Good clinical practices tutorial-june-21-09 shehnaz-v7.0

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  • When we say via DCGI No Objection Letters we mean this! It is ‘ NO OBJECTION ’ to conduct clinical trials in India under supervision of investigators mentioned in the submission letter THE LETTER STATES: You are requested to follow Ethical aspects of the clinical trial as described in the booklet ‘Ethical Guidelines for Biomedical Research on Human Subjects’ published by Indian Council of Medical Research (ICMR), New Delhi, and ‘GCP’ Guidelines issued by this department and to obtain ethical committee clearance of the institution before initiation of the study.
  • Good clinical practices tutorial-june-21-09 shehnaz-v7.0

    1. 1. Agenda <ul><li>  </li></ul><ul><li>1:00 PM – 3:00 PM </li></ul><ul><ul><ul><li>Overview of Clinical Trial Regulations in India, China and Russia (SV) </li></ul></ul></ul><ul><ul><ul><li>GCPs in India, China & Russia, Similarities and Differences (SV) </li></ul></ul></ul><ul><li>3:00 PM – 3:15 PM – Break </li></ul><ul><li>3:15 – 5:00 PM </li></ul><ul><ul><ul><li>Practical Experiences with QA Audits (SV) </li></ul></ul></ul>
    2. 2. Overview of Clinical Trial Regulations in India, China and Russia
    3. 3. India
    4. 4. A Brief History of Regulating Medicinal Products in India 1940 Drug and Cosmetics Act (British India) 1970 Indian Patents Act (Only Recognizing Process Patents and Not Composition of Material) 1945 Drug and Cosmetics Rule India gains Independence from Britain in 1947 1988 Schedule Y Requirements & guidelines for permission to import and/or manufacture new drugs for sale or to undertake clinical trials in India 2000 ICMR issues “Ethical Guidelines for Biomedical Research on Human Subjects” 2002 ICMR issues “Good Clinical Practices for Clinical Research in India” Indian government allowed for 100% direct foreign ownership of Pharmaceutical companies
    5. 5. Indian Government eliminated import duties for investigational drugs to be used in clinical trials <ul><li>Updated Schedule Y Regulations </li></ul><ul><li>CDSCO GCP </li></ul>2005
    6. 6. <ul><li>India categorizes clinical trials as Category A (Expedited Review) and Category B (Regular review and sets metrics ) </li></ul>2006 <ul><li>Category A </li></ul><ul><li>Any trials that are currently approved to be conducted in USA, UK, Switzerland, Australia, Canada, Germany, South Africa, Japan or EMEA </li></ul><ul><ul><li>Approval Timeline Metric – </li></ul></ul><ul><ul><li>within 2–4 weeks </li></ul></ul><ul><li>Category B </li></ul><ul><li>All other Trials </li></ul><ul><ul><li>Approval Timeline Metric - within 8–12 weeks </li></ul></ul>
    7. 7. <ul><li>CDSCO publishes Requirements For Filing Applications for Global Clinical Trial </li></ul><ul><li>CDSCO publishes Requirements in case of amendments </li></ul><ul><li>http://www.cdsco.nic.in/Global%20Trials.htm </li></ul>2006
    8. 8. Revised requirements posted on CDSCO Website for Protocol Amendments <ul><li>http://cdsco.nic.in/Global%20Trials.htm </li></ul><ul><li>Those amendments which do not require notification to or permission of the Licensing Authority </li></ul><ul><ul><li>  i) Administrative and Logistic changes </li></ul></ul><ul><ul><li>ii) Minor protocol amendments and additional safety assessments in case the institutional ethic s committee has already approved these changes </li></ul></ul>
    9. 9. <ul><li>Those amendments which require notification to the Licensing Authority but need not wait for permission </li></ul><ul><ul><li>i)   Additional Investigator sites </li></ul></ul><ul><ul><li>ii)    Change in investigator with the consent to withdraw from the earlier investigator </li></ul></ul><ul><ul><li>iii) Amended Investigators Brochure, amended informed consent </li></ul></ul><ul><ul><li>  </li></ul></ul>Revised requirements posted on CDSCO Website for Protocol Amendments
    10. 10. <ul><li>Those amendments which require prior permission of the Licensing Authority </li></ul><ul><ul><li>i) Additional Patients to be recruited </li></ul></ul><ul><ul><li>ii) Major changes in protocol with respect to study design, dose and treatment options </li></ul></ul><ul><ul><li>iii) Any change in inclusion or exclusion criteria </li></ul></ul><ul><li>  </li></ul>Revised requirements posted on CDSCO Website for Protocol Amendments Note: All amendments must be approved by the concerned Institutional Ethics Committee before their implementation
    11. 11. <ul><li>Registration of clinical trial mandatory w.e.f.15th June 2009 </li></ul>2009 F.No. 12-01/09-DC-(Pt-32) Directorate General of Health Services Office of Drugs Controller General (India) (New Drug Division) Subject: Registration of Clinical Trial in ICMR Clinical Trial Registry www.ctri.in -reg. It has been decided to make registration of clinical trial mandatory w.e.f.15th June 2009, which will be applicable for clinical trials initiated after 15th June 2009. Accordingly, while granting permission for Clinical Trials, applicants are now being informed that registration of clinical trial in ICMR Clinical Trial Registry www.ctri.in before its initiation will be mandatory from June 15th 2009.
    12. 12. <ul><li>Change in requirements for export of blood samples </li></ul>2009 NOTIFICATION No. 88 (RE-2008) / 2004-2009 New Delhi, Dated the 26th February, 2009 The entry at Sl. No. 124, Chapter 30, regarding ‘Pharmaceutical products’ under Schedule 2 of ITC (HS) Classification of Export and Import Items stands amended as follows: Exports of Whole human blood plasma and all products derived from human blood except gamma globulin and human serum albumin manufactured from human placenta and human placental blood; Raw placenta; Placental blood Plasma permitted after obtaining No Objection Certificate (NOC) from Directorate General of Health Services under Ministry of Health.
