RCT 3

Ethical Issues in Clinical Research

Applicability of RCT methods to all new health interventions

Notes from Page 223 handbookPowerpoint slides on HaDPoP Website

Study Designs in Epidemiology

Observational Studies Experiments

Prevalence surveys Randomised Controlled Trials

Analytical studies

Cohort Studies Case Control studies

Learning Outcomes

Demonstrate an understanding of the ethical issues inherent in experimental research on human subjects

Be able to discuss the historical and contemporary efforts to overcome the ethical problems related to the use of experimental study designs in clinical practice

Recognise the wide applicability of RCT methods in areas other than the testing of new drugs.

Be able to describe how a new drug and a new medical or surgical technique should be evaluated using RCT methods

Expertise in the Medical School

• Jane Hutton - written extensively on ethical aspects of clinical trials, informed consent in clinical research

• Jenny Kurinczuk - member of the Leicestershire Research Ethics Committee

All patients should have treatments which are

properly tested

• Collective ethic

• Not logical because there would be no opportunity to test new interventions

• Many treatments in current use have not been properly evaluated

It is the individual ethic

that patients in clinical trials should come to no harm

with which we are mainly concerned today

The problems with Randomised controlled trials

include:-• Treatment choice is dictated by

chance

• We don’t know how well the new treatment works - are we placing the patients at risk?

• The answer will be of benefit to future not current patients

Patients are being used by researchers to test out

whether the intervention is any good – research

subjects are used as a means not an end in

themselves

Two groups of Ethical issues

ONEResearch should be scientifically

sound conducted to the highest standard and research findings should be made accessible

TWOPatients used as research subjects

should be treated with respect and dignity as human beings

Research should be sound

Robust study design– Control biases

– Make sure the trial is big enough: if sample size is too small error factors will be big – you may miss a real difference

Very important to involve statisticians early

Research findings should be accessible:

• Non-publication of important findings– Drug companies burying results

• Publication of results in a misleading way– Statistical as opposed to clinical significance

• Non-publication of negative results– ‘Publication bias’– This may cause work to be repeated unnecessarily

Research should be conducted to the highest standard

Treating patients with respect and dignity important considerations…..

• Clinical equipoise

• Address patient centred issues

• Approval by Research Ethics Committee

• Full informed consent

• Complete freedom to refuse to take part incurring no penalties

Research Ethics CommitteeApplication form …..

• Investigators; sponsors; payments

• Aims and benefits of project & scientific background in layman’s terms– Is it asking an important question?

• Study design including size and power– Will the question be answered? – Are the procedures acceptable?

• Selection, recruitment & payment of subjects

• Copies of consent form & information sheets for subjects

Research Ethics Committeeconsiders …..

• Details of drugs/devices/investigations

• Potential hazards/side effects & possibility of discomfort or distress

• Ethical considerations

• Information to GP & hospital consultant

• Will patients be compensated if harm caused?

• Arrangements for data protection/storage – confidentiality is protected but data not discarded

Treating patients with respect and dignity important PROBLEMS…..

• Clinical equipoise – some say impossible

• Approval by research ethics committee – not universally obtained

• Full informed consent – difficulties in children/unconscious patients. Some say impossible anyway

• Complete freedom to refuse to take part incurring no penalties -Some new treatments are only accessible in trials

• Interfering with trust in the doctor-patient relationship

Ongoing debate in many areas:

• The lack of inclusion of children and elderly in RCTs affecting licensing of drugs

• The standard to which full informed consent can be achieved

• The lack of availability of treatment except as part of an RCT

• Placebo controlled trials – new drug compared with placebo not standard treatment

Be able to discuss the historical and

contemporary efforts to overcome the ethical

problems related to the use of experimental study designs in clinical practice

(Historical and current aspects of research ethics)

Hippocratic Oath (page 232)• Around 470 BC • Some of its principles held sacred by

doctors to this day:– Treat the sick to best of ability– Preserve patient privacy– Teach the secrets of medicine to the next

generation

• Modern version states:– I will neither treat any patient nor carry out

any research on any human being without the valid informed consent of the subject or the appropriate legal protector thereof………

Nuremburg Code 1947

• Following the atrocities in Nazi concentration camps

• Basis for ethical conduct of human experimentation

• Internationally agreed• 10 standards • ???means of enforcement

Declaration of Helsinki

• Recommendations guiding physicians in biomedical research involving human subjects

• Adopted by World Medical Assembly 1964 and amended several times since

• Supposed to extend and clarify the Nuremburg code but has caused some controversy

Initiatives to disseminate Knowledge of RCTs

• Consort Statement (CONsolidated Standards of Reporting Trials 1996 & 2001)

• Checklist of essential items and a flow diagram to be used in reporting trials

• Used by several eminent journals now

Initiatives to disseminate Knowledge of RCTs

• Register of ongoing Controlled Trials• Major international searchable database

of ongoing RCTs in all areas of healthcare

• Active involvement of major drug company GlaxoSmithKlein

• BUT NOT COMPREHENSIVE• Current Controlled Trials Website:

Info@controlled-trials.com

Research Governance for Health & Social Care

Department of Health 2001

Summarises key responsibilities• Researchers• Research ethics committees• Sponsor• Employing organisation• Care organisation

Research Governance for Health & Social CareDepartment of Health 2001 - Responsibilities

Principle investigator and other researchers

Develop proposals which are ethicalSeek ethics approvalConduct research according to agreed

protocol and legal requirements e.g. about consent

Ensure welfare of participantsFeed back results to participants (Last 2 = ensuring respect and dignity)

Research Governance for Health & Social CareDepartment of Health 2001 - Responsibilities

Research ethics committee Proposed research is ethical Respects dignity, rights, safety and well-being of

participants

SponsorScientific qualityResearch ethics committee approval obtainedArrangements for management and monitoring

