Human Experimentation with Drugs

Law > Medical Jurisprudence > Law and Medicine > Medico-Legal Aspect of Human Experimentation with Drugs

Human experimentation can be broadly defined as anything done to an individual to learn how it will affect him. The main objective of human experimentation with drugs is the acquisition of new scientific knowledge rather than therapy. Human experimentation becomes most critical in the field of medicine, where the relationship between the experimenter and his subject is on a direct individual basis and the experiment may affect the subject’s health or life. Medical experimentation is therefore of vital interest to law and society. The traditional physician regarded his patient primarily as a subject for treatment rather than for experimentation. The traditional doctor-patient relationship gets affected by the pressures of experimentation so that now the physician is also an investigator, and the patient is also a subject.

Clinical Trials:

A clinical trial is a systematic study to generate data for discovering or verifying the clinical and pharmacological profile (including pharmacodynamic and pharmacokinetic) or adverse effects of a new drug on humans. Clinical trial is the only way of establishing the safety and efficacy of any drug before its introduction in the market for human use and is preceded by animal trials where the efficacy and side effects are observed in animals and an estimated drug dose is established.

Requirements of Clinical Trials:

• Fully informed consent of all participants
• Full information to be given about the experiment, including its benefits and risks
• Attentions are to be drawn to possible alternatives
• If clinical trial involves a pregnant woman, extra care and protective measures must be taken

Need of Clinical Trials:

• For finding out bioequivalence data volunteer subjects, generally healthy individuals but occasionally in patients are used.
• For testing a drug usually Serum/plasma samples are obtained at regular intervals and assayed for parent drug concentration.
• But these alone neither feasible nor possible to compare the two products of various means of use for instance if drug is to be consumed by inhaling etc.
• Thus testing will be conducted to clinical trials at several different doses to derive expected results.

Phases of Clinical Trial:

There are 4 phases of biomedical clinical trials:

• Phase I studies usually test new drugs for the first time in a small group of people (20 – 80) to evaluate a safe dosage range and identify side effects.
• Phase II studies test treatments that have been found to be safe in phase I but now need a larger group of human subjects (100 – 300) to monitor for any adverse effects.
• Phase III studies are conducted on larger populations (3000) and in different regions and countries, and are often the step right before a new treatment is approved.
• Phase IV studies take place after country approval and there is a need for further testing in a wide population over a longer timeframe.

Participating in Clinical Trials:

A clinical study is conducted according to a research plan known as the protocol. The protocol is designed to answer specific research questions and safeguard the health of participants. It contains the following information:

• The reason for conducting the study
• Who may participate in the study (the eligibility criteria)
• The number of participants needed
• The schedule of tests, procedures, or drugs and their dosages
• The length of the study
• What information will be gathered about the participants

Concerns with Clinical Trials in India:

• The big problem plaguing clinical research is an over-representation of low-income groups among trial subjects.
• Sometimes Clinical research organizations (CROs) recruit them selectively, exploiting financial need and medical ignorance.
• Because these subjects are well-paid, and get no therapeutic benefit, their only reward from the trial is financial.
• Such deception is a risk not only to volunteer health but also to society, because it can throw off the trial’s results.
• Due to this unethical practices unsafe drugs can make their way into the market and safe drugs can get rejected.
• Selectiveness in recruiting subjects for clinical trials leads to human rights violations and to bad science.

Functions of Ethics Committee in Clinical Trials:

According to the Drugs and Cosmetics rules, 1945. an Ethics Committee is a committee comprising of medical, scientific, non-medical and non-scientific members, whose responsibility is to ensure the protection of the rights, safety and well-being of human subjects involved in a clinical trial and it shall be responsible for reviewing and approving the protocol, the suitability of the investigators, facilities, methods and adequacy of information to be used for obtaining and documenting informed consent of the study subjects and adequacy of confidentiality safeguards. In the case of any serious adverse event occurring to the clinical trial subjects during the clinical trial, the Ethics Committee shall analyze and forward its opinion as per procedure specified under APPENDIX XII of Schedule Y.

If the Ethics Committee fails to comply with any of the conditions of registration, the Licensing Authority may, after giving an opportunity to show cause why such an order should not be passed, by an order in writing stating the reasons therefor, suspend or cancel the registration of the Ethics Committee for such period as considered necessary.