    13. 13. Important definitions to consider while understanding the Indian Regulations <ul><li>The Drugs and Cosmetics Act, 1940 defines ‘Drug’ as follows: </li></ul><ul><li>all medicines for internal or external use of human beings or animals and all substances intended to be used for or in the diagnosis, treatment, mitigation or prevention of any disease or disorder in human beings or animals, including preparations applied on human body for the purpose of repelling insects like mosquitoes; </li></ul><ul><li>(ii) such substances (other than food) intended to affect the structure or any function of human body or intended to be used for the destruction of 6(vermin) or insects which cause disease in human beings or animals, as may be specified from time to time by the Central Government by notification in the Official Gazette;] </li></ul>
    14. 14. Important definitions to consider while understanding the Regulatory scenario in India <ul><li>The Drugs and Cosmetics Act, 1940 defines ‘Drug’ as follows: </li></ul><ul><li>(iii) all substances intended for use as components of a drug including empty gelatin capsules; and </li></ul><ul><li>(iv) such devices intended for internal or external use in the diagnosis, treatment, mitigation or prevention of disease or disorder in human beings or animals, as may be specified from time to time by the Central Government by notification in the Official Gazette, after consultation with the Board </li></ul>
    15. 15. Important definitions to consider while understanding the Regulatory scenario in India <ul><li>Definition of Clinical trial (Rule 122-DAA) </li></ul><ul><li>“ Clinical trial” means a systematic study of new drug(s) in human subject(s) to generate data for discovering and / or verifying the clinical, pharmacological (including pharmacodynamic and pharmacokinetic) and /or adverse effects with the objective of determining safety and / or efficacy of the new drug. </li></ul>
    16. 16. Important definitions to consider while understanding the Regulatory scenario in India <ul><li>Definition of New Drug (Rule 122 E): </li></ul><ul><li>A new substance of chemical, biological or biotechnological origin ; in bulk or prepared dosage form; used for prevention, diagnosis, or treatment of disease in man or animal; which, except during local clinical trials, has not been used in the country to any significant extent; and which, except during local clinical trials, has not been recognized in the country as effective and safe for the proposed claim </li></ul><ul><li>A drug already approved by the licensing authority mentioned in Rule 21 for certain claims, which is now proposed to be marketed with modified or new claims, namely, indications, dosage forms (including sustained release dosage form) and route of administration </li></ul>
    17. 17. Important definitions to consider while understanding the Regulatory scenario in India <ul><li>Definition of New Drug (Rule 122 E): </li></ul><ul><li>A fixed dose combination of two or more drugs , individually approved earlier for certain claims, which are now proposed to be combined for the first time in a fixed ratio, or if the ratio of ingredients in an already marketed combination is proposed to be changed, with certain claims, viz ., indications, dosage form (including sustained release dosage form) and route of administration </li></ul><ul><li>All vaccines shall be new drugs unless certified otherwise by the licensing authority under Rule 21 </li></ul>
    18. 18. Important definitions to consider while understanding the Regulatory scenario in India <ul><li>A new drug shall continue to be considered as new drug for a period of four years from the date of its first approval or its inclusion in the Indian Pharmacopoeia, whichever is earlier </li></ul>
    19. 19. CDSCO Central Government Directorate General of Health Services Drugs Controller General of India Permissions for Clinical Trials with New Drugs Test Import Licenses New Drug Approvals Ministry of Health & Family Welfare
    20. 20. CDSCO Central Government Statutory Functions <ul><li>Laying down standards of drugs, cosmetics, diagnostics and devices </li></ul><ul><li>Laying down regulatory measures, amendments to Acts and Rules </li></ul><ul><li>To regulate market authorization of new drugs </li></ul><ul><li>To regulate clinical research in India </li></ul><ul><li>To regulate the standards of imported drugs. </li></ul><ul><li>Monitoring adverse drug reactions (ADR) </li></ul>
    21. 21. <ul><li>Licensing of drug manufacturing and sales establishments </li></ul><ul><li>Approval of drug formulations for manufacture </li></ul><ul><li>Monitoring of quality of Drugs & Cosmetics, manufactured by respective state units and those marketed in the state </li></ul><ul><li>Pre- and post- licensing inspection </li></ul><ul><li>Recall of sub-standard drugs </li></ul>CDSCO State Government Statutory Functions
    22. 22. DCGI Permission Drugs Manufactured In India Permission to Conduct Clinical Trials Drugs Manufactured Outside India Test Import License Permission to Conduct Clinical Trials + DGFT Approval for export of samples As we speak, this is no longer a requirement!
