Regulatory agencies

Main regulatory agencies involved in Clinical Trial in nutshell

1. Clinical Trials regulations Dr Urmila M. Aswar Department of Pharmacology, SIOP, Narhe

2. Investigational New Drug Application Current Federal law requires that a drug be approved for marketing application before it is transported or distributed across state lines. But in case of investigational drug, it is required by clinical investigators in many states. IND is an exemption.

3. FDA's role in the development of a new drug begins when the drug's sponsor (usually the manufacturer or potential marketer) having screened the new molecule for pharmacological activity and acute toxicity potential in animals, wants to test its diagnostic or therapeutic potential in humans.   At that point, the molecule changes in legal status under the Federal Food, Drug, and Cosmetic Act and becomes a new drug subject to specific requirements of the drug regulatory system.

4. Animal Pharmacology and Toxicology Studies

5. Manufacturing Information   Composition, manufacturer, stability, and controls used for manufacturing the drug substance and the drug product.  This information is assessed to ensure that the company can adequately produce and supply consistent batches of the drug. Lic form-29 is taken for mfg of new drug

6. Clinical Protocols and Investigator Information Detailed protocols for proposed clinical studies to assess whether the initial-phase trials will expose subjects to unnecessary risks.  Information on the qualifications  of clinical trial team. Informed consent  from the research subjects, to obtain review of the study by an institutional review board (IRB) , Adherence to the investigational new drug regulations.

7. Review by FDA Once the IND is submitted, the sponsor must wait 30 calendar days before initiating any clinical trials.  During this time, FDA (DCGI/CDSCO)   has an opportunity to review the IND for safety to assure that research subjects will not be subjected to unreasonable risk.

8. Summary An application to conduct clinical trials in India should be submitted along with the data of chemistry, manufacturing, control and animal studies to DCGI. The date regarding the trial protocol, investigator's brochures, and informed consent documents should also be attached. A copy of the application must be submitted to the ethical committee and the clinical trials are conducted only after approval of DCGI and ethical committee. To determine the maximum tolerated dose in humans, adverse reactions, etc.

9. New Drug Application The new drug registration (using form no. 44 along with full pre-clinical and clinical testing information) is applied after the completion of clinical trials. The comprehensive information on the marketing status of the drug in other countries is also required other than the information on safety and efficacy. The information regarding the prescription, samples and testing protocols, product monograph, labels, and cartons must also be submitted. Schedule Y of D&C act, provides the guidelines and requirements for clinical trials. The application can be reviewed in a range of about 12- 18 months Then the permission is granted.

10. Regulatory bodies in World USA: FDA, Dept of health and human services Canada: Health Canada UK: Medicines and Healthcare products regulatory agency (MHRA) EU: European Medicines Agency (EMEA) Japan: Pharmaceutical and Medical Devices agencies (PMDA) India:

11. Regulating bodies in India The Drug and Cosmetic Act 1940 and Rules 1945 were passed by the India's parliament to regulate the import, manufacture, distribution and sale of drugs and cosmetics. The Central Drugs Standard Control Organization (CDSCO), The Drugs Controller General (India) [DCGI] was established.

12. NDA

13. Regulatory requirements for clinical trials Before starting trial Consent of investigator Approval by IRB..approval of protocol, site, Approval from ICMR in case of new molecules developed in India Informed consent Insurance cover for trial related injury

14. During the conduct Compliance with the trial protocol Reporting protocol violations to EC Seek approval for protocol amendments Adherence to GCP Record all adverse effects Record of all serious adverse effects to sponsor in 24 hr Notification of fatal adv effect to RB Review the progress of results of study Send periodic status of study.

15. Post trial requirement Site close out Check investigational product utilization Analyze the data using statistical softwares Forward the report from investigator to EC Seek new drug approval. Prepare and submit the prescribing information for ND to the authorities

16. Newly approved drugs Gilotrif  ( afatinib ) Tablets: for lung cancer Boehringer Ingelheim Pharmaceuticals Khedezla  ( desvenlafaxine ): for depression Osmotica Pharmaceutical Corp.

