The Anatomy of a Good Clinical Study

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The Anatomy of a Good Clinical Study

• Joseph X. Kaufman
• Director of Quality Assurance Community Research
• 4460 Red Bank Expressway
• Cincinnati, Ohio 45227
• Phone [phone]

2
Learning Objectives

• The role of the Institutional Review Board (IRB)
• Protocol Adherence
• The Informed Consent Process
• Test Article Accountability Records
• Case Report Forms versus Source Documents
• Adverse Events Serious Adverse Events
• Training Training Files
• FDA Site Selection
• FDA Inspections

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The Institutional Review Board(IRB)

• An IRB A group of people, formally designated
  to review and monitor biomedical research
  involving human subjects (Drugs Devices).
• The IRB has the authority to approve, require
  modifications and disapprove research.
• If necessary suspend research 21 CFR
  56.113
• This group review serves an important role in the
  protection of the rights and welfare of human
  research subjects.
• Code of Federal Regulations 21 CFR Part 56.109

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The Institutional Review Board(IRB)

• Prior to the initiation of any clinical study,
  the Principal Investigator must secure IRB
  approval for the following
• Protocol
• Informed Consent
• Advertising means to recruit subjects
• (Radio, Television, Pamphlets, Newspapers,
  Magazines)
• The Principal Investigator - Qualifications
• Location of clinical study Study site
• Written approval from IRB must be secured prior
  to enrolling subjects or initiating study.

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Protocol Adherence

• Principal Investigators must
• Submit all amendments/addendums to the protocol
  and informed consent for IRB review/approval
  prior to implementation.
• Report all Serious Adverse Events within a
  twenty-four hour period to the IRB and Sponsor.
• Complete Continuing Review every 12 months or so
  designated by the IRB. Some IRBs will request
  continuing review every three or six months
  pending the nature of the study.

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Protocol Adherence

• 21 CFR 312.66
• The Principal Investigator will not make any
  changes in the research activity without IRB
  approval, except where necessary to eliminate
  apparent immediate hazards to human subjects.
• If you do make changes, you must received Sponsor
  and IRB approval prior to implementing that
  change.

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Protocol Adherence

• Example Inclusion criteria specifies a total
  cholesterol count of 50-200 mg/dl. If a subject
  has a total count of 222 mg/dl, you place him in
  the study and suffers a heart attack and dies.
  You now have a reported serious adverse event for
  a subject who should have never been permitted to
  enter the clinical study.
• You are gambling when you fail to follow the
  protocol. The IRB authorized permission for a
  specific protocol, not the one amended that they
  have never seen.

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PROTOCOL ADHERENCE

• Lori A. Nesbitt Author
• Book Clinical Research - What It is and How it
  Works
• Page 25 Because of the difficult balance in
  creating appropriate inclusion and exclusion
  criteria, many sponsors will grant waivers or
  exceptions to these criteria based on a
  case-by-case basis.

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Protocol Adherence

• Continue
• Despite the fact that this is a common
  practice, the Investigator should neither pursue
  nor accept these exceptions, unless these
  exceptions are approved by the IRB prior to
  implementation.

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INFORMED CONSENT

• When a participant signs/dates an Informed
  Consent, this is not the end of Informed Consent.
  But, a continuing process that carries through
  to the end of the individuals participating in
  the trial.
• Informed Consent must be signed/dated prior to
  study participation.
• Provide quiet place, ample time and privacy to
  review the document and ask the subject if they
  have any questions in private.
• Explain the informed consent and answer
  questions. If you cannot answer the question,
  have the Principal Investigator address the
  question.
• Provide subject with photocopy (Complete
  Document), not just the signature page, emergency
  contact phone numbers may precede the
  signature/date page. Place original in their
  charts/files.

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Informed Consents

• Ask subjects if they fully comprehend the
  clinical aspects of the investigational study
• (Blood Draws, EKGs, Urinalysis, Food,
  Diaries)
• Verbally quiz the subject on a few key aspects of
  the clinical study to make sure they fully
  comprehend their consent, time factors,
  scheduling visits, communication etcCan they
  read?

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INFORMED CONSENT

• What happens when a subject signs his/her name
  with an X ?
• Can they enter the clinical study?
• Glaucoma subjects, elderly population.
• Make sure a witness signs/dates informed consent

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Informed Consents

• Date Mix-Ups
• When subject signs/dates informed
• consent, check for correct date.
• Example September 10, 2005
• 09/10/2005 and/or 10/09/2005

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INFORMED CONSENTS

• FDA During an FDA Inspection, the Investigator
  will look at each Informed Consent to verify
  signature/date prior to entering the clinical
  study.
• Informed Consents with Signature/Date/Time
  provide excellent evidence compared with an EKG
  that may be required during screening.
• FDA will collect a copy of the Informed Consent.
  Verify it meets the required elements of informed
  consent. 21 CFR 50.25

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TEST ARTICLE ACCOUNTABILITY RECORDS

• Maintain all shipping receipts of test article-
  Fed-Ex, UPS, Air-Borne Shipping receipts.
• Storage of test article Room Temperature
• The dispensing/return of test article must be
  immediately recorded in the subjects source
  documents.
• Monitors packing/accountability - Document
• The Principal Investigator/Sub-Investigators or
  Coordinator may dispense the test article, just
  not anyone in the office. Remember, Delegation
  of Authority Log.
• Most common mistake Simple addition/subtraction.
  

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CASE REPORT FORMS VS.SOURCE DOCUMENTS

• Source Documents All information in original
  records of clinical findings, observations or
  other activities in a clinical trial necessary
  for the reconstruction and evaluation of a
  trials.
• Post-It Notes?
• Case Report Forms A printed or electronic
  document designed to record all of the protocol
  required information to be reported to the
  sponsor. Case Report Form data is derived from
  the source documents.

