Operation Management of Clinical Trials

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					The Importance of Standard Operating
 Procedures (SOPs) in Clinical Trials
           The Main Objective:

• Be a GREAT clinical research site
  – For the sponsor
  – For your patients
  – For your organization
  – For your own professional development
          Presentation Objectives
At the conclusion of this discussion, participants
  will be able to:
   – Define standard operating procedures (SOPs)
     as they pertain to the clinical trial environment
   – Describe key components of an SOP
   – List SOPs that exist in your institution and
     department that pertain to clinical research
   – Understand what additional SOPs will aid in
     performing high quality clinical research
   – View SOPs from the perspective of the
     sponsor
              What are SOPs?
• Standard Operating Procedures (SOP) are:
  – a set of instructions with the force of a
    directive that defines or standardizes a
    procedure or specific function
  – an effective catalyst to drive performance
    improvement and improve organizational
    results
  – create the level of quality and accepted
    practice for a specific procedure
  – the foundation of every good quality system
    SOPs for Clinical Research


Clinical research SOPs are an important way
               to help you follow
      Good Clinical Practices
                  (GCPs)
              What are GCPs?

• Good Clinical Practices are guidelines for
  conducting sponsored clinical research
• Published by the International Conference on
  Harmonization (ICH)
                          ICH

• International Conference on Harmonization
• ICH consists of regulatory authorities from
  Europe, Japan and the United States and
  experts from the pharmaceutical industry in the
  three regions to discuss scientific and technical
  aspects of clinical research.
• ICH is considered the authority on clinical
  research theory and principles.



                                               www.ICH.org
               ICH Principles

• The guiding principles of ICH are to:
   – develop scientific consensus through
     discussions between regulatory and industry
     experts
   – assure wide consultation of draft consensus
     documents through normal regulatory
     channels before a harmonized text is adopted
   – secure commitment by regulatory parties to
     implement the ICH harmonized text

                          The Pharmaceutical Journal Vol 273, No. 7312, pp 24-226
                       ICH

• Publications of the ICH include:
  – Safety management in clinical trials, including
    periodic safety updates of research and
    marketed drugs
  – Dose response data collection
  – Statistical principles for clinical trials
  – Publication of the final study report
  – Choice of control groups in clinical trials
  – Pediatric clinical trials
  – Good Clinical Practices
     ICH E6: Good Clinical Practice
• Contents:
  1. Glossary
  2. The Principles of ICH GCP
  3. Institutional Review Boards
  4. Investigator
  5. Sponsor
  6. Clinical Trial Protocol(s)
  7. Investigator Brochure
  8. Essential Documents for the Conduct of a
    Clinical Trial

• Get to know this document!
              US regs vs. ICH?

• The ICH does not override US regulations
  governing clinical research; instead they are
  complimentary
   – 21 CFR 312      (Requirements for an IND)
   – 21 CFR 50       (Protection of Human Subjects)
   – 21 CFR 56       (IRBs)
   – 45 CFR 46       (HIPAA)
   – 21 CFR 812      (Investigational Devices)
              US regs and ICH

• Pharmaceutical and device sponsors know and
  follow both ICH and federal regulations
  governing clinical research
• Sponsors expect clinical sites to be familiar with
  the ICH and the federal regulations
           SOPs and Regulations

• SOPs are not specifically mentioned in the FDA
  regulations
   – HOWEVER there is guidance and regulations
     that infer responsibility and SOPs formalize
     investigator responsibilities.
   – 21 CFR312.53 mandates that the investigator
     will “ensure that all associates, colleagues,
     and employees assisting in the conduct of the
     study are informed of their obligations in
     meeting the above commitments.”
           SOPs and Regulations

• Additionally, SOPs are mentioned repeatedly in
  the ICH GCP Guidelines.
• ICH GCP 2.13 -“Systems with procedures that
  assure the quality of every aspect of the trial
  should be implemented.”
               Benefits of SOPs
• Ensures that all research conducted within the
  clinical site follows federal regulations, ICH GCP,
  and institutional policies to protect the rights and
  welfare of human study participants
• Improves the quality of the data collected,
  thereby improving the science of the study.
• Utilized as a reference and guideline as to how
  research will be conducted within the clinical site
• Excellent training source for new employees
  and/or fellows
      SOPs for Imaging: Benefits

