CLINICAL STUDY AND BASIC CONCEPT GOOD CLINICAL PRACTICE

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CLINICAL STUDY AND BASIC CONCEPTGOOD CLINICAL
PRACTICE

• Presented by
• Aarohi Shah
• M.Pharm

Dept of Pharmaceutics and Pharmaceutical
Technology
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CLINICAL STUDY AND BASIC CONCEPT

• What is a Clinical Trial?
• A clinical trial (clinical research) is a
  research study in human volunteers (preclinical
  trail in animals) to answer specific health
  questions.
• Carefully conducted clinical trials are the
  fastest and safest way to find treatments that
  work in people and ways to improve health.

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CLINICAL STUDY AND BASIC CONCEPT

• Types of clinical trials
• Treatment trials
• Prevention trials
• Diagnostic trials
• Screening trials
• Quality of Life trials

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CLINICAL STUDY AND BASIC CONCEPT

• Clinical trials, FDA approval
• Before a company initiates clinical trials (i.e.
  testing in humans), it must conduct extensive
  experiments in animal and human cells and in live
  animals (Preclinical Trial)
• If this stage of testing is successful, the
  company files an Investigational New Drug (IND)
  application with the Food and Drug Administration
  (FDA) to request permission to conduct clinical
  trials.

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CLINICAL STUDY AND BASIC CONCEPT
Clinical Trials Clinical Trials Clinical Trials Clinical Trials Clinical Trials Clinical Trials Clinical Trials Clinical Trials Clinical Trials Clinical Trials
Preclinical testing F I L E IND at FDA Phase I Phase II Phase III F I L E NDA at FDA FDA Phase IV
Years 3.5 F I L E IND at FDA 1 2 3 F I L E NDA at FDA 2.5 12 Total Additional post marketing testing
Test population Lab and Animal Studies F I L E IND at FDA 20 to 80 healthy volunteers 100 to 300 patient volunteers 1000 to 3000 patient volunteers F I L E NDA at FDA Review process/ Approval Additional post marketing testing
Success rate 5000 compounds evaluated F I L E IND at FDA 5 enter trials 5 enter trials 5 enter trials F I L E NDA at FDA 1 approved Additional post marketing testing
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CLINICAL STUDY AND BASIC CONCEPT

• Preclinical trials
• Trial carried out on to the animal species
• Objective To evaluate safety, toxicity and
  tolerance data (by applying the factor for
  conversion of animal data to human data)
• Study
• Drug metabolism pathway
• PK of the drug
• PK-PD relation
• Protein binding
• Tissue distribution
• Development of methodology for quantification of
  drug and metabolite in biological fluid
• Long term toxicity
• Placental transfer kinetic

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CLINICAL STUDY AND BASIC CONCEPT

• Phase 1
• Trial carried out on healthy volunteers except
  AIDS or Cancer.
• Study
• Dose-concentration (in plasma)-response-toxicity
  study
• IV, single dose study (for checking
  bioavailability)
• Radioactive tracer study (for evaluation of first
  pass metabolism)
• Evaluation of suitability of preclinical animal
  model (to predict pharmacological effect in
  human)
• Effect of food

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CLINICAL STUDY AND BASIC CONCEPT

• Phase 2
• First time trial on patient and conducted in OPEN
  manner
• Study
• Evaluation of difference in PK and PD between the
  healthy volunteer and patient
• To search new therapeutic effect of the drug

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CLINICAL STUDY AND BASIC CONCEPT

• Phase 3
• Study
• Search less common side effect of drug (which is
  conc. independent)
• Comparison with the marketed drug
• Drug-drug interaction
• Study in special population like age, sex race
  etc.
• Develop the dosage form

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CLINICAL STUDY AND BASIC CONCEPT

• Phase 4
• Post marketing surveillance
• Not well planned study but random study
• Some rare side effect or toxicity may come out

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GOOD CLINICAL PRACTICE

• Good Clinical Practice (GCP) is an international
  ethical and scientific quality standard for
  designing, recording and reporting trials that
  involve the participation of human subjects.
• Compliance with this standard provides public
  assurance that the rights, safety and well being
  of trial subjects are protected, consistent with
  the principles that have their origin in the
  Declaration of Helsinki, and that the clinical
  trial data are credible.
• Regulations tell you what you are required to do
  by law. Guidelines tell you the best way to do it

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GOOD CLINICAL PRACTICE

• FDA GCP Regulations
• Regulations contained in 21 CFR Part 50, 56, and
  312
• Part 50 (applies to consenting of subjects),
• Part 56 (applies to IRB responsibilities) and
• Part 312 (applies to IND submissions, sponsor
  responsibility, and investigator responsibility)
• GCP Guidelines- International Conference on
  Harmonization
• The objective of ICH GCP Guidelines is to provide
  a unified standard for European Union, Japan and
  United States to facilitate the mutual acceptance
  of clinical data by the regulatory authorities in
  the jurisdiction.
• Published by the FDA in Federal Register in May,
  1997
• Adopted by all parties as GCP standard
  (considered law in European Union considered
  final guidance in the US)
• Based on the Declaration of Helsinki

