150217L - ETHICAL ISSUES IN RESEARCH

Lecture for students at the Faculty of Medicine King Fahad Medical City February 17, 2015 by Professor Omar Hasan Kasule Sr.

 

HISTORICAL BACKGROUND 1

• Modern research ethics triggered by violations committed by the Germans and the Japanese in the Second World War (1939-1945) when they carried out cruel experiments on prisoners of war and other victims without consent.
• The Nurenberg trials of Nazi doctors resulted in 10 principles to be followed in human research, the most important of these being informed and free consent. 
• These principles were updated in the Helsinki declaration of 1964 and its subsequent amendments.
• The Belmont report of 1979 in the US re-stated similar principles.

HISTORICAL BACKGROUND 2

• In 1996 the International Conference on Harmonization published Good Clinical Practice (GCP) guidelines that are followed by clinical researchers world-wide.
• The GCP guidelines are based on the Helsinki declaration and its amendments and have two main objectives: (a) protect the subject/patient (b) ensure credible and accurate data. Patient protection is assured by informed consent as well as independent review and approval of the research protocol.

 

INFORMED CONSENT FOR RESEARCH

• The subject must voluntarily and freely agree to participate in the study after full disclosure of the study details to enable the subject to make an informed decision.
• The information given to the subject must be in writing and must have been approved by the IRB/REC.
• The subject must be given time to ask questions.
• The consent form must be signed by the subject, dated and witnessed. The subject must be given a copy of the consent.

PATIENT SAFETY: BENEFIT VS. RISK CONSIDERATIONS

• The benefits of the study, whether individual or communal, have to be considered against the risk that the study subject faces.
• It is however not possible to envisage all risks in advance so we need systems of ensuring patient safety.
• Patient safety is ensured by monitoring and reporting adverse events. An adverse drug reaction is any bad and unintended response to the investigational product.
• The consideration of benefit vs. risk is undertaken by IRBs/RECs

PRIVACY AND CONFIDENTIALITY

• The study subject has rights to privacy and confidentiality.
• Study data should not be disclosed to any third parties. Even within the study team, data should be disclosed on a need to know basis.
• To protect confidentiality, study documents should be locked up or should be saved on password protected computers.
• The sponsor has no right to access patient notes, only anonymized data from CRFs can be submitted.

RIGHTS AND OBLIGATIONS: INVESTIGATOR, SPONSOR AND PATIENT

• The investigator must be qualified to undertake the study by education, training and experience.
• The main investigator responsibilities are: commanding adequate human and other resources for the study, providing medical care for the study subjects, dealing with the IRB/REC, making sure that all study procedures conform to the protocol, assuring that all study subjects gave free and voluntary informed consent, keeping all records of the study, accounting for the investigational product, providing progress and final reports.
• The main responsibilities of the sponsor provide the investigational product, funding of the study, and follow up and monitoring.
• The patient has the responsibility to comply with study procedures and to report any adverse events promptly.

THE BALANCE BETWEEN CLINICAL CARE AND CLINICAL RESEARCH

• The clinician investigator faces the dilemma of prioritizing between research and patient care that is a difficult task.
• On one hand the investigator may violate the doctor’s duty to treat in pursuit of science. On the other hand lack of good research may lead to poor clinical care.
• This dilemma may manifest as the conflict between the role of the doctor (best interests of the patient) and the role of the researcher (produce knowledge that may not immediately benefit the patient).
• The primary role of the doctor is to treat the patient. Research is a secondary role and should never be allowed to interfere with patient care and patient safety.

REVIEW GOVERNANCE: IRB/REC

• IRB/REC is an independent body whose main function is protecting the safety, welfare and rights of the patient. It reviews and approves the research protocol as well as all trial documents making sure that the investigators are qualified and that the risk-benefit ratio is favourable.
• It also has to monitor the conduct of the study to make sure it adheres to the protocol.

GOOD CLINICAL PRACTICE 1

• The main principles of ICH-GCP focus on patient protection:
• Favourable risk-benefit ratio
• Safety and welfare of the patient come before scientific interests,
• The study must be carried out according to a protocol approved by an ethical committee
• The researchers must be qualified

GOOD CLINICAL PRACTICE 2

• Informed consent must be obtained,
• Patient safety must be assured,
• Patient confidentiality,
• Compensation for study related injury, must be obtained,
• Accurate and reliable, products used must conform to Good Manufacturing Principles (GMP), and systems must exist to ensure quality.

ETHICS OF RESEARCH PUBLICATION

• Researchers tend to submit positive findings for publication and suppress negative ones.
• Authorship and plagiarism

 

CONFLICT OF INTEREST (COI) ISSUES

• COI situations occur when the sponsor of the study influences reported outcomes to be favourable to the new investigational product. The investigator, consciously or unconsciously, produces results favourable to the sponsor and gets rewarded for this either financially or otherwise.
• In some cases the investigator may not be after material rewards but may want promotion and recognition. C
• The best protection against COI is full disclosure of such interests at all levels of the research process: IRB/REC must disclose their interests; authors must disclose their interests when they submit work for publication.

Case 1:

Scenario: The commander of an army brigade asked the brigade physician to undertake research on causes of very high sick leaves. The physician took blood from all soldiers to look for their immune profiles. When some soldiers protested that they were not asked for consent he told him he was following military orders

Hint: voluntary consent

Case 2:

Scenario A physician was recruiting patients for a large multi-center study of myocardial infarction. The informed consent sheet was 10 pages long because there were many procedural details and adverse effects to disclose.  Most of the subjects were bored reading through or listening to the details and were ready to sign because they trusted the physicians doing the study.

Hint: informed consent after full disclosure.

Case 3:

Scenario A new drug that had proved efficacy against leukemia in invitro, animal and phase 2 trials was submitted for human trials. Its risk profile was not well understood from earlier studies. It was to be tested against a placebo. There was no known effective treatment for this disease.

Hint: high potential benefit.

Case 4: 

Scenario A physician in a local hospital agreed to be an investigator of a multi-center international trial sponsored by the pharmaceutical company. He regularly completed and sent CRFs to the sponsor overseas. On one occasion the sponsor questioned the data submitted and insisted that the original patient’s chart be shipped to him for inspection and verification

Hint: hint confidentiality.

Case 5:

Scenario: A multi-center trial of a new medication was carried out at a local hospital; the hospital was among the last to join the 5-year trial. Local results showed that the drug was effective and patients were satisfied. Interim analysis of the data by the sponsor showed the superiority of the new drug. The sponsor also noticed that if the results of the local hospital were eliminated, the sample size of the remaining sites would be adequate. He therefore decided to terminate the study at the hospital prematurely and cut off the supply of the drug.  

Hint: investigator responsibility.