CLINICAL STUDY AND BASIC CONCEPT GOOD CLINICAL PRACTICE

1. CLINICAL STUDY AND BASIC CONCEPTGOOD CLINICAL PRACTICE Presented by: Aarohi Shah M.Pharm Dept of Pharmaceutics and Pharmaceutical Technology

2. CLINICAL STUDY AND BASIC CONCEPT What is a Clinical Trial? • A clinical trial (clinical research) is a research study in human volunteers (preclinical trail – in animals) to answer specific health questions. • Carefully conducted clinical trials are the fastest and safest way to find treatments that work in people and ways to improve health.

3. CLINICAL STUDY AND BASIC CONCEPT Types of clinical trials • Treatment trials • Prevention trials • Diagnostic trials • Screening trials • Quality of Life trials

4. CLINICAL STUDY AND BASIC CONCEPT Clinical trials, FDA approval • Before a company initiates clinical trials (i.e. testing in humans), it must conduct extensive experiments in animal and human cells and in live animals (Preclinical Trial) • If this stage of testing is successful, the company files an Investigational New Drug (IND) application with the Food and Drug Administration (FDA) to request permission to conduct clinical trials.

5. CLINICAL STUDY AND BASIC CONCEPT

6. CLINICAL STUDY AND BASIC CONCEPT Preclinical trials Trial carried out on to the animal species Objective: To evaluate safety, toxicity and tolerance data (by applying the factor for conversion of animal data to human data) Study • Drug metabolism pathway • PK of the drug • PK-PD relation • Protein binding • Tissue distribution • Development of methodology for quantification of drug and metabolite in biological fluid • Long term toxicity • Placental transfer kinetic

7. CLINICAL STUDY AND BASIC CONCEPT Phase 1 Trial carried out on healthy volunteers except AIDS or Cancer. Study • Dose-concentration (in plasma)-response-toxicity study • IV, single dose study (for checking bioavailability) • Radioactive tracer study (for evaluation of first pass metabolism) • Evaluation of suitability of preclinical animal model (to predict pharmacological effect in human) • Effect of food

8. CLINICAL STUDY AND BASIC CONCEPT Phase 2 First time trial on patient and conducted in OPEN manner Study • Evaluation of difference in PK and PD between the healthy volunteer and patient • To search new therapeutic effect of the drug

9. CLINICAL STUDY AND BASIC CONCEPT Phase 3 Study • Search less common side effect of drug (which is conc. independent) • Comparison with the marketed drug • Drug-drug interaction • Study in special population like age, sex race etc. • Develop the dosage form

10. CLINICAL STUDY AND BASIC CONCEPT Phase 4 • Post marketing surveillance • Not well planned study but random study • Some rare side effect or toxicity may come out

11. GOOD CLINICAL PRACTICE Good Clinical Practice (GCP) is an international ethical and scientific quality standard for designing, recording and reporting trials that involve the participation of human subjects. Compliance with this standard provides public assurance that the rights, safety and well being of trial subjects are protected, consistent with the principles that have their origin in the Declaration of Helsinki, and that the clinical trial data are credible. Regulations tell you what you are required to do by law. Guidelines tell you the best way to do it

12. GOOD CLINICAL PRACTICE FDA GCP Regulations • Regulations contained in 21 CFR Part 50, 56, and 312 • Part 50 (applies to consenting of subjects), • Part 56 (applies to IRB responsibilities) and • Part 312 (applies to IND submissions, sponsor responsibility, and investigator responsibility) GCP Guidelines- International Conference on Harmonization • The objective of ICH GCP Guidelines is to provide a unified standard for European Union, Japan and United States to facilitate the mutual acceptance of clinical data by the regulatory authorities in the jurisdiction. • Published by the FDA in Federal Register in May, 1997 • Adopted by all parties as GCP standard (considered law in European Union; considered “final guidance” in the US) • Based on the Declaration of Helsinki

13. GOOD CLINICAL PRACTICE Some important terms (Glossary) • Investigator • Sponsor • Subject /Trial Subject • Investigator’s Brochure • Non Clinical Study • Protocol • Blinding (Masking) • Institutional Review Board (IRB) • Adverse Event (AE) • Serious Adverse Event (SAE)