    23. 23. Current Applicable Clinical Trials Regulations in India <ul><li>Amended (2005) Schedule Y of Drugs and Cosmetics Act, 1940 </li></ul>Indian GCP (CDSCO) Ethical Principles of Biomedical Research published by ICMR
    24. 24. Clinical Trial Application (CTA), India <ul><li>Name of the Applicant </li></ul><ul><li>Authorization letter from the Sponsor </li></ul><ul><li>Name of the Drug </li></ul><ul><li>Regulatory status of the drug in other countries (Names of countries where the drug is approved along with international package insert or where IND application is filed) </li></ul><ul><li>Objective of the Study </li></ul><ul><li>Phase of Study </li></ul><ul><li>Names of the Participating Countries /Investigator sites </li></ul><ul><li>Total no. of patients to be enrolled globally </li></ul><ul><li>No. of investigator sites to be enrolled in India </li></ul><ul><li>No. of patients to be included in India </li></ul><ul><li>Regulatory/ IRB approvals from participating countries </li></ul><ul><li>Status of the study in other countries </li></ul><ul><li>Suspected Unexpected Serious Adverse Reaction (SUSAR) from other participating countries </li></ul><ul><li>Affidavit from the sponsor that the study has not been discontinued in any country </li></ul><ul><ul><ul><li>(I n case of discontinuation the reasons for such a discontinuation) </li></ul></ul></ul>
    25. 25. CTA, India (contd) <ul><li>Data Submitted </li></ul><ul><ul><li>Chemical and Pharmaceutical data </li></ul></ul><ul><ul><ul><li>Generic name and chemical name </li></ul></ul></ul><ul><ul><ul><li>Dosage form </li></ul></ul></ul><ul><ul><ul><li>Composition </li></ul></ul></ul><ul><ul><li>Animal Pharmacolog y Data </li></ul></ul><ul><ul><li>Animal Toxicology data </li></ul></ul><ul><ul><li>Clinical data </li></ul></ul><ul><ul><ul><li>Phase I </li></ul></ul></ul><ul><ul><ul><li>Phase II </li></ul></ul></ul><ul><ul><ul><li>Phase III </li></ul></ul></ul><ul><ul><ul><li>Phase IV </li></ul></ul></ul><ul><ul><li>Rationale for selecting the proposed dose (s) and indication(s) </li></ul></ul>
    26. 26. CTA, India (contd) <ul><li>Documents Submitted </li></ul><ul><ul><li>Form 44 and Treasury chalan </li></ul></ul><ul><ul><li>Form 12 and Treasury chalan (for Import License; T-License) </li></ul></ul><ul><ul><li>Details of Biological specimens to be exported </li></ul></ul><ul><ul><li>Protocol </li></ul></ul><ul><ul><li>Informed C onsent Documents (ICD) </li></ul></ul><ul><ul><li>Case Report F orm </li></ul></ul><ul><ul><li>I nvestigator’s Brochure duly supported by an affidavit that the summarized information submitted is based on facts </li></ul></ul><ul><ul><li>Undertakings by the Investigators </li></ul></ul><ul><ul><li>Ethics committee approvals (if already available ) </li></ul></ul>
    27. 28. China
    28. 29. Brief History of Regulations - China Ministry of Health Administration Guidance for Drug Manufacturing 1982 Ministry of Health Administration Guidance for New Drug 1979 State Council Provisional Guideline for Drug Administration 1978 Ministry of Health Provisional Administration of New Drugs 1962 Conception (1962-1982) Issued By Regulations / Laws Year Stage
    29. 30. Brief History of Regulations - China SDA Quality Control Guideline for Drug Clinical Trials 1999 SDA Guidance for New Drug Evaluation and Approval (revised) 1999 State Council Establishment of SDA 1998 Ministry of Health Administration Guidance for Clinical Trials of New Drug 1997 Ministry of Health Guidance for New Drug Evaluation and Approval 1985 State Council Regulations for Implementation of Drug Administration of Law of the People’s Republic of China 1985 National People’s Congress Drug Administration of Law of the People’s Republic of China 1984 Development (1984-1999) Issued By Regulations / Laws Year Stage
    30. 31. Brief History of Regulations - China SFDA Quality Control Guideline for Drug Clinical Trials (Revised) 2003 State Council Establishment of SFDA 2003 SDA Provisions for Drug Registration (Draft) 2002 State Council Regulations for Implementation of Drug Administration of Law of the People’s Republic of China 2002 National People’s Congress Drug Administration of Law of the People’s Republic of China (Revised) 2001 SFDA Provisions for Drug Registration 2005 National People’s Congress Administrative Permission 2004 Maturation (2001-2005) Issued By Regulations / Laws Year Stage
    31. 32. Brief History of Clinical Trial Guidelines - China <ul><li>1985 version of Guidance for New Drug Evaluation and Approval </li></ul><ul><ul><li>Required results from Phase I and Phase II for submission of New Drug Approval Applications </li></ul></ul><ul><ul><li>Phase III was conducted after drug approval </li></ul></ul><ul><li>1999 version of Guidance for New Drug Evaluation and Approval </li></ul><ul><ul><li>Required results from Phase I and Phase II for submission of New Drug Approval Applications. </li></ul></ul><ul><ul><li>Phase IV was to be conducted after drug approval </li></ul></ul>
    32. 33. GCP - China <ul><li>Chinese Good Clinical Practice </li></ul><ul><ul><li>Adopted from ICH GCP </li></ul></ul><ul><ul><li>Current Version Effective 2003 </li></ul></ul>
    33. 34. Regulatory Framework in China State Food and Drug Administration (SFDA) State Ministry of Health Issued Provisions for Drug Registration (SFDA Order No.28)
    34. 35. Regulatory Framework in China <ul><li>SFDA Oversees Review and Approval of </li></ul><ul><li>Drug Registration </li></ul><ul><li>Drug Manufacturing </li></ul><ul><li>Inspection </li></ul><ul><li>Licensing for drug importation </li></ul><ul><li>Clinical Trials </li></ul>Center for Drug Evaluation (CDE)
