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Clinical Trials and Drug Development


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Clinical Trial and Drug Development

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Clinical Trials and Drug Development

  1. 1. Clinical Trial Phases Dr. Lokendra Sharma Professor Pharmacology
  2. 2. Introduction Clinical trial is a systematic investigation in human subjects for evaluating the safety & efficacy of any new drug. Clinical trials are a set of tests in medical research and drug development that generate safety and efficacy data for health interventions in human beings.
  3. 3. What are Clinical Trials? Research studies involving people Try to answer scientific questions and find better ways to prevent, diagnose, or treat disease Translate results of basic scientific research into better ways to prevent, diagnose, or treat disease 4
  4. 4. Clinical Trials Timeline ( 605 BC - 1986 AD ) • 605 - 562 BC : The first clinical trial was carried out by King Nebuchadnezzar II . • 1537 : It was by chance surgeon Ambroise Pare 5
  5. 5. Turning Point Emerged the Nuremburg Code
  6. 6. "Doctors' Trial."
  7. 7. "Doctors' Trial." The Medical Case, U.S.A. (the Doctors' Trial) 1946-47. Twenty-three German doctors and administrators accused. War crimes and crimes against humanity. Medical experiments and medical procedures on prisoners and civilians. >Twelve series of medical experiments concerning 9
  8. 8. Turning Point • Emerged the Nuremburg Code - basic principles to be observed when conducting research involving human subjects. • Subsequently formed the basis for international guidelines on medical research, such as the Declaration of Helsinki. 10
  9. 9. Drug Development Process • Investigational New drug (IND) • Pre clinical studies (animal studies) • USFDA- ask for – Description of drug – Chemistry – Preclinical information – Any previous human study – Investigators Brochure – Clinical development plan – Protocol and Investigator submission for first Phase-1 11
  10. 10. Different Phases of Clinical Trials In Phase I trials, small group of healthy people ( 20 -50) the first time to evaluate its safety, determine a safe dosage range.  In Phase II trials, group of patients (100 – 300) effective and evaluate its safety.  In Phase III trials,large group of patients ( 1000 – 3000)effectiveness, monitor side effects, compare it to commonly used treatments, and used safely. In Phase IV trials, post marketing studies drug’s risks, benefits and optimal use. 12
  11. 11. Drug review Before one can initiate testing in human beings, extensive pre- clinical or laboratory research is required. Research usually involves years of experiments in animal and human cells. If this stage of testing is successful, the sponsor then provides this data to the FDA requesting approval to begin testing in humans. This is called an Investigational New Drug (IND) Application
  12. 12. Preclinical evaluation phase ( animal studies) Pharmacodynamic studies in vivo in animals, in vitro preparation Absorption, distribution , elimination studies (Pharmacokinetics) Acute ,sub acute, chronic toxicity studies (toxicity profile) Therapeutic index (safety & efficacy evaluation)
  13. 13. Prephase I A-Preclinical Data Review : Drug Discovery Team Efficacy Safety Pharmacology Toxicology ADME B-Preparation of Investigator’s Brochure Summaries of Preclinical data with clinical Extrapolation. Prediction of Clinical Effects & Safety C–Filing of Investigational New Drug Application with DCGI.
  14. 14. IND Application Clinical Evaluation needs Prior Regulatory and IRB Clearance. Phase-wise clearances have to be obtained. The End Result of Phase I-III studies is the filing of NDA (New Drug Application) for obtaining Marketing Permission from DCGI.
  15. 15. Microdosing / Phase 0 study Early studies of the pharmacodynamic and pharmacokinetic properties of a potential drug in humans. Microdosing approach could‘accelerate’ drug development without compromising clinical safety Microdosing helps researchers select better drug candidates for clinical trials by providing early human PK and bioavailability data.
  16. 16. Microdosing / Phase 0 study Advantages: Less chances of adverse effects , Short duration Less no. of volunteers Reduced cost of development Reduced drug development time Limitations: Study mainly based on PK parameters - not efficacy and safety based Agents having different kinetic characteristics between microdose and full dose are not evaluated by phase 0 trials Of Limited use for agents having Non linear PKs The laboratory parameters are very limited and expensive, researchers have to depend on BA/BE labs
  17. 17. Phase I First stage of testing in human subjects Designed to assess the safety, tolerability, PK and PD of drug. 20-25 healthy volunteers Patients: Anticancer drugs, AIDS therapy Duration: 6-12 months No blinding / Open labelled
  18. 18. Phase 1 Basic pre-requisites Preclinical data IND application Approval by the regulatory authority Protocol approval by the Ethics Committee Informed consent Adherence to Declaration of Helsinki /ICH- GCP guidelines, at the start as well as from time to time, during the study
  19. 19. Phase I Study/ Clinical trial The aim of a Phase I trial is to determine the maximum tolerated dose (MTD) of the new treatment. The MTD is found by escalating the treatment dose until the dose-limiting toxicity (DLT) is reached. Kinds of Phase I SAD: single ascending dose studies MAD: multiple ascending dose studies Food Effect: investigates differences in absorption caused by food
  20. 20. 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).
