public through publications or other means. Even before publication, the detailed information of clinical trials should be made public before start of recruitment via clinical trial registry systems that allow free online access like: www.ctri.in/ ; www.actr.org.au/ ; www.clinicaltrials.gov/ or www.isrctn.org/ .

Principle of totality of responsibility:

All those directly or indirectly connected with the research should take the professional and moral responsibility, for the due observance of all the principles, guidelines or prescriptions laid down in respect of the research.

Principle of compliance:

All those associated with the research work should comply by the guidelines pertaining to the specific area of the research.

For research to be conducted ethically we need to follow these twelve general principles laid down by the ICMR. In order to follow these principles we should be aware about the informed consent process, vulnerable population, therapeutic misconception, post trial access and structure and role of ethics committees. These concepts hold special importance in developing countries like ours, as most of the research participants are uneducated and economically backwards, hence we discuss them here.

INFORMED CONSENT[ 8 , 9 ]

A well-documented informed consent is the hallmark of any ethical research work. It is the responsibility of the investigator/researcher to obtain the informed consent of the prospective participant or in the case of an individual who is not capable of giving informed consent, the consent of a legal guardian. Informed consent respects individual's autonomy to participate or not to participate in research. Adequate information about the research is given in a simple and easily understandable vernacular language in a document known as the ‘Participant/Patient Information Sheet’ attached along with the ‘Informed Consent Form (ICF)’. The patient information sheet should include: A statement that the study involves research; an explanation of the purpose of the research and the expected duration of the subject's participation; a description of the procedures to be followed and identification of any procedures which are experimental; a description of any reasonably foreseeable risks or discomforts to the subjects; a description of any benefits to the subjects or to others which may reasonably be expected from the research; trial treatment schedule(s) and the probability for random assignment to each treatment (especially in randomized placebo controlled trials); a disclosure of appropriate alternative procedures or courses of treatment, if any, that might be advantageous to the subjects; a statement describing the extent, if any, to which confidentiality of records identifying the subjects will be maintained; for research involving more than minimal risk, an explanation as to whether any compensation and an explanation as to whether any medical treatments are available if injury occurs and, if so, what they consist of, and where further information may be obtained; an explanation of whom to contact for answers to pertinent questions about the research and research subjects’ rights, and whom to contact in the event of a research-related injury to the subjects; a statement that participation is voluntary and refusal to participate will involve no penalty or loss of benefits to which the subjects are otherwise entitled, also the subjects may discontinue participation at any time without penalty or loss of benefits.

The ICF should specify that the participant has read and understood the patient information sheet; no further permission is required to look into his health records for study purpose until his identity is not revealed; the results arising from the study can be used only for scientific purposes and he voluntarily agrees to take part in the study. The ICF should have space for signature/thumb print of the participant, the principal investigator, a witness and a legally acceptable representative when required.

The ICF with participant/patient information sheet should be approved by the EC before use. The ICF should have the sign or thumb impression of the prospective participant before start of the experiment. If the participant is illiterate, the document should have the signature of a witness, who has seen that the contents of the patient information sheet were adequately explained to the participant. If the participant is a minor or not capable of giving consent, a verbal assent should be taken from him and the consent form should be signed by his legally acceptable representative. If the treating physician of a prospective participant is also the investigator, the informed consent should be taken by any other neutral physician to prevent biased decision of the participant. Informed consent if properly taken protects the rights of prospective participants and thus forms the basis of ethical research work.

VULNERABLE POPULATION

Persons who are relatively or absolutely incapable of protecting their own interests are termed as vulnerable research population. The very poor, illiterate patients, children, individuals with questionable capacity to give consent (including psychiatric patients), prisoners, foetuses, pregnant women, terminally ill patients, students, employees, comatose patients, tribals and the elderly are examples of vulnerable population. Declaration of Helsinki[ 4 ] states that ‘Medical research involving a underprivileged or vulnerable population or community is only justified if the research is responsive to the health needs and priorities of that population or community and if there is a reasonable likelihood that this population or community stands to benefit from the results of the research.’ It is the responsibility of the EC to see whether the inclusion of vulnerable populations in the study is justifiable or the population is just being exploited to generate clinical data. To prevent even minor exploitation the EC should consult the representative of vulnerable population that is to be researched upon while reviewing the protocol.

