Importance of clinical trials

Clinical Trials

1. I mportance of clinical trials Dr Sharanya Sreekumar Postgradute Student Public Health Dentistry

2. Contents Introduction Historical perspective Importance of clinical trial Types of clinical trials Design of clinical trial Phases of clinical trial Important regulations and guidelines New clinical trial regulations rules in India PHACT Conclusion References 2

3. Introduction Trial is from the Anglo–French term, meaning to try. Broadly, it refers to the action or process of putting something to a test or proof. Clinical is from clinic, from the French cliniqu ´ e and from the Greek klinike , and refers to the practice of caring for the sick at the bedside . Broadly clinical trial refers to any testing done on human beings for the sake of determining the value of a treatment for the sick or for preventing disease or sickness. 3

4. Historical perspectives First trial was carried by J ames L ind for treatment of scurvy . 12 scurvy patients in the year 1747 cider Elixir of vitriol Vinegar Sea water Orange and lemons Barley water 4

5. Johannes Fibiger’s 1898 study of diphtheria antitoxin in 484 patients in Copenhagen, alternate allocation entailed treating every other patient. Alternate allocation considered as ancestor of RCT By 1940’s Sir Austin Bradford Hill brought out strict concealed randomization of patients to treatment or control groups. 5

6. Importance of clinical trial A clinical trial is a research study that tests a new medical treatment or a new way of using an existing treatment to see if it will be a better way to prevent and screen for diagnose or treat a disease. Trials are said to be controlled if the effect of a treatment is measured against a comparison treatment administered over the same time period and under similar conditions . Uncontrolled trials 6

7. Types of clinical trial Treatment trials Prevention trials Diagnostic trials Screening trials Quality of Life or Supporting care trials Genetic trials Compassionate use clinical trials: critical ill patients 7

8. CHIM ( Controlled H uman I nfection M odel ) CHIM (for malaria, Controlled Human Malaria Infection, CHMI) provides a platform to reasonably evaluate the protective efficacy of a vaccine candidate without going out for larger trials. The term “Controlled” in CHMI reflects the requirement of highly controlled settings such as well- characterised parasite strains, effective drug(s) for infection elimination and highly efficient diagnostic system for stringent monitoring. The term “infection” reflects that the experimental protocol intends to induce controlled infection and not cause disease. The term “Human” reflects that the subject will be human, as with any clinical vaccine research evaluating protective efficacy. 8

9. Design of clinical trial Parallel study design Cross over study design Factorial study design 9

10. Parallel group design A parallel group design is a complete randomized design in which each patient receives one and only one treatment in a random fashion Run in periods : Before patients enter a clinical trial, a run-in (or lead-in) period of placebo, no active treatment, dietary control, or active maintenance therapy (e.g., diuretic and/or digoxin in heart failure studies) is usually employed prior to randomization 10

11. Advantages of Run in Periods It acts as a washout period to remove effects of previous therapy. It can be used to obtain baseline data and to evaluate if patient fulfils study entry criteria. It can be used as a training period for patients, investigators and their staff It can be used to estimate and compare the magnitude of possible placebo effects between groups. 11

12. Cross over design 12

13. Factorial study design Factorial study design are commonly used to test multiple treatments in a single study 13

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15. What to do before a clinical trial? For any new drug to enter in clinical trial, it must pass preclinical studies. Preclinical studies involve in vitro (i.e. test-tube or Laboratory) studies and trials on animal populations. Wide range of dosages of the study drug is given to animal subjects or to an in-vitro substrate in order to obtain preliminary efficacy, toxicity and pharmacokinetic information. 15

16. Phase 0 clinical trial The Phase 0 clinical trial is the latest designation for the exploratory, First-In-Humans trials conducted according to the FDA 2006 Guidance on exploratory Investigational New Drug (IND) studies. The purpose of Phase 0 trial is to aid in a “go versus no-go” decision making process D rug’s fate early in the development process, using relevant human models rather than relying on sometimes inconsistent animal data. 16

17. There are three types of Phase 0 clinical trials: C linical trials to determine drug pharmacokinetics (also known as microdose trials), T o establish pharmacologically relevant doses T o study the mechanisms of action ( pharmacodynamics ) 17

