The document discusses the history and ethics of clinical research involving human subjects. It summarizes key codes and guidelines such as the Nuremberg Code, Declaration of Helsinki, and ICH Good Clinical Practice guidelines. It outlines the dual responsibilities of physician-investigators to provide care for individual patients while also conducting research for the benefit of society. The role and 13 responsibilities of the principal investigator are then described in detail according to ICH Good Clinical Practice guidelines, including obtaining informed consent, ensuring safety monitoring, adherence to protocols, and independent ethics review.

1. An Investigator’s Responsibility for
Protection of
Research Subjects:
History, Ethics & Good Clinical
Practice
Susan Kornetsky, MPH
Children’s Hospital, Boston

2. Presenter Disclosure Information
Susan Kornetsky, MPH
An Investigator’s Responsibility for Protection of
Research Subjects: Ethics & Good Clinical
Practice
Financial Disclosure: None
Unlabeled/Unapproved Use Disclosure: None

3. Goals:
Physicians as Investigators.
History: Ethical Codes and
Guidelines.
Good Clinical Practice: The
Role and Responsibility of
the Investigator.

4. Physician Investigators
It is the duty of the physician to promote
and safeguard the health of patients,
including those who are involved in
medical research. The physician's
knowledge and conscience are
dedicated to the fulfillment of this duty.
WMA Declaration of Helsinki

5. Moral Problem in Clinical Research
• The goal of clinical research is generation
of useful knowledge about human health
and illness.
• Benefit to participants is not the purpose of
research (although it can occur).
• People are the means to developing useful
knowledge; and are thus at risk of
exploitation.

6. Physician/Investigators
Have a dual responsibility and a potential
conflict of commitment, if not interest.
• Goal of clinical care is to diagnose, treat, and
cure disease or to reduce pain and suffering in
individual patients - Patient care oriented.
• The goal of clinical research is to systematically
collect information from groups of persons to
produce generalizable findings … in a whole
population –Goal is obtaining data.

7. Research/Therapy Spectrum
Pure Research Pure Therapy
Subjects Patients
Knowledge Cure
Researchers Physicians

8. Achieving Ethical Clarity
To view clinical trials as therapeutic and
as falling under the physician-patient
relationship because some aspects of
research are associated with care
constitutes an ethical distortion that
ought to be scrupulously resisted.
Miller & Rosenstein, NEJM 2003; 348(14):1383-1386

9. Early History Clinical Research Ethics
• Moses Maimonides (1135-1204), Jewish physician,
philosopher taught physicians to help individual
patients, not use them merely as a way of learning
new facts.
• Roger Bacon (1214-1294), English scientist,
philosopher, and Franciscan monk, noted it was
difficult for the physician to conduct experiments on
living humans, "because of the nobility of the material
in which he works; for that body demands that no error
be made in operating upon it.
• Claude Bernard (1865), Walter Reed (1900) (and
others) wrote of need for consent and need for
balancing risk against benefit in research.

10. History:Berlin Code of 1900
…medical interventions for purposes other than
diagnosis, therapy, and immunization… are
absolutely prohibited if:
1. human subject is a minor or not competent;
2. human subject has not given unequivocal
consent;
3. consent is not preceded by proper explanation of
possible adverse consequences of intervention…
Directive to medical directors of all hospitals from the Royal
Prussian Minister of Religious, Educational and Medical Affairs,
Berlin City Council, Dec 1900

11. History: Reich Circular of 1931
 Medical science must advance, but individual
physician has special duty and major responsibility for
life and health of patient-subject;
 Risks proportionate to anticipated benefits;
 Tested in advance on animals;
 Unambiguous consent;
 Special caution if minors;
 Exploitation of social hardship is unethical;
 Academic training should stress special obligations
when conducting research or publishing.
“Regulations on New Therapy and Human Experimentation” from the
Reich Minister of the Interior, Feb 1931

13. NUREMBERG CODE 1947
 Voluntary consent of the subject is
absolutely essential;
 Research must be for benefit of society;
 Research should build on animal
experiments and previous knowledge;
 Procedures must avoid unnecessary
mental and physical suffering, and include
provisions to avoid risk of injury and death;

14. NUREMBERG CODE
(continued)
Degree of risk must not exceed the
importance of the problem;
Adequate facilities and qualified
investigators;
Subject must be free to stop at any time;
Investigator must be prepared to stop if
there is risk of injury, disability or death.