    35. 36. Clinical Trial Pre- Requisite <ul><li>A Clinical Trial Approval (CTA) Application must be filed by the Sponsor or its designated agency with the SFDA prior to initiation of Phase I through Phase III Clinical Trials or Bio-Equivalence (BE) studies </li></ul>Receipt of a CLINICAL TRIAL APPROVAL (CTA) issued by SFDA is a pre-requisite to commencement of clinical trials
    36. 37. Steps leading to Clinical Trial Approval in China <ul><li>Step I: </li></ul><ul><li>Sponsor or its application agency prepare and sort the application dossier according to requirements set by the SFDA </li></ul><ul><li>Submit application to SFDA </li></ul>All Key Dossier Items must be translated to CHINESE
    37. 38. Steps leading to Clinical Trial Approval in China <ul><li>Step II: </li></ul><ul><li>The Application Receiving Center (ARC) of SFDA completes a format review of the application dossier submitted by the Sponsor or its agency in 05 workdays </li></ul><ul><li>If the dossier meets the SFDA requirements, the ARC will forward the application dossier to Center for Drug Evaluation (CDE) for formal technical review and evaluation </li></ul><ul><li>If the dossier does not meet the SFDA requirements, the ARC will withdraw the application and return to the Sponsor. </li></ul>For local manufacturers, SFDA’s provincial affiliates will perform an on-site (research site) inspection to check the application dossier authenticity and completeness and issue one inspection report to SFDA (30 workdays)
    38. 39. Steps leading to Clinical Trial Approval in China <ul><li>Step III: </li></ul><ul><li>The CDE performs formal technical evaluation of sponsor’s application dossier (90 workdays) </li></ul><ul><li>Issue a Notice of Evaluation Opinion </li></ul><ul><li>The CDE Notice of Evaluation Opinion will require the Sponsor to </li></ul><ul><li>Do a Quality Verification (QV) by and at the NICPBP </li></ul><ul><li>(National Institute for Control of Pharmaceutical and Biological Products) </li></ul><ul><li>Provide supplemental data, in event of CDE concerns </li></ul>Without the certificate of analysis issued by NICPBP , the institutional ethics committee (IEC) will not approve the clinical study
    39. 40. Steps leading to Clinical Trial Approval in China <ul><li>Step IV: </li></ul><ul><li>Sponsor or its agency must do Quality Verification (QV) at the NICPBP and provide supplements to the dossier as required by CDE </li></ul><ul><li>Step V: </li></ul><ul><li>CDE will evaluate the Quality Verification (QV) Report released by NICPBP and the supplementary dossier provided by the Sponsor (within 30 workdays) </li></ul>CDE will send the Final Technical Evaluation Opinion to the Department of Drug Registration attached to SFDA
    40. 41. Steps leading to Clinical Trial Approval in China <ul><li>Step VI: </li></ul><ul><li>The Department of Drug Registration does the administrative examination of CDEs technical opinions and then issues the Clinical Trial Approval (CTA). </li></ul>Clinical trial must be initiated within 3 years from date of Clinical Trial Approval
    41. 42. Time frame <ul><li>The Technical Review and Approval for Clinical Trial in China takes on an average: </li></ul><ul><ul><li>90 days for a new clinical study, 80 days if a drug meets the requirements of special approval from SFDA to expedite. This can be granted if the drug in question addresses an urgent need within China. </li></ul></ul><ul><ul><li>150 days for production of new drug, 120 days if a drug meets the requirements of special approval; </li></ul></ul><ul><ul><li>160 days for registration of generic drugs or a change in dosage form of a marketed drug; and </li></ul></ul><ul><ul><li>40 days for a supplemental application if a technical review is needed </li></ul></ul>
    42. 43. Challenges for conducting clinical trials in China <ul><li>The following requirements must be fulfilled for an overseas applicant to submit an application to SFDA </li></ul><ul><ul><li>Drugs used for clinical trials shall be already approved or in Phase II or III clinical trials overseas. </li></ul></ul><ul><li>While approving to conduct a international multi-center clinical trial, the SFDA may require the applicant to conduct Phase I clinical trial first in China </li></ul><ul><li>An application of a new preventive vaccine from a foreign sponsor will not be accepted unless the vaccine is already registered and approved in a foreign country </li></ul>
    43. 44. Challenges for conducting clinical trials in China (contd) <ul><li>Phase I to Phase III clinical trials and BE studies must normally be conducted in China Mainland Hospitals qualified for clinical trials by SFDA . </li></ul><ul><ul><li>China also accepts clinical trial results performed by three Hong Kong hospitals such as Prince of Wales Hospital, Mary Hospital and Ophthalmic Hospital of Hong Kong </li></ul></ul><ul><li>Principal Investigator must be from a hospital qualified by SFDA </li></ul><ul><li>A drug can be used for clinical trial only after tested as qualified </li></ul><ul><ul><li>The drug products used in the clinical trials must be submitted to National Institute of the Control of Pharmaceutical and Biological Products (NICPBP) for an assay. Without the certificate of analysis issued by NICPBP, the institutional ethics committee (IEC) will not approve the clinical study </li></ul></ul>
