Ethical Considerations In Clinical Trials

Ethical Considerations in Clinical Trials Krathish Bopanna PhD DSc. Senior Vice President, Manipal Acunova Ltd, India [email_address] Visit: www.acunovalife.com 22 nd December, 2007 59 th Indian Pharmaceutical Congress Varanasi, India Ethics is not a natural science, it’s a creation of human mind!

Overview Background Development and practice of guidelines & principles Ethical considerations during various parts of the study Planning and conceptualization of the Study Conduct of study Analysis of study data Publication of report Trial is completed Justice & Conclusion Ethics is a subject that deals with values, beliefs and opinions

Science How science has changed our lives? Discovery of DNA

Medicine When cancer plagued mankind, medicine of hope!

Health Research Its not immutable! Being open to the influence of time, place and situation; MAY BENEFIT OR CAUSE HARM

Health & Business No man cared less for the profits of the profession, or more for the honour of it!

The Demands of Society Are we meeting expectations with the advances in medicine?

Ethics of clinical trials E = E mpowering the subject for the consent T = T ransparent processes to follow H = H umane thinking in the clinical trial I = I nternationally accepted data by following ethics C = C onsult the guidance regularly A = A uthenticity of trial objectives L = L egal representation How can our society promote clinical research?

What should we expect from a Good Clinical Practice framework for clinical trials? vis-à-vis India? vis-à-vis the United States & Europe? globally? What does GCP mean? to me ?

Ethical Issues in Biomedical Research The use of control arms (placebo) ‘ Standard of care’ Informed consent process Community consultation Individual and community access to research The role & responsibility of ethics committees (ECs) Compensation for trial injury Counselling Patient/Participant Confidentiality and Privacy Locating phase I, II, and III trials Falsification, Alteration of data, plagiarism, favourtism

Ethical Issues in Biomedical Research (cont.) Medical treatment during the course of research Product availability Sponsorship Liability & Insurance Tissues Stem Cell Research Gene Transfer Data Protection Monitoring (DSMBs) Data Ownership Proprietary Information/Knowledge Botanical/Traditional Medicines Respect for human dignity includes beneficence / non-maleficence, utility, justice

M.H. Pappworth in 1967 “ No physician is justified in placing science or the public welfare first and his obligation to the individual, who is his patient or subject, second. No doctor, however great his capacity or original his ideas, has the right to choose martyrs for science or for the general good.” ‘ My proposal is that researchers and reviewers should be expected to contemplate and sign a statement that says: ‘‘I would not hesitate to submit myself, or members of my own family, or anybody for whom I have any respect or affection, if in circumstances identical to those of the intended subjects’’’. Pappworth M.H. Human Guinea Pigs; Boston: Beacon Press, 1967; pg. 27

Codes of Ethics, Guidelines & Regulations 1000 BC : Caraka Samhita to 1-2 AD 1947 : Nuremberg Code 1956 : Code of Medical Ethics, MCI 1964 : Helsinki Declaration 1979 : Belmont Report (USA) 1980 : Policy Statement on Ethical Considerations involved in research on Human Subjects 1982/1992 : Proposed International Guidelines (WHO/CIOMS) 1986 : EPA Act for r-DNA products 1997 : Guidelines for Exchange of Human Biological Material for Biomedical Research Purposes 2000 : Delhi Medical Council Regulations 2000 : Revised ICMR Ethical guidelines 2001 : Indian GCP Guidelines 2004 : ART Guidelines What is the minimum that I can do?

EU Directive 2001/20/EC Good clinical practice is a set of internationally recognised ethical and scientific quality requirements which must be observed for designing, conducting, recording and reporting clinical trials that involve the participation of human subjects. Compliance with this good practice provides assurance that the rights, safety and well-being of trial subjects are protected, and that the results of the clinical trials are credible. Article 1, Scope

Good Clinical Practice A set of responsibilities Shared responsibilities Individual responsibilities ‘’ Makes all parties to a study responsible for patient safety and study quality

ICH GCP ‘ The objective of this ICH GCP guidance is to provide a unified standard for the European Union (EU), Japan, and the United States to facilitate the mutual acceptance of clinical data by the regulatory authorities in these jurisdictions.’

