ICH-GCP (Aarti pal).pptx M PHARMACY Regulatory perspective of clinical trials

Regulatory perspective of clinical trials, phases of clinical trials,ICH-GCP Principles

1. PRESENTATION ON Regulatory Perspectives of Clinical Trials: origin and principles of (ICH-GCP) guidelines SUBMITTED BY- AARTI PAL ROLL NO:13 M. PHARM (PHARMACOLOGY) 2 nd SEMESTER SUBMITTED TO- DR. MANJUSHA CHAUDHARY ASSISTANT PROFESSOR INSTITUTE OF PHARMACEUTICAL SCIENCES,KUK

2. CONTENTS : Introduction i ) clinical trial ii) Drug review steps iii) phases of clinical trial iv) Drug development phases v) Drug development process Clinical Research Regulations Clinical Research Regulation in India Regulatory bodies 5) ICH (International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use 7) GCP (Good Clinical Practices) 8) Principles of ICH-GCP Guidelines

3. 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. Clinical trials are conducted only when : satisfactory information has been gathered on the quality of the nonclinical safety health authority/ethics committee approval is granted in the country where approval of the drug is sought. Clinical Trial is the mainstay for bringing out New Drugs to the Market. INTRODUCTION:

4. 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

5. 1 . Preclinical (animal) testing. 2. An investigational new drug application (IND): outlines what the sponsor of a new drug proposes for human testing in clinical trials. 3. Phase 1 studies 4. Phase 2 studies 5. Phase 3 studies 6. Submission of New Drug Application (NDA) is the formal step asking the FDA to consider a drug for marketing approval. 7. FDA reviewers will approve the application or find it either "approvable" or "not approvable." 8. Phase 4 studies Drug Review Steps:

6. Clinical Drug Development Phase

7. Phases of clinical trial

8. Drug Development Process

9. Study of new drug in microdoses to derive PK information in human before undertaking phase I studies is called PHASE O Microdose: Less than 1/100 of the dose of a test substance calculated to produce pharmacological effect with a max dose ≤100 micrograms Objective: To obtain preliminary Pharmacokinetic data. Preclinical Data: Subacute toxicity study in one species by two routes of administration. These are very 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. Phase 0 study / Microdosing

10. First stage of testing in human subjects Designed to assess the safety, tolerability, PK and PD of drug. 20-100 healthy volunteers Patients: Anticancer drugs, AIDS therapy Duration: 6-12 months No blinding / Open labelled 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 Phase 1

11. 1. Primary i . Tolerability and Safety ii. Pharmacokinetics 2. Secondary iii. Pharmacodynamics Phase 1 study: objectives

12. 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 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 Phase II:

13. 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. • 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 Phase III Objectives

14. 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 NDA : New Drug Application

15. 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 Done after drug has been marketed Post Marketing Surveillance (PMS). No fixed duration / patient population studies continue to collect data about effects in various populations & side effects from long term use. These are primarily observational or non- experimental in nature . Phase IV

16. 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 Phase IV : Objectives

17. Why are Regulation important to clinical Research? Regulations has been set to Ensure integrity of data collected from clinical trials which assure the safety, right and welfare of the subject. Clinical trials are the only way of establishing the safety and efficacy of any new drug before its introduction in the market for human use. Clinical trials (with safeguards) are necessary for introduction of new drugs for a country like India, considering its disease burden and emergence of new variants of disease. The regulatory bodies need to frame guidelines and regulatory approval processes on a par with international standards. Many of the new laws, guidance documents, notifications and initiatives for regulating pharmaceutical industry were in the charts for quite a long time. Indian regulatory authorities have started looking into speedy implementation and providing support in terms of necessary infrastructure and investment. CDSCO which comes under the Ministry of health and family welfare Is the main body which works On development of regulatory Procedures And standard for drugs, cosmetics, diagnostics and devices. It lays down regulatory guidance by amending acts and rules; and regulate new drugs approvals. Its main objective is to standardize clinical research and bring safer drugs to market. Clinical Research Regulations

18. Schedule y allows Clinical trials to be carried out in India. India has appropriate provisions to ensure the human subjects used for the trails are informed Well and their participation is voluntary. CDSCOs priorities to enhance the current mechanism Establish single window clearance for approvals. Fix timelines for each application(2-6 weeks). Subject experts-reviewers - internal/external. Staff and infrastructure at one site. Continuous training for the officers. Clinical Research Regulations in India

19. Central Drugs Regulatory body Standard Control controlled and Organization governed by (CDSCO) drug directorate General of Health Services of Ministry of Health and Family Welfare which regulates drugs in India Drugs Controller Regulatory agency General India (DCGI): Under the government of India whose function is to assess the quality, safety and efficacy of a drug. Indian Council of Medical Research (ICMR); Apex body in India that formulates, co-ordinates and promotes biomedical research Drugs consultative committee (DCC); Provides technical guidance to the central drug standard control organization Central Drugs Laboratory (CDL); National statutory laboratory of the Indian government for quality control of drugs. Drugs Technical Advisory Board (DTAB) Provides technical guidance to the CDSCO Regulatory bodies in India

