Phases 3,4 and 5 of clinical trials

A comprehensive review of phase 3, 4 and 5 clinical trials

1. Phases 3, 4 and 5 of clinical trials Dr. Shrey Bhatia Junior Resident Pharmacology GMC, Patiala 1

2. Phase 3 of clinical trials 2

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4. To demonstrate the therapeutic efficacy of the drug in a representative sample of the patient population, generally by means of at least two well-designed and adequately performed independent studies. To demonstrate the safety and tolerability of the drug in a sufficiently large sample of the patient population, by means of studies of sufficiently long duration, compared to the intended duration of the treatment in clinical practice. to gain additional information regarding the effectiveness and safety that is required to evaluate the overall benefit-risk ratio 4

5. a larger patient population 500-3000 Multicentric Length of study- 1 to 4 years 5

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7. Objectives : To confirm safety and effectiveness of the drug Basis for marketing approval Phase 3 A Active controlled studies Conducted in patients in whom the drug will be eventually intended. Inclusion and exclusion criteria relatively relaxed Different dosages, schedules and combinations with other drugs 7

8. Phase 3 A Different patient population ( Multicentre/ Multinational trial ) Also conducted in special group patients (e.g. elderly, renally impaired, etc) Comparison PK/PD with current Gold Standard 8

9. Phase 3 A Information obtained Definitive proof of efficacy Additional safety data in large patients Adverse effects with longer duration of treatment Information for package insert and labelling of medicine 9

10. Objectives : Further explore dose-response relationship in different stages of the disease and in combination with another drug Phase 3 B Clinical trial after regulatory submission of an NDA ( New Drug Application ) but prior to approval and launch Supplement earlier trials, complete earlier trials, directs towards new trials or phase IV evaluations 10

11. Difference between 3A and 3B Phase 3 a Phase 3 b Trials carried out on a large number or in a special category Regulatory requirement for NDA Generates data on safety and efficacy Extended trials of 3a after applying for approval but before launch Also known as ‘ label expansion’ To show the drug works for additional types of patients/ diseases beyond the original use for which the drug was approved for marketing These may supplement or complete the earlier trials or may be directed to Phase IV 11

12. End of Clinical Trial Activities Sponsor : Expert Committee review of Efficacy, safety and potential sales (Profit). Go-No Go decision to file New Drug Application ( NDA) to the competent authority of the concerned country (DCGI in India/FDA in the US) for the approval of drug for marketing Expert review by competent authority Approval by competent authority Drug marketed  Phase IV begins 12

13. Phase 1 Phase 2 Phase 3 Phase 4 NDA Phase 1 Phase 2 Phase 3 Phase 4 Phase 3 Phase 4 13

14. NDA: New Drug Application The New Drug Application (NDA) is the vehicle through which drug sponsors formally propose that the DCGI ( in India) or FDA ( in the US) approve a new pharmaceutical product for sale and marketing The goals of the NDA are to provide enough information to permit FDA/DCGI reviewers to establish the following: Drug is safe and effective. Benefits outweigh the risks. Proposed labelling is appropriate 14

15. NDA: New Drug Application NDA contains all of the information gathered during preclinical to phase III NDA can be thousands of pages long Can take 2-3 years for FDA/DCGI to review NDA used in India is called Form # 44: Application for grant of permission to import or manufacture a new Drug or to undertake clinical trial . 15

16. Form 44 Contents: Full pre-clinical and clinical testing information Information of efficacy, safety and marketing status of the drug in other countries Prescription, samples and testing protocols, Product monograph, labels, and cartons. 16

17. MAA-Marketing Authorization Application, IND-Investigational New Drug, CTA-Clinical Trial Authorization, DNA-Data Not Available. Comparison of drug approval process in different countries 17

18. In case of urgent need of therapy ( eg cancer chemotherapy) For serious disease, or life threatening diseases approval of controlled marketing of new drug before phase 3 or even phase 2 is completed Fast track/priority/accelerated drug approval by FDA 18

19. Phase 4 and Post Marketing Surveillance The real test of the drug in real world 19

20. Studies (other than routine surveillance) performed after drug approval and are related to the approved indication(s). These trials go beyond the prior demonstration of the drug's safety, efficacy and dose definition Include additional drug-drug interaction(s), dose-response or safety studies and trials designed to support use under the approved indication(s) Phase 4 20