    44. 45. Challenges for conducting clinical trials in China (contd) <ul><li>The clinical institution MUST set up a special administrative office with full-time staff to provide oversight on clinical trial activities and outcomes. The responsibilities of this office include </li></ul><ul><ul><li>Implementation of relevant laws and regulations </li></ul></ul><ul><ul><li>Establishment of a quality assurance system for the clinical trials according to GCP </li></ul></ul><ul><ul><li>Quality assurance </li></ul></ul><ul><ul><ul><li>Auditing the authenticity and standardization of the clinical research </li></ul></ul></ul><ul><ul><ul><li>Ensuring that SOPs are adhered to, </li></ul></ul></ul><ul><ul><ul><li>Ensuring the science and compliance in the clinical trials </li></ul></ul></ul><ul><ul><ul><li>Ensuring that the safety and rights of the subjects are protected </li></ul></ul></ul><ul><ul><ul><li>Ensuring the accuracy and completeness of the clinical data obtained </li></ul></ul></ul>
    45. 46. Challenges for conducting clinical trials in China (contd) <ul><li>Clinical studies cannot be initiated at clinical institutions until the sponsor and investigator receive the approval letter issued by SFDA </li></ul>
    46. 47. Russia
    47. 48. Brief History of Regulations - Russia <ul><li>1998: Federal “Law about drug agents (86-FZ) </li></ul><ul><li>The law was updated as follows: </li></ul><ul><li>2000: Federal law No 5-FZ </li></ul><ul><li>2001: N 15-FZ and N 196-FZ </li></ul><ul><li>2003: N 86-FZ </li></ul><ul><li>2004: N 122-FZ and N 199-FZ </li></ul><ul><li>2006: N 160-FZ </li></ul>
    48. 49. Brief History of GCP - Russia <ul><li>1989 First translation of GCP Guidelines </li></ul><ul><ul><li>Carried out by Clinical Pharmacological Research Institute (CPR) </li></ul></ul><ul><li>1999 Official Text of ICH GCP Guidelines in Russian </li></ul><ul><li>1999 Russian language version of GCP became a part of national regulations on Clinical Research </li></ul>
    49. 50. <ul><li>The health authority controlling the conduct of clinical trials in Russia is the Federal Supervision Service for Public Health and Social Affairs (FSS), Sector of State Control for Pre-Clinical and Clinical Studies of the Medicinal Products </li></ul><ul><li>In order to initiate and conduct a clinical trial in human subjects in the Russian Federation (RF), the written approvals of both the Russian Regulatory Authorities and the local Ethics Committee of a participating medication institution (LEC) are needed </li></ul>Competent Authority, Russia
    50. 51. Regulations & Guidelines <ul><li>OST 42-511-99 “The Rules of Good Clinical Trials in the Russian Federation” </li></ul><ul><li>“ The Rules of Clinical Practice in Russian Federation” (19/June/2003) </li></ul><ul><li>National Standard of Russian Federation GOST R 52379-2005 “Good Clinical Practice” identical to ICH GCP </li></ul>
    51. 52. <ul><li>The sections of Federal Law about drug agents, relevant to clinical trial conduct are: </li></ul><ul><ul><li>Article 37: Describes rules for obtaining regulatory approval for clinical trials in Russia. The law provides for mandatory approval of the National Ethics Committee (NEC) </li></ul></ul><ul><ul><li>Article 38: Contains provisions regarding mandatory insurance to cover the risk of injury of trial participants and regarding the civil liability of investigators responsible for the conduct of a clinical trial </li></ul></ul><ul><ul><li>Article 39: Describes the responsibilities of the Principal Investigator and in particular, responsibilities in case of violations and fraud </li></ul></ul><ul><ul><li>Article 40: Establishes requirement that written informed consent must be obtained from all clinical trial participants </li></ul></ul>Rules
    52. 53. Procedure for permission to Conduct Clinical Trials in Russia <ul><li>Step I: </li></ul><ul><li>The Sponsor (or authorized representative) submits the clinical trial application letter along with the following documentation to the Federal Services (FSS) </li></ul><ul><ul><li>List of Investigational Sites </li></ul></ul><ul><ul><li>CV of Principal Investigators (in Russian) </li></ul></ul><ul><ul><li>Insurance Policy, Certificate </li></ul></ul><ul><ul><li>Protocol (English and Russian translation) </li></ul></ul><ul><ul><li>Informed Consent (in Russian) </li></ul></ul><ul><ul><li>IB (English & Russian translation of Summary and Toxicological Report), addendums to IB </li></ul></ul><ul><ul><li>SAE and other reports to current IB version </li></ul></ul><ul><ul><li>Patient Registration Card (PRC) sample </li></ul></ul><ul><ul><li>Information for the comparator drugs and concomitant medication (optional) along with cover letter </li></ul></ul>
    53. 54. Procedure for permission to Conduct Clinical Trials in Russia <ul><li>Step I Pre-Requisite: </li></ul><ul><li>Before submitting the clinical trial documentation to the Regulatory Authorities, patient insurance and clinical site personnel civil liability insurance certificates should be received. </li></ul><ul><li>The information on local patient insurance should be incorporated into the patient information and informed consent document </li></ul><ul><li>Agreement should be signed by the Study Site and the Organization which submits the package (CRO or Sponsor) </li></ul><ul><li>If the applicant is a CRO, a Notarised ‘delegation of authority letter’ is required prior to signing the agreement </li></ul>