• Image standardization
   – All technologists doing the same task in the
     same way
   – Reproducible camera performance
   – Documentation of deviations
• Standardization of patient data
   – Blood and urine samples
   – Vital signs
   – ECGs
        Key Components of SOPs
• Description of the purpose of the procedure/task
• Background information and definitions
• Specific components to successfully perform the
  task/procedure
   – Required personnel to perform all aspects of
     the procedure
   – Appropriate patient population (as applicable)
   – Required equipment, supplies, information
     and/or data
       Key Components of SOPs (cont.)
  – Equipment settings, as appropriate and/or
     necessary to acquire/process data
  – Quality control procedures to assure optimal
     results
  – Interpretation and reporting criteria, as
     necessary for consistent and uniform review
     of data
• Effective date and expiration date
        SOPs: An Educational Tool
• SOPs may be used as an educational tool to:
  – familiarize the entire research team on the
    specific tasks performed by the departments
    participating in the research protocol
  – educate the drug company/investigator on
    regulatory guidelines and SOPs already in place
    for departments such as radiology, nuclear
    medicine and radiation therapy in the
    performance of day-to-day procedures
  – train current and new employees to assure
    consistent performance of the research protocol
      SOPs: Institutional Examples

• Examples of Institutional SOPs:
  – Patient identification
  – Patient confidentiality (HIPAA)
  – Patient safety and incident reporting
  – Infection control
  – Hazardous waste disposal
  – Use/repair of medical equipment
          SOPs: Nuclear Medicine
• Examples of SOPs in Nuclear Medicine:
  – receipt, administration, disposal and storage of
    radioactive materials
  – ALARA protocols
  – Personnel monitoring
  – Pregnancy protocols (patient/employee)
  – Radioactive spills
  – Quality control procedures
  – Safety training (ie, CPR, fire extinguisher, patient
    transfers)
    SOPs: Nuclear Medicine (cont.)
• Examples of SOPs in Nuclear Medicine:
  – Specific imaging/non-imaging protocols
     • Quality control
     • Patient assessment
     • Patient education/preparation/discharge
     • Acquisition
     • Processing
     • Data storage/transfer
  – Adverse drug events/misadministrations
           Patient Privacy SOPs
• Sometimes these get complicated with nuclear
  medicine data –
  – Can data go to PACs with a research code
    number?
  – Is the data sent to the sponsor with the
    identifiers stripped?
  – Is there a backup copy of identifiable data in
    the department?
  – Who has access to the images or biologic
    data?
      Patient Privacy SOPs (cont.)

• Electronic data transfer
  – Firewall issues
  – Patient ID issues
  – May have to work with IT department
  – May need administrative approval
      Investigational Product SOPs

• Regulatory (NRC or state) guidelines direct the
  receipt, handling, storage and disposal of
  radioactive materials; however, sponsors may
  not be familiar with those guidelines and
  appreciate seeing SOPs to meet ICH E6 and
  21CFR312 guidelines
      ICH E6 : Investigational Product

4.6.3 The investigator/institution and/or a
pharmacist or other appropriate individual, who
is designated by the investigator/institution,
should maintain records of the product's delivery
to the trial site, the inventory at the site, the use
by each subject, and the return to the sponsor or
alternative disposition of unused product(s).