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GOOD CLINICAL PRACTICE

• Some important terms (Glossary)
• Investigator
• Sponsor
• Subject /Trial Subject
• Investigators Brochure
• Non Clinical Study
• Protocol
• Blinding (Masking)
• Institutional Review Board (IRB)
• Adverse Event (AE)
• Serious Adverse Event (SAE)

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GOOD CLINICAL PRACTICE

• Elements of GCP
• IRB
• Investigator
• Sponsor
• Clinical trial protocol and protocol amendments
• Investigator Brochure
• Essential documents

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GOOD CLINICAL PRACTICE

• Institutional review board (IRB) or Independent
  Ethics Committee (IEC)
• It consists of reasonable number of members, who
  collectively have qualifications and experience
  to review and evaluate the science and medical
  aspects as well as ethics of proposed trials.
• It should perform the functions in accordance
  with written procedures, maintain written records
  of its activities and minutes of its meetings and
  should comply with GCP.
• Acts as a safe guard to the rights of the trial
  subject
• Should consider the qualification of the
  investigator for the proposed trial
• Should conduct continuing review of each ongoing
  trial at intervals appropriate to the degree of
  risk.

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GOOD CLINICAL PRACTICE

• Investigator
• Qualified to perform study should have
• Appropriate education, training and experience to
  assume responsibility and should provide evidence
  of such qualifications.
• Sufficient time to devote to study timelines.
• Personally conduct or supervise study.
• Adequate and qualified staff and facilities.
• Awareness of and compliance with GCP.
• Familiar with the investigational product and
  inventory.
• Adherence to protocol requirements.
• Inform subjects primary physician
• Ensure adequate medical care for SAEs.
• Maintained records should be accurate, complete,
  legible and timely.

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GOOD CLINICAL PRACTICE

• Investigator-Communication with IRB
• Obtaining written and dated IRB approved consent
  form
• Submission of Investigational Brochure
• Ongoing communication
• Report of SAEs
• IND Safety Reports
• Significant protocol deviations
• The investigator should submit written summaries
  of the status of the trial to the IRB annually or
  more frequently, if requested by the IRB

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GOOD CLINICAL PRACTICE

• Investigator- Communication with the Sponsor/CRO
• Reporting of any AEs or SAEs
• Notification of changes in staff and address
• Retention of all pertinent study information and
  records until notified in writing that records
  are no longer required
• Coordination of publication plans
• If trial is blinded, the investigator should
  promptly document and explain to the sponsor any
• Premature unblinding
• Accidental unbliniding
• Unblinding due to serious adverse events

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GOOD CLINICAL PRACTICE

• Investigator-Communication with Study Subjects
• Obtaining valid written informed consent
• The information language should be non-technical
  and understandable to the subject/LAR/impartial
• Provide subject a copy of a fully executed
  consent
• Provide subject with any new information
• Answer questions at any time
• The investigator must inform the subject when
  medical care is needed for inter-current
  illness(es) of which investigator becomes aware.
• It is recommended that the investigator inform
  subjects primary physician about subjects
  participation in study.
• If subject wishes to withdraw from the study, the
  investigator should make reasonable effort to
  ascertain the reasons while fully respecting
  the subjects rights.

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GOOD CLINICAL PRACTICE

• Investigator- Investigator Compliance with
  Protocol
• The investigator should conduct the trial in
  compliance with
• The protocol agreed to by the sponsor
• If required, protocol agreed to by the
  regulatory authority(ies)
• Ultimately given approval by the IRB
• The investigator should not implement any
  deviation from, or changes of the protocol
  without
• Agreement by the sponsor
• Prior review and documented approval from the
  IRB of an amendment
• Exception where necessary to eliminate an
  immediate hazard (s) to trial subjects or when
  the changes involve only logistical or
  administrative aspects of the trial. However, as
  soon as possible, the implemented deviation or
  change, the reason for it, and, if appropriate,
  the proposed protocol amendment(s) should be
  submitted to
• The IRB for review and approval
• To the sponsor for agreement
• If required, to the regulatory authorities

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GOOD CLINICAL PRACTICE

• Investigator Investigational Products
• It is the investigators responsibility for
  investigational product(s) accountability at the
  trial site
• The investigator or person who is designated by
  the investigator should maintain records of
• The product(s) delivery to the site
• The inventory at the site
• The use by each subject
• The return to the sponsor or disposition of
  unused products
• The records should include
• Date, quantities, batch/serial numbers,
  expiration dates and the unique code numbers
  assigned to the product(s) and subjects
• Products should be stored as specified by the
  sponsor and in accordance with applicable
  regulatory requirements
• Should explain to the subject
• Correct use of the product
• Should check at appropriate intervals that the
  subject is following the instructions properly to
  use the product

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GOOD CLINICAL PRACTICE

• Investigator Records and Reports
• Records should be accurate, complete, legible and
  timely pertinent to the data reported to the
  sponsor in the CRFs (Case Report Forms) and other
  required reports
• All corrections to a CRF should be dated,
  explained and should not obscure the original
  entry whether the entry is written or electronic
  changes or corrections.
• The investigator should retain records of the
  changes and corrections.

