Effectively Incorporating Good Clinical Practices (GCPs)( )

and Good Laboratory Practices (GLPs)

Dr. Bhaswat S. ChakrabortySenior VP Research & DevelopmentSenior VP, Research & Development

Cadila Pharmaceuticals Ltd.

Theme of this PresentationTheme of this Presentation

• Uniform ethics and transparency in conduct and reporting • Ensuring compliance with multi-regulator GCP

requirementsE i th t th li i l t i l f ll t l SOP d• Ensuring that the clinical trials follow protocol, SOPs and applicable guidelines

• Incorporating Quality Assurance as a culturep g Q y• What NOT to do with regards to GLP and GCP• Implementing QMS and QA systems in trial and site

tioperations • Best practice for GCP Compliance of Clinical Sites and

Trials in India

Hi t f Cli i l T i lHistory of Clinical Trials

Jewish Chronic Disease Hospital StudyJewish Chronic Disease Hospital Study• 1963, New York City's Jewish Chronic Disease Hospital

di d l i f i h f h h l j i– studies to develop information on the nature of the human transplant rejection 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 unnecessaryfelt 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– good cause

• Researchers were found guilty of fraud, deceit and unprofessional conduct

Cincinnati Radiation ExperimentsCincinnati Radiation Experiments

• 1960-72, Cancer patients mostly Blacks of below-average i lliintelligence– Exposed to large doses of whole body radiation as part of an

experiment sponsored by the U.S. militaryNone of the subjects gave informed consent they thought they were– None of the subjects gave informed consent, they thought they were receiving treatment for their cancer

– Subjects experienced nausea and vomiting from acute radiation sickness, pain from burns on their bodies, and some died prematurely

lt f di tias result of radiation exposure.

• In re Cincinnati Radiation Litigation, 874 F.Supp. 796 (S D Ohio 1995)(S.D.Ohio 1995)

• May 1999, a settlement was announced

Guidelines on the Ethics of Biomedical Research with Human Subjectswith 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 20081989, 1996, 2008

Belmont Report National Commission for the Protection of Human Subjects of Biomedical and Behavioural Research, USA

1979

International Ethical Guidelines for Biomedical Research Involving Human Subjects

Council for International Organizations of Medical Sciences in collaboration with WHO

1982, 1993

G id li f G d Cli i l WHO 1995Guidelines for Good Clinical Practice for Trials on Pharmaceutical Products

WHO 1995

Good Clinical Practice: Consolidated G idance

ICH GCP 1996Consolidated Guidance………………………

Schedule Y Govt. of India 1988, 2003, 2005

Principles of Harmonized GCPPrinciples 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• Risks and inconveniences be weighed against anticipated benefitfor 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• Non clinical & clinical information on an IP should be adequateto support the proposed clinical trial

• Scientifically sound, clear & detailed protocol with prior approval by IRB/ IEC

Principles of Harmonized GCP contd.Principles of Harmonized GCP contd.

• Medical care & medical decisions made on behalf of, subjects , jshould always be the responsibility of a qualified physician

• Individuals involved in conducting trial should be qualified by education training and experience to perform there respectiveeducation, 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 verificationf d• Confidentiality of records

• IP should be manufactured, handled, and stored by GMP rules• Assure the quality of every aspect of the trial• Assure the quality of every aspect of the trial

GLPGLP• In early 1970s, research laboratories were found doing work in unethical

a s like data generation itho t cond ct of st d ; falsification ofways like data generation without conduct of study; falsification of 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 G id li f i f h i l O C i d– 1981 – OECD: Guidelines for testing of chemicals – OECD Paris and Guidelines for National GLP inspections – Paris

– 1982 – OECD: GLP in testing of chemicals - Paris– 1984 – Japan: GLP proposals and notification to agricultural1984 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

f li i h GLPof compliance with GLP– 1989 – UK: GLP compliance program

Board and Dent 1996

Scope Demarcation: GCP and GLPScope 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

ffi di i l di i l ffi diefficacy studies including animal efficacy studies

• Good QA is applicable to all biomedical research practices

Ensuring compliance with multi-l iregulator GCP requirements

• Understand the rules of central and de-centralUnderstand the rules of central and de central requirements