Nuremberg Code:

A major issue at Nuremberg was defining the criteria for ethical human experimentation. Consequently, the Articles of the Nuremberg Tribunal developed as the first formal attempt to create a legal framework governing human experimentation. The Nuremberg Code aimed to protect human subjects from enduring the kind of cruelty and exploitation the prisoners endured at concentration camps. The 10 Articles provide:

1. The voluntary consent of the human subject is absolutely essential. This means that the person involved should have legal capacity to give consent; should be so situated as to be able to exercise free power of choice, without the intervention of any element of force, fraud, deceit, duress, overreaching, or other ulterior form of constraint or coercion; and should have sufficient knowledge and comprehension of the elements of the subject matter involved as to enable him to make an understanding and enlightened decision. This latter element requires that before the acceptance of an affirmative decision by the experimental subject there should be made known to him the nature, duration, and purpose of the experiment; the method and means by which it is to be conducted; all inconveniences and hazards to be expected; and the effects upon his health or person which may possibly come from his participation in the experiment. The duty and responsibility for ascertaining the quality of the consent rests upon each individual who initiates, directs, or engages in the experiment. It is a personal duty and responsibility which may not be delegated to another with impunity.
2. The experiment should be such as to yield fruitful results for the good of society, unprocurable by other methods or means of study, and not random and unnecessary in nature.
3. The experiment should be so designed and based on results of animal experimentation and a knowledge of the natural history of the disease or other problems under study that the anticipated results will justify the performance of the experiment.
4. The experiment should be so conducted as to avoid all unnecessary physical and mental suffering and injury.
5. No experiment should be conducted where there is an a priori reason to believe that death or disabling injury will occur; except, perhaps, in those experiments where the experimental physicians also serve as subjects.
6. The degree of risk to be taken should never exceed that determined by the humanitarian importance of the problem to be solved by the experiment.
7. Proper preparations should be made and adequate facilities provided to protect the experimental subject against even remote possibilities of injury, disability or death.
8. The experiment should be conducted only by scientifically qualified persons. The highest degree of skill and care should be required through all stages of the experiment of those who conduct or engage in the experiment.
9. During the course of the experiment the human subject should be at liberty to bring the experiment to an end if he has reached the physical or mental state where continuation of the experiment seems to him to be impossible.
10. During the course of the experiment the scientist in charge must be prepared to terminate the experiment at any stage, if he has probable cause to believe, in the exercise of the good faith, superior skill, and careful judgment required of him, that a continuation of the experiment is likely to result in injury, disability, or death to the experimental subject.

Helsinki Declaration:

The concepts of Nuremberg were re-evaluated at the meeting of the World Medical Association in Helsinki in Finland, in June of 1964, and were incorporated into the Code of Ethics on Human Experimentation of the World Medical Association. Helsinki declaration of 1964 serves as Bible for all doctors doing biomedical research involving human participants. It is a set of ethical principles relating to human experimentation developed for the medical community by the World Medical Association in 1964, at Helsinki in Finland. It is very important and  best-known policy statement. The first version was adopted in 1964 and has been amended seven times since, most recently at the General Assembly in October 2013. The current (2013) version is the only official one; all previous versions* have been replaced and should not be used or cited except for historical purposes.

The fundamental principle underlying the declaration is respect for individual, his right to self-determination and his right to make an informed decision as regard s to his participation in research, both initially and during the course of research.

Medical research involving human subjects must conform to generally accepted scientific principles and must be based on a thorough knowledge of the scientific literature, other relevant sources of information, and adequate laboratory and animal experimentation. Medical research involving human subjects must be conducted only on individuals with appropriate ethics and scientific education, training and qualifications. Appropriate compensation and treatment for subjects who are harmed as a result of participating in research must be ensured.

Based upon those underlying concepts the final Code (64th WMA General Assembly, Fortaleza, Brazil, October 2013) embodied the following basic principles:

Preamble

1. The World Medical Association (WMA) has developed the Declaration of Helsinki as a statement of ethical principles for medical research involving human subjects, including research on identifiable human material and data. The Declaration is intended to be read as a whole and each of its constituent paragraphs should be applied with consideration of all other relevant paragraphs.
2. Consistent with the mandate of the WMA, the Declaration is addressed primarily to physicians. The WMA encourages others who are involved in medical research involving human subjects to adopt these principles.

