LEPTOSPIROSIS

HUMAN SUBJECT PROTECTION IN CLINICAL RESEARCH

Human subject:

Under FDA regulations, a “Human Subject” is defined as An individual who is or becomes a participant in research, either as a recipient of the test article or as a control. A participant can be a healthy person or a patient.

Clinical Research:

Any research study that prospectively assigns human participants or groups of humans to one or more health-related interventions to evaluate the effects on health outcomes.

EVOLUTION OF HUMAN SUBJECT PROTECTION:

The protection of human research subjects is crucial. It is critical because we are ethical people, and society has established norms to provide baseline ethical standards in subject protection. Subject protection is also important for society's research aims since study subjects would not volunteer if they are afraid of being harmed.

Infamous research brings regulations. After World War II, human research subjects were more discussed and protected. It was triggered by Nazi doctors' cruel experiments on people exposed in the Nuremberg Military Tribunal. The Nuremberg Code (1947) highlighted important ideas such as “the voluntary consent of the human person is absolutely essential,” which demands the capacity to consent, freedom from compulsion, and comprehension of the risks and benefits involved. It also outlines the principles of risk and harm minimization, a favorable risk/benefit ratio, qualified investigators employing acceptable study methodologies, and the subject's right to withdraw at any time. Some other Infamous research is listed in the table below

Dates	Study	Details
Pre-1946	Nuremberg War Crimes Trials	Twenty-three German doctors were charged with crimes against humanity for "performing medical experiments on concentration camp inmates and other living human subjects, without their consent, in the course of which experiments the defendants committed the murders, brutalities, cruelties, tortures, atrocities, and other inhuman acts."
1932-72	Study of Untreated Syphilis in the Negro Male (Tuskegee Study)	Even after penicillin was available in the 1950s, patients were deceived into thinking they were getting treatment of some kind, and their real diagnosis was not disclosed. The death rate in the infected group was twice that of the control group
1944-74	Radiation Experiments	Of 18 people given plutonium injections, only one had documented informed consent. Over 100 prisoners were given non-therapeutic testicular radiation. About 2000 cancer patients were exposed to total body irradiation to help in atomic weapon development.
1950-61	Thalidomide Studies	Even though FDA did not approve the drug, samples were distributed to US physicians to research' its safety and efficacy on their patients. By 1961 it was shown to be extremely damaging to the fetus.
1956-72	Willowbrook State School for the Retarded Study	Mentally retarded children were deliberately infected with the hepatitis virus.
1960s	Jewish Chronic Disease Hospital	Live cancer cells were injected into 22 senile patients.
1963	Milgram Study	Behavioral study of obedience. Subjects were told to give electric shocks to those who missed the right answers to questions. While the electric shocks were not real, great psychological pain was noted in the subjects who thought they were hurting others, as ordered by the investigator. Subjects had been deceived, so no true consent was possible.
1966	Henry Beecher, NEJM 274:1354-60	Twenty-two published medical studies presented a risk to subjects without their knowledge or approval.

Table.1: Infamous research

HUMAN SUBJECT PROTECTION (HSP) PROGRAM:

It is the administrative and regulatory support program for the Institutional Review Board (IRB), which collaborates with the research community to keep the research program ethical and compliant. The IRBs are independent review boards responsible for ensuring the safety of human research subjects.

The backbone of an HSP program is the fulfillment of nine functions delineated in federal regulations (Department of Health and Human Services, 2009):

1. The risks of research are minimized.

2. Subjects' risks are reasonable in relation to the anticipated benefits;

3. The selection of the subjects is fair.

4. Each participant gives voluntary and informed consent;

5. When appropriate, the research plan monitors the data collected to ensure the subjects' safety.

6. Adequate safeguards are in place to protect subjects' privacy and data confidentiality.

7.  Conflicts of interest are transparent and adequately managed; 

8. Further protections for vulnerable populations, if any, are considered; and 

9. Research employees receive training on human subjects and their protection.

Human research ethics principles (Belmont report)

The first and possibly most crucial step toward research subject protection is to secure appropriate informed consent, which identifies respect, beneficence, and justice for the enrolled research subjects.

1. Respect for a person

2. Beneficence

3. Justice

1. Respect for persons:

Respect for humans contains at least two ethical convictions: Respect for humans contains at least two ethical convictions: 

• first, individuals should be treated as autonomous agents, and 

• secondly, persons with diminished autonomy deserve protection.

