Effectively Incorporating Good Clinical Practices (GCPs) ( )and Good Laboratory Practices (GLPs) Dr. Bhaswat S. Chakraborty Senior VP, Research & Development VP Cadila Pharmaceuticals Ltd.
Theme of this Presentation• Uniform ethics and transparency in conduct and reporting• Ensuring compliance with multi-regulator GCP requirements• E Ensuring that the clinical trials follow protocol, SOPs and i th t th li i l t i l f ll t l SOP d applicable guidelines• Incorporating Q p g Quality Assurance as a culture y• What NOT to do with regards to GLP and GCP• Implementing QMS and QA systems in trial and site operations ti• Best practice for GCP Compliance of Clinical Sites and Trials in India
History of Cli i l TrialsHi t f Clinical T i l
Jewish Chronic Disease Hospital Study• 1963, New York Citys Jewish Chronic Disease Hospital – studies to develop information on the nature of the human transplant rejection di d l i f i h f h h l j i process – involved the injection of live cancer cells into patients who were hospitalized with various chronic debilitating diseases• Researchers said that consent had been given orally, but was not documented – felt that documentation was unnecessary – because much more dangerous medical procedures are undertaken without the use of consent forms – would frighten the patients unnecessarily – good cause• Researchers were found guilty of fraud, deceit and unprofessional conduct
Cincinnati Radiation Experiments• 1960-72, Cancer patients mostly Blacks of below-average intelligence i lli – Exposed to large doses of whole body radiation as part of an experiment sponsored by the U.S. military – None of the subjects gave informed consent, they thought they were consent receiving treatment for their cancer – Subjects experienced nausea and vomiting from acute radiation sickness, pain from burns on their bodies, and some died prematurely as result of radiation exposure. lt f di ti• In re Cincinnati Radiation Litigation, 874 F.Supp. 796 (S.D.Ohio (S D Ohio 1995)• May 1999, a settlement was announced
Guidelines on the Ethics of Biomedical Research with Human Subjects Guideline Issuing Authority Year of Issue/Revisions Nuremberg Code Nuremberg Tribunal, USA 1947 Declaration of Helsinki World Medical Association 1964, 1975, 1983, 1989, 1996, 1989 1996 2008 Belmont Report National Commission for the Protection of 1979 Human Subjects of Biomedical and Behavioural Research, USA International Ethical Council for International Organizations of 1982, 1993 Guidelines for Biomedical Medical Sciences in collaboration with Research Involving Human WHO Subjects Guidelines for Good Clinical G id li f G d Cli i l WHO 1995 Practice for Trials on Pharmaceutical Products Good Clinical Practice: ICH GCP 1996 Consolidated G idance Guidance ……………………… Schedule Y Govt. of India 1988, 2003, 2005
Principles of Harmonized GCP• Clinical trials should be conducted in accordance with the ethical principles originating in the Declaration of Helsinki, and applicable regulatory requirement (s)• Risks and inconveniences be weighed against anticipated benefit for the trial subject & society, trial should be initiated & continued only if the anticipated benefits justify the risks• Rights, safety, and well-being of the trial subjects are the most important & prevail over interests of science and society• Non clinical & clinical information on an IP should be adequate to support the proposed clinical trial• Scientifically sound, clear & detailed protocol with prior approval by IRB/ IEC
Principles of Harmonized GCP contd.• Medical care & medical decisions made on behalf of, subjects , j should always be the responsibility of a qualified physician• Individuals involved in conducting trial should be qualified by education, training, education training and experience to perform there respective task• Freely given informed consent• Trial information should be recorded, handled, and stored in a way that allows its accurate reporting, interpretation, and verification• Confidentiality of records f d• IP should be manufactured, handled, and stored by GMP rules• Assure the quality of every aspect of the trial
GLP• In early 1970s, research laboratories were found doing work in unethical ways like data generation without cond ct of st d ; falsification of a s itho t conduct study; laboratory work; replacement of dead animals and fabrication of test results etc.• Evolution of GLPs – 1976 – USA: FDA proposals – 1978 – USA: FDA final rules – 1980 – USA : FDA amendment to GLP – 1981 – O C OECD: G id li Guidelines for testing of chemicals – O C Paris and f i f h i l OECD i d Guidelines for National GLP inspections – Paris – 1982 – OECD: GLP in testing of chemicals - Paris – 1984 – Japan: GLP proposals and notification to agricultural production bureau – 1987 – USA: FDA amendment final rule – 1988 – OECD: Final report for working group on mutual recognition of compliance with GLP f li ih – 1989 – UK: GLP compliance program Board and Dent 1996
Scope Demarcation: GCP and GLP• GCP: relate to clinical studies using human volunteers patients and also relate to most of the clinical procedures that can be carried out without a laboratory test – Includes all clinical phase I-IV studies• GLP apply to all analytical and testing process all safety studies for human health market approval and include QC assays, clinical chemistry and tests by instruments and certain bioanalytical procedures – Excludes validation studies, cosmetic safety, bioanalytical for efficacy studies including animal efficacy studies ffi di i l di i l ffi di• Good QA is applicable to all biomedical research practices
Ensuring compliance with multi- regulator GCP requirements l i• Understand the rules of central and de central de-central requirements• Follow harmonized guidelines g• Understand peculiar and particular requirements• Prepare annual compliance reports where required• Report serious breaches all pertinent jurisdictions• Different jurisdictions may have different comments after review – respond them separately
Uniform Ethics and Transparency in i Conduct and Reporting d d i• Train and re-train until the culture becomes ethical and documentation based d t ti b d – Train investigators, IRB, lab scientists & technicians, writers, data- analysts, QA …everyone• T i Trainers should be experts and “transformers” h ld b t d “t f ”• Associate self-respect and reward with ethics• “No deviation attitude No deviation”• SOP training 3600• Strict monitoring and QA• Thorough knowledge of all documentations needed before, during and after trials• Follow CTD for final reports
