Clinical trials

clinical trials history and types

1. CLINICAL TRIALS HISTORY AND TYPES Presented by PAVAN REDDY 2 nd SEM M.PHARM (PHARMACOLOGY) COPS ,DSU

2. Introduction to clinical trials A clinical trial or study is defined by the International Conference on Harmonisation Principles of Good Clinical Practice (ICH GCP) as being any investigation in human subjects intended to discover or verify the clinical, pharmacological and/or other pharmacodynamic effects of an investigational product(s), and/or to identify any adverse reactions to an investigational product(s), and/or to study ADME of an investigational product(s) with the object of ascertaining its safety and/or efficacy .

3. History of CT before 1750 Persian physician and philosopher, Avicenna In The Canon of Medicine, he laid down rules for the experimental use and testing of drugs and wrote a precise guide for practical experimentation in the process of discovering and proving the effectiveness of medical drugs and substances. He laid out the following rules and principles for testing the effectiveness of new drugs and medications.

4. History Perhaps the first ever clinical trial was James Lind’s demonstration in 1753 that citrus fruits cured scurvy. He compared the effects of various different acidic substances ranging from vinegar to cider, on groups of sailors, and found that the group who were given oranges and lemons had largely recovered from scurvy after 6 days.

5. Why do we need clinical trial? Clinical trials also allow testing and monitoring of the effect of a treatment on a large number of people to ensure that any improvement as a result of the treatment occurs for many people and is not just a random effect for one person. Most modern medical treatments are a direct result of clinical research

6. Why clinical trials standardized? Untill 19 th century there was no proper standard image for conducting trials. On literature review it was found that that there was no focus on ethical consideration from year 1930 to 1960 During the clinical trials as a consequence, there were tragedies associated with high morbidity and mortality. Potential rationale behind all these tragedies were non scientific conduct, misinterpretation of safety data, inadequate preclinical data on safety and efficacy, victims treated as guinea pigs, lack of pharmaco-vigilance evidence, lack of attentiveness in clinical researchers engaged in patient care, inappropriate patient consent, hindrance/slow withdrawal even

7. Tragedies Tuskegee Syphilis study (1932-1972) : In Albama Conducted for 40 yrs Participants were not informed about studies Aim was to investigate the progression of syphilis National research act founds national commission on for the protection of human subjects Sulfanilamide disaster 1937 East virginia Death of 100 Sulfanilamide as antibacterial for streptococcal infection Federal Food and Drug Act, 1938 was established in response to this tragedy making the premarketing safety data for novel drugs mandatory.

8. Regulatory bodies USA : FDA UK : MHRA (medicines and healthcare products regulatory agency) EU : EMEA (European medicines agency) INDIA : CDSCO (Central drugs standard control organization)

9. Phases of Drug Development

10. Phase IV of Clinical Trial Post Marketing Trials Objectives : -fulfill post approval regulatory requirements -differentiate the new drug from other marketed products

11. Pre-clinical studies Preclinical studies involves in-vitro and in-vivo (animal or cell culture) Therapeutic index (safety and efficacy evaluation) PHARMACOKINETICS study of a drug toxicity information. These studies help pharmaceutical companies to decide whether a drug candidate has scientific merit for further development as an investigational new drug (IND)

12. IND Application Once preclinical studies indicated the safety and efficacy of a drug an IND application has to be filed with regulatory authorities For obtaining regulatory approval for phase 1, 2 and 3 clinical evaluation

13. Phase 0/ Microdosing Study of new drug in micro doses to derive pk info in human before undertaking phase1 studies is called phase 0 Objective: T o obtain preliminary pk data Preclinical data: sub acute toxicity in one species by 2 ROA Micro dose: less than1/100 of the dose of a test substance calculated to produce pharmacological effect with a max dose 100 micrograms

14. Phase I First stage of testing in human subjects Designed to assess the safety, tolerability, PK and PD of drug 20-25 volunteers Duration : 6-12 months Aim : to determine maximum tolerated dose (MTD) of the new treatment

15. Phase II Consists of 20-300 subjects To confirm effectiveness, monitor side effects and further evaluate safety Duration: 6 months to several years First in patients who have the disease that the drug Is expected to treat For new actions of a marketed drug, start with phase2

16. Phase II

17. Phase III (Most typical kind of study: Therapeutic Confirmatory) Phase III are randomized controlled multicenter trials on large patient groups (300-3000) or more depending upon the disease/medical condition studied. Phase III has two key goals: 1. To demonstrate the therapeutic efficacy of the drug in a representative sample of the population at which the treatment is targeted. 2. To demonstrate the safety and tolerability of the drug in a sufficient large sample of the population at which the drug is targeted.

