The Ethics and Regulations of Clinical Research - UKM Medical ...

Scope of Lecture• Case studies• Definitions• General principles of ethical researchInformed consentIndependent review• CIOMS Guidelines• Summary4Ethics and regulation of clinical trials

Experiments On Prisoners• Nazi experiment on prisoners in concentration camps– Bone, muscle, and nerve transplantation experiments– Freezing experiments– Malaria experiments– Sulfonamide experiments– Sea water experiments– Sterilization experiments– Incendiary bomb experiments• Imperial Japanese Army Unit 731– Similar sort of experiments.Ethics and regulation of clinical trials

Principles of Ethics - Hippocrates• ―Primum non nocere‖• …..Whatever houses I may visit, I will come for thebenefit of the sick, remaining free of all intentionalinjustice, of all mischief and in particular of sexualrelations with both female and male persons, be theyfree or slaves….Ethics and regulation of clinical trials

Tuskegee syphilis experiment• A clinical study conducted between 1932 and 1972 inTuskegee, Alabama, by the U.S. Public HealthService• 400 impoverished black males who had syphilis, wereoffered observation by the researchers• At start of study, there was no therapy but whenpenicillin became available, the drug was withheld sothey could observe the effects of syphilis on thehuman body.Ethics and regulation of clinical trials

Tuskegee syphilis experiment• By the end of the study in 1972, only 74 of thetest subjects were alive.– 28 of the original 399 men had died of syphilis, 100were dead of related complications.– 40 of their wives had been infected,– 19 of their children were born with congenital syphilis.• The study was not shut down until 1972,when its existence was leaked to the press,forcing the researchers to stop in the face ofpublic outcry.Ethics and regulation of clinical trials

Scientific misconduct• Dr. SSR, an anesthesiologist, who practiced at BMedical Center, has admitted that he neverconducted the clinical trials that he wrote about in 21journal articles dating back to at least 1996.– Company P Inc. underwrote most of the trials in whichDr. R found that their painkiller drugs C and L wereeffective against post-operative pain.– Questions were raised about two study abstracts thathe filed. BMC determined that he had not receivedapproval to conduct human research for these studies.– This led to the discovery Dr. R had concocted data for21 studies.Ethics and regulation of clinical trials

And more…• Company P Inc. acquired WL in 2000, a company that sold―N‖, a medication approved by FDA for the treatment ofepileptic fit seizures, and for pain related to shingles.• P pleaded guilty in 2004, to felony charges that it promotedthe drug for uses that were not approved by the FDA.– P is being sued by consumer groups and third-party payers who areseeking $4.9 billion in repayment for fraudulent misrepresentation inpromoting the off-label usage of N.• Company P sought to conceal harmful studies and clinicaltrials involving ―N‖.– MR, the N team leader wrote in an e-mail in 2000 saying, " I think wecan limit the potential downsides of the …. Study by delaying thepublication for as long as possible,".Ethics and regulation of clinical trials

And lastly….• The study's scientific manager, wrote in an email toemployees after P had acquired WL that she hadbeen instructed "that we should take care not topublish anything that damages N marketing success.―• In 2002, AC, then N senior marketing manager,emailed an outside firm that was contracted to writeup the study's results, "We are not interested at all inhaving this paper published because it is negative!!".Ethics and regulation of clinical trials

General Ethical Principles• Research in human subjects should be done inaccordance to 3 basic principles– respect for persons,– respect for autonomy– protection of persons with impaired or diminished autonomy– beneficence– maximize benefits and to minimize harms– justiceInternational Ethical Guidelines for Biomedical Research Involving Human Subjects Prepared by theCouncil for International Organizations of Medical Sciences (CIOMS) in collaboration with the WorldHealth Organization (WHO) CIOMS, Geneva 2002Ethics and regulation of clinical trials

Codes and Regulationsfor Ethical Clinical Research• Nuremberg Code(1947) - Nazi• Belmont Report(1979) - Tuskegee• U.S. Common Rule (1991)• Declaration of Helsinki (2000)• CIOMS (2002)Ethics and regulation of clinical trials

How do you evaluate if a proposedresearch is ethical?

