1. "Medical Care in Clinical Trials-what does it mean?":
Dr Nakwagala Frederick Nelson
Senior Consultant Physician
08 Dec 2017

2. Key outputs
Provide a moral foundation for respect of research participants involved in clinical trials. 
Provide an ethical framework for rational use of placebos.
Clarify on the roles and responsibilities of researchers, sponsors, Institutions and regulators in clinical trials.
Share common observations in this regard relevant to Ugandan contexts

3. Path of Scientific development
Concept development
Basic Scientific studies = Lab
Preclinical Studies = Animals
Clinical Trials
Phase 1
Phase 2
Phase 3
Phase 4
Investigating old drugs for new indications

4. Categorical moral imperatives
Never to use humans as mere means to an end and to consider them as an end in themselves.
To leave research participants and their communities better off after the research is over.
The humanitarian importance of the research project should always override the interests of science.
To avoid torture, exploitation, discrimination, corruption, abuse, injustice and unnecessary exposure to risk or harm in the name of research.
To respect the rights and deliver welfare of research participants.

5. Medical care in clinical Trials
Involves provision of:
General medical care for examination, investigations and treatment of medical/surgical conditions
Management of research related injury injuries.
Referral
Management of adverse events and the costs thereof.
Compensation for resultant harm from research injury.
Treatment after studies are over
Follow up of chronic conditions or slow onset complications.
Care of unrelated conditions - Ancillary care

6. Controversial studies
PMTCT Trials in Uganda
DART trials here and Zimbabwe
The PROMISE Trial
The COAST Trial
TB prophylaxis studies

7. Responsiveness of research to community needs- CIOMS guidelines
Before instituting a plan to undertake research in a population or community in low resource settings, the sponsor, researchers, and relevant public health authority must ensure that the research is responsive to the health needs or priorities of the communities or populations where the research will be conducted.

8. Responsiveness of research to community needs- CIOMS guidelines
Sponsors, and researchers must also:
Make every effort, in cooperation with government and other relevant stakeholders, to make available as soon as possible any intervention or product developed, and knowledge generated, for the population or community in which the research is carried out,
To assist in building local research capacity.
Additional benefits such as investments in the local health infrastructure should be provided to the population or community;
consult with and engage communities in making plans for any intervention or product developed available, including the responsibilities of all relevant stakeholders.

9. UNCST guidance on Post Trial Obligations
Once the intervention being studied has been demonstrated to be superior, the sponsor(s) shall promptly offer to research participants in the control arm the intervention free of charge. However, sponsors are encouraged but not obliged to provide lifelong care and treatment for chronic and relapsing illnesses.

10. UNCST CARE PACKAGE
A care package for research participants should be stated before initiation of a research project. Care and treatment for research participants should be provided with the ideal aim of providing the best proven intervention and, at the least, should be in accordance with the current Uganda Clinical Guidelines and other national health guidelines and standards.
In the absence of these national health standards, the researcher, REC, sponsor, UNCST in collaboration with UNHRO and other regulatory bodies shall agree on the care
and treatment package to be provided.

11. UNCST CARE PACKAGE
The duration and sustainability of care and treatment for the research participant after the study should be negotiated before initiation of the study.
Sponsors are encouraged, but not obliged, to provide care for concurrent illnesses not associated with the research project.
However, researchers and sponsors are obliged to manage serious adverse events related to the study (including paying for
associated costs thereof) until they are fully resolved or stabilized.
Researchers should provide relevant follow up procedures for
research participants for an appropriate period of time after the trial.

12. CIOMS PROVISIONS ON PLACEBO
As a general rule, the research ethics committee must ensure that research participants in the control group of a trial of a diagnostic, therapeutic, or preventive intervention receive an established effective intervention.
Placebo may be used as a comparator when there is no established effective intervention for the condition under study, or when placebo is added on to an established effective intervention.
When there is an established effective intervention, placebo may be used as a comparator without providing the established effective intervention to participants only if:
there are compelling scientific reasons for using placebo; and
delaying or withholding the established effective intervention will result in no more than a minor increase above minimal risk to the participant and risks are minimized,
including through the use of effective mitigation procedures.

13. UNCST ON PLACEBO
In certain circumstances, and as may be advised by a REC, a placebo or no intervention may be used in the control group where:
A. Based on knowledge that is currently available, a proven intervention does not exist.
B. Withholding a proven intervention would expose the research participant to at most a mild and temporary discomfort or delay in
relief of symptoms.
C. Use of a proven intervention as comparator would not yield scientifically reliable results and where use of a placebo or no
intervention would not add any risk of serious or irreversible harm to the research participant.

14. UNCST STANDARDS FOR REFERRAL
The researcher shall undertake to refer all research participants whose conditions may not be managed adequately within the expertise and licensure of the medical professionals at the study site, and/or where
facilities or supplies at the study site do not allow adequate handling of the condition.
The referral process should be adequately documented and all referral guidelines should be adhered to as stipulated in national guidelines on referral.

15. UNCST STANDARDS FOR REFERRAL
researchers should have prior arrangements with the referral facility to receive referred patients.
Research participants should always be informed of all options available for management of their conditions including those outside the country.
Where a referral has been made for a research related injury or a serious adverse event related to the study, the cost of referral and management of the condition shall be paid by the researcher and/or study sponsor.

16. Research related Injury
Subject to applicable laws in Uganda, research participants shall be entitled to compensation when injury is classified as “Probably” or “Definitely” related to their participation in a research project.
Sponsors shall ensure that research participants who
suffer injury as a result of their participation in a research project are entitled to free medical treatment for such injury and to such financial or other assistance as would compensate them equitably for any resultant impairment, disability or handicap.

17. Legal rights to compensation for injury
Research participants shall not be asked to waive the right to compensation, and shall retain legal rights to seek monetary compensation for research related injuries including settlements out of court, in accordance with applicable laws in Uganda.

18. Compensation mechanisms
The sponsor and researcher shall put in place a mechanism for compensating research related injury at the commencement of a study.
The mechanism, which may include, inter alia, insurance and medical care, should be acceptable to the REC. The REC, research participant and/or researcher may initiate the compensation process.
The REC, sponsor and researcher shall agree on an appropriate mechanism for arbitration.

19. Common Pitfalls in Uganda
Tendency by Ugandan researchers to abuse clients using lower or suboptimal care packages.
Non compensation of research related injury
Poor adverse events management.
Referral by dumping patients to public health units.
Non payment for care of adverse events
Use of placebos against guidelines

20. Conclusions
Adequate provision of medical care for participants in research is a moral imperative we must all ascribe to fulfill.
National standards of care should e used to define minimum standards of care.
Special considerations need to be made for participants involved in clinical trials in resource limited settings.