21. Need of Phase 4 studies Pre-marketing phase are incomplete with regard to possible ADRs Number of patients one would need to observe to have a 95% chance of detecting 1, 2, or 3 cases of adverse reaction 21

22. Need of Phase 4 studies New knowledge about a drug is obtained when doctors all over the world use the drug in a wide spectrum of patients, with varied ethnicity, various underlying diseases, and a range of concomitant medication Additional knowledge about drugs comes from scientific, rather than commercial interest, done by individual workers in universities and research institutions which are possible only after the drug receives regulatory approval and becomes commercially available Complements the efficacy data that results from a pre-marketing randomized controlled trial (RCT). 22

23. Types of Phase 4 studies Pharmacoepidemiology Post marketing surveillance Pharmacovigilance Pharmaco-economic studies Case control Cohort Cross sectional Drug utilization studies Meta analysis Patient registries Automated linkage data Large simple trial Descriptive- case reports, case series. 23

24. Post marketing surveillance Not all Phase IV studies are post- marketing surveillance (PMS) studies but every PMS study is a phase IV study Real world effectiveness of a drug is evaluated Observational, non-interventional trial in a naturalistic setting Complements the efficacy data that results from a pre-marketing randomized controlled trial (RCT). 24

25. PMS study is a non-interventional study requested by regulatory authorities to verify the safety, tolerability and effectiveness of a marketed drug in a particular population per the locally approved label. Regulatory requirement in countries such as Japan and the Philippines Open studies where unlike pre-marketing studies, no strict inclusion & exclusion criteria, but governed by the permissible indications and contra-indications of the drug as stated in prescribing information Post marketing surveillance 25

26. In India, PMS data used to be submitted to the Drugs Controller General of India (DCGI) within 2 years of launch. Now Periodic Safety Update Reports (PSURs) are filed at regular intervals PSUR are reports that provide an evaluation of the benefit-risk balance of a medicine, submitted every six months for the first two years after approval of the drug and for subsequent two years - annually. Post marketing surveillance 26

27. Current worldwide market authorization status, Update of actions taken for safety reasons, Changes to reference safety information, Estimated patient exposure, PSUR Presentation of individual case histories, Studies, Other information, Overall safety evaluation, Conclusion PSUR should contain the following information: 27

28. Pharmacovigilance is the science and activities relating to the Detection, Assessment, Understanding and Prevention of adverse drug reactions or any other possible drug related problems. In India, Pharmacovigilance activities are done under Pharmacovigilance Program of India ( PVPI) Indian Pharmacopoeia Commission (IPC) in an autonomous institution of Ministry of Health and Family Welfare, GOI, functions as National Coordination Center for PvPI Pharmacovigilance 28

29. Initiated by GOI in July 2010 Follows spontaneous reporting system for data collection SPONTANEOUS REPORTING : All unsolicited reports of suspected adverse events (AEs) from health care professionals or consumers or pharmaceutical companies, received by the regulatory authorities ( FDA, CDSCO,NCC, AMC etc)* PvPI 29

30. 30 Ensure quality, integrity, completeness Causality assessment of reports Reviewing, analysing, forwarding reports to WHO-UMC, CDSCO Regulatory decisions PvPI

31. Changes to a drug’s label Black-box warnings Approval: new users/indications Changes in a drug’s manufacturing process New CTs & analyses (economic/efficacy/safety) Drug withdrawals Consequences of Phase 4 studies 31

32. Clinical Endpoints. Practice based drug evaluation. Large and heterogeneous population. Long-term use. Pharmaco-economic considerations. Establishing methods of prescribing and utilization. Meaningful role in drug development. Advantages of phase 4 studies 32

33. No or little supervision. Fewer data collected from each patient. Non-compliance. Self-medication. Identification of new indications may promote off-label use. Unregulated environment Disadvantages of phase 4 studies 33

34. Phase V clinical trials refer to comparative effectiveness research and community-based research Research is done on data collected. All reported uses are evaluated. Patients are not monitored. Its main focus is to determine integration of a new therapy into wide spread clinical practice Phase 5 34

35. Pragmatic trial/ translational research Decision makers, whether patients, physicians or policy makers need to know what they can expect from the available diagnostic or therapeutic option when applied to day to day life ( external validity ) should allow minimum constrains of usual practice of prescribing and using medicine Explanatory trials seek to maximize the probability that the intervention and not some other factor causes the study outcome ( internal validity) Pragmatic trials place a premium on external validity while maintaining as much internal validity as possible Phase 5 35

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