    54. 55. Procedure for permission to Conduct Clinical Trials in Russia (contd) <ul><li>Step II: </li></ul><ul><li>FSS issues accompanying letters to expert bodies Federal Ethics Committee (FEC) and Federal State Institution “Scientific Center of Medicines Expert of RZN (FSI SCMER) </li></ul><ul><li>Sponsor submits the application with the FSS accompanying letters to the FEC and FSI SCMER </li></ul><ul><li>FSI SCMER forwards the documentation to their sub-unit ‘Institute of Preclinical and Clinical Expertise of Medicines (IPCEM). </li></ul><ul><li>IPCEM is responsible for pharmacological expertise of the clinical trial documentation. This takes about 6-8 weeks . </li></ul><ul><li>The FEC is a part of the Regulatory Authorities review and approval process. </li></ul><ul><li>FEC may require additional information and may involve experts. The FEC decision takes about 3-4 weeks </li></ul>
    55. 56. Procedure for permission to Conduct Clinical Trials in Russia (contd) <ul><li>Step III: </li></ul><ul><li>FSS issues permission to conduct clinical study on the basis of: </li></ul><ul><li>Positive decision of FEC </li></ul><ul><li>Expert Report prepared by FSI SCMER </li></ul>Timeframe: 3-4 weeks
    56. 57. <ul><li>Import & Export licenses are granted by the Regulatory Authority </li></ul><ul><li>Licenses are valid for a particular courier company and for a particular custom office for a specified period of clinical trial. </li></ul><ul><li>The quantity of investigational product (and equipment) to be imported and the bio-samples to be exported are listed in the licenses </li></ul>IMPORT & EXPORT LICENSE
    57. 58. Drug Shipment Challenges <ul><li>Approval from the Ministry of Health is required for each shipment and should be obtained every time the study drug is shipped to Russia. </li></ul><ul><li>A Proforma invoice needs to be completed for each shipment of clinical supplies, including the study drug. It should exactly match the shipment content and must be identical to the Proforma invoice submitted to the Ministry of Health for drug shipment approval. </li></ul><ul><li>There are certain Proforma invoice requirements, which are specific to each courier. </li></ul><ul><li>Upon receipt and review of the study drug documentation, including a Proforma invoice, the Ministry of Health will forward the documents to the Commission on Narcotic Drugs for their stamp of approval. </li></ul>
    58. 59. <ul><li>Ethics committee approval are also required from the local Ethics Committee (LEC) </li></ul><ul><li>Some LEC may require the applicant to submit the FEC and Regulatory Authorities approval with the clinical trial application </li></ul><ul><li>LEC can delegate the ethical expertise of a particular study to another LEC with a higher level of expertise in appropriate therapeutic area </li></ul>LEC
    59. 60. GCP Overview (India, China and Russia)
    60. 61. Overview of Indian GCP <ul><li>Includes elements from WHO, ICH, USFDA and European GCP guidelines as well as the Ethical Guidelines for Biomedical research on Human Subjects issued by the Indian Council of Medical Research. </li></ul>
    61. 62. Overview of Indian GCP <ul><li>Structure: </li></ul><ul><ul><li>Divided into Sections (1 to 7) and Appendices (I to V) </li></ul></ul><ul><ul><ul><li>Section 1 : Introduction </li></ul></ul></ul><ul><ul><ul><li>Section 2 : Pre-Requisites for the Study </li></ul></ul></ul><ul><ul><ul><li>Section 3 : Responsibilities </li></ul></ul></ul><ul><ul><ul><li>Section 4 : Record Keeping and Data Handling </li></ul></ul></ul><ul><ul><ul><li>Section 5 : Quality Assurance </li></ul></ul></ul><ul><ul><ul><li>Section 6 : Statistics </li></ul></ul></ul><ul><ul><ul><li>Section 7 : Special Concerns </li></ul></ul></ul><ul><ul><ul><li>Appendix I: Declaration of Helsinki </li></ul></ul></ul><ul><ul><ul><li>Appendix II: Schedule Y </li></ul></ul></ul><ul><ul><ul><li>Appendix III: Format for submission of Pre-Clinical and Clinical data for r-DNA based vaccines, diagnostics and other biologicals </li></ul></ul></ul><ul><ul><ul><li>Appendix IV: Investigator’s Brochure </li></ul></ul></ul><ul><ul><ul><li>Appendix V: Essential Documents </li></ul></ul></ul>
    62. 63. Overview of Indian GCP <ul><li>Section 2: Pre-Requisites for the Study </li></ul><ul><ul><li>2.1 Investigational Pharmaceutical Product </li></ul></ul><ul><ul><li>2.2 Pre-Clinical Supporting Data </li></ul></ul><ul><ul><li>2.3 Protocol </li></ul></ul><ul><ul><li>2.4 Ethical & Safety Considerations </li></ul></ul><ul><li>Section 3: Responsibilities </li></ul><ul><ul><li>3.1 Sponsor </li></ul></ul><ul><ul><li>3.2 The Monitor </li></ul></ul><ul><ul><li>3.3 Investigator </li></ul></ul>
    63. 64. Overview of Indian GCP <ul><li>Section 4: Record Keeping & Data Handling </li></ul><ul><ul><li>4.1 Documentation </li></ul></ul><ul><ul><li>4.2 Corrections </li></ul></ul><ul><ul><li>4.3 Electronic Data Processing </li></ul></ul><ul><ul><li>4.4 Validation of Electronic Data Processing Systems </li></ul></ul><ul><ul><li>4.5 Language </li></ul></ul><ul><ul><li>4.6 Responsibility of Investigator </li></ul></ul><ul><ul><li>4.7 Responsibilities of Sponsor and Monitor </li></ul></ul><ul><li>Section 5: Quality Assurance </li></ul>
    64. 65. Overview of Indian GCP <ul><li>Section 6: Statistics </li></ul><ul><ul><li>6.1 Role of Biostatistician </li></ul></ul><ul><ul><li>6.2 Study Design </li></ul></ul><ul><ul><li>6.3 Statistical Analysis </li></ul></ul><ul><li>Section 7: Special Concerns </li></ul><ul><ul><li>7.1 Clinical Trials of Vaccines </li></ul></ul><ul><ul><li>7.2 Clinical Trials of Contraceptives </li></ul></ul><ul><ul><li>7.3 Clinical Trials with Surgical Procedures / Medical Devices </li></ul></ul><ul><ul><li>7.4 Clinical Trials for Diagnostic agents – Use of radioactive materials and X-rays </li></ul></ul>