14. GOOD CLINICAL PRACTICE Elements of GCP • IRB • Investigator • Sponsor • Clinical trial protocol and protocol amendments • Investigator Brochure • Essential documents

15. GOOD CLINICAL PRACTICE Institutional review board (IRB) or Independent Ethics Committee (IEC) • It consists of reasonable number of members, who collectively have qualifications and experience to review and evaluate the science and medical aspects as well as ethics of proposed trials. • It should perform the functions in accordance with written procedures, maintain written records of its activities and minutes of its meetings and should comply with GCP. • Acts as a safe guard to the rights of the trial subject • Should consider the qualification of the investigator for the proposed trial • Should conduct continuing review of each ongoing trial at intervals appropriate to the degree of risk.

16. GOOD CLINICAL PRACTICE Investigator Qualified to perform study should have • Appropriate education, training and experience to assume responsibility and should provide evidence of such qualifications. • Sufficient time to devote to study timelines. • Personally conduct or supervise study. • Adequate and qualified staff and facilities. • Awareness of and compliance with GCP. • Familiar with the investigational product and inventory. • Adherence to protocol requirements. • Inform subject’s primary physician • Ensure adequate medical care for SAEs. • Maintained records should be accurate, complete, legible and timely.

17. GOOD CLINICAL PRACTICE Investigator-Communication with IRB • Obtaining written and dated IRB approved consent form • Submission of Investigational Brochure • Ongoing communication Report of SAEs IND Safety Reports Significant protocol deviations • The investigator should submit written summaries of the status of the trial to the IRB annually or more frequently, if requested by the IRB

18. GOOD CLINICAL PRACTICE Investigator- Communication with the Sponsor/CRO • Reporting of any AEs or SAEs • Notification of changes in staff and address • Retention of all pertinent study information and records until notified in writing that records are no longer required • Coordination of publication plans • If trial is blinded, the investigator should promptly document and explain to the sponsor any: Premature unblinding Accidental unbliniding Unblinding due to serious adverse events

19. GOOD CLINICAL PRACTICE Investigator-Communication with Study Subjects • Obtaining valid written informed consent • The information language should be non-technical and understandable to the subject/LAR/impartial • Provide subject a copy of a fully executed consent • Provide subject with any new information • Answer questions at any time • The investigator must inform the subject when medical care is needed for inter-current illness(es) of which investigator becomes aware. • It is recommended that the investigator inform subject’s primary physician about subject’s participation in study. • If subject wishes to withdraw from the study, the investigator should make reasonable effort to ascertain the reasons – while fully respecting the subject’s rights.

20. GOOD CLINICAL PRACTICE Investigator- Investigator – Compliance with Protocol • The investigator should conduct the trial in compliance with: • The protocol agreed to by the sponsor • If required, protocol agreed to by the regulatory authority(ies) • Ultimately given approval by the IRB • The investigator should not implement any deviation from, or changes of the protocol without: • Agreement by the sponsor • Prior review and documented approval from the IRB of an amendment • Exception: where necessary to eliminate an immediate hazard (s) to trial subjects or when the changes involve only logistical or administrative aspects of the trial. However, as soon as possible, the implemented deviation or change, the reason for it, and, if appropriate, the proposed protocol amendment(s) should be submitted to: • The IRB for review and approval • To the sponsor for agreement • If required, to the regulatory authorities

21. GOOD CLINICAL PRACTICE Investigator – Investigational Products • It is the investigator’s responsibility for investigational product(s) accountability at the trial site • The investigator or person who is designated by the investigator should maintain records of: • The product(s) delivery to the site • The inventory at the site • The use by each subject • The return to the sponsor or disposition of unused products • The records should include: Date, quantities, batch/serial numbers, expiration dates and the unique code numbers assigned to the product(s) and subjects • Products should be stored as specified by the sponsor and in accordance with applicable regulatory requirements • Should explain to the subject: • Correct use of the product • Should check at appropriate intervals that the subject is following the instructions properly to use the product

22. GOOD CLINICAL PRACTICE Investigator – Records and Reports • Records should be accurate, complete, legible and timely pertinent to the data reported to the sponsor in the CRFs (Case Report Forms) and other required reports • All corrections to a CRF should be dated, explained and should not obscure the original entry whether the entry is written or electronic changes or corrections. • The investigator should retain records of the changes and corrections.