  21. 21. Multiple ascending dose studies (MAD) Conducted to understand the pharmacokinetics and pharmacodynamics of multiple doses of the drug. A group of patients receives multiple low doses of the drug Samples (of blood, and other fluids) are collected at various time points Analyzed: How the drug is processed within the body.
  22. 22. Phase I studies: Need To make reliable and rapid Prediction of human response, from Preclinical Data (PD, PK, Toxicity) Involves Extrapolation from Animal data to first human exposure. Phase I serves as an interface between Preclinical Research and Clinical Drug development. Once Phase I is complete, Human beings become first-choice test species (Human Guinea- pigs).
  23. 23. Phase I study: Objectives 1. Primary : i. Tolerability and Safety ii. ii. Pharmacokinetics 2. Secondary iii. Pharmacodynamics
  24. 24. Phase I Studies: Subjects Healthy human volunteers: Most commonly used. (Non-Therapeutic Research) Subjects receive no therapeutic benefit by participation - Ethical issue. Patient Volunteers: Cytotoxic drugs, AIDS therapy Patients in advanced stage of disease
  25. 25. Phase I: Reasons for Using Healthy Volunteers Large numbers available (vs. Patients) Rapid recruitment rate Potential risks are considerably reduced Results not confounded by presence of disease variables More homogenous group Greater compliance with Protocol In case of ADR’s Chances of Speedy and Complete recovery are better Advantages > Disadvantages
  26. 26. Phase I: Patient Volunteers Whenever Preclinical Toxicity Data indicates potential risks for subjects & Ethical Concerns preclude use of healthy human subjects e.g. Cancer/AIDs/Psychiatric patients Dose range of interest is appropriate to determine in patients than in healthy volunteers
  27. 27. Phase I: Special Population Healthy Volunteers It is now a regulatory requirement to include: -Women of child bearing age -Children, if NCE is proposed to be used in them. -Elderly (>65 years) of age.
  28. 28. Limitations of Phase I Trial restricted to homogenous subjects Performance extrapolated to heterogeneous market place
  29. 29. Phase II Therapeutic Exploratory Trial 20-300 Subjects To confirm effectiveness, monitor side effects, & further evaluate safety First in patients (who have the disease that the drug is expected to treat) Duration: 6 months to several years.
  30. 30. Phase II: Objectives Efficacy in patients (primary objective) Safety issues (secondary objective) Optimum dose finding Dose efficacy relationship :  Therapeutic dose regimen  Duration of therapy  Frequency of administration  Therapeutic window
  31. 31. Phase II studies : Pre-requisites Review of Phase I data Innovator/ Experts IRB DCGI Prior approval by IRB and DCGI is Mandatory For New Actions of a marketed drug, start with Phase II (Phase I exemption obtained)
  32. 32. Phase II Study/ Clinical trial Phase II Types: Phase IIA: Designed to assess dosing requirements Phases IIB: Designed to study efficacy
  33. 33. :
  34. 34. Phase III Therapeutic confirmatory trials. Large scale, multicentre, Randomised, Controlled trials . Target population: several 100’s to 3000 patients. Takes a long time: up to 5 years To establish efficacy of the drug against existing therapy in larger number of patients, method of usage, & to collect safety data etc.
  35. 35. Phase III: Objectives To assess overall and relative therapeutic value of the new drug Efficacy, Safety and Special Properties To determine optimal dosage schedule for use in general The dosage schedule in C.T.’s should be as close as possible to its anticipated clinical use
  36. 36. Phase III : Prerequisites Efficacy and dose schedule defined in Phase II studies No gross ADR’s Long term preclinical safety studies completed -Chronic Toxicity - Reproductive toxicity - -Carcinogenicity - Marketing inputs favourable - IRB and DCGI approval obtained
  37. 37. Phase III studies Subtypes Phase IIIA: to get sufficient and significant data. Phase IIIB: allows patients to continue the treatment, Label expansion, additional safety data. Phase III B studies are 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
  38. 38. Phase III Phase IIIa • Prior to NDA • Generates data on safety and efficacy Phase IIIb • After the NDA but prior to the approval and launch. • These may supplement or complete the earlier trials or may be directed to Phase IV trials.
