Dr. S. ManikandanAssistant Professor of Pharmacology

JIPMER, Pondicherry.

Research Ethics

1. What is medical ethics?

2. History of biomedical ethics

3. Principles of ethics

4. Informed consent

5. Assessing risk and harm

6. Implications of justice and equality

What is health research?

A biomedical activity that entails systematic collection and analysis of data with the intention to generate new knowledge in which humans are exposed to new interventions.

Practice Vs Research

Medical practice – best known methods / medicines should be used while treating.

Research – Unproven and risky new interventions are used.

Is this justifiable?

By following certain guiding principles that can protect the participants

Medical Ethics

The study of a moral ideals, rules and codes of conduct

that govern behavior of medical professionals. (Grenz & Smith, 2003)

Is there any difference between ethics and morals?

Ethics - Greek word; moral - Latin word for the same idea.

Strictly, ‘ethics’ refers to a set of principles, whereas ‘morals’

refers to individual behavior and often has emotional

component.

History of Biomedical Ethics

Romanian Gypsy in Potable Seawater, Hypothermia & High Altitude Experiments at Dachau

Nazi Experiments on Jews – cont…

15 of 23 guilty, 7 hanged, 5 life sentences

Nuremberg Code (1947) – An international statement on the ethics of medical research on humans

Nuremberg Code (1947) – An international statement on the ethics of medical research on humans

Dr. Leo Alexander with Survivor of Experiments at Ravensbrueck

Defendants and Defense Counsel

Tuskegee Study “Bad Blood” 1932-1972

28 deaths 100 cases of disability 19 cases of congenital Syphilis

Apology 65 years late

Herman Shaw, study participant

Research Ethics Milestones*

Trigger Events Ethics Milestones

*Syphilis Study Begins *The Nazi Experiments *Human Radiation Experiments Nuremberg Code 1947 *The Thalidomide Tragedy

Amendments to the Food, Drug, Cosmetic Act 1962

*Milgram Study Declaration of

Helsinki 1964 Belmont

Report 1979

Principles of Ethics

Autonomy Beneficence & Non-maleficence

Justice & Equality

Autonomy

Ability of a person to make his or her own decision

How is this principle implemented?

By obtaining full written informed consent

Components of Informed Consent

Voluntary participation.

Option to withdraw at any time.

Right to services.

Privacy and confidentiality.

Explanation in lay terms in regional language

Privacy & Confidentiality

Privacy

Right of study participants to decide the extent to which there is access to their personal data.

Confidentiality

Preservation of the participants anonymity when handling data during research and publication.

Informed Consent Form (ICF)

Has two parts.

Part 1 – Participant information sheet.

Part 2 – Signed document.

Adequate time should be provided for the participants to read, think and decide, before signing the document.

Elements of ICF – Part 1

Nature & purpose of study.

Complete procedure – Inc. & Exc. criteria, investigations, interventions, duration, follow up, etc.

Foreseeable risks and benefits.

Storage period of biological samples & data.

Compensation

Contact details of P.I. & Chairman of IEC

Elements of ICF – Part 2

Explains participation is voluntary.

Can withdraw from study at any time without loss of routine patient care.

Voluntarily agree to participate in the study after knowing the risks and benefits

Signatures of participant & witness. (At least one should be a signature)

Waiver of Consent

When participant & researcher does not come into contact.

Research involving not more than minimal risk.

Minimal Risk

Harm or discomfort not greater than that encountered in routine daily life activities of general population or during the performance of routine physical or psychological examination/tests.

Waiver of informed consent should be decided by the ethics committee and NOT by the investigator.

Re-consent

When investigator deviates from protocol.

When a participant regains consciousness from unconscious state or becomes mentally competent.

Informed Consent in Children

Parent / legally accepted representative (LAR) should sign consent.

Assent of child should also be obtained (mandatory for child

> 7 years; advisable for all children).

If child refuses to participate, the consent of parent/LAR becomes invalid.

Buzz 1

A study was conducted to evaluate the efficacy of an analgesic. The investigator approached the head of a remote village and explained all the details of the study. The head of the village instructed that one person from every house should participate in the study.(Everyone in this

village obeys the chief in all matters) The investigator recruited these people and completed the study.

The investigator’s friend feels that he was unethical. The investigator argues that he has explained all the details completely to the village head and hence was right.

Did the investigator violate any principle(s) of ethics?

Buzz 2

Research was undertaken to evaluate the quality of care in family welfare program. Investigators wanted to interview all healthcare workers in PHC. IEC recommended that all information that could lead to identification of specific PHC should be avoided. An investigator noticed a health worker is reusing disposable needles. Without mentioning the name, the investigator reported this to the supervisor. A week later he observed that the health worker is still reusing the needles and nothing has been done. He knows that confidentiality to the clinic and its workers was assured.

Should the principle of confidentiality be strictly upheld in this case?

When can identity be revealed?

When there is a threat to a person’s life (e.g. infant fed with dirty water, child abuse, needle being reused).

Risk to public health (e.g. diagnosis of contagious disease).

In court of law when ordered by a judge.

Buzz 3

The Head of the Department of Pharmacology wanted to conduct a bioavailability study for a new drug. He asked the undergraduate (3rd and 4th semester) students and pharmacology PGs to participate in the study as healthy volunteers. Written informed consent was obtained from all volunteers.

Are there any ethical issues involved in this study?

Vulnerable Population & Diminished Autonomy

People who lack decision making capacity.

Patients of questionable capacity.

People having decision making capability but vulnerable because of culture, disease or inability to speak.

They have a diminished autonomy.

Justified only if the research is responsive to the health needs or priorities of this group and it cannot be carried out in a nonvulnerable group. (Declaration of Helsinki)

Vulnerable Population & Diminished Autonomy

Orphans, prisoners.