• Follow harmonized guidelinesg• Understand peculiar and particular requirements• Prepare annual compliance reports where requiredPrepare annual compliance reports where required• Report serious breaches all pertinent jurisdictions• Different jurisdictions may have different comments• Different jurisdictions may have different comments

after review – respond them separately

Uniform Ethics and Transparency i d d iin Conduct and Reporting

• Train and re-train until the culture becomes ethical and d t ti b ddocumentation based– Train investigators, IRB, lab scientists & technicians, writers, data-

analysts, QA …everyone

T i h ld b t d “t f ”• Trainers should be experts and “transformers” • Associate self-respect and reward with ethics• “No deviation” attitudeNo deviation attitude• SOP training 3600

• Strict monitoring and QA

• Thorough knowledge of all documentations needed before, during and after trials

• Follow CTD for final reports• Follow CTD for final reports

Protocol SOPs and GuidelinesProtocol, 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

i l ti d tl t t l l d li blviolations and promptly report to local and applicable 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 groupby 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 yregulatory inspection related queries

Protocol SOPs and GuidelinesProtocol, SOPs and Guidelines..

• Thorough understanding of the scientific rationaleThorough 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 QAQMS and QA• Set up a QMS that follows the principles of total quality with QA p Q p p q y Q

assuring traceability, integrity, accountability and compliance of documents and standard procedures

• QA does not perform any evaluation of data/procedureQA 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• QA should independently report to the head of the organization and send periodic problem solving report

Critical Violations GCPCritical 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– the safety, well-being or confidentiality of trial subjects either have been or have significant potential to be jeopardised, and/or

– the clinical trial data are unreliable and/or h b f j li (d fi d i ( ) d (d))– there are a number of Major non-compliances (defined in (c) and (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 but Major Violation of GCPNon Critical but Major Violation of GCP

• A non-critical finding where evidence exists that aA non critical finding where evidence exists that a 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

t bli h d GCP id li h d ithiestablished GCP guidelines have occurred within a single area of responsibility, indicating a systematic quality assurance failurequality assurance failure

Examples of Critical Violations GCPExamples of Critical Violations GCP• Fabrication or falsification of data• Evidence that formal procedure/systems were not in place or weak• 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 toInaccurate information about investigational product is supplied to

regulatory agency• Use of expired/recalled/non GMP manufactured investigational product • Poor/ineffective blinding systemg 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

Littl i ht f h i il i t• Little or no oversight of pharmacovigilance requirements

Critical GLP ViolationsCritical GLP Violations

• Fabrication or falsification of dataFabrication or falsification of data• No Quality Assurance • No study allotmentNo study allotment • No approved written study plans • Failure to date initial or sign data entries• Failure to date, initial or sign data entries • No training records and / or no job descriptions for

study personnelstudy personnel • Absence of required information in final reports

Responses to GCP Inspection FindingsResponses to GCP Inspection Findings• Example 1

“Control of database access post database lock was inadequate For– Control of database access post database lock was inadequate. For 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 i l f h l b i ( d) h i dcorrective plan for the actual observation (red) so that it does not

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 FindingsResponses to GCP Inspection Findings

• Example 2p• “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

d h i iwere reported to authorities.

• 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 Thehas been brought to the attention of the CRO is not sufficient. The GCP inspector will expect the inspected organization to supply responses for all findings (i.e. liaise with the CRO).

A Good Response to GCP I i Fi dia GCP Inspection Finding

• Example 3– “The investigational product recall procedure has not been tested.”The investigational product recall procedure has not been 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 actionA mock recall will be carried out following part 1 & 2 of preventative action– A mock recall will be carried out following part 1 & 2 of preventative 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

l t d b 15/03/09 C li ith th l t ti i t illcompleted by 15/03/09. Compliance with the regular testing requirements will be determined by audit by the internal QA group. The first audit is planned to take place by 31/03/09.

AcknowledgmentsAcknowledgments

• MHRA guidances and examples• Dr. Paresh Dadhaniyay• Dr. Vikas Vaishnavi• Dr. Alit Bhatt

Thank You Very Much