18. Advantages Early selection of promising compounds Unsuitable molecules can be eliminated earlier Risk of human toxicity is less Approximate drug dosage can be established Disadvantages Difficult to motivate human subjects Certain drugs have different metabolism at microdosing and clinical ( larger ) doses Ethical issues 18

19. Phase 1 clinical trial Phase I trials are the first stage of testing in human subjects. Normally, a small (20-80) group of healthy volunteers will be selected. This phase includes trials designed to assess the safety (pharmacovigilance), tolerability, pharmacokinetics, and pharmacodynamics of a drug. These trials are often conducted in an inpatient clinic, where the subject can be observed by full-time staff. The subject who receives the drug is usually observed until several half-lives of the drug have passed. 19

20. Safety in phase 1 trials It is evaluated by observing any adverse events , ECG, vital signs, and physical examination Special attention given to changes in liver and renal function tests Any clinical chemistry changes observed during animal studies 20

21. The selection of initial dose is based on results of preclinical studies Phase I trials most often include healthy volunteers . Different kinds of phase 1 studies SAD ( S ingle Ascending D ose): MTD MAD( Multiple Ascending Dose) 21

22. Information obtained from Phase I studies Maximum tolerated dose Nature of adverse reactions that can be expected Preliminary characterization of the drug Accumulation of parent drug/ metabolites Bioavailability in presence of food 22

23. Phase 2 trials Once the initial safety of the study drug has been confirmed in Phase I trials Phase II trials are performed on larger groups ( 20-300) It is designed to assess how well the drug works, as well as to continue Phase I safety assessments in a larger group of volunteers and patients. Duration of phase 2 trials can be months or years It will have more stringent inclusion criteria 23

24. Phase 2 trials gives a successful design for phase 3 trials which carried out in multiple centres Key factors to be learned from phase 2 is To obtain optimal safety dosing regimen To obtain a clinical end point To prove clinical efficacy 24

25. Phase 2 trials divided into Phase 2a( how drug should be given and how often) Phase 2b ( how well drug works at prescribed doses ) 25

26. Information obtained from Phase IIa studies Dose-response Efficacy Effect Size Adverse events (ADR of special interest) Biomarker profiling 26

27. Information obtained from Phase IIb studies Proves primary hypothesis Frequency Additional ADR Identifying confounding factors Type of patients more responsive to treatment 27

28. Phase 3 ( Confirmatory trials) Phase 3 is the primary basis for marketing approval. Phase 3 is carried out in multiple centers and involves a sample size of 1000 to 3000. They require more complex , experienced , diverse and collaborative team to conduct them. Phase 3 usually involves randomization and masking ( blinding ) Require a prior review by IRB and continual oversight by an independent group ( Data safety and monitoring committee) 28

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30. BARI Trial ( Bypass Angioplasty Revascularization Investigation) BARI was multicenter clinical trial designed to assess long term safety and efficacy of CABG or PTCA. This trial involve 14 enrollment centers 4 satellite sites, a clinical coordinating center and separate ECG and radiographic central laboratory. It took 1 year to plan the trial. Over a 3yr period 25,000 people were screened. Participants were followed for 8 years. 30

31. Who’s who in a clinical trial Experienced –clinician scientists Research designer / biostatistician Research assistants Data collectors Data analyzers Clinical trialists / methodologist Site coordinators Bioethicists Participants 31

32. Key elements in phase 3 trials Basically all Phase 3 trials will have a manual of procedures (MOP) In MOP they include the all procedures to be carried out throughout the trial Clinical protocol is the most important part It can be modified and it should be recorded It can also act as the historical record of the trial 32

33. Masking procedures( Blinding ) Single masked studies Double masked studies: most frequently done Triple masked Unmasked studies or open label studies : in which all are aware of the study eg : a new restorative material. 33

34. Trial end point It is the objective measurement that reflects the impact or effect of an intervention Primary end point : it can be single or combination of events eg : children’s amalgam trial uses a composite neurobehavioral endpoint as it measures memory, attention, and motor/visual skills. Surrogate endpoint : it is another measure in place of an endpoint. i.e biomarker in place of long term assessment eg tooth loss and periodontal disease 34