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GOOD CLINICAL PRACTICE

• Investigators Brochure
• For investigational (not FDA-approved) drug
  trials
• Summary of significant physical, chemical,
  pharmaceutical, pharmacological, toxicological,
  pharmacokinetic, metabolic, and clinical
  information that is relevant to the
  investigational product
• Relevant animal and clinical studies, adverse
  events, etc.

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GOOD CLINICAL PRACTICE

• FDA Form 1572 to initiate clinical trials
• Investigator agrees to comply with conditions
  required by FDA for use of investigational
  articles
• Contract that the investigator signs/dates
• Warning A willing false statement is a criminal
  offense
• Content of Form 1572
• Principal Investigator name/address
• Name/address of site(s) of study conduct
• Name/address clinical labs (local/central)
• Name/address IRB
• Names of key personnel with study participant
  contact
• Submit CVs of key personnel (signed/dated) listed
  in form

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GOOD CLINICAL PRACTICE

• Progress Reports
• The investigator should submit written summaries
  (where required by applicable regulatory
  requirements) of the trials status to the
  institution.
• The investigator should submit written summaries
  of the status of the trial to the IRB annually or
  more frequently, if requested by the IRB
• The investigator should promptly provide written
  reports to the sponsor and the IRB and where
  required by the regulatory authorities, the
  institution on any changes significantly
  affecting the trial and/or increasing the risk to
  subjects.

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GOOD CLINICAL PRACTICE

• Safety Reporting
• All serious adverse events (SAE) should be
  reported immediately to the sponsor except for
  those SAEs that the protocol or other document
  identifies as not needing immediate reporting
• The immediate and follow up reports should
  identify Subjects by unique code numbers assigned
  to trial, but not with identifiers (name,
  address, identification numbers)
• The immediate reports should be followed promptly
  by detailed, written reports
• Adverse events and/or laboratory abnormalities
  identified in the protocol as critical to safety
  evaluations should be reported to the sponsor
  within the time periods specified by the sponsor
  in the protocol
• For reported deaths, the investigator should
  supply the sponsor and the IRB with any
  additional requested information (e.g., autopsy
  reports and terminal medical reports)

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GOOD CLINICAL PRACTICE

• Premature Termination or Suspension of a Trial
• If the trial is suspended or prematurely
  terminated for any reason the investigator should
  promptly Inform the trial subjects, should assure
  appropriate therapy and follow-up and where
  required, should inform the regulatory
  authorities and the IRB
• If the investigator terminates or suspends a
  trial without prior agreement of the sponsor, the
  investigator should inform the institution,
  regulatory authorities(if required), the sponsor
  and the IRB with detailed written explanation of
  the termination or suspension
• If the sponsor terminates/suspends a trial, the
  investigator should promptly inform the
  institution (per applicable regulatory
  requirements) and the IRB and provide written
  explanation of the termination/suspension
• If the IRB terminates/suspends its approval, the
  investigator should inform the institution and
  the investigator should promptly notify the
  sponsor and provide the sponsor with a detailed
  written explanation of the termination or
  suspension

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GOOD CLINICAL PRACTICE

• Final Report
• Upon the completion of the trial, the
  investigator should inform and provide the IRB
  and the sponsor
• All required reports
• Summary of the trials outcome
• Reports to regulatory authorities if applicable

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GOOD CLINICAL PRACTICE

• Records Retention Requirements
• Essential documents should be retained until at
  least two (2) years after the last approval of a
  marketing application in an ICH region.
• These documents should be retained, however, if
  required by the applicable regulatory
  requirements (state or federal) or by an
  agreement with the sponsor.
• It is the responsibility of the sponsor to inform
  the investigator as to when these documents no
  longer need to be retained.
• Upon request of the monitor, auditor, IRB or
  regulatory authority, the investigator/institution
  should make available for direct access all
  requested trial-related records.

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References

• www.fda.gov
• www.google.com
• EMEA, Inspections
• Stanford school of medicine FACILITATING
  TRANSLATIONAL RESEARCH AND MEDICINE
• CLINICAL RESEARCH

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Thank You