  39. 39. 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 with DCGI  Expert review by DCGI’s Committee  DCGI approval  NCE marketed ….. Phase IV begins
  40. 40. NDA: New Drug Application NDA Refers to New Drug Application Formal proposal for the FDA/DCGI to approve a new drug for sale Sufficient evidences provided to FDA/DCGI to establish: -Drug is safe and effective. -Benefits outweigh the risks. -Proposed labeling is appropriate. 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 to review
  41. 41. Phase IV Study / Clinical trial Harmful effects discovered may result in a drug being no longer sold, or restricted to certain uses. On September 30, 2004, Merck withdrew rofecoxib from the market because of concerns about increased risk of heart attack and stroke associated with long-term, high-dosage use.
  42. 42. Phase IV: Objectives Confirm the efficacy and safety profile in large populations during practice Detect the unknown/rare adverse drug reaction/s Evaluation of over-dosage Identifications of new indications Dose refinement: Evaluation of new formulations, dosages, durations of treatment
  43. 43. Phase IV: Objectives Evaluation in different age groups / types of patients Comparative Benefit-Risk assessment Benefit-Cost assessment (Pharmaco- economics) Drug usage in the community Quality Of Life assessment
  44. 44. REPORTING of ADR If Health care personal suspects that a particular medication is associated with an adverse event observed during the course of caring for a patient, he can report the ADR to a formal reporting system. Various reporting systems are: WHO International System USFDA –Medwatch UK –Yellow card system INDIA – National Pharmacovigilance Programme (CDSCO)
  45. 45. Unexpected SAE Reporting timelines in India Clinical Trials Site To sponsor: 24 hrs Site to EC : 7 working days Sponsor to DCGI: 14 calendar days Sponsor to Other Investigators: 14 calendar days Post-marketing • Site To sponsor: 24 hrs • Sponsor to DCGI: 15 calendar days
  46. 46. Clinical Trial Design
  47. 47. Types of Trials • Open Label Trial – Both Investigator and Patients knows the full details of the treatment • Single Blind- Investigator knows the details of the treatment but patient does not. • Double Blind- Neither investigator nor patients is aware of the treatment details. • Triple Blind- Investigator, Patients and statistician are blinded
  48. 48. Randomized Controlled Trials (RCT) Randomization • Participants are allocated at random . Control • It may be standard practice (an active comparator), placebo or no interventions. • The RCT is one of the simplest and most powerful tools in clinical research
  49. 49. DCGI : (Drugs Controller General of India) • Approval for marketing a new drug in India requires DCGI approval • Drug approval process in India is as per Schedule Y guidelines • Process is closely associated with ICH GCP guidelines
  50. 50. The journeyThe journey towards becoming an attractive new destination fortowards becoming an attractive new destination for clinical researchclinical research Acceleration Acceptance Attraction 1992 1996 2000 2004 2008 2012 61 Companies 100 CROs 80 Hospitals 150 Investigators registered with US FDA
  51. 51. Growth of Indian Clinical Trial IndustryGrowth of Indian Clinical Trial Industry 35 120 160 300 1000 0 200 400 600 800 1000 1200 2002 - 03 2005 - 06 2006 - 07 2007 - 08 2009 - 2010 USD(Million) Year Growth of Indian Clinical Trial Industry As per FICCI - Ernst & Young Survey Report 2008, India can attract between 5 - 10% of the global contract research outsourced market (all services including chemistry, toxicology and clinical research) over next 5 years.
  52. 52. Clinical Trial Registry India • An online register of clinical trials being conducted in India • Mission • Registration with full disclosure of clinical trials to be conducted in India • Registration of trial prior enrollment of first participant 60
  53. 53. An Overview: Drug DevelopmentAn Overview: Drug Development TimelineTimelineCONCEPT CLINIC Pre-clinical Clinical
  54. 54. Clinical Trials from IndiaClinical Trials from India (; 15 Apr08)(; 15 Apr08) 1 10 100 1000 10000 100000 Phase of trial No.Trials(Logtransformed) India 32 165 394 63 USA 6324 11305 5683 2474 All 8540 16878 11662 6142 Phase-1 Phase-2 Phase-3 Phase-4
  55. 55. Clinical Trial - Phases 63 1-5 yrs Hundreds- thousands Subjects with indications New indications, QoL, surveillance IV 2-3 yrs Hundreds- thousands Subjects with indications Safety & efficacy Basis for labeling, new formulations III 1-2 yrsSeveral hundred Subjects with indications Short-term side effects & efficacy II 6-12 months 20-100 Healthy volunteers or subj. w/ indications Safety, ADME, bioactivity, drug-drug interaction I Length (per Phase) ScopeSubjectsPurposePhase 21 CFR 312.21
  56. 56. Conclusion Clinical trial is a human experiment designed to study the efficacy and safety of a new drug/intervention involves Phase 1-4 with specific objectives and end results Application to Regulatory authority: IND – Permission to conduct CT • NDA – Permission to Market New drug Well designed and effectively executed clinical trials form the base of therapeutic decisions CT must follow guidelines & protocol to ensure well- being of participants