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

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

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

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

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

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

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

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

2. Stepped wedge CRTs

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

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

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?

3. Platforms trials

Platform trials No guidance & regulation

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

Controlled human infection models (CHIMs)

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)

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.”

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.”

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”.

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

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”

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

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)