15. Declaration of Helsinki (DoH)
• Adapted from the Nuremberg Code by The World
Medical Association to address the needs of the
biomedical community;
• Initial publication in 1964, revised multiple times
most recently in 2008( living document);
• International standard for the conduct of clinical
research;
• CIOMS Guidelines follow Helsinki quite closely;
• ICH-GCP Guidelines require adherence to “the
principles that have their origin in Helsinki.

16. United States Public Health Service
Syphilis Experiments

17. NEJM, 274:1354-60, June 16, 1966

18. Codes and Guidelines
• Nuremberg Code (1947)
• Belmont Report (USA) (1979)
• World Medical Association Declaration of Helsinki (1964-
2008)
• Council for International Organizations of Medical Sciences
(CIOMS) 1993 updated 2002
• International Conference on Harmonisation of Technical
Requirements for Registration of Pharmaceuticals for Human Use
(ICH), in 1996, Guideline on Good Clinical Practice,E6 (GCP)
• Other International Guidelines
– European Commission: Directive on Implementing Good
Clinical Practice in the Conduct of Clinical Trials (2001, 2005)
– Council of Europe: Additional Protocol to the Convention on
Human Rights and Biomedicine concerning Biomedical
Research (2004)
– World Health Organization (WHO): Operational Guidelines for
Ethics Committees that Review Biomedical Research

19. Ethics of Clinical Research
• Ethical requirements in clinical research
aim to:
– ensure that the rights and welfare of subjects
are respected and protected while they
contribute to the generation of knowledge;
– minimize the possibility of exploitation.

20. Ethical Pillars of Research Codes
• Autonomy
– Individuals have the right to decide for
themselves;
– Protect those with diminished capacity;
– Freely-given voluntary informed consent;
– Informed participants.
• Beneficence
– Maximize benefit;
– Acceptable risk/benefit.
• Non malfeasance
– Avoid/minimize harm.

21. Ethical Pillars of Research Codes
• Fidelity-Duty to care
– Conform to accepted scientific principles,
based on a knowledge of the scientific
literature, other relevant sources of
information, and on adequate laboratory
studies;
– Qualified individuals;
– Provisions for those who may be harmed.
• Truthfulness
– To subjects regarding research;
– To community in publications.

22. Ethical Pillars of Codes
• Confidentiality/Privacy
– Privacy of the subject;
– Confidentiality of the subject information.
• Justice
– Fair sharing of burdens and benefits of
research;
– Those who bear the burden share in the
benefit;
– Access to what is studied.
• Independent Review
– IRB/REC

23. Good Clinical Practices
• Derived from the International Conference on
Harmonization (ICH).
• Based on the Declaration of Helsinki.
• Assures protection of human subjects.
• Assures unified, high standards for designing,
conducting, recording and reporting trials.
• Provides public assurance that the:
– Rights, safety and well-being are protected and
consistent with the Declaration of Helsinki.
• Ensures that clinical trial data and reported
results are:
– Accurate
– Credible

24. E6 - Good Clinical Practice
1. Glossary
2. Principles of ICH GCP
3. The IRB / REC (Research Ethics Committee)
4. The Investigator (13 responsibilities)
5. The Sponsor
6. The Trial Protocol and Amendments
7. The Investigators Brochure
8. Essential Documents

25. Investigator Responsibilities
ICH - E6
4.1 - Investigators qualifications
4.2 - Adequacy of resources
4.3 - Medical care of study participants
4.4 - Communication with the IRB / REC
4.5 - Compliance with the protocol
4.6 - Investigational product care

26. Investigator Responsibilities
ICH - E6
4.7 - Randomization & unblinding
process
4.8 - The informed consent
4.9 - Records and reports
4.10 - Progress reports
4.11 - Safety reporting
4.12 - Stopping or suspending a study
4.13 - Reporting

27. Investigator Qualifications
ICH - E6 4.1
Are you?
Properly qualified to assume the
responsibilities for conduct of the study;
Familiar with the discipline of research, the
drug/device disease management, side effects
and research protocol;
Willing to comply with regulations and be
prepared for audits and monitoring;
Delegation of Responsibility.