    65. 66. Overview of Schedule Y (Amended 2005, India) <ul><li>Describes the requirements and Guidelines for Permission to IMPORT and / or Manufacture of New Drugs for Sale or to Undertake Clinical Trials </li></ul>
    66. 67. Overview of Schedule Y (Amended 2005, India) <ul><li>Structure: </li></ul><ul><ul><li>Divided into Sections (1 to 2 ) and Appendices (I to IX) </li></ul></ul><ul><ul><ul><li>Section 1 : Application for Permission </li></ul></ul></ul><ul><ul><ul><li>Section 2 : Clinical Trial </li></ul></ul></ul><ul><ul><ul><li>Appendix I : Data to be submitted along with application to conduct clinical trials / import / Manufacture of New Drugs for Marketing in the country </li></ul></ul></ul><ul><ul><ul><li>Appendix II : Structure Content and Format for Clinical Study Reports </li></ul></ul></ul><ul><ul><ul><li>Appendix III : Animal Toxicology (Non-Clinical Toxicity Studies) </li></ul></ul></ul><ul><ul><ul><li>Appendix IV : Animal Pharmacology </li></ul></ul></ul>
    67. 68. Overview of Schedule Y (Amended 2005, India) <ul><li>Structure: </li></ul><ul><ul><ul><li>Appendix V: Informed Consent </li></ul></ul></ul><ul><ul><ul><li>Appendix VI: Fixed Dose Combinations </li></ul></ul></ul><ul><ul><ul><li>Appendix VII: Undertaking by the Investigator </li></ul></ul></ul><ul><ul><ul><li>Appendix VIII: Ethics Committee </li></ul></ul></ul><ul><ul><ul><li>Appendix IX: Stability Testing of New Drugs </li></ul></ul></ul><ul><ul><ul><li>Appendix X: Contents of the Proposed Protocol for Conducting Clinical Trials </li></ul></ul></ul><ul><ul><ul><li>Appendix XI: Data Elements for reporting serious adverse events occurring in a clinical trial </li></ul></ul></ul>
    68. 69. Overview of Schedule Y (Amended 2005, India) <ul><li>Section 2: Clinical Trial </li></ul><ul><ul><li>1 Approval for clinical trial </li></ul></ul><ul><ul><li>2 Responsibilities of Sponsor </li></ul></ul><ul><ul><li>3 Responsibilities of Investigator </li></ul></ul><ul><ul><li>4 Informed Consent </li></ul></ul><ul><ul><li>5 Responsibilities of Ethics Committee </li></ul></ul><ul><ul><li>6 Human Pharmacology (Phase I) </li></ul></ul><ul><ul><li>7 Therapeutic Exploratory Trials (Phase II) </li></ul></ul><ul><ul><li>8 Therapeutic Confirmatory Trials (Phase III) </li></ul></ul><ul><ul><li>9 Post Marketing Trials (Phase IV) </li></ul></ul>
    69. 70. Overview of Schedule Y (Amended 2005, India) <ul><li>Also includes </li></ul><ul><ul><li>Studies in Special Population </li></ul></ul><ul><ul><ul><li>Geriatrics </li></ul></ul></ul><ul><ul><ul><li>Pediatrics </li></ul></ul></ul><ul><ul><ul><li>Pregnant or nursing women </li></ul></ul></ul><ul><ul><li>Post Marketing Surveillance </li></ul></ul><ul><ul><li>Special Studies: BA / BE </li></ul></ul>
    70. 71. Overview of Ethical Guidelines for Biomedical Research on Human Participants (ICMR 2006, India) <ul><li>1980: ICMR released a ‘Policy Statement on Ethical Considerations involved in Research on Human Subjects’ </li></ul><ul><li>2000: Second Version </li></ul><ul><li>2006: Third Version </li></ul>
    71. 72. <ul><li>Chapter I: Statement of General Principles on Ethical Considerations involving Human Participants </li></ul><ul><li>Chapter II: Ethical Review Procedures </li></ul><ul><li>Chapter III : General Ethical Issues </li></ul><ul><li>Chapter IV: Statement of Specific Principles for Clinical Evaluation of Drugs / Devices / Diagnostics / Vaccines / Herbal Remedies </li></ul><ul><li>Chapter V: Statement of Specific Principles for Epidemiological Studies </li></ul><ul><li>Chapter VI: Statement of Specific Principles for Human Genetics and Genomics Research </li></ul><ul><li>Chapter VII: Statement of Specific Principles for Research in Transplantation </li></ul><ul><li>Chapter VIII: Statement of Specific Principles for Assisted Reproductive Technologies </li></ul>Overview of Ethical Guidelines for Biomedical Research on Human Participants (ICMR 2006, India)
    72. 73. Overview of China GCP <ul><li>Structure: </li></ul><ul><ul><li>Divided into Chapters (1 to 13) and Appendices (1 to 3) </li></ul></ul><ul><ul><ul><li>Chapter 1: General Provisions </li></ul></ul></ul><ul><ul><ul><li>Chapter 2: Preparations and Prerequisites for a Clinical Trial </li></ul></ul></ul><ul><ul><ul><li>Chapter 3: Protection of Trial Subjects’ Rights & Benefits </li></ul></ul></ul><ul><ul><ul><li>Chapter 4: The Protocol </li></ul></ul></ul><ul><ul><ul><li>Chapter 5: Responsibilities of the Investigator </li></ul></ul></ul><ul><ul><ul><li>Chapter 6: Responsibilities of the Sponsor </li></ul></ul></ul><ul><ul><ul><li>Chapter 7: Responsibilities of the Monitor </li></ul></ul></ul><ul><ul><ul><li>Chapter 8: Recording and Reporting </li></ul></ul></ul><ul><ul><ul><li>Chapter 9: Statistical Analysis and Data Processing </li></ul></ul></ul><ul><ul><ul><li>Chapter 10: Management of Investigational Products </li></ul></ul></ul>
    73. 74. Overview of China GCP <ul><li>Structure: </li></ul><ul><ul><ul><li>Chapter 11: Quality Assurance </li></ul></ul></ul><ul><ul><ul><li>Chapter 12: Multi-Center Trials </li></ul></ul></ul><ul><ul><ul><li>Chapter 13: Supplementary Articles / Additional Rules </li></ul></ul></ul>