Protocol, Protocol SOPs and Guidelines• Follow them as though they are the main body of the law as g y y far as possible• In Protocol Consider IP dose adjustments / overdose as GCP violations and promptly report to local and applicable i l ti d tl tt l l d li bl regulatory agency with due update on current health status of study subjects• SOPs should be detailed, practical, easily understandable and to the point for systematic approach toward any activity even by most inexperienced associate of the monitoring group• Amongst all applicable guidelines most astringent guidelines should be considered for all practical purposed to avoid any p p p y regulatory inspection related queries
Protocol, Protocol SOPs and Guidelines.. Guidelines• Thorough understanding of the scientific rationale behind these documents and adherence to them is important• Understanding of the scientific question being addressed in the study and clinical importance of endpoints being evaluated is required
QMS and QA• Set up a Q p QMS that follows the p principles of total quality with QA p q y Q assuring traceability, integrity, accountability and compliance of documents and standard procedures• QA does not perform any evaluation of data/procedure• QA ensures that GCPs/GLPs and SOPs and Protocols are followed and accurate data go into final reports• They must keep COPIES of all final and amended versions of all protocols, SOPs, IBs. Originals of operations SOPs and their own should be with QA unit.• Review all data and documents and amendments for source and integrity• QA should independently report to the head of the organization and send periodic problem solving report
Critical Violations GCP• Where evidence exists that significant and unjustified g j departure(s) from applicable legislative requirements has occurred with evidence that – the safety well-being or confidentiality of trial subjects either have safety, well being been or have significant potential to be jeopardised, and/or – the clinical trial data are unreliable and/or – there are a number of Major non-compliances (defined in (c) and (d)) h b f j li (d fi d i ( ) d across areas of responsibility, indicating a systematic quality assurance failure, and/or• b) Where inappropriate, insufficient or untimely corrective action has taken place regarding previously reported Major non-compliances (next slide) p ( )
Non Critical Non-Critical but Major Violation of GCP• A non-critical finding where evidence exists that a non critical significant and unjustified departure from applicable legislative requirements has occurred that may not have developed into a critical issue, but may have the potential to do so unless addressed, and/or• Where evidence exists that a number of departures from applicable legislative requirements and/or established GCP guidelines have occurred within a t bli h d id li h d ithi single area of responsibility, indicating a systematic quality assurance failure
Examples of Critical Violations GCP• Fabrication or falsification of data• Evidence that formal procedure/systems were not in place or weak• Lack of/inadequate Quality Certification.• Importation and mfg. of investigational product without regulatory licence• Inaccurate information about investigational product is supplied to regulatory agency• Use of expired/recalled/non GMP manufactured investigational product• Poor/ineffective blinding system g y• Poor accountability of investigational product• Poorly documented/incorrect sponsorship/Legal Representative arrangements• Uncontrolled site to site transfer• Failure to observe IND conditions• Failure to report serious breaches of trial protocol/GCP• Little Littl or no oversight of pharmacovigilance requirements i ht f h i il i t
Critical GLP Violations• Fabrication or falsification of data• No Quality Assurance• No study allotment• No approved written study plans• Failure to date initial or sign data entries date,• No training records and / or no job descriptions for study personnel• Absence of required information in final reports
Responses to GCP Inspection Findings• Example 1 – “Control of database access post database lock was inadequate For Control inadequate. study XXX the database was frozen FEB 06, 2009. However, the Data Manager was able to (and did) delete a SAS dataset during the Inspection. Inspection ”• The SAS dataset tested was not secure – this would need to be investigated and could be corrected. Why wasn’t the database secure as the organization intended?• Don’t try to deny the evidence (green) or defend it. Give a detailed corrective plan for the actual observation (red) so that it does not i l f h l b i ( d) h i d happen. If all other datasets were secure and this happened for some reason, tell that and make plans for securing all datasets. If it requires training to be undertaken give timelines. Tell the agency the methods to assess the effectiveness of your preventative action.
Responses to GCP Inspection Findings• Example 2 p• “The SAE and USAE reporting systems/procedures by your CRO is not documented. There are no records of any transmittance to DCGI of the 6 SAEs reported finally.” p f y• The final report for NDA shows six SAEs in one pivotal trial. The TMF with the sponsor did not have any evidence that these SAEs were reported to authorities. d h ii• A response along the lines of “The point raised has been noted and has been brought to the attention of the CRO” is not sufficient The CRO sufficient. GCP inspector will expect the inspected organization to supply responses for all findings (i.e. liaise with the CRO).
A Good Response to a GCP I Inspection Fi di i Finding• Example 3 – “The investigational product recall procedure has not been tested. The tested.”• Response – We acknowledge that the investigational product (IP) recall procedure has not been tested. The IP recall procedure is described in SOP X123 “Complaints and Product Recall”, however, on review this currently has no requirement for testing.• Corrective action – A mock recall will be carried out following part 1 & 2 of preventative action, action according to the revised SOP X123. This will be undertaken by March 31, 2009.• Preventive action – SOP X123 will be updated by the SOP Review Team by 01/03/09 to contain a requirement for regular testing of the IMP recall. Training of relevant personnel in this SOP (and documentation of this) will be provided by the “job title” and completed by 15/03/09. C l t d b 15/03/09 Compliance with th regular t ti requirements will li ith the l testing i t ill be determined by audit by the internal QA group. The first audit is planned to take place by 31/03/09.
Acknowledgments• MHRA guidances and examples• Dr. Paresh Dadhaniya y• Dr. Vikas Vaishnavi• Dr. Alit Bhatt Thank You Very Much