Main Principles of Ethical Clinical Research• Social and clinical value• Scientific validity• Fair Subject selection• Favourable risk-benefit ratio• Independent review• Informed consent• Respect for potential and enrolled subjectsEthics and regulation of clinical trials

1. Social and clinical value• Every research is designed to answer a specificquestion.– should contribute to understanding of health or improveour ways of treating a disease.• Consider how research would benefit– Research participant– Society– Nation etc• For clinical trials, there should be equipoise ie.uncertainty which is the better treatment.Ethics and regulation of clinical trials

2. Scientific validity• A study should be designed in a way that will get anunderstandable answer to the research question.– Is the research question answerable?– Is the research methods are valid, rigorous and feasible?– Is the study is designed with a clear scientific objectiveand using accepted principles, methods, and reliablepractices.• The trial should be of sufficient power to definitively testthe objective• Invalid research is unethical because it is a waste ofresources and exposes people to risk for no purpose.Ethics and regulation of clinical trials

3. Fair subject selection• Who does the study need to include, to answer thequestion it is asking?• The basis for recruiting individuals should be thescientific goals of the study — not vulnerability,privilege, or other factors.– Participant should be chosen in a way that minimizesrisks and enhances benefits to individuals and society.• Groups and individuals who accept the risks andburdens of research should be in a position to enjoyits benefits, and those who may benefit should sharesome of the risks and burdens.Ethics and regulation of clinical trials

Studies on Vulnerable patients• Study done in Nigeria on meningitis• Company X study protocol called for the children to have their• blood tested on arrival and then five days later. If a child was notresponding well to the oral Drug T, Company X was to switchthe treatment to Ceftriaxone.• The patients claim that Company X neglected to analyze theirblood samples and therefore did not determine if a patient had anegative reaction until the manifestation of visible andpermanent injury.• After two weeks, Company X team left Kano and did not returnfor any follow-up evaluations.• Five children who received drug T and six children who werelow-dosed died. Others suffered paralysis, deafness, andblindness. Prior to Kano, only one child had ever been treatedwith T, and then only after all other antibiotics failed; no childhad ever received T orally.MA Pagnattaro The Journal of Legal Studies EducationEthics and regulation of clinical trials

4. Favorable risk-benefit ratio• Clinical research should be done in a mannerconsistent with the standards of clinical practice– This may differ between hospitals, states & countries• There is always uncertainty about the degree of risksand benefits associated with a drug, device, orprocedure• Evaluate1. Risks– Minor or major, short term or long term etc.– Includes physical, psychological, economic, or social– Identify mechanisms to minimize risk eg additionaltests, monitoring etcEthics and regulation of clinical trials

Favorable risk-benefit ratio2. Potential benefits to individuals– Physical, psychological etc.– Consider ONLY benefits from research– Not added services eg payment etc3. If potential benefit outweights risk, proceed4. If risk outweigh benefit to the individual, thenevaluate risk against social benefit of knowledgeEthics and regulation of clinical trials

5. Independent review• To minimize potential conflicts of interest and makesure a study is ethically acceptable, an independentreview panel should review the proposal– Are those conducting the trial sufficiently free of bias?– Is the study doing all it can to protect researchvolunteers?– Has the trial been ethically designed and is the risk–benefit ratio favorable?• Independent evaluation of research projects is donethrough local institutional review boards (IRBs), anddata and safety monitoring boards.Ethics and regulation of clinical trials

Investigator Conflicts of Interest• Professional gain: publications/promotion• Financial gain– Patient finder’s fee to collaborators– Recruitment bonuses• Affiliation with/funding from sponsor for future studies,consultant relationships• Other incentives (e.g., travel, presentations)• Per patient payment system presents conflicts ofinterest inherent in capitalist societyEthics and regulation of clinical trials

Potential Consequences of Investigator COI• Attempting to increase study enrollment• Coercing subjects to enroll and discouragingwithdrawal, treatment alternatives• Enrolling fictitious or ineligible patients• Bias trial toward positive results• Failure to report adverse events• Failure to comply with protocol regimens• Alteration of outcome data• Data fabricationEthics and regulation of clinical trials

