Running a Successful Clinical Trial

1
Running a Successful Clinical Trial

• GCP Standards Investigators
• Need to Know

John Farley, MD, MPH Center for Clinical Trials
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Good Clinical (research)Practices (GCPs)

• International ethical and scientific quality
  standards for designing, conducting, recording,
  and reporting trials that involve the
  participation of human subjects.
• Purpose
• Protect human subjects during clinical studies
• Protect patients who might receive approved
  products in the future
• Not just one document
• Several different components which vary by
  country and research setting

3
Components of GCPs at UMB

• 45 CFR (Code of Federal Regulations) part 46
  applies to all institutions receiving federal
  funds for research (ex. NIH grants) (Office for
  Human Research Protection (OHRP))
• 21 CFR parts 11, 50, 54, 56 and 312 applies to
  all research involving investigational drugs or
  devices (Food and Drug Administration (FDA))
• UMB policies

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Components of GCPs at UMB

• International Conference on Harmonization
  (international standards) (ICH) major sections
  published in the Federal Register representing
  FDA current thinking)
• Section E2A, Guideline on Clinical Safety Data
  Management published Federal Register March 1,
  1995
• Section E6, Good Clinical Practice Consolidated
  Guideline published Federal Register May 9, 1997
• IF REGULATIONS/GUIDELINES NOT CONSISTENT, CHOOSE
  THE MOST CONSERVATIVE OPTION.

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Scope of 21CFR

• Applies to all clinical investigations regulated
  by the Food and Drug Administration (FDA) under
  the Federal, Food, Drug, and Cosmetic Act as well
  as clinical investigations that support
  applications for research or marketing permits
  for products regulated by the FDA (research
  usually conducted under IND, IDE).

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Investigator Responsibilities

• Sponsor shall select only investigators qualified
  by training and experience.
• Investigators must sign the FDA 1572
• Conduct study per protocol (exception safety of
  subjects)
• Personally conduct or supervise investigation
• Inform all potential subjects that drugs are
  investigational and obtain proper informed
  consent
• Report to the sponsor adverse experiences
• Has read and understands Investigators Brochure
• Ensures all other study staff are informed of
  their obligations
• Sponsors obtain other verifying documentation
  (CV, Financial Disclosure)
• (21CFR 312.53)

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More on Investigator Responsibilities

• Ensuring that investigation is conducted in
  accordance with investigational plan and
  applicable regulations
• Protect the rights, safety, and welfare of
  subjects
• Control of drugs under investigation
• Obtain informed consent
• (21CFR312.60)

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Investigator Record Keeping

• Adequate records of the disposition of the drug.
• Maintain adequate and accurate case histories.
• Retain records for 2 years after a marketing
  application is approved.
• Furnish progress, safety, and financial
  disclosure reports to the sponsor
• (21CFR 312.62, 312.64)
• Must permit inspection of records and reports
  (including copying) by an officer of the FDA
• (21CFR 312.68)

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Investigator Financial Disclosure(21CFR54)

• Investigator Financial Disclosure Insures steps
  are taken to minimize potential bias
• What 21CFR54 says must be disclosed
• Compensation affected by outcome of clinical
  studies
• Significant equity interest in sponsor of a study
• Proprietary interest in the tested product
• Significant payments of gt US25,000. exclusive
  of the costs of conducting the study
  (unrestricted research grants, honoraria)
• QUESTIONS? contact Mr. Joe Giffels, UMB
  Compliance Officer, at x6-6631,
  joegiffels_at_ordmail.umaryland.edu

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Incentives are NOT allowed under UMB policyAn
incentive is a monetary payment or other gift
which UMB, an investigator, nurse coordinator,
research coordinator, or other staff member
receives from the sponsor of a clinical study
which is contingent upon meeting a particular
productivity standard. Ex. An additional 500
payment sent to an investigator for each patient
entered onto a study within 90 days of study
initiation. This payment would be above and
beyond the contractually obligated per patient
amount. Ex. A gift certificate offered to a
nurse coordinator for every additional subject
entered onto a study beyond a certain minimum
number.
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Who Is the Sponsor

• The sponsor of a study (to whom the IND is
  issued) has extensive obligations under 21CFR314
  (e.g. study monitoring, adverse event and other
  reporting to the FDA)
• Usually, the pharmaceutical company or NIH will
  hold the IND and have the sponsor
  responsibilities.
• In investigator-initiated studies, you as the
  investigator may hold the IND and also have all
  the sponsor responsibilities.