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Case Report Forms vs. Source Documents

• FDA The Case Report Forms are the documents the
  Sponsor submits to the FDA. This information is
  derived from the Source Documents.
• During an FDA Inspection, the Investigator will
  compare the source documents with the case report
  forms to verify data, the accuracy in recording
  and transcription.
• Source Documents must mirror Case Report Forms
  and vice-versa.

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ADVERSE EVENTS

• Adverse Events Broadly defined as a medical
  complaint, change or possible side effects of any
  degree of severity that may or may not be
  attributed to the test article.
• If the subject makes mention of any discomfort,
  its an adverse event. Record/Document, no
  matter how minor ie..Hangnails, dizziness,
  coughing, broken ankle, headache, cold, flu etc

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SERIOUS ADVERSE EVENT

• Serious Adverse Event An event that is life
  threatening, permanently disabling, requires
  in-patient hospitalization.hospitalization must
  be 24 hours or more.
• Pregnancy Follow-up with subject and birth of
  baby
• Serious Adverse Events need to be immediately
  reported to the Sponsor AND the IRB, within a
  24-hour period.
• Mis-Dosing a subject is a serious adverse event.

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Training Training Files

• The FDA will evaluate Training Files based on who
  is listed on the Delegation of Authority Log.
• Their capabilities and job functions must be
  supported by their curriculum vitae,resume,trainin
  g,continuing education, medical nursing
  licenses etc

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TRAINING

• Code of Federal Regulations Parts 50,54,56, 312
  314.
• Ethical Conduct Belmont Report, Declaration of
  Helsinki, Nuremberg Code
  (World War II)
• Guidance Documents 1998 FDA Information Sheets
  for Institutional Review Boards and Clinical
  Investigators. (www.fda.gov.oc/ohrt/irbs)
• FDA Website www.fda.gov/oc.gcp
• Ethics Training
• Good Clinical Practices (At least once per year)
• Society of Clinical Research Associates (SOCRA)
• www.SoCRA.org
• FDA Regulations relating to Good
  Clinical Practices
• http//www.fda.gov/oc/gcp/reg
  ulations.html

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Training Files

• Training Files should reflect the following
  categories
• Curriculum Vitae/Resume updated once per year.
• Job Description
• Medical/Nursing Licenses (Current)
• Standard Operating Procedure Training
• Certifications CPR
• Continuing Education Good Clinical Practices
  (GCPs), Conferences, Seminars

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LOST SUBJECTS

• Subjects who fail to return for visits
• Document/Document/Document
• E-Mail attempts
• Phone-Calls to residence/work/cell-phone
• Letter via U.S. Mail/Fed-Ex/UPS
• Certified letter via U.S. Mail
• Do not go to their residence!!!

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MONITOR VISITS

• The Monitor Site Visit Log is used to record
  visits made to the study site by the Sponsors
  authorized representative.
• Make sure visiting representative signs their
  name/title/date's) of visit etc
• Data Queries/Monitors Summary Reports
• Put them in a separate file folder, do not
  leave them in subjects folders or case report
  forms.

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FDA Site Selection

• How does the FDA choose inspection sites?
• High enrollment - Not the time to be a gold
  medalist
• Complaints from subjects, employees, former
  employees, sponsors and IRBs.
• Results appear to good to be true
• No adverse event reports
• Logistics Cin-Do FDA is approximately six miles
  from Cincinnati Childrens Hospital Medical Center

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Compliance Program 7348.811

• Compliance Program 7348.811
• If you are a Principal Investigator, this is
  what the FDA will inspect your study with!
• First sentence of every establishment inspection
  report the FDA Investigator writes
• The inspection of John Q Investigator, M.D., was
  conducted in accordance with FDA Compliance
  program 7348.811
• http//www.fda.gov/ora/compliance_ref/bimo/7348_81
  1/48-811-1.html

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FDA Inspection

• Routine Inspection Surveillance
• Inspection Notice 7-10 days by phone
• For Cause Inspection
• Just show up!!!
• A particular event or circumstance triggered
  the inspection
• (An unusual Serious Adverse Event /
  Disgruntled Employees)
• Subjects have access to the internet. Very easy
  to contact the FDA and file a complaint.
• http//www.fda.gov/oashi/clinicaltrials/default.ht
  m Basic Questions and Answers about clinical
  trials for the consumer.
• Regulatory Compliance and Data Validation Main
  objective

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FDA Inspection

• Do not fabricate your answers.
• Do not feel a need to fill silence.
• Only answer the questions you are asked.
• Photocopy for the FDA Investigator, make
  duplicates for yourselves. Do not let the FDA
  Investigator access to the photocopier.
• Offer beveragessocial drinks like coffee, tea
  etc..
• No dinner/no lunches/no breakfast/no sporting
  event tickets.
• Do not ever, ever, ever sign an FDA-463a
  Affidavit.

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Results of an Inspection

• Courtesy copy will be provided to you in its
  entirety.
• NAI No Action Indicated
• (No deviations found, no FDA-483).
• VAI Voluntary Action Indicated
• (Deviations were found, but not serious)
• OAI Official Action Indicated
• (Deviations were found and are serious.
  Followed by a Warning Letter with a 15 day
  response).

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FREEDOM OF INFORMATION

• FDA's Electronic Freedom of InformationReading
  Room - Warning Letters and Responses
• http//www.fda.gov/foi/warning.htm

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Conclusion

• An FDA Inspection verifies you, the Principal
  Investigator followed the protocol!
• Do not deviate from the protocol unless you have
  IRB and Sponsor permission.
• Qualified people through good training
• Document/Document/Document
• Regulatory Compliance and Data Validation