Mentally challenged.

Tribals.

Students.

Pregnant women & children.

Beneficence

To act in a way that benefits the patient.

Nonmaleficence

Obligation not to inflict harm intentionally.

In medical practice, the most important tenet (primum non nocere)

Difficult to comply by, as almost all interventions have some adverse effect.

Hence need to weigh the risks and benefits.

Are research benefits and harm fairly distributed?

Research raises concern when the knowledge obtained does not serve participants best interest.

When research coincides with participants interest they are usually unproblemistic.

Research should be in line with national priorities and sensitive to social, cultural and economic context of the region.

How to maximize benefits?

1. Good study design

Improperly designed study cannot yield any benefit.

Rather can harm the participants.

Hence it is unethical to carry out a study with flaws in design.

How to maximize benefits? Cont…

Issues in study design

Less sample size and hence results are invalid.

Inappropriate selection criteria, incomplete blinding.

Subclinical doses of the comparator drug.

End points chosen to favour the test arm.

Buzz 4

A drug company wanted to test a new antiepileptic and contacted a neurologist. It was proposed to administer the new drug to one group of epilepsy patients and placebo to another group of epilepsy patients. The neurologist was hesitant to use placebo, but the company assured him that the primary aim of this study is to establish the safety of new drug and not evaluation of efficacy. Hence comparing with a placebo is more appropriate for such studies. The neurologist agreed to this and undertook the study.

Are there any ethical issues involved in this study?

How to maximize benefits? – cont…

2. Use of placebo

Effectiveness of a new intervention must be tested against the best proven intervention.

Where no proven intervention exists, the use of placebo or no intervention is acceptable. (Declaration of Helsinki)

Placebo or no intervention is justifiable, if it does not lead to additional risk or irreversible harm. (Declaration of Helsinki)

Buzz 5

A drug company from Europe conducted a clinical trial (with three years follow up) for a new antiretroviral drug in Africa. After two years, the interim analysis clearly showed that the new drug is very effective. The drug company stopped the trial, filed application for approval of the new drug in Europe. Later the drug was made available in Europe but not in Africa.

Are there any ethical issues involved in this study?

How to maximize benefits? – cont…

3. Benefits after trial (Post trial access)

At the end of trial every participant should be assured of access to the best proven prophylactic, diagnostic and therapeutic methods identified by the study. (Declaration of Helsinki)

Rationale – The patient has voluntarily taken the risk and has aided in the development of this drug. Hence he should be supplied the drug free of cost. Moreover, harm might be inflicted if we withdraw the drug.

Nonmaleficence

1. Professional Competency

Investigator should be competent enough to do the various procedures involved in research.

Should have good knowledge about research methodology.

Buzz 6

Ayusoft, an Ayurveda company approached a famous cardiologist to conduct a trial for their new ayurvedic drug for angina. Approval was obtained from the Independent Ethics Committee and after this the cardiologist obtained full written informed consent from all the participants and completed the study successfully.

Did the cardiologist violate any principle(s) of ethics?

Incompetency can lead to maleficence

It would neither be ethical nor morally justifiable if an allopathic physician carries out clinical evaluation of a plant product without any concept or training in these systems of medicine (ICMR Guidelines 2006, p. 55).

It is essential that such clinical trials be carried out only when a competent Ayurveda, Siddha or Unani physician is a coinvestigator (ICMR Guidelines 2006, p. 55).

Nonmaleficence – cont…

2. Compensation for participation

Can be paid for the time spent, expenses incurred for participation in research.

When a participant withdraws for any reason, he should be paid a proportionate amount.

This compensation cannot be termed as benefit.

The amount should be approved by the ethics committee.

Nonmaleficence – cont…

3. Compensation for injury

Participants who suffer physical injury during research are entitled for financial and medical assistance.

In a clinical trial conducted for regulatory approval, this is an obligation of the sponsor.

An Arbitration Committee or Appellate Authority could be setup to decide the issue of compensation on a case by case basis.

Participants should not be asked to waive their right to compensation.

Justice and Equality

Treat people fairly.

Fair sharing of burdens and benefits of research.

An injustice occurs when:

Benefits to which a person is entitled are denied without good reason.

Burdens are imposed unduly.

Buzz 7

A drug company conducted a multinational, multicentric, clinical trial to evaluate the efficacy of a new drug for a metabolic disease. For the sites in USA & Europe, the new drug was compared with the drug that is already available in these countries. Placebo was used as a comparator for the sites in Africa. Some investigators in Africa objected to this. The drug company argued that there is no drug available for this disease in Africa and hence the use of placebo in these sites is justified. It also stated that if this trial is done in Africa, this new drug will be introduced and their patients will be benefitted

Did the drug company violate any principle(s) of ethics?

Not publishing your research is unethical

Researchers have ethical obligations with regard to the publication and dissemination of the results of research.

Researchers have a duty to make publicly available the results of their research on human subjects and are accountable for the completeness and accuracy of their reports. (Declaration of Helsinki, 2013).

Summary

Autonomy, beneficence & nonmaleficence, justice and equality are the three tenets of ethics.

Informed consent should be obtained from all patients.

Voluntariness, option to withdraw at any time, right to services, privacy and confidentiality are components of informed consent.

Unethical to carry out a research with flaws in study design.

Incompetency of the researcher can lead to maleficence.

Historical Movies on Ethics to Watch

‘Toons on (Un)Ethical Dilemma

It is an ethical dilemma now. We have solved the problem but have two years of funding through our research grant

Give the new drug to rich patients and placebo to the poor. No sense getting their hopes up. They wouldn’t be able to afford even if it works.

Our scientists say it would be a public health hazard. But our market research shows it would sell like hot cakes. What do you think?