Clinical Research - What, Why, How

Transcription

1 Clinical Research - What, Why, How SCAGO Learning for Life, April 2013 Dr. Richard Ward Red Blood Cell Disorders Program, University Health Network Disclosures - None relevant

2 What do you think of when you hear the word.? Research

3 Objectives What is Research Types of Research Ethical Lessons from History Taking Part in Research How Research can help Sickle Cell Disease Current Research in Sickle Cell Disease

4 Laboratory research

5 Observing Things

6 Development of a new drug Phase 1 Phase 2 Phase 3 Phase 4 healthy early more after approval data information volunteers on effectiveness of a about drug safety in patients and effectiveness most safety studying gather frequent continues additional different and to information populations serious be evaluated side about effects a drug's safety or how Trying optimal the different use drug is dosages metabolized

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9 The Doctors' Trial 23 doctors and administrators accused of crimes against humanity in the form of medical experiments inflicted on prisoners and civilians. Medical experiments conducted for benefit of German armed forces high altitude conditions freezing malaria poison gas saltwater consumption sterilization poisons, etc

10 The Nuremberg Code The voluntary consent of the subject is absolutely essential legal capacity to give consent free power of choice, without duress have sufficient knowledge to understand The responsibility for ascertaining the quality of the consent rests upon each individual. It is a personal duty and responsibility which may not be delegated to another with impunity The experiment should be such as to yield fruitful results for the good of society, unprocurable by other means The experiment should be so designed that the anticipated results will justify the performance of the experiment

11 Declaration of Helsinki Doctors Trial was a legal response to atrocities committed by physicians. but a response from the medical profession was also necessary A statement of ethical principles intended to guide medical research involving human subjects No legal force, but a source document for research ethics guidelines around the world Medical progress is based on research that ultimately must include studies involving human subjects

12 The experiment should be conducted as to avoid all unnecessary suffering No experiment should be conducted where there is reason to believe that death or injury will occur The degree of risk to be taken should never exceed that determined by the importance of the problem to be solved Proper preparations should be made to protect the subject against even remote possibilities of injury or death The experiment should be conducted only by scientifically qualified persons subject should be at liberty to bring the experiment to an end the scientist in charge must be prepared to terminate the experiment at any stage, if he believe that continuation of the experiment is likely to result in injury, or death to the subject

13 Tuskegee Study Study initiated by the US Public Health Service in poor, black men enrolled, offered free health care, and free burial if agreed to autopsy, not told they had syphilis Penicillin available in early 1940 s, became standard of care for syphilis by 1947 Participants were not offered treatment Some subjects coerced into receiving lumbar punctures, told receiving treatment, but none given

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15 Peter Buxtun, a researcher, wrote a letter of concern to CDC in , CDC reaffirmed need to continue the study, AMA supported this position Buxtun went to the press in 1972 By then, only 74 subjects remained alive, 28 had died of syphilis, 100 died of complications of syphilis, 40 wives infected, 19 documented cases of congenital syphilis Led to the Belmont Report In 1997 Clinton formally apologized for study

16 Cincinnati Radiation Experiments Research funded by the US Dept of Defense to investigate the effects of radiation 88 cognitively impaired, mostly black men, with cancer, were given large doses of total or partial body radiation to observe its effects At least 8 patients died

17 The Belmont Report The National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research, 1979 Ethical Principles and Guidelines for the Protection of Human Subjects of Research Very similar to Nuremberg Code to identify the basic ethical principles that should underlie the conduct of biomedical and behavioral research involving human subjects and to develop guidelines which should be followed to assure that such research is conducted in accordance with those principles.

18 Tricouncil Policy Statement: medical and other human research in Canada 1. Respect for human dignity 2. Respect for free and informed consent 3. Respect for vulnerable persons 4. Respect for privacy and confidentiality 5. Respect for justice and inclusiveness 6. Balancing harms and benefits 7. Minimizing harm 8. Maximizing benefit

19 Is there equal access to research? 60 s and 70 s focus was on increasing protections for patients involved in research In 80 s, increasing pressure from women with breast cancer and men with HIV for access to research trials Concern that particular subgroups have been systematically excluded from research SCD is now a priority for the NHLBI and ASH

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21 Challenges in Sickle Cell Research Needs to be a multicenter collaborative effort Canadian Hemoglobinopathy Group SCDAC Lack of local basic science collaborations Lack of interest from the public and funding Lack of clinical and research infrastructure

22 Why Sickle Cell Disease?

23 Early Detection of Increased Risk for Stroke Transcranial Doppler (TCD) > 200 cm/s (abnormal) associated with 40% risk of stroke within 3 years

24 STOP Study Design SS, S/b 0 Age 2-16 TCD Velocity > 200 cm/s R Excluded Prior stroke No Transfusion Standard of Care at the time Transfusion Pre-HbS < 30% Hb < 120 Outcome Cerebral infarction and intracranial hemorrhage as diagnosed by MRI Adams RJ, McKie VC, Hsu L, et al. Prevention of a first stroke by transfusions in children with sickle cell anemia and abnormal results on transcranial Doppler ultrasonography. N Engl J Med Jul 2;339(1):5-11

25 STOP Study Results Study or Subgroup Transfusion No Transfusion Odds Ratio Odds Ratio Events Total Events Total Weight M-H, Fixed, 95% CI M-H, Fixed, 95% CI Adams % 0.07 [0.01, 0.53] Total (95% CI) % 0.07 [0.01, 0.53] Total events Heterogeneity: Not applicable Test for overall effect: Z = 2.56 (P = 0.01) RR = NNT = Favours transfusion Other NNTs for Comparisons Favours no transfusion Compression stockings prevent VTE 9 (7 13) Anti-hypertensives preventing CV 18 (14 25) ASA preventing CV death post-mi 40 Adams RJ, McKie VC, Hsu L, et al. Prevention of a first stroke by transfusions in children with sickle cell anemia and abnormal results on transcranial Doppler ultrasonography. N Engl J Med Jul 2;339(1):5-11

