Clinical trials

clinical trials phases in india

1. CLINICAL TRIALS Dr. Nilesh Siddhawar, JR1, Dept. of Pharmacology, VNGMC, Yavatmal

2. Introduction Aims and Objectives History Drug development process and Phases Phases of clinical Trials Conclusion

3. Clinical trials Any research study that prospectively assigns human participants or group of humans to one or more health related interventions to evaluate the effect on health outcomes

4. AIMS AND OBJECTIVES Discovering and confirming the role of new drugs for the future pharmacotherapy To evaluate safety and efficacy of experimental drug relative to its adverse drug reactions To change behaviour,habbits or other lifestyle factors Licensing process of a new drug

5. History The first documented experiment resembling a clinical trial was conducted by King Nebuchadnezzar He ordered people to eat only meat and drink only wine, a diet he believed would keep them healthy . He permitted the dissenters to instead follow a diet of legumes and water — but only for 10 days, after which he would assess their health. When experiment ended, the bean-loving people appeared better nourished than the mandated meat-eaters, so the king allowed them to continue their diet

6. The first person to conduct a parallel-arm medical experiment was British physician Dr. James Lind.

7. Lind selected 12 ill sailors and divided them into groups of 2. All the subjects displayed similar symptoms. Men were given the same rations, but each pair received a different scurvy treatment: either cider, a few drops of a weak acid, vinegar, sea-water, nutmeg and barley water, or oranges and lemons. After 6 days, the ship's supply of fruit was spent, but by then ; the 2 men on the citrus treatment were already back on their feet

8. The word Placebo first appeared in medical literature in the early 1800s. 1863 that US physician Austin Flint conducted the first medical experiment comparing a dummy remedy to an active treatment. He treated 13 patients suffering from rheumatism with an herbal extract instead of an established remedy. The first widely publicized randomized clinical trial was a 1948 test of streptomycin for treating pulmonary tuberculosis

9. International clinical trials day is celebrated on 20th May In 1906 : FDA was founded. In 1923 : Concept of randomization. In 1943 : The UK Medical Research Council’s (MRC) trial to treat the common cold is the first double blind controlled study.

10. Types of Clinical Trials Treatment Trials Prevention Trials Diagnostic trials Screening Trials Quality of life Trials

11. 1. Drug discovery : -During which the candidate molecules are chosen on the basis of their pharmacological properties Preclinical : -During which a wide range of animal studies are performed, e.g. Pharmacokinetic, pharmacodynamic and toxicity studies Clinical Trial : -During which the lead compound is evaluated for efficacy, safety, and adverse effects in human volunteers and patients Drug development process

12. Drug Discovery Drug, target or targeted chemical moiety is identified and then validated. Lead compound is identified Lead compound optimisation

13. Preclinical evaluation Toxicity Testing PK &PD Pharmacological effects Time required: 1.5-3yrs IEC approval

14. Pre-clinical Evaluation Phase (Animal Studies) Wide range of animals studies are performed Involves screening, evaluation, pharmacokinetics and short-term toxicity in animals The aim is to satisfy all the requirements that are needed before a compound is considered fit to be tested for first time in humans Pre-clinical phase usually require – 2 to 4 yrs. for completion

15. Toxicological studies Acute toxicity : 2 animal species Subacute toxicity : 2 animal species Chronic toxicity : 2 animal (1 rodent and other non rodent) Special toxicity: Effect on reproductive performance Teratogenicity Carcinogenicity (Same dose for 2 yrs ) Mutagenicity Local toxicity: dermal, ocular, vaginal etc

16. Core Components of Clinical Trials Involve human subjects Must have method to measure intervention Focus on unknowns: effect of medication, any adverse reaction Must review existing scientific data & build on that knowledge Test a certain hypothesis Study protocol must be built on sound & ethical consideration Control for any potential biases

17. Different Phases Of Clinical Trials

18. Phase 0 Administration of single sub therapeutic doses Small number of healthy subjects (10 to 15)  Limited dosing duration(< 7 days ) No therapeutic or diagnostic intent Provides agent's pharmacodynamics and pharmacokinetics Assist in the go vs no-go decision making process of drug.

19. Advantages – Save the investment Shorten development timeline Improve the efficiency and success of subsequent trials Require lesser preclinical testing data. Limitations- False negative results can lead to discontinuation of promising drug Non linear pharmacokinetic if present can create problems in dose extrapolation

20. Investigational New Drug Application When the new drug passes the pre-clinical pharmacological screening, the manufacturer may file a ‘ Investigational new drug’ ( IND) to an authorized drug control body. In UK- CSM In USA- FDA In INDIA- Drugs controller general, Govt. of India, New Delhi.

21. Phase I Limited number (25-100 in number) Healthy volunteers If drug has excessive toxicity, volunteers with particular disease can be used. To determine appropriate dose range with regard to safety and toxicity Used to document pharmacokinetics of drug Take 9-18 months to complete. It is open label or non-blind trial.

