Ethical Aspects in Clinical Research

Hippocratic oath

Emphasis on ethics related to “medical practice” and NOT “research ethics”

Historical Events that have Influenced Human Research

First human subject research experiments:

Vaccination trials in the 1700’s.

Edward Jenner (1749-1823) : Smallpox vaccines on his son and neighborhood children.

Johann Jorg (1779-1856) swallowed 17 drugs in various doses to record their properties.

Loius Pasteur : Rabies vaccine in a child whose death was otherwise inevitable

  • Nazi Medical War Crimes – Harmful research on World war II prisoners

Led to development of: Nuremberg code in 1949

 First set of code of International Ethics : 10 points

  • Informed consent is essential.
  • Research should be based on prior animal work.
  • Risks should be justified by the anticipated benefits.
  • Only qualified scientists must conduct research.
  • Physical and mental suffering must be avoided.
  • Freedom to withdraw

Late 1950s : Thalidomide tragedy

Declaration of Helsinki June 1964, Helsinki, Finland

  • Important in history of research ethics as the first effort of medical community to regulate itself
  • Need for Independent Ethics committees recommended
  • Modified and updated from time to time
  • 11 paragraphs – 37 paragraphs
  • 2013 : Post-trial access, Compensation for research injury

The Willowbrook Study  (1956-71)

Mentally defective children were intentionally given a mild form of a hepatitis virus in an attempt to study whether  this could be an effective strategy to confer long lasting immunity after administration of gammaglobulin.

The Jewish Chronic Disease Hospital Study (1963)

Studies were conducted at the Jewish Chronic Disease Hospital in New York City to develop information on the nature of the human transplant rejection process. Chronically ill patients who did not have cancer were injected with live human cancer cells.

The physicians did not inform the patients as to what they were doing. The physicians’ rationalization for their actions was as follows:

(i) they did not want to scare the patients and (ii) they thought the cells would be rejected.

The Tuskegee Syphilis Study  (1932- 1971)

   Study conducted by  U.S. Public Health Service

  • To document the natural progression of  syphilis
  • 600 low-income African-American  males
  • Participants were not informed about their disease
  • Penicillin not administered even after availability

The Belmont Report 1979

The Belmont report identified and discussed the distinction between research and practice, a discussion of the three basic ethical principles, and remarks about the application of these principles.

3  fundamental ethical principles

  1. Respect for persons/ Non-maleficence -first do no harm

Incorporates two ethical convictions

  1. Treat individuals as autonomous human beings
  2. Protect persons with diminished autonomy

Application

  1. Conduct initial and continuing informed consent 
  2. Allow the participant to withdraw from the research
  1. Beneficence

2 complementary expressions of beneficent actions

  1. Do not harm
  2. Maximize possible benefits and minimize possible harms.

Application

  1. Determine whether the research has a favourable risk-benefit ratio
  2. Ensure that the research is scientifically valid
  1. Justice

The requirement to

  • select subjects equitably
  • avoid exploitation of vulnerable populations

Application

  • Determine whether there is a fair subject selection
  • Evaluate the inclusion and exclusion criteria and the methods of recruitment

Basic ethical principles that underlie all human subject research

  • Other international guidelines –Council for International Organizations of Medical Sciences (CIOMS) guidelines 1982,1993,2002
  • ICH GCP guidelines, 1996
    • GCP is an international ethical and scientific quality standard for designing, conducting, recording and reporting clinical trials
    • Compliance with these guidelines provides public assurance that the rights safety and well-being of trial subjects are maintained  and that the clinical trial data are credible.
    • The objective of ICH GCP is to provide a unified standard for EU, Japan and the United States to facilitate the mutual acceptance of clinical data by the regulatory authorities under these jurisdictions

National guidelines-  

  • ICMR – Ethical guidelines for biomedical research on human subjects, 2006 and 2017 – general principleà
    • Essentiality
    • Voluntariness, informed consent
    • Non-exploitation
    • Privacy and confidentiality
    • Precaution and risk minimisation
    • Professional competence
    • Accountability and transparency
    • Institutional arrangements
    • Public domain
  • Roles and responsibilities of –    Institutional Ethics Committees
  • Ethical Issues – Informed consent process, confidentiality, compensation, vulnerable groups
  • Specific principles pertaining to vaccines trial, medical devices, diagnostics, herbal products, genetics, transplantation research
  • Indian GCP Guidelines, CDSCO, New Delhi  2001
  • Revised Schedule Y: January 2013
    • Reporting of SAEs occurring during clinical trials and payment of compensation in case of trial related injury or death
    • Inspection of clinical trial sites by inspectors authorized by CDSCO
    • Mandatory registration of the Ethics Committees

Ensuring ethics in research

  1. Submit it to your Institutional  Ethics Committee (IEC)  for review

     By safeguarding the dignity, rights, safety, and well-being of research participants

  Documents to be submitted to IEC for review

  1. Project submission application form
  2. Summary of protocol
  3. Protocol
  4. Informed consent document in English and Regional languages
  1. Case Record Form
  2. Patient instruction card, identity card, diary, etc.
  3. Questionnaire/s
  4. Investigator Brochure
  5. Insurance policy
  6. Investigator’s undertaking to DCG(I)
  7. Clinical Trial Agreement
  8. Signed and dated brief current CV of the study team members
  1. Subject recruitment procedures: advertisement, notices
  2. Compensation for participation
  3. Compensation for research related injury
  4. Regulatory approvals
    1. DCGI
    1. HMSC approval for foreign collaborative studies
    1. BARC for radioisotope studies
    1. Admin approval of collaborating institutes
  1. Log of delegation of responsibility of the study team members
  2. Current Status of Ongoing Studies conducted by PI
  3. Documentation of CTRI registration/ any other WHO platform registry (whenever applicable)
  4. GCP training certificates of PI and Co-I

Elements of Review

  1. Scientific Design and Conduct of the Study
  2. Risk-benefit Assessment
  3. Recruitment of Research Participants
  4. Care and Protection of Research Participants
  5. Protection of Research Participant Confidentiality
  6. Informed Consent Process

Role of Investigator

Requirements of Investigator-

  • Medically qualified, Competent
  • Experienced
  • Trained in GCP
  • Responsible
  • Infrastructure – Adequate number of patients, qualified staff , facilities
  • Time to conduct study
  • Integrity

 Responsibility

  • Scientific aspects
  • Communication with IEC
  • Patient enrolment
  • Investigational product
  • Medical care of trial subjects
  • Reporting to sponsor
  • Record keeping
  • Documents  (Preparation & Submission) Protocol amendments
  • SAEs, Protocol deviations/violations
  • Undertake informed consent process (or supervise this, if delegated)
  • Ensure staff qualifications and training

Informed consent -Essential Information to be given

  • Statement that the study involves research
  • Purpose of the research
  • Approximate number of subjects
  • Duration of the subject participation
  • Description of procedures to be followed
  • Aspects that are experimental
  • Subject’s responsibilities
  • Treatment options and probability for random assignment
  • Benefits expected from research to the subject or others
  • Risks or discomforts expected
  • Need to take measures to prevent pregnancy
  • Alternative procedures or courses of treatment available
  • Freedom to participate and to withdraw from research
  • Payment for participation
  • Treatment & compensation for research related injury
  • Maintenance of confidentiality of records
  • Identity of the research teams and contact persons
  • Whom to contact for rights of subjects

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