26 STOP2 Study Design SS, S/b 0 Age 5-20 Prior enrolment in the transfusion arm of STOP 2 consecutively normal TCD velocities R Excluded Prior stroke Moderate-to-severe intracranial arterial disease on MRA Halt Transfusion Continued Transfusion Outcome Abnormal TCD velocity or stroke Adams RJ, Brambilla D. Discontinuing prophylactic transfusions used to prevent stroke in sickle cell disease. The New England journal of medicine 2005;353(26):

27 STOP2 Study Results Study or Subgroup Continued Transfusion Transfusion Halted Odds Ratio Odds Ratio Events Total Events Total Weight M-H, Fixed, 95% CI M-H, Fixed, 95% CI Adams % 0.02 [0.00, 0.35] Total (95% CI) % 0.02 [0.00, 0.35] Total events 0 Heterogeneity: Not applicable Test for overall effect: Z = 2.68 (P = 0.007) Favours Transfusion Favours No Transfusion Adams RJ, Brambilla D. Discontinuing prophylactic transfusions used to prevent stroke in sickle cell disease. The New England journal of medicine 2005;353(26):

28 SWiTCH Study Design SS, S/b 0 Age < 18 2 nd stroke prophylaxis > 18 months LIC > 5 mg/g dw R Hydroxyurea + Phlebotomy Outcome 2 nd stroke + reduction in LIC Transfusion + Chelation Ware RE, Helms RW; SWiTCH Investigators. Stroke With Transfusions Changing to Hydroxyurea (SWiTCH). Blood Apr 26;119(17): doi: /blood Epub 2012 Feb 7.

29 SWiTCH Study Results Study or Subgroup Ware 2011 Hydroxyurea + Phlebotomy Transfusion + Chelation Odds Ratio Odds Ratio Events 7 Total 67 Events 0 Total 66 Weight 100.0% M-H, Fixed, 95% CI [0.92, ] M-H, Fixed, 95% CI Total (95% CI) Total events 7 Heterogeneity: Not applicable Test for overall effect: Z = 1.90 (P = 0.06) % [0.92, ] Hydroxyurea + Phlebotomy Transfusion + Chelation No difference in LIC Hydroxyurea + Phlebotomy (N = 67) Transfusion + Chelation (N = 66) P value Median IQR

30 Unanswered Questions Should patients continue on lifelong chronic transfusion? What is the optimal measure of success? HbSC disease? Strategies to optimize transfusions

31 Knowledge gap from kids to adults

32 Finding Research Let s search for something. Online dating for researchers and patients

33 Getting involved in research

34 What is a clinical trial? A clinical trial is a research study in which volunteers receive investigational treatments These treatments are usually developed by pharmaceutical and biotechnology companies Investigators are qualified physicians selected to conduct the clinical trial

35 Who can take part in a clinical trial? Before joining, a volunteer must qualify for the study The factors that allow volunteers to participate in a clinical trial are called inclusion and exclusion criteria These can include age, gender, previous treatment Criteria are used to identify appropriate participants, promote their safety, and ensure that researchers learn the information they need

36 How does a clinical trial work? Placebo Drug Medical Device Standard of Care Treatment A Inclusion and Exclusion criteria R Outcome Treatment B Was it successful?

37 What questions should be asked before choosing to participate? How long will the trial last? Where is the trial being conducted? What treatments will be used and how? What is the main purpose of the trial? How will patient safety be monitored, and are there any risks? What are the possible benefits? What are the alternative treatments besides the one being tested in the trial? Who is sponsoring the trial? How do I find out the results of the trial?

38 What questions should be asked before choosing to participate? What will happen if I stop the trial treatment or leave the trial before it ends? How much of my time will be needed? What extra tests or appointments will I have? Will I need to take time off work? Will the costs of my travel to take part in the trial be covered? Will I have to complete questionnaires or keep a diary? Who can I contact if I have a problem? What happens if I am harmed by the trial? Can I opt to remain on this treatment, even after termination of the trial?

39 What are the benefits of joining a trial? Play an active role in your health care Gain access to research treatments before they are widely available Help others by contributing to medical research participate in the development of medical therapies that may offer better treatments and even cures for life-threatening and chronic diseases

40 What are the risks of joining a trial? There may be unpleasant, serious, or even lifethreatening side effects to experimental treatment The experimental treatment may not be effective The protocol may require more time and attention than standard care trips to the study site more treatments hospital stays complex dosage

41 What can volunteers expect if they choose to participate? physical examination medical histories are reviewed the volunteers' health will continue to be monitored during and after the trial a detailed description of what's expected of will be outlined in the consent form

42 What happens after the trial? Data is collected to determine the drug's effectiveness, if it is safe and if there are any side effects Researchers then determine whether to stop testing or move to the next phase of study May submit findings to a medical journal for peerreview Data then may be submitted to Health Canada for approval

43 Sickle Cell Studies Stem cells to help with hip replacement for AVN Growing red blood cells in the lab from skin Optimising exchange transfusions protocols New iron chelation medication Diagnosis of Pulmonary Hypertension New drug to stimulate HbF Low bone density

44 Let s design a study! R

45 How to design a study! What is the research question? What sort of study do you want to perform? What s the outcome we are interested in? Who s the population you re targeting? Patients with Sickle Cell Any inclusion/exclusion criteria? How long will it last? When will we know when it s finished? Statistics Who s going to fund it?

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47 Final Thinking