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Sponsor Site Monitoring

• Act of overseeing the progress of a clinical
  trial
• Ensures study is conducted, recorded, and
  reported in accordance with
• Protocol
• Standard Operating Procedures
• Good Clinical Practices
• Applicable regulatory requirements
• (ICH E6 5.18 21CFR312.56)

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GCPsPre-Study, Screening, and Enrollment
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Pre-Study To Do List

• IRB Submission
• Develop recruitment materials (must be IRB
  approved)
• Develop Inclusion/Exclusion Checklist to use for
  screening/enrollment
• Develop Regulatory Binder for the study (see next
  slide, some of these documents must be submitted
  to the sponsor (reg docs))
• Plan protocol implementation (physician
  investigator contact procedure, drug storage and
  dispensing plan, visit logistics, specimen
  processing plan, etc., etc.)
• Site registration following IRB approval

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Regulatory Binder (Essential Documents, ICH E6
8.2)

• Protocol (current version)
• Investigators Brochure (current version) or
  package insert copy
• 1572 (up to date) (1571 if PI is IND Sponsor)
• CVs of PI and Co-Investigators, Human Subjects
  Training Certificates, other credentials
• Clinical Investigator Financial Disclosure Forms
• Drug Data Sheet
• Letter re IRB membership and assurance
• Standard Operating Procedures (SOPs) for this
  protocol at this site (source doc procedures
  etc.)
• Emergency Un-blinding Procedure

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Regulatory Binder (cont)

• IRB Correspondence (approvals, modification
  requests, AE reports)
• Site Quality Assurance records of activities
• Site Monitor Reports and DSMB Reports
• Normal lab values for the lab and tests you will
  use
• CLIA certification for lab (if sponsor requires)
• Correspondence with sponsor, FDA, others
• Staff signature and initials log
• Screening/Enrollment log
• As the study proceeds, file external adverse
  event reports and IND safety reports with the
  current Investigators Brochure.

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• A multi-center trial is planned to determine the
  safety of Varicella vaccine administered to
  HIV-infected children with a history of severe
  immune suppression who now have reconstituted CD4
  counts.
• Inclusion requirements
• A CD4 count gt 350 within 60 days of enrollment
• A negative cytotoxic T lymphocyte assay for
  varicella antigen
• Can any of the lab tests be done prior to IRB
  approval?
• Can any of the lab tests be done prior to
  informed consent?
• What documentation is recommended at the time of
  enrollment?

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Consent and Screening - 1

• NEVER use an outdated Informed Consent Form or
  one that is not IRB approved (45CFR46 SubpartA,
  21CFR50.27).
• NEVER perform any invasive screening procedures
  prior to Informed Consent (an initial Screening
  Consent is acceptable if IRB approved) (45CFR46
  Subpart A, 21CFR50.20).
• Document the Informed Consent process in a
  progress note in the research record
  (recommended).

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Consent and Screening - 2

• Consent Caveats
• If required by protocol or IRB, document ability
  for subject to give informed consent using
  Evaluation to Sign Consent or Mini-Mental
  instrument and file in subject research chart
  (45CFR46.107(a),111(a) ,ICH E6 4.8.12).
• If the subject is not competent to consent,
  document in a note the relationship of the
  surrogate guardian to the subject and why they
  are consenting for the subject (ICH E6 4.8.12).
  Follow protocol specific IRB approved procedures.
• Follow Maryland law re hierarchy of
  guardianship.
• If a legal guardian consents for the subject,
  have copy of proof of legal standing (example
  adoptive parent of a child) in research record
  (ICH E6 4.8.12).

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Consent and Screening - 3

• More Consent Caveats
• For children, document consent of parents (both
  may be required) and assent of children (verbal
  age 7-12, written signed Assent Form age 13-18 at
  UMB) (special requirements for wards of the
  state). (45CFR46 Subpart D)
• NEVER enroll a prisoner unless the protocol is
  specifically approved for prisoner participation.
  (45CFR46 Subpart C)
• If the study involves pregnant women and the
  prospect of benefit is solely to the fetus and
  not the mother, consent of the biological mother
  and father is REQUIRED unless father is not
  reasonably available, identity or whereabouts
  cannot be ascertained, or pregnancy resulted from
  rape. (45CF46 Subpart B)

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Consent and Screening - 4

• More Consent Caveats
• The subjects must sign AND date the Consent
  themselves. If they are unable to do this, a
  witness (who is not involved with the study and
  not the person obtaining consent) can sign and
  date to verify the subjects mark. (ICH E6 4.8.8
  and 4.8.9)
• For non-English speaking subjects, a translated
  Consent if usually required by the IRB.
• All those signing the Consent must sign and date
  themselves. All dates must be prior to any
  invasive screening procedures. (ICH E6 4.8.8)

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Consent and Screening - 5

• Maintain a Screening/Enrollment Log to
  demonstrate the absence of enrollment bias (store
  in Essential Documents Binder) (ICH E6 8.2.18)
• Initials of all patients screened (if they have
  singed a HIPAA release)
• PID (if patient receives one)
• Date Screened
• Date Randomized (indicate specific reason if not
  randomized)

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Consent and Screening - 6

• Double lock the patient identification number
  (PID) and name link (HIPAA, ICH E6 4,8,10).
• File the original Consent in the research record
  and a copy in the patients medical record (place
  on inpatient chart if admitted). (req by UMMC)
• Give a copy of the Consent to the subject (ICH E6
  4.8.11).
• Create an individual research record
  (recommended)
• Complete Inclusion/Exclusion checklist, sign and
  date it, and file in the research record (ICH E6
  4.6.5, 4.7).