THERAPEUTIC MISCONCEPTION[ 10 , 11 ]

The therapeutic misconception (TM) is a vexing ethical issue for obtaining valid informed consent. A patient coming to a physician may misinterpret and enrol in a research study thinking it to be routine medical care without understanding the experimental nature of the treatment given. He may misinterpret the information given about the research, such that he believes that aspects of the research will directly benefit him.

Thus, it is important that investigators should make efforts to dispel the TM in order to promote ethical and valid informed consent. ICFs should clarify the salient features of research: The purpose of randomized controlled trials (RCTs), random selection of treatment, masking of treatment, meaning and rationale of placebo, restrictions on treatment flexibility and how treatment decision making differs in RCTs compared with routine medical care. Thus to safeguard the ethical rights of the participants therapeutic misconception needs to be taken care of.

POST-TRIAL ACCESS[ 8 , 12 ]

The concept of post trial access holds special importance for clinical research works in the less developed countries. Pharmaceutical companies from developed countries collect the clinical data for their new and experimental drugs from the population in less developed countries. Most of these drugs would never be used by the communities from where the experimental data are collected and here comes the importance of post trial access for safeguarding the rights of such communities. The Helsinki Declaration of WMA, 2000 states that at the end of the trial, every participant should be assured of access to the best proven prophylactic, diagnostic and therapeutic methods identified by the study. The Declaration of the WMA in 2004 reaffirmed 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 that ethical review committee may consider such arrangements during its review.” Therefore, whenever possible EC should consider such an arrangement in the a priori agreement. Sometimes more than the benefit to the participant, the community may be given benefit in indirect way through improving their living conditions, establishing counselling centres, clinics or schools and giving education on maintaining good health practices.

ETHICS COMMITTEE[ 8 , 13 ]

The first appearance of need of ethics committee (EC) was made in Declaration of Helsinki in 1964, while in India it appeared in 1980 in the ICMR Policy Statement. EC also called as the Institutional Review Board or the Ethics Review Board stands as the bridge between the researcher and the ethical guidelines of the country.

The establishment of EC requires 5-15 members with at least one basic medical scientist (preferably one pharmacologist), one clinician, a legal expert, a social scientist / representative of NGO / philosopher or theologian and a lay person from the community. Every institute, where research is going on should have its own EC with its head preferably from outside the institute.

Individuals carrying out research can approach to independent ECs. The decisions of EC should be taken only after quorum formation with a minimum of five members having at least one basic medical scientist, one clinician and one legal expert or retired judge. The ECs should have independence from political, institutional, professional, and market influences, in their composition, procedures, and decision-making. As there are no laws governing the registration, formation or working of ethics committees in India, each ethics committee should have their own standard operating procedures for proper functioning.

ECs are responsible for carrying out the review of proposed research before the commencement of the research. The basic responsibility of EC is to ensure an independent, competent and timely review of all ethical aspects of the project proposals received in order to safeguard the dignity, rights, safety and well-being of all actual or potential research participants. The scientific design and conduct of the study should also be reviewed at the outset as poor science is poor ethics. The appropriateness of the study design in relation to the objectives of the study, the statistical methodology (including sample size calculation) and the potential for reaching sound conclusions with the smallest number of research participants should be assessed. The EC should also look into matters like informed consent process, qualifications of principal investigator and supporting staff, adequacy of infrastructure and facilities, risk benefit ratio, plans to maintain confidentiality and plans for post trial access and compensations. They also need to ensure that there is regular evaluation of the ongoing studies that have received a positive decision. EC is the most important check point for promoting ethical research in the country.

THE WAY AHEAD

Though we have formulated many ethical guidelines for clinical research, are we adequately following them? The answer is ‘No’. This is because the ethical guidelines in India are just the recommendations and not a law. For proper enforcement of these guidelines should be made a part of the law as has been done in US and other countries of the world. Another issue lies with the training of doctors and research scientists in our institutions. Doctors are specially trained to be good clinicians but are never taught even the fundamentals of ethical clinical research. The post graduate dissertation or the PhD thesis is a precious opportunity to train tomorrow's investigators in the elements of ethical clinical research. Undergraduates should also be involved in simple observational research.

Finally if we can overcome these challenges, we will make India a competent and credible place of ethical clinical research.

ACKNOWLEDGEMENTS

We extend our sincere thanks to Dr. J. C. Sanmukhani, Head, Department of Internal Medicine, Pushpa Mission Hospital, Ujjain, MP (India), for critical review of the manuscript.

Sanmukhani and Tripathi: Ethics in Clinical Research