Dimensions of GCP General Frameworks WHO GCP ICH GCP Regional/Applied Frameworks EU GCP US CFR National/Applied GCP Guidelines India, China, Russia, Singapore, Malaysia, Indonesia, South America, South Africa, Turkey GCP is universally accepted as the standard for accepting data across borders.

India In letter and spirit to follow GCP; covers prophylactic, treatment, diagnostic and epidemiology

Clinical Development Was there really a need for this CT? Literature available? Scientific advice sought? Studies in sub-groups? Are sample size and statistical power adequate to show an effect? Were calculations based on Potential previous experience Validated end points Clinically relevant differences Were patient’s chances of receiving an active medicines acceptable? Treatment ratio balanced towards Equal chances Sample size Severity of disease What type of patients should have been entered? Volunteers or patients In/Out patients Vulnerable groups Relevance of standard of care in design of the study! Freedman. Volume 317:141-145 July 16, 1987 Number 3

Planning of Study Age: Younger or older populations or dementia patients Gender: Women of childbearing potential Present clinical status: Unstable / emotional patients History of other diseases: anticipated benefits outweigh the risks associated with the trial . Wash out period of non-trial medicinal products: duration of wash out with drug and its risks Occupation: ambulatory patients involved in heavy machinery work Trial involving human not fulfilling simple scientific demand is unethical

Conduct of the Study Violations Minor/Major Extent of the violation Risks for the patient due to violation in trial Compliance Checking signed ICF for signature of patient and the investigator Invasion of patient privacy Compliance to the local and regulatory guidance Discontinuation from the Clinical Trial Obligation to take care of the patient until recovery or improvement to prior state Risk of rechallenging Early termination Investigator’s decision Justifiable reasons Getting into details

Analysis and Reporting of Trial Results Power of the study Sufficient sample size critical to have power of the study Statistical significance vs clinical significance Communication of the study for validity, timeliness and accessibility of new knowledge for patients, physicians and regulatory Safety of the study Withholding data on ADRs highlights the threat of unethical reporting of research results to public safety and physician’s trust in research Just because it is recorded doesn’t mean its done!

Publication of trial results Over interpretation of “significant” findings in small trials Selective reporting based on p values Selective reporting of outcomes in the abstracts Subgroup analysis done without interaction tests Negative or detrimental studies not published Putting undue stress on results from subgroup analysis Inappropriate subgroup analysis Selective reporting of (1) subgroups, (2) outcomes, (3) time points Selective reporting of positive results or omission of adverse events data Failure to report results or long delays in reporting Post hoc analysis not admitted Giving incomplete information about analysis with no significant results Analysis conducted by the sponsor of the trial. CONSORT guidelines

When trial is completed? What responsibilities are owed to the research community? Encourage access to the benefits from findings Train researchers and care providers in the community Ensure privacy of participants and researchers

Justice Vulnerability : In research ethics, the principle of distributive justice forbids research risks and burdens being borne disproportionately by vulnerable groups within society ; Benefits: Privileged in society cannot disproportionately reap research benefits Distribution : Research may be impossible to achieve in settings where equality, fairness, and the distribution of social good and harm are routinely abrogated Potential Misuse : Where permission is granted by the very people who are oppressing the potential participants, researchers must be aware of potential misuse of findings . Permission : there may be instances in which participation would be in the best interests of the minority group, but government officials deny access Beyrer C, Kass NE Human rights, politics, & reviews of research ethics. Lancet 2002 Jul 20;360(9328):246-51.

Conclusion Research entails risk Should we permit high risk research? (e.g. Gelsinger, Roche) Respect for persons + Beneficence = Paternalism or Disclosure of Risk subject as individual overrides all scientific hypothesis Controlled environment to practice environment Homogeneity of the data Pursuit of knowledge vs fame/fortune

Ethical Considerations In Clinical Trials

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