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Consent and Screening - 7

• If special requirements are required of the
  subjects (for example not of childbearing
  potential or two methods of contraception),
  document in a note in the research chart that
  this was reviewed with the subject and
  specifically how the subject will comply). (ICH
  E6 4.5)

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GCPsStudy Records
26

• Definitions Source Documents (Source Doc)
• Original (medical) records including hospital
  records, clinics visit records, lab reports,
  memos, subject diaries, evaluation checklists,
  pharmacy records, recorded data from automated
  instruments, radiology reports and X-rays, etc
  related to the study.

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• Definitions Research Record
• Often,a separate research record is maintained in
  addition to the patient medical record, however
  the original is always the source doc and a site
  monitor will need to see the source doc. A
  separate research record is recommended if the
  medical record is stored in a remote location not
  under the control of research staff. SOPs
  regarding this are sponsor specific.

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• Definitions Case Report Form (CRF)
• A standardized form used to abstract study data
  from the source doc and report it to the sponsor
  data management center. All data reported on the
  CRF must exactly match the source doc and be
  verifiable using the source doc alone. (ICH E6
  4.9.2).

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• Documentation Guidelines Every person making an
  entry must sign and date the document and should
  be on the signature/initials log.
• NEVER obliterate. Correct errors with single
  line, initial, date. (ICH E6 4.9.3)
• If serial evaluations or entries in a note, write
  the time.
• Follow-up on the status of diagnoses at the prior
  visit.

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Study visit 3 activities / CRF data list the
required source doc

• Subject arrives, varicella vaccine is
  reconstituted in the pharmacy
• CRF history negative for local site reactions,
  rash, fever post vaccine 1.
• CRF PE negative for fever, skin lesions
• Vaccine 2 is administered
• Blood drawn for CTL assay to varicella antigen
  and CD4 count
• Adherence to concomitant medications interview
  completed
• Subject is observed 2 hours in the clinic and
  then PE above repeated.
• Parent is phoned 48 hours later and queried re
  fever, local site reactions

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There must be source doc for everything

• Dispensing of additional study drug,
  administration of study vaccine
• Completion of questionnaires or instruments
• Venipunctures or injection (include how
  tolerated)
• Follow-up observations in clinic or phone calls
• Patient compliance with protocol requirements
  (for example fasting or not taking other meds)
• The absence of complications or events
  specifically asked for on the CRF
• Required laboratory tests obtained (or missed)
• Develop checklists or use a copy of the CRF
  (signed and dated) as source doc if needed.

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Electronic Documents and Signatures (21CFR11),
Faxes

• Electronically signed documents as source doc
  UMMS Radiology/Laboratory Reports and new scanned
  medical records are fully compliant with 21CFR11
  requirements. UMMS Discharge Summary/Dictated
  Report system is not compliant. For those
  records, obtain written signature and date
  (hybrid system).
• Emails are not compliant with 21CFR11. If used
  as source doc, they must be printed. Obtain
  written signature and date, but maintain original
  email electronically.
• Know the sponsor SOPs re faxed copies.

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GCPs Adverse Event Monitoring and Reporting
34

• Three days after receiving study vaccine, the
  child is admitted to the hospital after an
  apparent seizure at home which resolved
  spontaneously after about 5 minutes time. Mental
  status was normal on admission.
• What are the investigator/study staff
  responsibilities?

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Adverse Event

• An untoward medical occurrence in a subject
  enrolled in a clinical investigation involving
  administration of a drug or device. Does NOT
  necessarily have a causal relationship with the
  research drug or device. May or may not be
  expected. Includes laboratory abnormalities.
• Adverse events need to be evaluated by the
  investigator and reported to the sponsor within
  specified time periods (ICH E6 4.11.1,2 and E2A)

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• Be sure to document (and report to sponsor if
  required) possible adverse events at study visits
  or as the study staff is aware.
• Grade all laboratory reports using protocol
  toxicity tables. Follow appropriate action
  outlined in the protocol and document the action.
• Use a log to follow-up on adverse events.
• When in doubt, report to sponsor.

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Is an Internal Adverse Event a Serious Adverse
Event (SAE)?

• Definition
• Results in death
• Life-threatening
• Requires or prolongs hospitalization
• Results in persistent/significant
  disability/incapacity
• Congenital anomaly/birth defect
• OR action on the part of a physician is necessary
  to avert any of the above
• (ICH E2A)
• Some sponsors/protocols include Grade III and IV
  laboratory abnormalities as requiring expedited
  reporting

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Serious Adverse Events

• A SERIOUS Adverse Event is a regulatory, not
  clinical definition
• Reporting for SAEs is expedited.
• Industry standard is to report all SAEs within 24
  hours to the sponsor who then must report to FDA
  within 7 days (death, life-threatening) or 15
  days (other SAE).
• Also notify UMB IRB within 48 hours (if deemed
  protocol related by the investigator).
• (ICH E2A 21CFR312.32)
• Adverse events not meeting the definition of an
  SAE or felt by the investigator not to warrant
  expedited reporting are usually reported by CRF.
  (If in doubt, report as an SAE).

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IND Safety ReportsExternal SAEs

• External Adverse Events (occur at other sites)
  are reported by the sponsor to other
  investigators as IND Safety Reports
• Summaries sent from sponsor to other sites on a
  periodic basis (within 15 days if SAE).
• Must be assessed by the PI and may need to be
  reported to UMB IRB.
• PI and IRB must decide if report of External AE
  impacts risk/benefit for subjects at this site
  and if so, decide on course of action.
• Intended as addenda to the Investigators
  Brochure.
• (21CFR312.32)

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UMB IRB Policy re External SAEs

• must be reported only if they are both serious
  and unexpected and probably related to the
  research.
• Use SAE Reporting Form in BRAAN
• If is reportable to our IRB, it is likely that a
  Protocol Modification or Amendment (change in
  procedure, addition of risk to the ICF) is needed
  as well.

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GCPsMisc. Study Conduct Issues
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Quality Assurance

• Quality Assurance (Conduct at least weekly)
• Verify inclusion/exclusion criteria met for new
  enrollees.
• Compare source doc and CRF for consistency.
• Be sure all documentation is signed and dated,
  proper corrections.
• Be sure all required activities completed at the
  visit, if not document reason.
• Verify that there are no missed AEs, clinical
  events, or study endpoints.
• Verify AEs, enrollment/protocol
  violations/deviations reported

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Study Drug Accountability

• Drug/Device Dispensing Accountability
• Maintain a dispensing log (if a
  medication/vaccine is reconstituted, log must
  note time and date reconstituted)
• Shipping receipt
• Script or order for dispensing drug on file
• Storage requirement compliance documented
• NEVER administer study med without a physician
  order or prescription. Maintain record of
  physician orders to administer.
• Consider using the UMMS Investigational Drug
  Service (x87748)

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Approval Lapses

• What if IRB approval for the protocol lapses
  (even passively due to late renewal submission)?
• All protocol-related activity involving subjects
  must cease until approval is renewed.
• Exception Protocol-related activity necessary
  for patient care (example- a blood test to
  monitor for adverse effects of study drug).
  However, must obtain written permission from the
  IRB Chair.
• What if the sponsor or the FDA puts the study on
  hold?
• Notify the IRB immediately and include reason.
• See above.

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FDA Site Inspections
46
FDA Inspections

• Are Conducted
• At high enrolling sites or sites with unusual
  data during the final stage of NDA review
• For cause
• Inspector must present Notice of Inspection
  Form Form FDA 482
• Inspector may write Inspectional Observations
  Form FDA 483
• INVESTIGATOR SHOULD NOTIFY THE IRB IMMEDIATELY IF
  A NOTICE OF INSPECTION IS RECEIVED.

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FDA Inspectors

• Give short notice of visit to site investigator
• Become suspicious of any attempt to delay
  inspection
• Bring a list of other studies performed by
  investigator
• May question any site staff member
• May make copies of study documents

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Resources for Investigators and Research Staff
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Learn even more about GCPs

• Association of Clinical Research Professionals
  (ACRP)
• www.arcpnet.org

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Campus Resources

• UMB Office for Research Subjects (IRB)
• http//medschool.umaryland.edu/ors ,6-5037
• Susan Buskirk, IRB Program Manager
• (6-4937, sbuskirk_at_som.umaryland.edu)
• VA Hospital
• Julie Doherty, Research Compliance Officer
• (5-6512, jdohe001_at_umaryland.edu)

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Campus Resources

• GCRC
• Kathy Palmer, Research Subject Advocate
• (8-7248, kpalmer_at_medicine.umaryland.edu)
• SOM Center for Clinical Trials
• http//www.umaryland.edu/cct/index.html, 6-2328
• John Farley, Medical Director Jfarley_at_som.umarylan
  d.edu
• Sue Hines, Research Nurse Manager
  shines_at_som.umaryland.edu

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Conclusion

• The interest of science should never take
  precedence over the well-being of the subject.
  Declaration of Helsinki