17. REGULATORY BODIES

18. Regulations: Actually not new

19. Clinical trials: World wide Follow ICH/WHO, GCP provides universal standards US, Canada, EU, Japan, Australia and India

20. USFDA: Achievements in Clinical Research (1975-2000) Ethical Principles and Infrastructure (IRBs) Evidence-Based Decision-Making Safety; Efficacy Standards of Research Conduct (GCP) International Harmonization Quality Improvement

21. Why so much strict: A Change in Clinical Trials More clinical investigators More studies More participation of vulnerable populations Children, Elderly, Ethnic Groups, etc. More “outsourcing” (CRO’s, SMO’s) New technologies Global expansion Countries/areas new to GCP

22. CT Disasters in history: A lesson May 1999: NY Times, “Research for Hire. A Doctor’s Drug Studies Turn into Fraud” September 1999: Death in gene therapy trial December 2000: Washington Post series “The Body Hunters” June 2001: Death in lung physiology trial

23. FDA’s Mission FDA has a broad public protection mission Ensure the safe use of regulated products that are themselves safe and efficacious Approvals: Based on complete and accurate information from well-designed, ethically-conducted, and well-monitored clinical research

24. FDA’s Mission in Clinical Research Ensure Implementation of Good Clinical Practice (GCP) Standards GCP is an international ethical and scientific quality standard for designing, conducting, recording, and reporting trials that involve the participation of human subjects GCP embraces trial objectives, trial design, study oversight, data collection and quality assurance, study analysis, as well as human subject protection in studies that support product applications

25. Good Clinical Practice GCP is most fundamentally a System of Shared Responsibilities Clinical Investigators Institutions/Institutional Review Boards Industry (Sponsors/Monitors) Government Regulators

26. FDA: Regulations Federal food, drug and cosmetic act, 1938 Orphan drug act 1983, Prescription drug user fee act, 1992 (PDUFA). Food and drug modernization act 1997, (FDAMA)

27. 3 approaches for treating serious diseases Fast track : to get important new drug to the patient ealier . For no therapy/ superior new drug. Accelerated approval : allows earlier approvals of drugs to treat serious diseases or fills an unmet medical need based on a surrogate endpoint. S.endpoint means a lab test or a physical sign or survival. Post marketing trials become important. Continue or remove Priority review: the drugs that offer major advantage in the treatment or provide a treatment where no adequate therapy exists. Review time is reduced.

28. Federal food, drug and cosmetic act, 1938 Basic food and drug law in the US Food are pure and safe to eat Drugs and devices are safe to use Cosmetics are safe and made from appropriate ingredients .

29. Code for federal regulations (CFR) The CFR is divided into 50 titles SECTION 21 OF CFR –regulations related to food and drugs. Part of CFR 21 give details of IND (312), NDA (314), orphan drugs (316)

30. Center for Biologics Evaluation and Research ( CBER) Section 505 of FD & C provide that no person can market a drug without filling IND. Dept of health and human services of FDA protects the rights of human in Clinical Trial. The   CBER is one of six main centers for the U.S. Food and Drug Administration, which is a part of the U.S. Department of Health and Human Services. CBER is responsible for assuring the safety, purity, potency, and effectiveness of biologics and related products (such as vaccines live biotherapeutics ( probiotics ), blood products, and cell, tissue, and gene therapies).

31. Center for Drugs Evaluation and Research ( CDER) The center reviews applications for new and generic pharmaceuticals, manages US current Good Manufacturing Practice ( cGMP ) regulations for pharmaceutical manufacturing, determines which medications require a medical prescription, monitors advertising of approved medications, and collects and analyzes safety data about pharmaceuticals that are already on the market. CDER reviews New Drug Applications to ensure that the drugs are safe and effective. Its primary objective is to ensure that all prescription and OTC medications are safe and effective when used as directed.

32. Bioresearch Monitoring Program FDA's Bioresearch Monitoring (BIMO) program is a comprehensive program of on-site inspections and data audits designed to monitor all aspects of the conduct and reporting of FDA regulated research. It assure the quality and integrity of data submitted to the agency in support of new product approvals. It provide for protection of the rights and welfare of the thousands of human subjects involved in FDA regulated research. It has become a cornerstone of the FDA preapproval process for new medicines, medical devices, food and color additives and veterinary products introduced to the U.S. consumer.

33. Post Ranbaxy, Wockhardt faces a hit as US FDA bans imports over quality concerns ET Bureau  May 24, 2013 The U.S. Department of Agriculture’s (USDA) Animal and Plant Health Inspection Service (APHIS)

34. Regulations-UK/EU Drugs are licensed for use in the UK with a European license or a national license. They are licensed through European Medicines Agency (EMEA) for Europe wide license and from Medicine and healthcare products regulatory agency (MHRA) for UK license. EMEA, Committee for orphan medicinal products (COMP): orphan drugs: 5/10,000

35. Centralized system in EMEA Drugs for AIDS NEURODEGENRATIVE DISEASES CANCER DIABETES ORPHAN DRUGS

36. Decentralized system in EMEA Other than the listed Apply for more than one country of EU With review of 1 country can be licensed in other.