20. USA : United States food and drug administration(USFDA) INDIA : Central drug standard control organization(CDSCO) CANADA : Health Canada – sante canada AUSTRALIA : Therapeutic goods administration( TDA) UK : Medicine and health care products and regulatory Agencies (MHRA). EUROPE : European medicines agency(EMEA) SWITZERLAND : Swissmedic JAPAN : Ministry of health and labour welfare(MHLW) The world wide Regulations

21. The Central Government constitute a Board (to be called the Drugs Technical Advisory Board) to advise the Central Government and the State Governments on technical matters arising out of the administration of D&C, Act 1940 Drug Technical Advisory Board (DTAB)

22. ICH is a joint initiative involving both the regulators and the industry as equal partners in the scientific and technical discussions of the testing procedures which are required to ensure and assess the safety, quality and efficacy of medicines. What is ICH How did it evolve? The need to harmonize Public disasters, serious fraud and abuse of human rights. Trials of War criminals-Nuremberg code 1949 Thalidomide- Declaration of Helsinki 1964 Belmont report 1978( Ethical Principles and guidelines for the protection of human subjects of research)-Tuskegee syphilis study

23. The thalidomide disaster

24. To discuss and define the minimum standards for the development and registration of investigational products 6 parties EU EFPIA : European federation of pharmaceutical industries' associations MHLW : Ministry of health, Labor and welfare, Japan JPMA: Japan Pharmaceuticals manufacturers Association US FDA PhRMA Observers: WHO, TPP ( canada ) International federation of Pharmaceutical manufacturer's association Key objective ICH parties

25. Efficacy: clinical trials etc Safety: pharmacovigilance, adverse drug reaction reporting Quality: raw materials, impurities, residual solvents etc Multidisciplinary: common technical document, electronic submission, coding systems ICH Guidelines: examples

26. A standard for the design, conduct, performance, monitoring ,auditing , recording, analyses and reporting of clinical trials that provide assurance that the data and the reported results are credible, accurate and that the rights, integrity and confidentiality of trial subjects are protected Why is it needed? To ensure the rights, safety and well being of the trial subjects are protected Ensure the credibility of clinical trial data GCP (Good Clinical Practices) :

27. Good clinical practice (GCP) is an international ethical & scientific standard for conducting clinical trials that involve the participation of human subjects Compliance with this standard provides public assurance that the rights, safety & well-being of trial subjects are protected, which is consistent with the principles outlined in the declaration of Helsinki . GCP also ensures the credibility of clinical trial data. ROLE OF GCP

28. 1 . Glossary Common language for investigators/sponsors/ethics committees 2. Principles of Good Clinical Practice : 13 tenets of ICH GCP 3. Requirements for IRB/IEC : Roles responsibility and composition 4. Responsibilities of the investigator 5. Responsibilities of the sponsor 6. Requirements for clinical trial protocol and protocol amendments 7. Responsibility of the sponsor in the development of investigator's brochure. 8. Essential documents ICH GCP guideline

29. 1 . Clinical trials should be conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki, and that are consistent with GCP and the applicable regulatory requirement(s) 2. Before a trial is initiated, foreseeable risks and inconveniences should be weighed against the anticipated benefit for the individual trial subject and society. A trial should be initiated and continued only if the anticipated benefits justify the risks. 3. The rights, safety, and well-being of the trial subjects are the most important considerations and should prevail over interests of science and society. Principles of ICH- GCP

30. The available nonclinical and clinical information on an investigational product should be adequate to support the proposed clinical trial. Clinical trials should be scientifically sound, and described in a clear, detailed protocol. A trial should be conducted in compliance with the protocol that has received prior institutional review board (IRB)/independent ethics committee (IEC) approval/favorable opinion. 7. The medical care given to, and medical decisions made on behalf of, subjects should always be the responsibility of a qualified physician or, when appropriate, of a qualified dentist.

31. Each individual involved in conducting a trial should be qualified by education, training, and experience to perform his or her respective task Freely given informed consent should be obtained from every subject prior to clinical trial participation. All clinical trial information should be recorded, handled, and stored in a way that allows its accurate reporting, interpretation and verification. The confidentiality of records that could identify subjects should be protected, respecting the privacy and confidentiality rules in accordance with the applicable regulatory requirement(s). Investigational products should be manufactured, handled, and stored in accordance with applicable good manufacturing practice (GMP). They should be used in accordance with the approved protocol. 13. Systems with procedures that assure the quality of every aspect of the trial should be implemented.

32. SAFEGUARD PUBLIC HEALTH ASSURE CONSUMER PROTECTION STANDARDS FACILITATE AVAILABILITY OF SAFE AND EFFECTIVE PRODUCTS ELIMINATE INCONSISTENT STANDARDS INTERNATIONALLY FACILITATE MUTUAL ACCEPTANCE OF DATA FROM CLINICAL TRIALS GOALS OF INTERNATIONAL HARMONIZATION OF REGULATORY REQUIREMENTS

33. Clinicaltrials.gov Wikipedia WWW.cancerresearchuk.org WWW.centrewatch.com > home > clinical trials Images: Google Images https://www.slideshare.net/VharshiniManoharan/phases-of-clinical-trials REFERENCE: