Good Clinical Practice - KSR

Good Clinical Practice (GCP)

Dr. K. Shiva Rama Prasad, at http://www.technoayurveda.com/




Introduction• Clinical Research and Practice looks similar with

variation – Research require to work in a stipulated frame work– Where in the practice is patient oriented /beneficial – The research do not require any clinical experience

and it starts with a research question – but clinical practice do require clinical experience and

regularity – To prevent undo practices in Clinical research and

practice “Good Clinical Practice” is brought out

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Clinical Research• Research is –

– A search for knowledge with Systematic investigation to establish facts in scientific manner

• Clinical Research is –– Fact establishment in a clinic /hospital

depending on direct observation of patients

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What is Clinical trial • A clinical trial is a prospective evaluating

the effect and value of intervention (s) in human beings under pre-specified conditions

• A controlled clinical trial is a clinical trial comparing an intervention group against controls

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Good Clinical PracticeGood Clinical Practice (GCP) is defined as –

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’

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GCP principles summary (1)• Patient

– Rights, safety & well being of subjects prevail over interests of science and society

– Individuals involved in trial should be qualified by education, training and experience to perform his/her tasks

• Data– Information recorded, handled and stored to allow

accurate reporting, interpretation and verification and confidentiality of subjects’ records

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GCP principles summary (2)• Study

– Trials shall be scientifically sound and guided by ethical principles in all their aspects

– Necessary procedures to secure the quality of every aspect of the trial shall be complied with

– Available non-clinical and clinical information shall be adequate to support the trial

– Conducted according to Helsinki Declaration (1996)– Protocol shall provide inclusion and exclusion criteria,

monitoring and publication policy– Investigator/sponsor shall consider all relevant

guidance

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WORLD MEDICAL ASSOCIATION DECLARATION OF HELSINKIEthical Principles for Medical Research Involving Human Subjects

• Adopted by the 18th WMA General Assembly Helsinki, Finland, June 1964 and amended by the

• 29th WMA General Assembly, Tokyo, Japan, October 1975

• 35th WMA General Assembly, Venice, Italy, October 1983

• 41st WMA General Assembly, Hong Kong, September 1989

• 48th WMA General Assembly, Somerset West, Republic of South Africa, October 1996

• 52nd WMA General Assembly, Edinburgh, Scotland, October 2000

• Note of Clarification on Paragraph 29 added by the WMA General Assembly, Washington 2002

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Declaration of Helsinki

• Basic Principles– Concern for the interests of the subjects must always

prevail over the interests of science and society.– Research must conform to accepted scientific principles;

design appropriate and clear in experimental protocol.– Research must be conducted by qualified persons.– Research must have importance proportionate to inherent

risk (risks acceptable given the benefits to individuals)– Safeguard subjects’ integrity & privacy.– Present results accurately in publications– Inform subjects of their right to withdraw. Obtain true

informed consent from the subject or legal guardian.

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41st World Medical Assembly, Hong Kong, September 1989.




• Medical Research Combined with Clinical Care (Clinical Research)– In the treatment of the sick person, the physician must be free to

use a new diagnostic and therapeutic measure– The potential benefits, hazards and discomfort of a new method

should be weighed against the advantages of the best current diagnostic and therapeutic methods

– In any medical study, every patient should be assured– The physician can combine medical research with professional

care– If the physician considers it essential not to obtain informed

consent, the specific reasons for this– proposal should be stated in the experimental protocol for

transmission to the independent committee (I.2).

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• Non-Therapeutic Biomedical Research Involving Human Subjects (Non-Clinical Biomedical Research)– it is the duty of the physician to remain the protector

of the life and health of that person, on whom biomedical research is being carried out.

– The subjects should be volunteers --either healthy persons, or patients for whom the experimental design is not related to the patient's illness.

– The investigator or the investigating team should discontinue the research, if in his/her or their judgment it may, if continued, be harmful to the individual.

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Note of Clarification on Paragraph 29 added by the WMA General Assembly, Washington 2002 on

Placebo controlled trial• Extreme care must be taken in making use of a placebo

controlled trial and that in general this methodology should only be used in the absence of existing proven therapy. However, a placebo-controlled trial may be ethically acceptable, even if proven therapy is available, under the following circumstances:– Where for compelling and scientifically sound methodological

reasons its use is necessary to determine the efficacy or safety of a prophylactic, diagnostic or therapeutic method; or

– Where a prophylactic, diagnostic or therapeutic method is being investigated for a minor condition and the patients who receive placebo will not be subject to any additional risk of serious or irreversible harm.

