The Informed Consent Process for Clinical Trials and Research – Best Practices Across Countries

  • By: Staff Editor
  • Date: September 30, 2011
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Clinical trials are experimental studies on health or delivery of medical care in human beings. Clinical trials follow a pre-defined protocol. Informed consent is the well-educated permission, usually in writing, given by the participants of the trial. Since clinical trials can adversely affect the health, well-being, or even the life of the human participants, there is an ethical necessity for an informed consent. The requirement to obtain voluntary informed consent for a clinical trial is a fundamental principle of research ethics. The patient should be given a chance to weigh all the benefits and risks before deciding.   Article 7 of the International Covenant on Civil and Political Rights (ICCPR), to which US is a party, states that “no one shall be subjected without his free consent to medical or scientific experimentation (United Nations 1996).”

Variations in the process of informed consent across regions and nations
Though all countries agree on the need to have an informed consent, the details generally vary across countries. In countries like UK, Malaysia and Singapore, informed consent in medical procedures requires proof – proof concerning the standard of care to be expected by way of recognized standard of acceptable professional practice - in other words, the risks that a medical professional would usually disclose in the circumstances. But this can at best be interpreted as “sufficient consent” rather than “informed consent”. In the United States, Australia, and Canada, a more patient-centered approach is taken. The patient is informed of any significant risks that he / she may be exposed to. Best practices in informed consent require adaptation to cultural and individual factors concerning the patients. For example, people from Arab and Mediterranean communities give more importance to the person giving the information rather than what is being said. In some states of the U.S, the local Independent Ethics Committee (IEC) must certify the research team before it can conduct clinical trials. It must understand the federal patient privacy law and good clinical practices.
Origin of informed consent and overview
Abuse of human rights during research involving humans, as in the case of Nazis during World War II or research in syphilis on black men by the U. S. Public Health Service in 1972, led to the development of codes and regulations for clinical trials. The six guidelines currently regarded as most influential internationally, are:

- The Nuremberg Code,

- The Helsinki Declaration,

- The Council for International Organizations of Medical Sciences (CIOMS) Guidelines,

- Article 7 of the ICCPR,

- The International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use/Good Clinical Practices (ICH/GCP), and

- The recently revised FDA’s “Good Clinical Practices” (GCP) guidelines for foreign clinical trials

