1. Rieke van der Graaf PhD UMC Utrecht, Julius Center
Current international ethical guidance and regulations on use of alternative research designs
Rieke van der Graaf PhD
UMC Utrecht, Julius Center

2. International ethical guidance & regulation
Cluster randomized trials
Stepped wedge trials
Adaptive platforms
CHIMs

3. 1. Cluster randomized trials (CRTs)
Cluster A Cluster B
Intervention A Intervention B

4. Ethical guidance & regulation CRTs
Ottawa statement on the Ethical Design and Conduct of CRTs (2012) & background papers
CIOMS guidelines 2016

6. CIOMS, guideline 21
Same ethical principles apply throughout guidelines
In advance of iniating a CRT (specifically) address:
who is research participant
informed consent feasible and required and from whom?
whether informed consent invalidates results
ethical acceptability of a no-intervention group, in particular in low-resource settings
gatekeeping

7. Differences Ottawa-CIOMS
Justification of CRT – part of gdl 5 (choice of control)
Independent ethics review – guideline as such is directed at RECs
Identifying who is the research participant -similar
Obtaining informed consent - similar
Role of gatekeepers in protecting group interests -similar
Assessing harms & benefits – withholding proven intervention, remainder in guideline 4
Protection of vulnerable participants – part of guideline 15

8. Differences between CIOMS and Ottawa
Status
Ottawa: position statement
International ethical guidance on CRTs
Focus:
Ottawa: focus on ethics of CRTs as such
CIOMS focus on what is different in CRTs

9. Challenges/Open issues on ethics CRTs
Specific guidance needed on CRTs?
Underlying ethical principles are similar
Many open issues in specification process.
Ottawa/CIOMS limited guidance on specific protection in case of CRTs in LMICs

10. 2. Stepped wedge CRTs

11. Ethical guidance & regulation on SW CRTs
Indirect guidance in Ottawa/CIOMS
2. No specific guidance > ethics issues in papers

12. Ethical issues in papers, examples:
not always seen as research > no REC review
Inf cs reported in 50%
Informed consent
Clinical equipoise
Social value

13. Open ethical issues SW CRTs
Ethical guidance needed:
Social value
Is the trial still (implementation) research or is it only implementation?
Clinical equipoise
To what extent is the control group withheld from an established effective intervention?
Informed consent:
Should we be specifically concerned about violation of informed consent?
Deserve special protection in LMICs?

14. 3. Platforms trials

15. Platform trials
No guidance & regulation

17. Deduced ethics issues NEJM paper
“Upfront planning due to more complex designs and real-time decision making” > when should REC be concerned?
“As new drugs are approved for marketing, the standard of care in clinical practice can change“. Redesign possible, advantage compared to standalone trial. However, marketplace changes can negatively affect protocols (= issues for RECs to consider):
“Temporary halt in recruitment
Changes in statistical analysis plan
Ability to attract new therapies when a more effective standard of care becomes the comparator”
“Masterprotocols can last many years, even decades” > what are implications for informed consent

18. Controlled human infection models (CHIMs)

19. Ethical guidance & regulation on CHIMs
WHO: Human Challenge Trials for Vaccine Development: regulatory considerations (2016)
Gordon et al. A framework for Controlled Human Infection Model (CHIM) studies in Malawi: Report of a Wellcome Trust workshop on CHIM in Low Income Countries held in Blantyre, Malawi, (2017)

20. General (ethical) issues in WHO document
Subjected to regulations: “important to consider the regulatory framework in which the human challenge trial may be conducted because, in some countries, challenge stocks are expected to be regulated in the same manner as vaccines and are expected to be studied with authorization in accordance with clinical trial regulations, whether or not an investigational vaccine is to be used in the same clinical investigation protocol.”

21. General (ethical) issues in WHO document
Social/scientific value: “purpose of the study would influence the design, which would in turn influence conclusions and decisions that might be made from the study results by regulators”
LMIC: “It should be noted that human challenge trials have been, and can be, successfully conducted in low- and middle-income settings. The same standards would apply as in more developed countries.”

22. Issues in ethics paragraph WHO document
Minimize risk/maximize benefit. Consider “potential individual risks and benefits, and potential societal benefits and risks, such as release into the environment of a pathogen that might not otherwise be present.”
“Minimize risks to subjects in clinical trials calls for the investigators to give due consideration to whether or not the challenge organism need be pathogenic or not, or to what degree”.

23. Issues in ethics paragraph WHO document
Participants should “truly” be informed about:
risks (which may be greater than minimal)
whether they receive a vaccine that will or will not protect them from the challenge organism, a placebo that will not protect them or only the challenge organism itself.
Complexity of risks and informed consent: not in children/incompetents, except if the challenge organism is a licensed live, attenuated vaccine.
Independent ethics review

25. Gordon et al – ethical considerations
“international standards for consent do not vary, but the means of information provision and of gaining a response are different in many LMIC”
Consultation with communities and with locally experienced researchers > “determine balance between incentivised research (too much perceived benefit) and lack of appropriate compensation for the negative impact on earnings and opportunity cost for participants (too little remuneration)”
“local RECs should be encouraged to develop relationships with CHIM-experienced RECs to seek advice and share experiences”

26. Gordon et al > legal/regulatory issues
Regulatory requirements differ between countries
Legal positions vary substantially and may include the Departments of Agriculture and Environment.
Not always classified as pharmaceutical products > different regulations

28. Conclusions
Limited international guidance & regulation on alternative trial designs
Scarce guidance for LMICs
Open ethical issues
Growing interest in use of alternative methods & designs
Need for international and LMIC-specific ethical guidance on use of alternative research designs
Uptake crucially dependent on international organizations (assist in writing and issuing these documents)