Definition of Independent EthicsCommittee (IEC)An independent body (a review board or acommittee, institutional, regional, national, orsupranational), constituted of medical/scientificprofessionals and non-medical/non-scientificmembers, whose responsibility it is to ensurethe protection of the rights, safety and wellbeingof human subjects involved in a trial andto provide public assurance of that protection,by, among other things…Ethics and regulation of clinical trials

Definition of Independent Ethics Committee(IEC), continued……reviewing and approving/providing favourable opinion on,the trial protocol, the suitability of the investigator (s),facilities, and the methods and material to be used inobtaining and documenting informed consent of thetrial subjects28Ethics and regulation of clinical trials

Main Tasks of EC• Review of– Scientific Design and Conduct of the Study– Recruitment of Research Participants– Care and Protection of Research Participants– Protection of Research Participant Confidentiality– Informed Consent Process– Community ConsiderationsEthics and regulation of clinical trials

EC - Composition• Chairperson– preferably be from outside the Institution andnot head of the same Institution to maintainthe independence of the Committee.• Member secretary– who generally belongs to the same institutionEthics and regulation of clinical trials

Non-scientific, non-medical members• Members of the community who are able toevaluate:– Social views and values– Religious issues– Legal implications– Environmental considerations• Age & gender balanced• Must have integrity• Examples:– Clergy, lawyers, environmentalists, pharmacists,dentists, teachers, etc.31Ethics and regulation of clinical trials

PPUKM IEC• Chairperson• 1-2 basic medical scientists. (Lab)• 1-2 clinicians from various departments– 1 permanent member, 1 reserve member• One legal expert or retired judge– Appointed by Bar Council• One philosopher / ethicist / theologian– Ustaz / Fakulti Islam• One lay person from the community• Member-Secretary• Co-opted / Ad-hoc memberEthics and regulation of clinical trials

Essential documents• Trial protocol/amendments• Investigator’s brochure + safety information• Subject information sheet• Consent form & updates• Indemnity/insurance coverage• Publication policy• Investigators’ current CVs• Payment• Subject recruitment procedures/advertisements33Ethics and regulation of clinical trials

EC Approval• Prompt notification in writing by IEC :– Decisions/Opinions– Reasons for its decisions/ opinions– Procedures for appeal of its decisions/opinions• Written approval :Minimum Information Required by ICH - GCP– Date of the meeting– Documents reviewed (versions & dates)– List of members present and quorum completeEthics and regulation of clinical trials

Some comments from MREC MOHEthics and regulation of clinical trials

NHS REC approval• Ethical advice is required for any research involving:– patients and users of the NHS.– individuals identified as potential research participantsbecause of their status as relatives or carers of patientsand users of the NHS, as defined above– access to data, organs or other bodily material of pastand present NHS patients– fetal material and IVF involving NHS patients– the recently dead in NHS premises– the use of, or access to, NHS premises or facilities– NHS staff – recruited as research participants by virtueof their professional role.Governance arrangements for NHSResearch Ethics Committees July 2001Ethics and regulation of clinical trials

Expedited Review• One experienced IRB member (Chairman)• Reported to full IRB• Study with minimal risk of harm, and…– 1. Drugs or devices - no IND– 2. Blood - healthy adults; others– 3. Hair, nails, teeth, excreta, secretions– 4. Non-invasive clinical procedures– 5. Data, documents, records– 6. Voice, video, image recordings– 7. Behavior or characteristicsEthics and regulation of clinical trials

Issues with IEC• Initial review done:– rarely follow-up review and monitoring.• No training in ethics review:– primarily scientific review done.• ECs are not completely independant– do not have any funds / office allocated– Most members UKM staffEthics and regulation of clinical trials

Issues with IEC (2)• Genetic research– Not standardised– Archiving specimens• Timely review– Too many projects– Varying level of projects– SSM– Masters– PhD– International Multicentre trialEthics and regulation of clinical trials

Issues with IEC (3)• Subjects in the study– Incentives?– Cost of treatment of injury due to trial– Advertisements– How will the patient be looked after the end of study– Information sheet and consent form– How much detail?Ethics and regulation of clinical trials