Research Governance for Health & Social CareDepartment of Health 2001 - Responsibilities

Employing organisation Promoting a quality research culture Ensuring researchers understand and discharge

responsibilities Ensuring proper management and monitoring

Care organisation/professional Ensure research on patients in their care meets

standards set down in the research governance framework

Ensure ethics approval was obtained Retain responsibility for care

Research Governance for Health & Social CareDepartment of Health 2001

For the first time this document suggests patients have a responsibility to consider whether or not they should become involved in clinical trials and contribute to medical progress

Clinical Ethics Committees

• Discussion of ethical issues arising in clinical practice NOT RESEARCH

e.g. do not resuscitate ordersliving willseuthanasiarationingoperating on Jehovah’s

witnessesconsent to treatment in children

Recognise the wide applicability of RCT

methods in areas other than the testing of new

drugs.

Same steps all new technologies?

• Drugs are subject to specific government regulations – licensing via Committee on Safety of Medicines (UK)

• Other interventions e.g. screening programme; new operation; rehabilitation programme – no legal requirements

We don’t want therapeutically useless procedures

Benefits of random allocation are UNIVERSAL

Whatever the intervention, well-designed and implemented RCTs give the best evidence that differences ARE NOT due to confounding

NOT too difficult IS very importantwe should be doing it

The importance of timing• New treatments deemed too

experimental – unethical to use in RCT• Suddenly widely accepted – unfair to

deprive half the patients by random allocation to control treatment

• Do not miss the window of opportunity• All new treatments should undergo

rigorous evaluation• ECMO page 229

(Extracorporeal Membrane Oxygenation)

NHS Health Technology Assessment Programme

• Commissions research and reviews of Health Technologies

(prevention; rehab; vaccines; pharmaceuticals; devices; medical and surgical procedures)

• Reports to NICE (National Institute for Clinical Excellence) about effectiveness and cost-effectiveness of Health Care interventions

• NICE appraises the reports and issues guidance to the NHS

NHS Health Technology Assessment Programme – cycle

of workAsks for suggestions of technologies

which need assessing

Determines a list of priorities for the year

Asks for proposals from University or NHS departments willing to evaluate the prioritised technologies

Chooses and funds the best proposals

NHS Health Technology Assessment Programme

The Website – lists completed technology assessments

• free download

– Lists activity (reviews/research) in progress– Every year lists areas for submission of research

proposals – competitive process

Problems– Many new technologies – limited resource –

prioritisation process– Delays in assessment– Delays in issuing guidance– Argument about guidance issued– Drug companies have the most money

Be able to describe how a new drug and a new medical or surgical

technique should be evaluated using RCT

methods

New drug

• Initial work on animals & cell cultures• Phase 1 – initial testing on humans Actions/metabolism/major side-effects (few dozen)

• Phase 2 – controlled experimentsEffectiveness and common side-effects (<1000)

• Phase 3 – clinical trialscomparison with standard treatments (thousands)

• Phase 4 – post licensing after releasemonitoring and new uses

New drug

• Licensing depend on results of phase 3 clinical trials

• No option with new drugs• This work is often supported by

money from drug companies

• The shape of an RCT testing drug A against drug B has been described

Screening Programme

• Does Screening for Colorectal cancer improve survival?

• Plan A – biased study:Offer screening to a population – measure

mortality from colorectal cancer in screened versus non-screened individuals

Very likely that more health conscious people present for screening

Screening Programme

• Does Screening for Colorectal cancer improve survival?

• Plan B - RCT:People in the target age range randomly

allocated to receive an invitation for screening or not

Measure mortality from colorectal cancer in those offered screening and compare with those not offered screening

Also measure side-effects of screening

Screening Programme

• Does Screening for Colorectal cancer improve survival?

• Three high quality RCTs of screening for colorectal cancer have been performed.

• Results show that mortality can be reduced by 15%

• But further evaluation is needed…..

Screening Programme

• Should we set up a screening programme?

• National Screening Committee considers• Evidence for benefit

• Quality of screening in non-research setting versus that in trial

• Costs

• Acceptability

• There are 2 pilots underway to answer these questions

RCT Operation

• The UK small aneurysm trial• Lancet 1998 1649-54• Early elective surgery prevents

rupture of abdominal aortic aneurysms but operative mortality is 5-6%

• Risk of rupture for aneurysms smaller than 5cm seems low

RCT Operation• The UK small aneurysm trialQuestion: Does prophylactic open surgery

decrease long-term mortality risk for small aneurysms?

Method:1090 patients aged 60-76 years with

symptomless aaas 4.0-5.5 cm diameterRandomly assigned to elective open surgery

OR ultrasound surveillanceFollow-up for 4.5 yearsPrimary end-point = death

RCT OperationThe UK small aneurysm trial - resultsOverall hazard ratio for all-cause mortality in

the early surgery group compared with the surveillance group was 0.94 (confidence interval 0.75-1.17 p=0.56).

Mortality did not differ between groups at 2, 4 or 6 years

Conclusion: Ultrasonographic surveillance for small aaa is safe, and early surgery does not provide a long-term survival advantage. Our results do not support a policy of open surgical repair for abdominal aortic aneurysm 4.0-5.5cm diameter

RCT Operation

• The UK small aneurysm trial

Problems in clinical research

• Conflict between the way Universities are assessed and NHS priorities

• Political aspects in the NHS - who decides the research priorities

• Pharmaceutical bias where drugs are assessed more than other technologies catch 22 situation cos once assessed there is pressure to introduce them into practice so other technologies lag even further

The Future

• Better understanding of the need to evaluate all Health Care interventions in the best possible way probably by RCTs

• Better participation and understanding and therefore empowerment of patients