# Presentation: 916120

## DO THE CODES APPLY TO MY RESEARCH?

- 45CFR46

## Codes/guidelines: Research Ethics

- The Nuremberg Code
- The Declaration Of Helsinki
- The Belmont Report
- CIOMS/WHO International Ethical Guidelines For Biomedical Research Involving Human  Subjects
- ICH/GCP-International Conference on Harmonization- Good Clinical Practice

**Notes:**
Codes of research ethics which may be familiar to you include:

## U.S. Regulations and Guidelines

- Title 45 US CFR.46
- The Common Rule
- Additional subparts
- NIH Policy and Guidelines on women, ethnic minorities and children
- 21 CFR. 50 AND 56- FDA Regulations
- NIH MPA and FWA

## Codes and guidelines

- Most developed in response to crisis or exposure of research abuse
- Primary focus is on protection of subjects
- Overlap
- Differences in interpretation

## How are guidelines to be used?

- Fundamental principles or rules?
- Universal?
- Absolute or subject to revision and interpretation?
- “Research ethics are broader and deeper than any actual or possible regulations could encompass”

**Notes:**
Many of these, including Nuremberg and Helsinki have significantly affected regulations and practices regarding human experimentation and have continuing legal and ethical influence, .  Helsinki may be the most widely accepted document around the world.
However,  neither has the force of law in the US, nor does the Belmont report which offers broad guidance or the CIOMS guidellines. Nonetheless, adherence to both  is thought to be extremely important, and violations may not  be tolerated and at the very least are heavily criticized.
CIOMS-newer and focus on international research- no force of law.

Required to follow the common rule, and the NIHMPA.  May also need to follow FDA regulations (which differ only in minor ways from the common rule).

## Nuremberg Code 1947

- Nazi doctor’s trial
- In response to ‘experiments’ done with prisoners in concentration camps
- Authors were American
- 10 principles

**Notes:**
Nuremberg code was the concluding decisions of the trials of the Nazi doctors by the Nuremberg Military Tribunal  at which horrific experiments were described. Experiments included putting people in pressure chambers where simulated altitude increased until lungs or other body organs exploded, cutting off limbs to test various surgical techniques, plunged into icy water or stripped and sent out into the cold until they froze to death.
The authors of the Nuremberg code were americans, predominantly an american physician, Andrew Ivy, representing the AMA

10 ethical tenets regarding human experimentation

## Nuremberg Code 1947

- 1. The voluntary consent of the human subject is absolutely essential
- 2. The experiment should be such as to yield fruitful results for the good of society unprocurable by other means... and not random and unnecessary in nature

**Notes:**
In addition to those mentioned on the slide- the other tenets of the code primarily have to do with limiting risk and making sure the study is worth doing and done well. (eg designed and based on animal studies and ...to justirfy the performance of the experiment;  adequate facilities; scientifically qualified persons...also spoke about protecting subjects against even remote possibilties of injury or death etc.

Influenced the formation of many other codes, continues to be regarded by some as the gold standard for all research with competent adults.  Regarded by others as politically naïve and unduly restrictive (esp wrt research with children or with patients)
Nuremberg authors and others believe in the universality of it s principles.  However, Nuremberg was an American creation, charges brought against Nazi physicians by the USA”, drafted primarily by 2 US physicians (Andrew Ivy and  Leo Alexander)
Although drafted in 1946, did not receive much attention until the 1970s. 
During 50s and 60s, investigators and government agencies conducted research that ignored the consent of individuals and put subjects at risk (eg radiation experiments)

## Declaration Of Helsinki 1964, 1975, 1983, 1989, 1996, 2000

- “World Medical Association has prepared the following recommendations as a guide to every physician in biomedical research*...standards as drafted are only a guide to physicians all over the world.”* (1983, 1989, 1996)
- WMA has developed the Declaration... as a *statement of ethical principles to provide guidance to physicians and other participants in medical research involving human subjects*” (2000)

**Notes:**
In 1964, after many years of drafting and revising, the World Medical Association , published the Declaration of Helsinki.  Recognizing that hsr is necessary for medical progress, the D of Helsinki was prepared by physicians as a guide to physicians, and stated clearly that it was only a guide, and should be kept in review in the future.  Has been reviewed and revised many times- including ...
Most recent revisions in 2000 generated a lot of debate.
Fundamental document in the field of ethics in biomedical research -has had considerable influence on the formulation of international , regional and  national legislation and codes of conduct. 