28. Adequacy of Resources
ICH - E6 4.2
– Is there an adequate patient population in
order to recruit enough subjects who are
eligible?
– Do you have enough time to complete the
study?
– Do you have enough qualified staff to assist
you?
– Are there adequate facilities to complete the
study safely?

29. Medical Care of Study Participants
ICH- E6 4.3
– Will all medical acts be performed by qualified
physicians?
– Will a qualified MD be responsible for trial-related
medical decisions?
– Is there adequate medical care for adverse
events or other significant medical condition?

30. Communication with the IRB/REC
ICH - E6 4.4
–Written approval must be obtained before
the research begins.
–You will need to provide the IRB/REC:
• a current Investigators Brochure;
• all documents when needed;
• adverse events;
• protocol amendments (do not begin until
approved);
• an annual report of each study (continuing
review).

31. Compliance with the Protocol
ICH - E6 4.5
–Sign off on protocol confirming agreement to
comply.
–Implement deviations to avoid risk but
immediately submit amendments to
IRB/REC, Sponsor and Regulatory
authorities.
–Document deviations when they occur.

32. Investigational Product Oversight
ICH - E6 4.6
–Accountability/Storage/Dispensation:
• Dates, quantities, serial numbers,
expiration date, unique code.
–Returned to sponsor any unused product.
–Only destroy with written instruction from
the sponsor.
–Even when distributed by a pharmacy, PI
remains responsible.

33. Randomization and Unblinding ICH -
E6 4.7
–Randomization procedures
(documented in the protocol) are
followed.
–Only break randomization code in
accordance with the protocol.
–Any unblinding was documented and
sponsor notified in writing.

34. Informed Consent–
ICH - E6 4.8
– Consent forms must be reviewed & approved
by IRB/REC.
– When new information becomes available and
is applicable, subjects need to be advised.
– No coercion or undue influence.
– No waiver of legal rights.
– Fully inform subject (or legally authorized
representative) of all aspects of the trial.
– Language must be understandable.
– Provide ample time to review & ask questions.

35. Informed Consent–
ICH - E6 4.8
• The consent form must be signed and
dated by subject or legal representative;
• If subject cannot read, require a witness to
process;
• Subject should be given a copy.

36. Records and Reports
ICH- E6 4.9
– Accuracy, completeness, legibility & timeliness
of data reported.
– Data gathering forms are consistent with source
documentation (original documents).
– Changes to forms should be dated, initialed &
explained.
– Maintain trial documents.
– Financial aspects noted in contract.
– All records need to be available for monitor,
IRB/REC, or other regulatory authority.

37. Progress Reports
ICH- E6 4.10
– Written report is submitted to the IRB /REC at
least annually but more frequently if IRB/REC
requires.
– A written report is submitted to the IRB /IEC
anytime if the PI notes changes that might
significantly impact the conduct of the trial.

38. Safety Reporting
ICH- E6 4.11
– All serious adverse events must be
immediately reported to the sponsor and
followed up by a written report.
– All adverse events critical to the safety
evaluation are reported to the sponsor per
protocol.
– Report death of any subject while on study.
– Follow IRB/REC requirements.

39. Premature Stopping/Suspending Research
ICH E6 4.12
–Inform subjects if a study is
terminated or suspended.
–Assure appropriate therapy or follow-
up.
–Inform the institution, the sponsor,
IRB/REC in writing if the PI/sponsor
terminates the study.

40. Investigator Responsibilities
ICH - E6 4.13
Final Report(s) by Investigator
– The Investigator is expected to file a written
report at the conclusion of a study.

41. Summary:
Role of Principal Investigator
• Is not a just a title, it implies assumption of
ethical and oversight responsibilities.
• Recognize difference between providing
clinical care and performing research.
• Ensure that the rights and welfare of
subjects are always respected and
protected.
• Consider the IRB/REC a collaborator.

42. Summary
“Ethical lapses are almost never cases
of bad people, doing bad things, for no
good reason. Rather, they are good
people, doing bad things, for good
reasons.”
quoting Marcia Angell, MD
(former) Editor-in-Chief, NEJM