18. Phase IV(post marketing surveillance) Within a regulatory framework, Phase IV trials are generally considered as ‘ post-registration’ trials : that is, trials of products that already have a marketing authorization. No fixed duration or patient population Helps to detect rare ADRs, drug interactions and also to explore new uses for drugs Phase IV is used to indicate the set of clinical studies performed after the approval indications and restrictions imposed by the Summary of Product Characteristics.

19. Periodic safety update reports To be submitted by the manufacturer every 6 months for 2 years and then annually for next 2 years after marketing approval Harmful effects discovered may result in a drug being no longer sold, or restricted to certain uses

20. Aims of phase IV Comparisons between the new treatment and frequently used current treatment Pharmaco-economic assessments , intended to extend the information obtained in phase I Pharmacodynamic assessments

21. PHASE I PHASE II PHASE III PHASE IV OBJECTIVE DETERMINE THE 1. PHARMACOLOGICAL ACTION 2. METABOLISM 3. MAXIMUM TOLERATED DOSE. EVALUATE EFFECTIVENESS SHORT-TERM SIDE EFFECTS IDENTIFY COMMON RISKS. OBTAIN ADDITIONAL INFORMATION ABOUT EFFECTIVENESS ON CLINICAL OUTCOME RISK-BENEFIT RATIO MONITOR ONGOING SAFETY IN LARGE POPULATION ADDITIONAL USES THAT MIGHT BE APPROVED BY FDA. FACTORS TO BE INDENTIFIED BIOAVAILABILITY BIOEQUIVALENCE DOSE P’DYNAMICS P’KINETICS BIOAVAILABILITY DRUG INTERACTIONS EFFICACY P’DYNAMICS P’KINETICS DRUG INTERACTIONS DOSAGE INTERVAL RISK-BENEFIT RATIO EFFICACY SAFETY EPIDEMIOLOGICAL DATA EFFICACY SAFETY P’ECONOMICS DATA FOCUS VITAL SIGNS PLASMA AND SERUM CONCENTRATIONS ADVERSE EVENTS DOSE RESPONSE TOLERANCE ADVERSE EVENTS LABORATORY DATA EFFICACY ADVERSE EVENTS ADVERSE EVENTS P’ECONOMICS EPIDEMIOLOGY ADVERSE EVENTS DESIGN FEATURES UNBLINDED PLACEBO CONTROLLED COMPARISONS ACTIVE CONTROLLED COMPARISONS RANDOMIZED CONTROLLED OBSERVATIONAL DURATION UPTO ONE MONTH SEVERAL MONTHS SEVERAL YEARS ONGOING(FOLLOWING FDA APPROVAL) POPULATION HEALTHY VOLUNTEERS OR INDIVIDUALS WITH TARGET DISEASE (CANCER, HIV) INDIVIDUALS WITH TARGET DISEASE INDIVIDUALS WITH TARGET DISEASE INDIVIDUALS WITH TARGET DISEASE AS WELL AS NEW AGE GROUPS, GENDERS SAMPLE SIZE 20-80 2000-300 HUNDREDS TO THOUSANDS THOUSANDS

22. Phase Objectives I The earliest types of studies that are carried out in humans. They are typically done using small numbers of healthy subjects and are to investigate pharmacodynamics, pharmacokinetics and toxicity . II Carried out in patients, usually to find the best dose of drug and to investigate safety . III Generally major trials aimed at conclusively demonstrating efficacy . They are sometimes called confirmatory trials and, in the context of pharmaceuticals, typically are the studies on which registration of a new product will be based. IV Studies carried out after registration of a product . They are often for marketing purposes as well as to gain broader experience with using the new product.

23. References Textbook of clinical trials, wiley G eneral c onsiderations for c linical t rials, current step 4 version dated 17 july 1997 www.clinicaltrials.gov https://www.nccn.org/patients/resources/clinical_trials/phases.aspx