## Declaration Of Helsinki pre-2000 contributions

- Therapeutic versus non-therapeutic research
- Independent review of the ‘Design and performance of each experimental procedure-clearly formulated in a specific protocol”

**Notes:**
Central to Helsinki is a distinction between  research done as part of clinical care (testing new diagnostic or therapeutic methods on patients) and  from “experiments undertaken for other purposes . Medical Research combined with Professional care (Clinical research) versus Non-therapeutic Biomedical Research Involving Human Subjects (Non-clinical biomedical research)

(not in first document, but later )Requires review of a carefully formulated experimental protocol by a ‘specially appointed committee independent of the investigator and sponsor

## Declaration Of Helsinki pre-2000 contributions

- Explicitly allowed informed consent from a legal guardian
- Research not in accordance with Helsinki principles should not be accepted for publication.

**Notes:**
Continues the American perspective from Nuremberg: ‘Informed consent’ of the individual required, although recognizes and accepts proxy consent for those who are not competent to consent for themselves.

Most medical and scientific journals state that they will not accept reports of research not done in accordance with helsinki

(!Protocols with helsinki attached)

## Declaration of Helsinki (pre 2000)

- In any medical study, every patient--including those of the control group, if any--should be assured of the best proven diagnostic and therapeutic method.  This does not exclude the use of inert placebo in studies where no proven diagnostic or therapeutic method exists.

## Declaration of Helsinki (2000)

- The benefits, risks, burdens and effectiveness of a new method should be tested against those of the best current prophylactic, diagnostic, and therapeutic methods.  This does not exclude the use of placebo, or no treatment, in studies where no proven prophylactic, diagnostic, and therapeutic method exists (#29)

## Declaration of Helsinki-clarification 2002

- Reaffirmed its position that in general placebo controls should only used in the absence of existing proven therapy.
- However... may be ethically acceptable, under the following circumstances:
-   - Where for compelling and scientifically sound methodological reasons its use is necessary to determine the efficacy or safety of a prophylactic, diagnostic or therapeutic method; or
-   - Where a prophylactic, diagnostic or therapeutic method is being investigated for a minor condition and the patients who receive placebo will not be subject to any additional risk of serious or irreversible harm.

## Declaration Of Helsinki 2000 additions

- Medical research is only justified if there is a reasonable likelihood that the populations in which research is carried out stand to benefit from the research (#19).
- At the conclusion of the study, every patient entered into the study should be assured of access to the best proven prophylactic, diagnostic, and therapeutic methods identified by the study (#30)

## The Belmont ReportNational Commission for the Protection of Human Subjects of Biomedical and Behavioral Research 1979

- A. Boundaries between research and practice
- B. Ethical principles underlying the conduct of research:
- Respect for persons
- Beneficence
- Justice

**Notes:**
National Research Act 1974 established the National commission for the ....  Which issued the Belmont Report in 1978.  Explicated three principles underlying the ethical conduct of research.