These records should include dates, quantities,
batch/serial numbers, expiration dates (if
applicable), and the unique code numbers
assigned to the investigational product(s) and
trial subjects.
    ICH E6 : Investigational Product

 4.6.3, cont. Investigators should maintain
records that document adequately that the
subjects were provided the doses specified by
the protocol and reconcile all investigational
product(s) received from the sponsor.
      ICH E6 : Investigational Product

4.6.4 The investigational product(s) should be
  stored as specified by the sponsor
4.6.5 The investigator should ensure that the
  investigational product(s) are used only in
  accordance with the approved protocol.
4.6.6 The investigator, or a person designated by
  the investigator/institution, should explain the
  correct use of the investigational product(s) to
  each subject and should check, at intervals
  appropriate for the trial, that each subject is
  following the instructions properly.
     21CFR312: Investigational Product

• Sec. 312.62 Investigator recordkeeping and
  record retention. (a) Disposition of drug. An
  investigator is required to maintain adequate
  records of the disposition of the drug, including
  dates, quantity, and use by subjects. If the
  investigation is terminated, suspended,
  discontinued, or completed, the investigator
  shall return the unused supplies of the drug to
  the sponsor, or otherwise provide for disposition
  of the unused supplies of the drug under 312.59.
     21CFR312: Investigational Product

• Sec. 312.61 Control of the investigational drug.
  An investigator shall administer the drug only to
  subjects under the investigator's personal
  supervision or under the supervision of a sub-
  investigator responsible to the investigator. The
  investigator shall not supply the investigational
  drug to any person not authorized under this
  part to receive it.
          Medical Records SOPs


• Electronic? Compliant with 21CFR 11?
• Nuclear medicine reports?
• Other documents – worksheets, H&P
  questionnaires?
• Radiopharmacy dosing records – integrated into
  medical records?
              Documentation SOPs
• 21CFR312.62 (b) Case histories. An investigator is
  required to prepare and maintain adequate and
  accurate case histories that record all observations
  and other data pertinent to the investigation on each
  individual administered the investigational drug or
  employed as a control in the investigation. Case
  histories include the case report forms and supporting
  data including, for example, signed and dated consent
  forms and medical records including, for example,
  progress notes of the physician, the individual's
  hospital chart(s), and the nurses' notes. The case
  history for each individual shall document that
  informed consent was obtained prior to participation in
  the study.
          Documentation SOPs

• An auditor has access to ALL records, including
  nuclear medicine worksheets, film jackets, digital
  copies of data

• Recordkeeping SOP: no white out, no erasures,
  signature and date by individual who made the
  entry, etc.
        Conditions of Participation

• 42 CFR 482.53 – Nuclear Medicine Services:
  If the hospital provides nuclear medicine
  services, those services must meet the needs of
  the patients in accordance with acceptable
  standards of practice.
   – a) Standard: organization and staffing. The
      organization of nuclear medicine service must
      be appropriate to the scope and complexity of
      the services offered
        Conditions of Participation
• Data acquisition must be accurate and
  consistent
• Acquisition protocols must be per
  sponsor’s/clinical investigator’s specifications
• Gamma camera must meet software and QC
  specifications
• Data transfer must meet sponsor’s
  specifications
• Patient information (demographics) must be
  stripped from the final study prior to transfer;
  essential acquisition/processing data must be
  retained
             Where do I start?

• Gather your institution’s SOPs that cover
  aspects of safety and patient care
• Gather your departmental SOPs that cover
  quality assurance, storage of
  radiopharmaceuticals, data management,
  processing of biologic samples
• Perform a gap analysis – what GCP aspects are
  not currently covered by an SOP?
• Write SOPs to cover the needed areas
       Sponsor Confidence Boosters

• Site personnel understanding of GCP
• SOPs that indicate quality assurance is
  important to the site
• Attention to image standardization via SOPs
• Attention to documentation via SOPs
                   Summary

• Sponsors expect you to be familiar with ICH
  GCP and the federal regulations
• Gather or develop SOPs that will provide clear,
  precise instructions/directions for tasks and
  conditions that are covered in the GCPs
   – Institutional and departmental SOPs will be
     useful
   – Create documentation SOP as a way to train
     all employees about appropriate record-
     keeping methods
                  Summary

• SOPs to cover aspects of GCP are sponsor
  confidence boosters
• Don’t stop at being a GOOD research site –
  become a GREAT research site!
Acknowledgements

Presentation writers:
   Rebecca Sajdak
   Kathy Thomas
Presentation Editor:
   Aileen Carey
Knowledge Assessment Writer:
   xxx
VOICE application:
   xxx

				
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