While the details of these codes vary, importance is given to informed consent after furnishing detailed explanations about the nature and risks of the trial to the patient, in a language that the patient easily understands. Participants should be free to decide whether to take part or not, or to withdraw after the trial has begun.
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The six guidelines are explained below:
1.       Nuremberg Code:   This code states that “voluntary consent of the human subject is essential.” The participants should be informed of the “nature, duration, and purpose…the methods and means, all inconveniences and dangers reasonably to be expected…and the effects upon his health or person which may possibly come from this participation.” The participant should then be able to “exercise the free power of choice” to make an “enlightened decision.” It does not provide specific measures of enforcement, and neither the United Nations nor the United States recognizes the code as a binding legal document.
2.       Helsinki Declaration: This code states that consent should “preferably” be in writing. The Declaration also states that every patient — including those in the control group — should be assured of the best proven diagnostic and therapeutic facilities. Critics argue that the code is weak regarding consent obligations, making it secondary to other concerns. Until 2008, the standards in this Declaration governed all clinical trials sponsored by US-based pharma companies outside US.
3.       International Covenant on Civil and Political Rights (ICCPR): In 1966, the concept of informed consent was incorporated by the UN into the ICCPR as a human right. Article 7 of this Covenant states that “no one shall be subjected to medical or scientific experimentation without free consent”. This obligation is legally binding on the 160 plus member-countries. It guarantees rights to individuals to decide freely, whether to join the clinical trials, whether conducted by state or private firms. Under ICCPR, sponsors are liable for failure to obtain informed consent. ICCPR is not self-enforcing and Article 7 of the ICCPR cannot be used as a legal document for action in the US.
4.       The Council for International Organizations of Medical Sciences (CIOMS) Guidelines: In 1982, the World Health Organization (WHO) and CIOMS created the “International Ethical Guidelines for Research Involving Human Subjects.” Amended in 2002, the goal of the Guidelines is to support and help in the implementation of the ethical principles of the Helsinki Declaration in developing countries. The CIOMS Guidelines list 26 separate items of information that must be provided to trial participants before obtaining their informed consent. Participants must also be informed of their right to free treatment for injuries related to research and the right to compensation for accidental injury resulting from the trial. These Guidelines are more specific compared to the Helsinki Declaration and require that the physicians make “every effort” to ensure that informed consent is obtained from the participants. The guidelines also specify five sponsor responsibilities, including: not using intimidation, renewal of consent if there is substantial change in trial conditions, and consent should be in written form. The CIOMS Guidelines too are not legally binding in the US.
5.       International Conference on Harmonization (ICH) Good Clinical Practice (GCP): To address the need for mutually acceptable standards in clinical research, representatives from European Union, United States, Australia, Canada, and the Nordic countries signed the “International Conference on Harmonization- WHO Good Clinical Practice document (ICH/GCP).” ICH/GCP is widely accepted as industry guidance standard for clinical trials involving human subjects.  The document has 13 principles intended to ensure the safety of participants and the accuracy of data in research trials. It refines the informed consent requirements contained in the Declaration. It states that participants should be given “ample time and opportunity to enquire about the details of the trial and to decide whether or not to participate,” and that all the participants’ questions about the trial should be answered. It defines the roles and responsibilities of researchers, independent Ethics Committees (IEC), and sponsors. It is the first document in international guidelines that recognizes sponsors as having obligations in clinical trials.    Since the sponsor can outsource trial-related activities to a contract research organization, most of the obligations are supervisory in nature. It creates stringent requirements for informed consent, but the day-to-day responsibility for compliance is with the investigator. The FDA has adopted these standards as guidance, but has declined to incorporate them into mandatory FDA regulations.
6.       FDA Good Clinical Practice (GCP): New regulations were issued by FDA in April 2008 for clinical trials conducted outside the US -- clinical trial procedures and informed consent processes that must adhere to the FDA’s good clinical practice. Prior to this rule, the FDA required data from outside US to comply with ethical principles furnished in the Helsinki Declaration or the regulations of the country where the research was conducted, whichever gave more protection. The biggest change is that the obligations for the sponsor are now considerable. The sponsors need to furnish documents:

- to show that they adhere to GCP and IEC methods for obtaining consent in non-US regions

- in respect of incentives provided to participants

- in respect of monitoring protocol, and furnishing documentation of IECs decisions

The only situation in which sponsors are not obliged to take consent is the life-threatening situation, since, according to the IEC, obtaining informed consent is not practical. The major criticism of the FDA’s GCP is the “flexibility” to permit countries to choose any one of the different approaches to regulate clinical trials and obtain informed consent.
Current disclosures to be furnished to participants according to 45 CFR (code of regulations), part 46
The following, in a nutshell, are the disclosures to be furnished, according to 45 CFR (code of regulations), part 46:

- Statement that the study is for research

- Details of the purpose of the study

- Details of procedures followed

- Details of future risks and benefits to participants and others

- Alternative courses of treatment

- Confidentiality of the records

- Compensation and notification in the event of injury

- Risks to embryo or fetus

- Costs to the participant

The FDA does not require the sponsors to make these disclosures for trials conducted outside US.
Information to be furnished to participants under 21 CFR 50 and ICH/GCP
The following, in a nutshell, is the information to be furnished to participants in line with the provisions of 21 CFR 50 and ICH/GCP:

- Relevant new information

- Approximate number of participants

- Trial procedures and treatments

- Subject responsibilities

- Payment for participation

- Access to data

- Time period of participation

- Option to discontinue participation without loss of benefits

- Personnel to contact for information in the event of injury

Information to be furnished to participants under CIOMS/WHO
The following, in a nutshell, is the information to be furnished to participants in line with the provisions of 21 CFR 50 and ICH/GCP:

- Right to access participant’s data

- Benefit of the trial to society

- Problems arising out of breach of confidentiality

- Use of genetic information

- Sponsor name, institutional affiliation, and sources of funding

- Incentives for participation

- Extent to which medical services will be provided

- Approval by Ethics Committee

- Compensation in case of death

- Role of investigator’s or patient’s physician




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