## Respect For Persons

- Individuals should be treated as autonomous agents (capable of self-determination)
- Persons with diminished autonomy deserve protection
**Application:**   Informed consent

**Notes:**

Provided a principle upon which the idea of informed consent was based, ie. Respecting autonomous decisions of informed individuals about whether or not they want to participate in research or continue to particiapte

## Beneficence

- Two general complementary rules:
- Do not harm
- Maximize possible benefits and minimize possible harms
**Application**:  Risk/Benefit assessment

**Notes:**
General prohibition against deliberately harming someone regardless of the possible benefits that might come to others. (transplant ex)
HOWEVER, benefitting and avoiding harm require learning what is beneficial and what is harmful-that is part of what research does.
Trick is making a decision beforehand re: are the potential benefits of doing this research worth the risks, or not? 
What are the benefits? Risks? And comparing them.   May be benefits to society or others rather than the individual participants.
Are there ways of achieving benefits with less risk?
What is the risk of not doing the research?

## Justice

- Fairness in the distribution of the benefits and burdens of research (distributive justice)
**Application:**
- Fair procedures and outcomes in the selection of subjects
- Protection of vulnerable subjects

**Notes:**
Justice conceived of as treating similars similarly and fairness in the distribution  of benefits and burdens of research.   Application to:
At  level of individual and group
Protection of those who were vulnerable so they would not bear burdens disproportionately or burdens they were less able to bear.

## International Ethical Guidelines for Biomedical Research Involving Human Subjects

- Council for International Organizations of Medical Sciences (CIOMS)/WHO
- Proposed guidelines 1982
- Ethical review of epidemiological studies 1991
- International guidelines 1993 and 2002
- Application of the Declaration of Helsinki in developing countries
- Externally sponsored research

**Notes:**
Council of International Organizations of Medical Sciences in collaboration with the World Health Organization published proposedin 1982 with proposed guidelines,  looking at application of principles of Declaration  of Helsinki to circumstances of developing countries, taking into account culture, socioeconomic circumstances, national laws, and executive and administrative arrangements.  Published in 93, currently revision.s being considered

Accepts Belmont principles, but recognizes that they may be “expressed differently and given different moral weight, and their application may lead to different decisions or courses of action”

## International Ethical Guidelines for Biomedical Research Involving Human Subjects (2002)

- 21 Guidelines with extensive commentary
- 2002 additions:
- Ethical justification and scientific validity (#1)
- Benefits and Risks (#8)
- Limitations on risk for those who cannot consent (#9)
- Choice of controls (#11)
- Strengthening capacity (#20)
- Obligation of external sponsors for health care services (#21)

**Notes:**
Guideline 1-4  Informed consent (need, info, investigator resp, and undue influence)
5- children, 6 mental or behavioral disorders, 7=prisoners; 8-underdeveloped communities, 9-ic in epidemiological studies
10- equitable distribution of benefits/burdens
11-pregnant women
12-safeguarding confidentiality
13-right of subjects to compensation for injury
14-responsibilities of ethics committees
15-obligations of host and sponsors in externally sponsored research

## International Ethical Guidelines for Biomedical Research Involving Human Subjects

- Responsiveness to the health needs and priorities of the community
- ‘Reasonable availability’
- Rights of subjects to compensation for research injury

## ICH Harmonised Tripartite Guideline-GCP (1996)

- Objective: “...to provide a unified standard for the European Union, Japan, and the U.S....for mutual acceptance of clinical data by regulatory authorities in those jurisdictions”
- GCP-”...an international ethical and scientific quality standard for designing, conducting, recording, and reporting trials that involve the participation of human subjects”

## ICH-Guideline for Good Clinical Practice

- “Compliance with this standard provides public assurance that the rights, safety, and well-being of trial subjects are protected, consistent with the principles that have their origin in the Declaration of Helsinki, and that the clinical data are credible” (ICH-E6)
- Adopted by US FDA as Good Clinical Practice: Consolidated Guideline (1997)

## 45CFR.46 Protection of Human Subjects

- PHS policy 1966
- National Research Act (1974)
- DHEW regulations (1981)
- The Common rule- 17 Federal agencies, including DHHS (1991)

**Notes:**
1966 PHS policy for the protection of hs- required institutions conducting hsr to provide assurances that the rights and welfare of subjects would be protected in ALL research conducted by that institution.  In response to the National Research Act of 1974 (pl93-348) National Commissions work and recommendations,, the policy was revised and reissued as a regulation Required that all research sponsored by DHEW comply with the regs. (45CFR46) with the force of law in 1981. 1991- based on recommendations of President’s Commission- extended to provide protections for hs in research funded by 16 agencies in the federal govt.  The common federal rule.