23. GOOD CLINICAL PRACTICE Investigator’s Brochure • For investigational (not FDA-approved) drug trials • Summary of significant physical, chemical, pharmaceutical, pharmacological, toxicological, pharmacokinetic, metabolic, and clinical information that is relevant to the investigational product • Relevant animal and clinical studies, adverse events, etc.

24. GOOD CLINICAL PRACTICE FDA Form 1572 – to initiate clinical trials • Investigator agrees to comply with conditions required by FDA for use of investigational articles • “Contract” that the investigator signs/dates • “Warning: A willing false statement is a criminal offense” Content of Form 1572 • Principal Investigator name/address • Name/address of site(s) of study conduct • Name/address clinical labs (local/central) • Name/address IRB • Names of key personnel with study participant contact • Submit CVs of key personnel (signed/dated) listed in form

25. GOOD CLINICAL PRACTICE Progress Reports • The investigator should submit written summaries (where required by applicable regulatory requirements) of the trial’s status to the institution. • The investigator should submit written summaries of the status of the trial to the IRB annually or more frequently, if requested by the IRB • The investigator should promptly provide written reports to the sponsor and the IRB and where required by the regulatory authorities, the institution on any changes significantly affecting the trial and/or increasing the risk to subjects.

26. GOOD CLINICAL PRACTICE Safety Reporting • All serious adverse events (SAE) should be reported immediately to the sponsor except for those SAEs that the protocol or other document identifies as not needing immediate reporting • The immediate and follow up reports should identify Subjects by unique code numbers assigned to trial, but not with identifiers (name, address, identification numbers) • The immediate reports should be followed promptly by detailed, written reports • Adverse events and/or laboratory abnormalities identified in the protocol as critical to safety evaluations should be reported to the sponsor within the time periods specified by the sponsor in the protocol • For reported deaths, the investigator should supply the sponsor and the IRB with any additional requested information (e.g., autopsy reports and terminal medical reports)

27. GOOD CLINICAL PRACTICE Premature Termination or Suspension of a Trial • If the trial is suspended or prematurely terminated for any reason the investigator should promptly Inform the trial subjects, should assure appropriate therapy and follow-up and where required, should inform the regulatory authorities and the IRB • If the investigator terminates or suspends a trial without prior agreement of the sponsor, the investigator should inform the institution, regulatory authorities(if required), the sponsor and the IRB with detailed written explanation of the termination or suspension • If the sponsor terminates/suspends a trial, the investigator should promptly inform the institution (per applicable regulatory requirements) and the IRB and provide written explanation of the termination/suspension • If the IRB terminates/suspends its approval, the investigator should inform the institution and the investigator should promptly notify the sponsor and provide the sponsor with a detailed written explanation of the termination or suspension

28. GOOD CLINICAL PRACTICE Final Report • Upon the completion of the trial, the investigator should inform and provide the IRB and the sponsor: • All required reports • Summary of the trial’s outcome • Reports to regulatory authorities if applicable

29. GOOD CLINICAL PRACTICE Records Retention Requirements • Essential documents should be retained until at least two (2) years after the last approval of a marketing application in an ICH region. • These documents should be retained, however, if required by the applicable regulatory requirements (state or federal) or by an agreement with the sponsor. • It is the responsibility of the sponsor to inform the investigator as to when these documents no longer need to be retained. • Upon request of the monitor, auditor, IRB or regulatory authority, the investigator/institution should make available for direct access all requested trial-related records.

30. References • www.fda.gov • www.google.com • EMEA, Inspections • Stanford school of medicine; FACILITATING TRANSLATIONAL RESEARCH AND MEDICINE CLINICAL RESEARCH

31. Thank You