1. Effectively Incorporating
Good Clinical Practices (GCPs)
( )
and Good Laboratory Practices (GLPs)
Dr. Bhaswat S. Chakraborty
Senior VP, Research & Development
VP
Cadila Pharmaceuticals Ltd.

2. 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

3. History of Cli i l Trials
Hi t f Clinical T i l

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

5. 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

6. 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

7. 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

8. 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

9. 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

10. 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

11. 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

12. 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

13. 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

14. 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

15. 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

16. 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 ( )

17. 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

18. 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

20. 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

21. 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.

22. 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).

23. 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.

24. Acknowledgments
• MHRA guidances and examples
• Dr. Paresh Dadhaniya
y
• Dr. Vikas Vaishnavi
• Dr. Alit Bhatt
Thank You Very Much