## 45CFR.46 Protection of Human Subjects

- Composition and function of a local institutional review board (IRB)
- IRB to assure that risks are minimized, research risks are reasonable in relation to expected benefits, subject selection is equitable, and informed consent will be obtained from each subject.

**Notes:**
Key feature of the regs: review by a local IRB to assure that informed consent will be obtained from each subject (or proxy), that research risks are reasonable in relationship to expected beneftis, and that subjects will be recruited in an equitable fashion.

## 45CFR 46.111 (2)

- “Risks  to subjects are reasonable in relation to anticipated benefits, if any, to subjects, and the importance of the knowledge that may reasonably be expected to result.”

## 45CFR 46

- Subpart B- Fetuses, pregnant women, and human *in vitro* fertilization
- Subpart C- Prisoners as subjects
- Subpart D- Children
- ?future subparts?

**Notes:**
Added additional regulations and protections for vulnerable populations in the years after 1981.

## NIH guidelines on the inclusion of women and minorities

- NIH Reauthorization Act   (1993).
- Women and members of ethnic minority groups are to be included (some exceptions)
- Outreach programs for recruitment
- Sufficient to provide for a valid analysis of differences between groups

**Notes:**
NIH policies added in 1993 that require inclusion of women and ethnic minorities unless a clear and compelling justification for exclusion.

## NIH Policy and Guidelines on the Inclusion of Children as Participants in Research

- “...children must be included in all human subjects research, conducted or supported by the NIH, unless there are scientific and ethical reasons not to include them...” (Effective October 1, 1998)

## Assurance of Compliance with Federal Regulations

- OHRP
- Assurance (FWA)
- Guided by the Belmont Principles

**Notes:**
OPRR- charged with overseeing compliance with the federal regulations requires that institutions file an assurance .  The NIH intramural program therefore has what is called a multiple project assurance,  In the MPA, it is spelled out how we intend to comply

## FDA REGULATIONS

- Primarily found in 21CFR.56  and 21CFR.50
- 21CFR.50 Protection of Human Subjects (informed consent)
- Subpart D on research with children
-  21CFR.56 IRB composition and function
- Some differences from the common rule.

## FDA REGULATIONS

- Part 54-Financial disclosure
- Part 312- IND applications
- Part 314- applications to market a new drug
- ICH-GCP- “represents the agency’s current thinking on good clinical practices”

## So, which rules must I follow?

- 45 CFR.46 –for federally funded research
- +Subparts B, C, D and NIH guidelines if funded by NIH
- +21 CFR. 50 and 56 and ICH/GCP-if testing a new drug, biologic, or device for which ultimately will seek FDA approval
- +Helsinki- if want to publish in a major medical journal

## ALPHABET SOUP

- CIOMS
- MPA
- OHRP
- 45CFR46
- ICH
- OHSR
- IRB

**Notes:**
CIOMS (CAN I OFFER MY SUGGESTIONS?)
MPA- MORE PROTECTIONS AGAIN
OHSR- OR HOW SHOULD RESEARCH 

## Links to more information

- _[http://www.wma.net](http://www.wma.net/)_
- _[http://www.cioms.ch](http://www.cioms.ch/)_
- http://www.hhs.gov/ohrp/
- _[http://206.102.88.10/ohsrsite/](http://206.102.88.10/ohsrsite/)_
- _[http://www.fda.gov/oc/gcp](http://www.fda.gov/oc/gcp)_
- http://www.ich.org