General Principles

• The Declaration of Geneva of the WMA binds the physician with the words, “The health of my patient will be my first consideration,” and the International Code of Medical Ethics declares that, “A physician shall act in the patient’s best interest when providing medical care.”
• It is the duty of the physician to promote and safeguard the health, well-being and rights of patients, including those who are involved in medical research. The physician’s knowledge and conscience are dedicated to the fulfilment of this duty.
• Medical progress is based on research that ultimately must include studies involving human subjects.
• The primary purpose of medical research involving human subjects is to understand the causes, development and effects of diseases and improve preventive, diagnostic and therapeutic interventions (methods, procedures and treatments). Even the best proven interventions must be evaluated continually through research for their safety, effectiveness, efficiency, accessibility and quality.
• Medical research is subject to ethical standards that promote and ensure respect for all human subjects and protect their health and rights.
• While the primary purpose of medical research is to generate new knowledge, this goal can never take precedence over the rights and interests of individual research subjects.
• It is the duty of physicians who are involved in medical research to protect the life, health, dignity, integrity, right to self-determination, privacy, and confidentiality of personal information of research subjects. The responsibility for the protection of research subjects must always rest with the physician or other health care professionals and never with the research subjects, even though they have given consent.
• Physicians must consider the ethical, legal and regulatory norms and standards for research involving human subjects in their own countries as well as applicable international norms and standards. No national or international ethical, legal or regulatory requirement should reduce or eliminate any of the protections for research subjects set forth in this Declaration.
• Medical research should be conducted in a manner that minimises possible harm to the environment.
• Medical research involving human subjects must be conducted only by individuals with the appropriate ethics and scientific education, training and qualifications. Research on patients or healthy volunteers requires the supervision of a competent and appropriately qualified physician or other health care professional.
• Groups that are underrepresented in medical research should be provided appropriate access to participation in research.
• Physicians who combine medical research with medical care should involve their patients in research only to the extent that this is justified by its potential preventive, diagnostic or therapeutic value and if the physician has good reason to believe that participation in the research study will not adversely affect the health of the patients who serve as research subjects.
• Appropriate compensation and treatment for subjects who are harmed as a result of participating in research must be ensured.

Risks, Burdens and Benefits

• In medical practice and in medical research, most interventions involve risks and burdens.
• Medical research involving human subjects may only be conducted if the importance of the objective outweighs the risks and burdens to the research subjects.
• All medical research involving human subjects must be preceded by careful assessment of predictable risks and burdens to the individuals and groups involved in the research in comparison with foreseeable benefits to them and to other individuals or groups affected by the condition under investigation. Measures to minimise the risks must be implemented. The risks must be continuously monitored, assessed and documented by the researcher.
• Physicians may not be involved in a research study involving human subjects unless they are confident that the risks have been adequately assessed and can be satisfactorily managed. When the risks are found to outweigh the potential benefits or when there is conclusive proof of definitive outcomes, physicians must assess whether to continue, modify or immediately stop the study.

Vulnerable Groups and Individuals

• Some groups and individuals are particularly vulnerable and may have an increased likelihood of being wronged or of incurring additional harm. All vulnerable groups and individuals should receive specifically considered protection.
• Medical research with a vulnerable group is only justified if the research is responsive to the health needs or priorities of this group and the research cannot be carried out in a non-vulnerable group. In addition, this group should stand to benefit from the knowledge, practices or interventions that result from the research.

Scientific Requirements and Research Protocols

• Medical research involving human subjects must conform to generally accepted scientific principles, be based on a thorough knowledge of the scientific literature, other relevant sources of information, and adequate laboratory and, as appropriate, animal experimentation. The welfare of animals used for research must be respected.
• The design and performance of each research study involving human subjects must be clearly described and justified in a research protocol. The protocol should contain a statement of the ethical considerations involved and should indicate how the principles in this Declaration have been addressed. The protocol should include information regarding funding, sponsors, institutional affiliations, potential conflicts of interest, incentives for subjects and information regarding provisions for treating and/or compensating subjects who are harmed as a consequence of participation in the research study. In clinical trials, the protocol must also describe appropriate arrangements for post-trial provisions.

Research Ethics Committees

• The research protocol must be submitted for consideration, comment, guidance and approval to the concerned research ethics committee before the study begins. This committee must be transparent in its functioning, must be independent of the researcher, the sponsor and any other undue influence and must be duly qualified. It must take into consideration the laws and regulations of the country or countries in which the research is to be performed as well as applicable international norms and standards but these must not be allowed to reduce or eliminate any of the protections for research subjects set forth in this Declaration. The committee must have the right to monitor ongoing studies. The researcher must provide monitoring information to the committee, especially information about any serious adverse events. No amendment to the protocol may be made without consideration and approval by the committee. After the end of the study, the researchers must submit a final report to the committee containing a summary of the study’s findings and conclusions.

Privacy and Confidentiality

• Every precaution must be taken to protect the privacy of research subjects and the confidentiality of their personal information.