35. Stopping rules A stopping rule specifies the conditions under which a trial will be stopped before its planned completion It should be clearly specified in MOP. Stopped early for 2 main reasons Statistical criterion has been met , determined by monitoring board Out of concern of safety of participants . Eg : CAST trial( cardiac arrhythmia suppression trial) stopped uneventful death of patients using IND( investigational new drug ) studies compared with placebo. 35

36. Control groups in phase 3 trials Three essential types No-treatment Placebo control Current standard of care : most appropriate control intervention in a trial. It helps researchers analyze current new treatment is superior or equivalent. 36

37. Information obtained from Phase III studies Definitive proof of efficacy Additional safety data in large patients Adverse effects with longer duration of treatment Information for package insert and labeling of medicine. 37

38. Phase 4 trials Phase IV trial is also known as Post Marketing Surveillance Trial. Phase IV trials involve the safety surveillance (pharmacovigilance ) and ongoing technical support of a drug after it receives permission to be sold. The safety surveillance is designed to detect any rare or long-term adverse effects over a much larger patient population and longer time period than was possible during the Phase I-III clinical trials. 38

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42. ICH GCP Guidelines It is a set of standards used internationally for the conduct of clinical trials. The guidelines aim to ensure that the "rights, safety and well being of trial subjects are protected". The declaration of Helsinki of the World Medical Association (1964) codifies recommendation for guidance of doctors in clinical research. 42

43. Principles of ICH GCP Clinical trials should be conducted in accordance with the ethical principles Before trial the risk benefit analysis should be done The rights, safety, and well being of the trial subjects should be the most important consideration Should be scientifically sound, and described in a clear, detailed protocol. IRB / IEC approval Informed consent should be mandatory Confidentiality of record should be protected Systems with procedures that assure the quality of every aspect of the trial should be implanted 43

44. Regulatory approval for India The Drug Controller General of India (DCGI) requires a confirmatory Phase III study that includes a proportion of local patients. The Central Drug Standard Control Organization (CDSCO) handles the approval process . Apart from the CDSCO approval, DCGI has given rights to each state’s drug control authority to regulate the manufacture, sale and distribution of drugs. 44

45. Challenges emerged between 2011-2013, when the Supreme Court of India had asked for several justifications from the Health Ministry around the conduct and continuance of clinical trials in India New Drugs Advisory Committee (now as SEC) , Technical Committee and Apex Committee to examine applications for clinical trials in India. 45

46. T he SEC( Subject E xpert C ommittee) acts as a gateway in the clinical trial approval process by advising the DCGI in the following matters: To undertake in-depth evaluation of non-clinical data, including pharmacological toxicological data, clinical trial data (Phase I, II, III, and IV) furnished by the applicant for approval of new drug substances of chemical and biological origin, global clinical trials, fixed-dose combinations and those of two or more drugs. Defining roadmap for research industry for appropriate development of new drugs relevant to Indian population. 46

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49. PHACT ( Public Health Alliance for Clinical Trials ) Ellen Morgan, Christian Sacher and Yaw Asare-Aboagye are the founders of Public Health Alliance for Clinical Trials (PHACT ). Public Health Alliance for Clinical Trials (PHACT) is the first non-profit Clinical Research Organization (CRO) dedicated to conducting clinical trials for products to treat diseases that affect the poorest people in developing countries. They collaborate with non-profit organizations to assist in reducing research costs, thus enabling clinical trials.   49

50. Conclusion With globalization the internet trials are being carried out in the world now a days. So harmonization between countries become a necessary factor for successful outcome of world wide trials. 50

51. References W V Giannobile , C linical R esearch in Oral Health,2010. Wiley – Blachwell ; 1 st edi . Information about clinical trial. Available from : URL http://www.temple.edu/pascope/about_trials.html Clinical trial wikipedia , the free encyclopedia. Available from: URL http://en.wikipedia.org/ wiki/ clinical_trial . Kulkarni S. K., Hand Book of Experimental Pharmacology, 3rd ed , Vallabh Prakashan New Delhi, 2004, 21. 4 S.Peter Essentials of Public Health Dentistry , 5 th edi.2015 51