    74. 75. Overview of China GCP <ul><li>Structure: </li></ul><ul><ul><ul><li>Appendix 1 </li></ul></ul></ul><ul><ul><ul><ul><li>Declaration of Helsinki </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Basic Principles </li></ul></ul></ul></ul><ul><ul><ul><li>Appendix 2 </li></ul></ul></ul><ul><ul><ul><ul><li>Definition </li></ul></ul></ul></ul><ul><ul><ul><li>Appendix 3 </li></ul></ul></ul><ul><ul><ul><ul><li>Documents for the Conduct of A Clinical Trial and the Filing Systems </li></ul></ul></ul></ul>
    75. 76. Russia GCP <ul><li>Russia’s GOST R 52379-2005 is identical to ICH GCP </li></ul><ul><li>The Russian Legislation however provides for additional requirements: </li></ul><ul><ul><li>NEC will approve a Russian investigator as PI only if he has at least two years experience in conducting clinical trials as PI or Co-Investigator </li></ul></ul><ul><ul><li>NEC developed table (in Russian) should be attached to CIOMS or MedWatch forms for submission of SUSARS </li></ul></ul>
    76. 77. Russia GCP <ul><li>According to the Russian Federal Drug Law, only drugs manufactured in Russia can be exported. </li></ul><ul><li>Therefore, the unused study drug cannot be returned to the sponsor and must be destroyed by the Pharmacy or local companies with special accreditation </li></ul>
    77. 78. Differences with ICH E6 Let’s Talk
    78. 79. <ul><li>The following guidelines have been provided to you: </li></ul><ul><ul><li>ICH GCP (E6) </li></ul></ul><ul><ul><li>Indian GCP (CDSCO) </li></ul></ul><ul><ul><li>Schedule Y </li></ul></ul><ul><ul><li>Ethical Guidelines for Biomedical Research on Human Participants </li></ul></ul><ul><ul><li>China GCP </li></ul></ul>
    79. 80. Identify differences between ICH E6 and the guidelines / regulations for India and China with respect to <ul><li>Institutional Review Board </li></ul><ul><li>Informed Consent and ICF Process </li></ul><ul><li>Sponsor Responsibilities </li></ul><ul><li>Investigator Responsibilities </li></ul><ul><li>Record Retention </li></ul>Exercises
    80. 81. Practical Experiences with QA Audits in India
    81. 82. Investigator Site Audits (Phase II-III Studies) <ul><li>Common findings </li></ul><ul><li>Inadequate Past Medical History </li></ul><ul><ul><ul><li>Ad hoc Prescriptions </li></ul></ul></ul><ul><ul><ul><li>Laboratory Reports </li></ul></ul></ul><ul><ul><ul><li>X-rays </li></ul></ul></ul><ul><li>Delayed implementation of amended EC approved informed consent forms </li></ul><ul><ul><ul><li>Most companies and investigators wait for DCGI approval prior to implementation of EC Approved ICFs </li></ul></ul></ul>
    82. 83. Investigator Site Audits (Phase II-III Studies) <ul><li>Common findings </li></ul><ul><li>Inadequate Facilities </li></ul><ul><ul><ul><li>No / Inadequate fire and water protection in hospitals / clinic </li></ul></ul></ul><ul><ul><ul><li>Absence of maintenance and calibration records for equipment used in the studies </li></ul></ul></ul><ul><li>Inadequate Training </li></ul><ul><ul><ul><li>No formal training on Indian Regulation Schedule Y </li></ul></ul></ul><ul><ul><ul><li>Inadequate training on ICH GCP for Staff </li></ul></ul></ul><ul><ul><ul><li>Absence of training for associated doctors mandated per protocol e.g Cardiologist </li></ul></ul></ul>
    83. 84. Investigator Site Audits (Phase II-III Studies) <ul><li>Common findings </li></ul><ul><li>Absence of SOPs at Investigator Sites </li></ul><ul><li>No working agreements / confidentiality agreements with consultants involved in reviewing test reports for study subjects </li></ul><ul><li>No accountability of blood / serum sample storage at the site </li></ul><ul><li>Inadequate understanding of the role of impartial witness </li></ul>
    84. 85. Investigator Site Audits (Phase II-III Studies) <ul><li>Common findings </li></ul><ul><li>Documentation Errors </li></ul><ul><ul><ul><li>EC Submission and Approval Letters </li></ul></ul></ul><ul><ul><ul><li>Within source documents </li></ul></ul></ul><ul><li>Clinical Trial Agreement and Payment and Compensation not submitted to EC during the initial submission as required by Schedule Y </li></ul>
    85. 86. <ul><li>Ethics Committees </li></ul><ul><li>Investigator’s Obligations </li></ul><ul><li>Informed Consent </li></ul><ul><li>Some CRITICAL Issues at Investigator Sites </li></ul>
    86. 87. Practical considerations <ul><li>Training and Experience of Principal Investigator </li></ul><ul><li>Ensure a Tri-Partite Agreement with the Institution </li></ul><ul><li>Ensure the CTA is submitted to the EC with the initial EC Submission </li></ul><ul><li>Involvement of a dedicated co-ordinator per study </li></ul><ul><li>Constant follow-up with the site </li></ul><ul><li>First monitoring within 2 weeks of the first subject screened and enrolled </li></ul><ul><li>Regular monitoring thereafter </li></ul><ul><li>Timely Escalation of Issues </li></ul><ul><li>Timely Corrective Action </li></ul><ul><li>Periodic Training of Site Staff </li></ul>
    87. 88. <ul><li>CDSCO – USFDA Training </li></ul><ul><li>Series of Mock Inspections </li></ul><ul><li>Registration of Clinical Trials </li></ul><ul><li>Possible registration of Ethics Committees </li></ul>Some positive initiatives in India
    88. 89. Questions? <ul><li>Munish Mehra, PhD Managing Director Global Drug Development Experts </li></ul><ul><li>United States </li></ul><ul><li>[email_address] </li></ul><ul><li>+1(240-477-3700) Shehnaz Kairas Vakharia, MS Principal Consultant, Theraverity India [email_address] </li></ul><ul><li>+(91) 9821543016 </li></ul>

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