Informed Consent

• Participation by individuals capable of giving informed consent as subjects in medical research must be voluntary. Although it may be appropriate to consult family members or community leaders, no individual capable of giving informed consent may be enrolled in a research study unless he or she freely agrees.
• In medical research involving human subjects capable of giving informed consent, each potential subject must be adequately informed of the aims, methods, sources of funding, any possible conflicts of interest, institutional affiliations of the researcher, the anticipated benefits and potential risks of the study and the discomfort it may entail, post-study provisions and any other relevant aspects of the study. The potential subject must be informed of the right to refuse to participate in the study or to withdraw consent to participate at any time without reprisal. Special attention should be given to the specific information needs of individual potential subjects as well as to the methods used to deliver the information. After ensuring that the potential subject has understood the information, the physician or another appropriately qualified individual must then seek the potential subject’s freely-given informed consent, preferably in writing. If the consent cannot be expressed in writing, the non-written consent must be formally documented and witnessed. All medical research subjects should be given the option of being informed about the general outcome and results of the study.
• When seeking informed consent for participation in a research study the physician must be particularly cautious if the potential subject is in a dependent relationship with the physician or may consent under duress. In such situations the informed consent must be sought by an appropriately qualified individual who is completely independent of this relationship.
• For a potential research subject who is incapable of giving informed consent, the physician must seek informed consent from the legally authorised representative. These individuals must not be included in a research study that has no likelihood of benefit for them unless it is intended to promote the health of the group represented by the potential subject, the research cannot instead be performed with persons capable of providing informed consent, and the research entails only minimal risk and minimal burden.
• When a potential research subject who is deemed incapable of giving informed consent is able to give assent to decisions about participation in research, the physician must seek that assent in addition to the consent of the legally authorised representative. The potential subject’s dissent should be respected.
• Research involving subjects who are physically or mentally incapable of giving consent, for example, unconscious patients, may be done only if the physical or mental condition that prevents giving informed consent is a necessary characteristic of the research  group. In such circumstances the physician must seek informed consent from the legally authorised representative. If no such representative is available and if the research cannot be delayed, the study may proceed without informed consent provided that the specific reasons for involving subjects with a condition that renders them unable to give informed consent have been stated in the research protocol and the study has been approved by a research ethics committee. Consent to remain in the research must be obtained as soon as possible from the subject or a legally authorised representative.
• The physician must fully inform the patient which aspects of their care are related to the research. The refusal of a patient to participate in a study or the patient’s decision to withdraw from the study must never adversely affect the patient-physician relationship.
• For medical research using identifiable human material or data, such as research on material or data contained in biobanks or similar repositories, physicians must seek informed consent for its collection, storage and/or reuse. There may be exceptional situations where consent would be impossible or impracticable to obtain for such research. In such situations the research may be done only after consideration and approval of a research ethics committee.

Use of Placebo

• The benefits, risks, burdens and effectiveness of a new intervention must be tested against those of the best proven intervention(s), except in the following circumstances: Where no proven intervention exists, the use of placebo, or no intervention, is acceptable; or Where for compelling and scientifically sound methodological reasons the use of any intervention less effective than the best proven one, the use of placebo, or no intervention is necessary to determine the efficacy or safety of an intervention and the patients who receive any intervention less effective than the best proven one, placebo, or no intervention will not be subject to additional risks of serious or irreversible harm as a result of not receiving the best proven intervention. Extreme care must be taken to avoid abuse of this option.

Post-Trial Provisions

• In advance of a clinical trial, sponsors, researchers and host country governments should make provisions for post-trial access for all participants who still need an intervention identified as beneficial in the trial. This information must also be disclosed to participants during the informed consent process.

Research Registration and Publication and Dissemination of Results

• Every research study involving human subjects must be registered in a publicly accessible database before recruitment of the first subject.
• Researchers, authors, sponsors, editors and publishers all have ethical obligations with regard to the publication and dissemination of the results of research. Researchers have a duty to make publicly available the results of their research on human subjects and are accountable for the completeness and accuracy of their reports. All parties should adhere to accepted guidelines for ethical reporting. Negative and inconclusive as well as positive results must be published or otherwise made publicly available. Sources of funding, institutional affiliations and conflicts of interest must be declared in the publication. Reports of research not in accordance with the principles of this Declaration should not be accepted for publication.

Unproven Interventions in Clinical Practice

• In the treatment of an individual patient, where proven interventions do not exist or other known interventions have been ineffective, the physician, after seeking expert advice, with informed consent from the patient or a legally authorized representative, may use an unproven intervention if in the physician’s judgement it offers hope of saving life, re-establishing health or alleviating suffering. This intervention should subsequently be made the object of research, designed to evaluate its safety and efficacy. In all cases, new information must be recorded and, where appropriate, made publicly available.

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