6. Informed consent• For research to be ethical, individuals should maketheir own decision about whether they want toparticipate or continue participating in research.• This is done through a process of informed consent inwhich individuals– (1) are accurately informed of the purpose, methods,risks, benefits, and alternatives to the research,– (2) understand this information and how it relates totheir own clinical situation or interests, and– (3) make a voluntary decision about whether toparticipate.Ethics and regulation of clinical trials

7. Respect for potential and enrolledsubjects• Individuals should be treated with respect from thetime they are approached for possible participation—even if they refuse enrollment in a study—throughouttheir participation and after their participation ends.• This includes:– Respecting their privacy and keeping their privateinformation confidential.– Respecting their right to change their mind, to decidethat the research does not match their interests, and towithdraw without penalty.Ethics and regulation of clinical trials

Respect for potential and enrolled subjects– Informing them of new information that might emerge inthe course of research, which might change theirassessment of the risks and benefits of participating.– Monitoring their welfare and, if they experienceadverse reactions, untoward events, or changes inclinical status, ensuring appropriate treatment and,when necessary, removal from the study.– Informing them about what was learned from theresearch.Ethics and regulation of clinical trials

Do we need clinical trials?The benefit of some therapies areobvious!

Evidence vs Eminence Based Medicine• We need good research to advance scienceThe Star Dec 12 2010Ethics and regulation of clinical trials

Ideas & Trends; Sham Surgery Returns As aResearch Tool• In 1939, to treat angina, an surgeon named Fieschi devised a simpletechnique. Reasoning that increased blood flow to the heart would easehis patients' pain, he made tiny incisions in their chests and tied knotsin two arteries. The results were spectacular. Three quarters of allpatients improved.'' One third were cured.‖• Two decades later, the National Institutes of Health paid a youngcardiologist in Seattle, Dr. LA. Cobb, to conduct a novel test of theFieschi technique. Dr. Cobb operated on 17 patients. Eight had theirarteries tied; the other nine got incisions, nothing more. In 1959, theNEMJ published his findings: the phony operations worked just as wellas the real thing.• That was beginning of the end of the procedure, known as internalmammary artery ligation; within two years, it became a footnote in themedical history texts. It was also the beginning and the end, apparently,for sham surgery in this country. By the early 1970's, an ethicsrevolution had transformed human experiments, and the idea of surgeryas placebo was unthinkable.Ethics and regulation of clinical trials

High dose chemotherapy in Breast CancerPeters WP et al J Clin Oncol 1: 1132-1143. © 1993Ethics and regulation of clinical trials

What we WANT from researchEthics and regulation of clinical trials

What we DON’T wantEthics and regulation of clinical trials

AUDIT FINDINGS – Breast trial• No signed informed consent forms for patientsparticipating in the trial• The trial was not approved by the University's InstitutionalReview Board.• The study shows little evidence of randomization• The study protocol was written nine years after the studywas started, and only after the investigation intoBezwoda's 1999 study was begunEthics and regulation of clinical trials

AUDIT FINDINGS (2)• There were at least three possibletreatment-related deaths althoughthe paper stated there were "notreatment-related deaths"• Records for 29 of the 90 patientscould not be located• There were insufficient records formany patients, and some patientswere treated with regimens andhormonal agents not consistentwith the published informationEthics and regulation of clinical trials

There are many whomistrust Medical ResearchEthics and regulation of clinical trials

Anti-arrythmic drugs• Flicanide an anesthetic agent was found to help incontrolling arrythmias.• Phase II results indicated excellent control ofarrythmias• As arrythmias was thought to be a prime cause ofcardiac death, controlling arrythmias should lead tobetter cardiac outcome.• Flicanide was prescribed in increasing numbers.• A placebo controlled trial was completed and shouldmore cardiac deaths in treatment armEthics and regulation of clinical trials

It is still happening!!Ethics and regulation of clinical trials

Good clinical research is necessary toadvance our knowledge base in medicineEthical research ensures theprotection of subjects whovolunteer to scientific research

In god we trust, ….Everyone else pays cashIn god we trust, … everyone else needsmonitoring

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