(The autonomous person is capable of making decisions about personal goals and acting on those decisions).

2. Beneficence:

Persons are treated ethically not only by respecting their decisions and protecting them from harm but also by securing their well-being. Such treatment falls under beneficence. The term "beneficence" refers to acts of kindness or generosity that go beyond the scope of strict obligation. Beneficience is interpreted as an obligation in this document. As complementary manifestations of helpful activities in this view, two broad norms have been developed:

(1) Do not harm and 

(2) maximize benefits and minimize harms.

3. Justice:

People are treated unfairly when some benefit they are entitled to be denied or when some burden is imposed unfairly. Equal treatment is another way to define justice. This statement, however, needs to be explained. Does everyone have equal rights or do they have unequal rights? Many commentators agree that experience, age, deprivation, competence, merit, and position can sometimes justify differential treatment. Equal treatment of people becomes essential. The distribution of burdens and benefits has several widely accepted formulations. Each formulation mentions a property that should be used to distribute burdens and benefits. 

The formulations are    (1) equal sharing, 

(2) based on individual needs, 

(3) based on individual effort, 

(4) based on societal contribution, and 

(5) based on individual merit.

Applications:

The Belmont Report's last part examines the implementation of these principles and the implications of their requirements when examining three essential aspects of human subjects research:

1. informed consent,

2. a risk/benefit assessment, and 

3. Subject selection.

Elements of an informed consent document:

Eight basic elements:

1. A statement that the study involves research

2. A description of the risks or discomforts

3. A description of the benefits for the subject or others

4. Disclosure of alternatives

5. A statement concerning record confidentiality

6. Description of compensation, if any, and the availability of medical treatment in injury cases

7. Contact for questions concerning research, research-related injuries, or research subjects' rights

8. A statement that all participation is voluntary

Six additional elements when appropriate:

1. Presence of unforeseeable risks

2. Circumstances under which a subject's participation may be terminated

3. Possible additional costs for the subject

4. Consequences of withdrawing

5. Assurance that any recent findings that might affect the subject's decision to participate will be communicated to the subject.

6. The approximate number of subjects involved in the study

ICMR code:

Ethical guidelines are given for biomedical research on human participants by ICMR, New Delhi. The general principles of ICMR

1. Essentiality

2. Voluntariness, informed consent, and community agreements

3. Non-exploitation

4. Privacy and confidentiality

5. Precautions and risk minimization

6. Professional competence

7. Accountability and transparency

8. Maximization of the public interest and distributive justice

9. Institutional agreements

10. Public domain

11. Totality of responsibility

12. Compliance

Conclusion:

A critical component of research is protecting human subjects. We have established regulatory standards to ensure minimum ethical standards when it comes to safeguarding subjects. This is quite important because we are ethical people. It is also essential to protect research subjects to achieve society's research goals since fear of harm will prevent volunteers from volunteering. Subject protection is a shared duty of everyone involved in research. IRBs play an important role because this is why they exist. While there are theoretical and practical controversies, most IRBs are becoming increasingly sophisticated and more able to provide effective oversight of human subject protection, even if it is not an ideal system. We all MUST find a way to promote high-quality research while protecting human subjects, and meticulously following federal regulations.

References:

1. Ross LF, Loup A, Nelson RM, Botkin JR, Kost R, Smith Jr GR, Gehlert S. Nine key functions for a human subjects protection program for community-engaged research: Points to consider. Journal of Empirical Research on Human Research Ethics. 2010 Mar;5(1):33-47.

2. Breault JL. Protecting human research subjects: The past defines the future. Ochsner Journal. 2006 Mar 20;6(1):15-20.

3. https://uaf.edu/ori/responsible-conduct/human-research-subjects/index.php#:~:text=The%20IRB%20must%20conduct%20periodic,and%20compliance%20with%20relevant%20regulations

4. https://www.hhs.gov/ohrp/regulations-and-policy/belmont-report/read-the-belmont-report/index.html#:~:text=Three%20basic%20principles%2C%20among%20those,of%20persons%2C%20beneficence%20and%20justice

5. https://www.rmc.edu/offices/institutional-review-board/irb-review-where-do-i-begin/what-is-human-subject-research#:~:text=Under%20FDA%20regulations%20

Student Name: R. Saraswathi

Student ID: 056/032023

Qualification: Pharm. D

e-Mail ID: saraswathiragiri@gmail.com