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GCP compliance• Who must comply with GCP?

– All individuals involved in any aspect of the trial must be suitably ‘qualified’ to be able to comply with GCP.

– Sponsors/CIs are responsible for ensuring that all staff are able to comply with GCP.

• ICH GCP section 5.18.3 allows individual researchers to assess the needs of their trial and apply GCP appropriately

‘central monitoring in conjunction with procedures such as investigators’ training and meetings and extensive written guidance can assure appropriate conduct of the trial in accordance with GCP.’ (On-site monitoring not compulsory)

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What counts as qualified?According to GCP each individual involved inconducting a trial ‘shall be qualified byeducation, training, and experience to performhis or her respective task (s)’ (GCP – principle 8)

• Education• Training• ExperienceThere is no GCP ‘qualification’

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GCP qualifications• Education

– Clinicians must be clinically qualified– Statisticians must be qualified– Managers must be appropriately educated

• Training– Employer induction courses– Industry courses– E-learning (Institute of Clinical Research)– Private courses (usually run by freelance consultant)– Host institution courses– Trial specific workshops– Investigators meetings

• Experience– Discovering what is required– Doing the job (sometimes wrongly) – Cascading information and knowledge through teams/units– Conversation to other trial makers

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Approvals and permissions• Ethics committee approval• Clinical Trials Authorisation • R & D permission• Sponsor approval

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Informed consent• Following the second world war and the Nuremberg trials,

the Nuremberg Code and Declaration of Helsinki was agreed worldwide as a charter to protect people/patients against human experimentation– Up until 1995 USA, Japan and Europe worked to different

standards in the conduct of clinical trials– 1995 ICH-GCP was implemented – a global standard– 2001 EU Directive set out regulations for clinical trials of medicines

conducted within the EU– 2004 (May) the UK implemented the Directive and the UK

Regulations became law

Informed consent – personal autonomy‘…a competent individual should have the right to determine

those discretionary risks he/she is willing to accept for whatever benefits he/she perceives may result.’

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Consent procedures• Given freely• Face to face• Telephone• Watch• Listen• Learn • What works well?• Share

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Good Clinical Practice (E6) • The GCP document describes the

responsibilities and expectations of all participants in the conduct of clinical trials, including investigators, monitors and sponsors.

• GCP covers the aspects of monitoring, reporting and archiving of clinical trials and incorporating addenda on the essential documents and on the investigators broacher which had been agreed earlier through consent process.

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Good Clinical Practice (GCP) 19



• Phase 1– First use in humans (healthy or ill)– Physiological observations (pre-clinical status)– Tolerance of different dosages– Finding optimal dose-relationship– Interactions with other treatments– Pre-finding of clinical indication

• Phase 2– Dose-relationship in patients– Treatment efficacy compared to an other method or

substance– Tolerance proof of dose (s)– Physiological observations of phase I results– Interactions with other treatments– Real finding of indication

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• Phase 3– Treatment efficacy compared to another method or

substance– Give reasons for effect (power, number of cases)– Tolerance proof of dose (s)– Physiological observations of phase I&II results– Interactions with other treatments– Confirmation interactions to be registered

• Phase 4– Additional findings under conditions of daily use– Periodic safety update to keep marketing

authorization (Vigoxx©, Lipoxx©)– Impressions about new indication (s)

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Designs of study• Randomized clinical trial • Parallel group design • Crossover design • Multi center studies (trials)• Active control trial

– Superiority trial (new advances)– Equivalence or non inferiority trial (safety

purpose)

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Principles of Research • Randomization principle • Blindness principle

– Single / Double • Placebo principle • Intent to treat principle

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Follow -• CONSORT checklist• Show proper reporting effects

– Acknowledgements – Statistics

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Acknowledgements • GCP - J. Hedderich - Institut für Medizinische

Informatik und Statistik• UKTMN

• MRC GUIDELINES FOR GOOD CLINICAL PRACTICE IN CLINICAL TRIALS, March 1998, Medical Research Council, 20, Park Crescent, London, W1N 4AL

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Good Clinical Practice - KSR

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