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Ethical Principles in Clinical Research
Suneel Kadekars
LEADS
Goal of clinical research is to generate useful knowledge about human health and illness. People are the means to develop useful knowledge and hence are at risk of exploitation. It should be kept in mind that benefit to the participant is not the purpose of the study.
Ethical requirement for clinical research aim to:
Minimize the possibility of exploitation.
Ensure that rights and welfare of the subjects are respected/protected.
Codes and Guidelines for ethics in clinical research:
1. Nuremberg Code- 1949
2. Declaration of Helsinki- 1964-2000
3. Belmont Report- 1979
4. CIOMS-WHO Guidelines (Council Of International Organization of Medical Sciences)- 1993,2002
5. ICH-GCP Guidelines- 1996
Distinction between Clinical Research and Clinical Practice
According to the Belmont report the 2 differ in the following 3 areas:
Goals:
Clinical research is done to answer useful questions and generate knowledge about human health and illness.
Clinical practice is to take care of the person/patient by the physician.
Methods
Clinical research involves dividing the participants into different groups and those taking part are put into one or other group at random and randomly assigning the treatment.
Clinical practice involves treating the patients with the established treatment for the particular disease to benefit him/her to the maximum with least amount of risk.
Risk s
In clinical research risks or at-least are always present with no compensating medical benefit.
In clinical practice risks are minimal and justified, as the treatment is needed for their own benefit as clinically indicated.
The Belmont Report.
The report was published by US National Commission for Protection of Subjects of Biomedical and Behavioral Research
The report explicitly describes the activities of clinical practice and clinical research and the ethical issues to be followed.
The basic principles involved in conduct of research are given in this report. These are:
Respect for humans:
Respect for the ability of the individual to make their own decisions about joining the clinical research and protection for those who cannot make their own decisions i.e. the process of informed consent should be followed.
Beneficence:
Do not harm
Minimize risks and maximize benefits
Risk-Benefit assessment should be compulsorily done before the research commences
Justice:
More equitable distribution risks, benefits and benefits to the society
US Regulations and guidelines:
It involves the following:
The Common Rule [US45CFR.46]
NIH Policy and Guidelines
FDA Regulations [US21CFR50 and 56]
NIH Assurance
The common rule (Title 45 CFR Part 46) involves guidelines for protection of human subjects and also involves:
Composition and function of local institutional review boards
Criteria for IRB approval of proposals
Requirements regarding informed consent
Subpart B of the common rule spells out the guidelines for protection of fetuses and pregnant women
Subpart C of the common rule spells out the guidelines for protection of prisoners
Subpart D of the common rule spells out the guidelines for protection of children
FDA Regulations:
21CFR.50: Guidelines for Protection of Human Subjects (Informed consent)
21cfr.56 IRB: Guidelines for composition and function
Existing guidance
- Most existing guidelines were developed in response to specific problems
- Need for a systematic, coherent, universally applicable framework
Ethical framework:
7 Principles involved are:
- Valuable scientific question
- Valid scientific methodology
- Fair Subject selection
- Favorable risk-benefit evaluation
- Independent review
- Informed Consent
- Respect for enrolled subjects
Essential Elements of Ethical Research
Valuable Scientific Question:
Is the research question (the proposed trial) one that will generate new knowledge or understanding about human health or illness, i.e. is it a socially, clinically, or scientifically useful question?
This is done to minimize exploitation of the study subjects and responsibly use the available resources
Valid Scientific Methodology:
Is the Study designed in a way (design methodology, statistical power and methods, etc.) that is feasible and will yield valid, reliable, generalizable, and interpretable data?
This is also done to minimize exploitation of the study subjects and responsibly use the available resources
Fair Subject selection:
- The subject should be selected for reasons of science and study purpose, not because of ready availability and vulnerability
- Consistent with scientific goals, selected so to minimize risks and maximize benefits, and fairly distribute research burdens and benefits
Vulnerability
- There is an order of preference in selecting subjects, for instance, adults before children (Belmont Report)
- Exclude vulnerable subjects unless their participation is needed for scientific reasons (CIOMS)
Balance of Risks and Benefits:
- Are risks to subjects necessary and minimized?
- Are risks justified by benefit to individual subjects and/or the importance of the knowledge to society?
- Are benefits maximized?
To follow Non-maleficence and Beneficence
Risks in research
- Defining risks
- Probability and magnitude
- Types of risk
- Uncertainty
- Minimizing risks:
- Limiting risk
Independent Review
This is done to ensure that the study received independent review to ensure the public that investigator biases have been checked, that ethical requirements have been fulfilled, and that subjects will not be exploited.
Minimize conflict of interest & Public Accountability:
To minimize conflict of interest and assuring the public that people are not unnecessarily subjected to risks
Criteria for IRB Review
(45CFR.46.111 and 21CFR56.111)
- Risks involved are minimized.
- Risks are justified by anticipated benefits, if any, to the subjects or the importance of the knowledge to be gained
- Subjects will be selected and treated fairly
- Informed consent is adequate
Informed consent
The subjects should have information of the study that the researchers are planning to do. Adequate opportunity should be given to the subject to consider their decision to take part in the study in the light of their own interest.
The Informed Consent process should be a process of engagement, information exchange, deliberation and decision-making.
The definition and guidelines for informed consent process show up in all the present codes of ethics. It is a universally held principle in clinical research
- The voluntary consent of the human subject is absolutely essential.
- For all biomedical research involving human subjects, the investigator must obtain the informed consent of the prospective subject or authorized representative. (CIOMS guidelines)
- Disclosure of information
- Understanding
- Voluntary decision making
- Authorization
The participant must understand information disclosed and they should authorize the decision voluntarily in a visible way so that it can be documented
Respect for Enrolled Subjects
- Adequate plans should be in place for respecting the rights and welfare of enrolled subjects during and at the end of the study. For example, plans for protecting confidentiality of data, monitoring their welfare, informing them of new information and of study results, respecting their right to withdraw at any time?
- Beneficence and Respect for persons a must.
For a randomized placebo controlled trial for a very serious disease:
Protocol should be prepared in such away that it answers the following questions:
- What is known about treating the disease?
- Are there other available treatments?
- How effective are those treatments and how available are they?
- What are the side effects?
- Is there a need for a new treatment?
- Is there a need for placebo-controlled trial for the new treatment?
- Will the subjects get the right kind of information before the start of the trials to help them make the right decisions
- Are there proper procedures to monitor the welfare of the participants in the course of the trial and to protect their confidentiality?
Decisions about these are dependent on the information available about the available treatments.
Inclusion of children in a study:
Depends on if it's a disease of the children?
Have there been studies in adults
What does the data show in adults, in terms of safety and efficacy
If its only a disease of the children
The risks involved in the procedure of the treatment?
Risks of not getting a treatment?
Benefits for the children involved in the trials
Can the benefits be maximized
Can more ancillary care be given to them
Has the study been adequately reviewed by a independent review body that can understand the clinical research
Summary
To know the effectiveness of a drug, clinical trials are a must. Clinical trials involve humans and hence in order to avoid exploitation of humans in the name of scientific research ethical guidelines are put in place, with codes and guidelines on how to conduct a clinical trial.
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Article submitted Friday, September 12, 2008
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