37. Prior to 2004 the standards were guidelines and dual standards existed For the first time ethical and scientific standards for the set up, and conduct of clinical research involving human subjects receiving investigational medicinal products, became subject to law CLINICAL TRIAL REGULATIONS

38. EU Directives are legislation issued by the European Union defining an outcome or change that is binding for each member state EU Directives must be transposed into law for each member state to become law in that country In the UK this is achieved by the introduction of a Statutory Instrument named within an Act of Parliament, which then becomes the law European Directives & UK Laws

39. EU Clinical Trials Directive 2001/20/EC EU GCP Directive 2005/28/EC EU Legislation UK Legislation Medicines for Human Use (Clinical Trials) Regulations 2004 (SI 1031) Medicines for Human Use (Clinical Trials) Amendment Regulations 2006 (SI 1928) Amendment 2006 (SI 2964) Amendment 2008 ( SI 941) Amendment 2009 ( SI 1164) ‘Guidance’ EC Commission Eudralex – Volume 10 Clinical Trial guidelines ICH GCP Topic E6 – Good Clinical Practice Organisation/Sponsor SOPs Research Governance Framework for Health and Social Care Amendment 2010 (SI 1882)

40. Introduced to ensure that everyone follows the same GCP standards Clarified and standardised practice for the safety of the subject and the quality of the data. Major areas of change included: - The ethics review system came under the law - Each member state had to appoint a Competent Authority (MHRA in UK) - Strengthened consent for vulnerable groups - Amendments required to follow a process - Additional safety reporting requirements - All results have to be made available even if negative findings were found European Clinical Trials Directive 2001/20/EC

41. GCP principles are a standard for the design, conduct, performance, monitoring, auditing, recording, analyses and reporting of clinical trials that provides assurance that the data and reported results are credible and accurate, and that the rights, integrity and confidentiality of trial subjects are protected

42. GCP elements : MHRA inspection areas Trial initiation, approvals and completion Responsibilities of organisations and individuals Recruitment and informed consent processes Documentation and data quality Safety reporting / pharmacovigilance

43. Statutory Instrument 2004/1031 Transposed European Clinical Trials Directive 2001/20/EC into UK Law from 1 May 2004 Made amendments to the Medicines Act 1968 which regulated the supply of medicines for a clinical trial, but did not cover standards of conduct on a clinical trial SI 2004/1031 regulates the commencement and conduct of a clinical trial and the manufacture of medicinal products to be used (including placebo) Legislation: Medicines for Human Use (Clinical trials) Regulations 2004

44. The second EU Directive clarified and extends the first Major areas of change included: - Duties can be delegated, but not responsibilities - New requirements on sponsor and investigators in relation to Trial Documentation - Notification of serious breaches Statutory Instrument 2006/1928 Transposed European Clinical Trials Directive 2005/28/EC into UK Law from 29 August 2006 Makes amendments to the Medicines for Human Use (Clinical Trials) Regulations 2004 European Clinical Trials Directive 2005/28/EC

45. There have also been subsequent Statutory Instruments which govern the conduct of clinical research in the UK. The Statutory Instruments are: 2004/1031 (1 May 2004) – EU Directive 2001/20/EC transposed into law 2006/1928 (29 August 2006) – EU Directive 2005/28/EC transposed into law 2006/2984 (12 December 2006) – A&E trials without consent for adults without capacity 2008/941 (1 May 2008) – Research Ethics Committee membership and approval 2009/1164 (8 May 2009) – Urgent safety measures 2010/1882 (19 August 2010) – Advanced Therapy Medicinal Products All are available on the MHRA website www.mhra.gov.uk Other UK Regulations

46. Researchers work within other guidelines and laws, including Data Protection Act (1998) Protection of Children Act (1999) Mental Capacity Act (2005) Human Tissue Act (2004) Equality and Diversity Legislation Freedom of Information Act (2000) Welsh Language Act 1993/ 2011 Health Board Policies In addition …

47. DRUGS REGULATORY SYSTEM IN INDIA 53

48. Drugs and Health is in concurrent list of Indian Constitution It is governed by both Centre and State Governments under the Drugs & Cosmetics Act, 1940 . MAIN BODIES: Central Drug Standard Control Organization (CDSCO) Ministry Of Health & Family Welfare (MHFW) Indian Council Of Medical Research (ICMR) Indian Pharmaceutical Association (IPA) Drug Technical Advisory Board (DTAB) Central Drug Testing Laboratory (CDTL) Indian Pharmacopoeia Commission (IPC) National Pharmaceutical Pricing Authority (NPPA) 54