22. Three different kinds of phase I trials include: Single ascending dose studies Multiple ascending dose studies Food effect

23. Single ascending dose studies (SAD) Small groups (3) of subjects are given a single dose of the drug while they are observed and tested for a period of time. If no adverse effects, dose is escalated with 3 new healthy subjects If toxicity is observed then 3 more subjects are given the same dose and if found toxic, the dose is considered as Max. Tolerated dose (MTD).

24. Multiple Ascending Dose (MAD) To understand the pharmacokinetics and pharmacodynamics of multiple doses of the drug. A group of patients receives multiple low doses of the drug Samples ( blood, and other fluids) are collected at various time points Analyzed: how the drug is processed within the body.

25. Food effects To investigate any differences in absorption of the drug by the body, caused by eating before the drug is given.  It is a crossover study, with volunteers being given two identical doses of the drug while being fasted, and after being fed

26. Once a drug has shown to be safe, then it must be tested for efficacy. Phase II Relatively limited (150-350) patients Focus on dose response, dosing schedule and issues related to preliminary safety and efficacy Often involve hospitalized subjects who can be closely monitored Take 1-3 yrs to complete Additional animal testing could be done simultaneously for long term safety information.

27. Phase II clinical trial is again divided into 1) Phase II a- Potential therapeutic benefits, side effects and adverse effects are observed Main obejective – to estabilish a dose response,type of patient,frequency of dosing and other characterastics of safety and efficacy. Ususally single blind trial &involve small no. Of patients (upto 200) 2) Phase II b- It usually represent most rigorous demonstration of medicines efficacy. Large no. of patients (200-400) in double blind manner.

28. Large scale multicentred (heterogenous population),Randomised ,Double blind ,Cross over trial . Large number of patients : 1000 – 5000 . Make comparison between new treatment and standard therapy / placebo Lasts an average of 5 – 6 years. Further estabilish safety and efficacy and possible drug and food interactions. Phase III

29. New Drug Application Sponsor submits “New Drug Application” for marketing approval NDA contains extensive data on test product efficacy and safety and may include copies of individuals subject data forms. Once DRA receives NDA it is distributed to FDA review group. FDA review group responsible for safety and efficacy of pharmaceutical agents, medical devices. FDA reviewers are also responsible for drug classification.

30. Subset of Phase III Trials Phase III a – Conducted prior to submission of “ New drug Application”. Generate additional data on safety and efficacy in relatively large no. of patients Often provide information for package insert and labelling of drug. Phase III b- Conducted after submission of NDA but prior to drugs approval and launch It supplement earlier trials or may be directed toward new type of trials

31. Phase IV Conducted after drug is marketed Evaluation of different formulations, dosages, duration of treatment ,drug interactions and other drug comparison. Monitor ongoing safety in large populations and identify additional uses It include sample size in thousands. Has no fixed duration. During New drug status period manufacturer are expected to submit PSUR to Drug controller authority.

32. Extension of phase IV clinical trials Phase V is a growing term used in the literature of translational research It refers to comparative effectiveness research and community-based research It is used to signify the integration of a new clinical treatment into widespread clinical practice Phase V Clinical Trials

33. Guidelines for Clinical Trials of New Drug

34. Bioethical code of Conduct Nuremberg Code 1947 Declaration of Helsinki 1964 ICMR Guidelines WHO & CIOMS Guidelines UNESCO Guidelines

35. Principles of Ethics Principle of autonomy: Welfare and rights need to be respected Principle of beneficence & non-maleficence: Minimise harms and enhance benefits Principle of Justice: Fair distribution of scarce resources and respect for morally acceptable laws

36. Rules for Ethical Clinical Research- Essentiality Scientific validity Favourable risk-benefit ratio Fair subject selection Voluntariness , informed consent Non-exploitation Privacy and confidentiality Professional competence Accountability and transparency

37. IEC/IRB - To safeguard the welfare and rights of the participants and to ensure Universal Ethical values Composition : 8-12 members Chairman should be from outside institution Member secretary from same institution Other members are medical/Non-medical or lay persons

38. Use of Placebo Placebo controls results in d/t associated smaller sample size less expensive and more rapid trials Several authors have argued that placebo control trials are invariably unethical Comparison of new treatment with old treatment is sufficient to establish efficacy They are allowed if disease is mild or no satisfactory treatment is available for disease

39. Conclusion The final outcome of clinical trials is improved clinical medicine. After preclinical development, investigational new drug passes through clinical phases I, II, III and IV. These phases provide in detail explanation of pharmacokinetic, pharmacodynamic profile and side effect which may be harmful or beneficial, adverse effect and post marketing surveillance. Clinical trial are conducted in human volunteers for confirmation of useful properties of new drug.

40. Collier R. Legumes, lemons and streptomycin: A short history of the clinical trial. CMAJ : Canadian Medical Association Journal . 2009;180(1):23-24. doi:10.1503/cmaj.081879. Mahan, Vicki L. "Clinical trial phases." International Journal of Clinical Medicine 5.21 (2014): 1374. Principles of Pharmacology, HL Sharma , KL Sharma 3 rd edition Postgraduate topics in pharmacology, Rituparna Maiti , 2 nd edition Referances