49. 55 Functions undertaken by Central Government Statutory function Laying down standards of drugs, cosmetics, diagnostics and devices. Laying down regulatory measures, amendments to Acts and Rules. To regulate market authorization of new drugs. To regulate clinical research in India To approve licenses to manufacture certain categories of drugs as Central Licence Approving Authority i.e. for Blood Banks, Large Volume Parenterals and Vaccines & Sera. To regulate the standards of imported drugs . Work relating to the Drugs Technical Advisory Board ( DTAB ) and Drugs Consultative Committee (DCC). Testing of drugs by Central Drugs Labs. Publication of Indian Pharmacopoeia .

50. Regulations: For conducting CT in India Permission is required from the DCGI for conducting CT phase 1-4. Also for BABE studies DD with in India/outside India The application for permission to initiate a specific phase of CT include Investigators Brochure Data: Pharmacological/kinetic/toxicological/clinical/therapeutic rationale Proposed trial protocol, case report form, informed consents, investigator undertaking, investigators CV Regulatory status in other countries.

51. If drug is developed in India, approval by ICMR is also required. Guidelines for CT in India are based on ICH-GCP. Lab used for studies sd be GMP and GLP approved.

52. Ministry of Health and Family Welfare DGHS ( Directorate General of Health Services ) CDSCO DCGI INDIA – WELL DEFINED DRUG REGULATORY SYSTEM Govt. of India DTAB Enforcement & GMP audit Div Quality Control Division – CDTL Registration Div New Drug Div Pharmacovigilance Trainings 58

53. APPROVAL OF INVESTIGATIONAL NEW DRUG (IND) 59

54. 61 61

55. 62 62

56. Central Drugs Standard Control Organization Organization Directorate General of Health Services Ministry of Health and Family Welfare, Government of India, FDA Bhavan , ITO, Kotla Road, New Delhi -110002 Phone: [phone]Fax: [phone]E-Mail:- [email protected]

57. Dr. Gyanendra Nath Singh M. Pharm., Ph.D., M.B.A. (U K) Drug Controller General of India

58. Approval of Biologics CDSCO AND DCGI Other than that Genetic engineering approval council Recombinant DNA advisory committee Review committee on genetic manipulation Institutional biosafety committee State biosafety coordination committee District level committee National Biotechnology ACT 2008

59. Approval of medical devices CDSCO By notification SO1468 (2005). The notification declares 10 categories of sterile devices to be considered as drugs under section 3 (b) of D&C act. These are cardiac stents, catherters , bone cement, heart valves, scalp vein sets, orthopaedic implants, cannulae intraocular lenses. Separate committees for evaluation of these..

60. Regulation of Clinical trials Schedule Y of D&C act GCP Guidelines for biomedical research on human participants, ICMR, 2006. Guidance on clinical trial inspection, CDSCO Guidance on submission of CT Applications for evaluating safety and efficacy. Guidelines on BABE studies, CDESCO Guidelines on GCLP

61. Data Monitoring Committee Sponsorer must establish a data monitoring committee or data safety committee. They assess the progress of a CT, data safety, efficacy endpoints at predetermined endpoints. They also recommend whether to continue/modify or stop the trial.

62. CTRI Contains registered clinical trials in India

63. Regulation regarding transport Committee on the transport of dangerous goods. Committee of the United Nations Economic and Social council. In india , ICMR has issued the guidelines on transfer of human development of commercial products.

64. 74 CENTRAL LICENSING

65. 75 National Institute of Health and Family Welfare (NIHFW) NIHFW is an Apex Technical Institute, funded by Ministry of Health and Family Welfare , for promotion of health and family welfare programmers in the country through education, training, research, evaluation, consultancy and specialized services. The NIHFW was established on March 9, 1977 by a merger of the National Institute of Health Administration and Education (NIHAE) with the National Institute of Family Planning (NIFP).

66. 76 DRUG TECHNICAL ADVISORY BOARD (DTAB) 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 The Board shall consist of the following members, 18 Members 10 ex-officio Members 5 Nominated Members 5 Elected Members

67. 77 CENTRAL DRUG TESTING LABORATORY (CDTL) The central drug laboratory, Kolkata is national statutory laboratory of the government of India for quality control of drug and cosmetic and established under the D&C act ,1940. Oldest quality control laboratory of the drug control authorities in India. Function under the director general of Health Services in the Ministry of Health and Family Welfare.