The Importance of Following the PROTOCOL in Clinical Trials

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The Importance of Following the PROTOCOL in
Clinical Trials
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What would you do if

• A study patient arrives two hours late for an
  image that is supposed to occur 24 1 hours after
  the injection?
• A study patient eats before the scan when she is
  supposed to be NPO?
• You are supposed to inject 10 mCi of the study
  drug but there is only 7.5 mCi in the syringe?
• You believe you can get better looking images
  with higher resolution if you tweak the
  acquisition parameters just a bit?

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To be a GREAT clinical research site, the answer
must always be one of the following1. Follow
the Protocol.2. If you cant do 1, call the
sponsor.
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The Main Objective

• Be a GREAT clinical research site
• For the sponsor
• For your patients
• For your organization
• For your own professional development

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Upon completion of this presentation,
participants will be able to
Presentation Objectives

• Describe the following terms Protocol, Protocol
  Deviation, Protocol Violation, Form FDA-1572,
  Protocol Exception
• Understand the importance of following the
  clinical trial protocol to exact specifications
• Create a list of questions that should be
  answered by the sponsor or trial organizers prior
  to patient enrollment.

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• But I know what a protocol is

• Protocol means something quite specific to the
  sponsor and the FDA
• Scanning protocols, injection protocols, patient
  identification protocols, radiopharmacy protocols
  are NOT what the sponsor means when they say the
  word protocol
• Imaging/scanning protocols are sometimes not
  completely defined in the clinical protocol

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• PROTOCOL Definition

• ICH Guidelines, E6 Good Clinical Practice
• A document that describes the objective(s),
  design, methodology, statistical considerations,
  and organization of a trial.

http//www.ich.org/cache/compo/276-254-1.html
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PROTOCOL Definition

• 21 CFR Part 312.23
• A protocol must contain
• A statement of the objectives and purpose of the
  study.
• The criteria for patient inclusion / exclusion as
  well as an estimate of the number of patients to
  be studied.
• A description of the design of the study,
  including the kind of control group to be used,
  if any, and a description of methods to be used
  to minimize bias on the part of subjects,
  investigators, and analysts.

http//www.accessdata.fda.gov/scripts/cdrh/cfdocs/
cfcfr/CFRSearch.cfm?CFRPart312
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PROTOCOL Definition (cont)

• The method for determining the dose(s) to be
  administered, the planned maximum dosage, and the
  duration of individual patient exposure to the
  drug.
• A description of the observations and
  measurements to be made to fulfill the objectives
  of the study.
• A description of clinical procedures, laboratory
  tests, or other measures to be taken to monitor
  the effects of the drug in human subjects and to
  minimize risk.

http//www.accessdata.fda.gov/scripts/cdrh/cfdocs/
cfcfr/CFRSearch.cfm?CFRPart312
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Types of Sponsored Protocols

• Radiopharmaceutical is the investigational
  product
• B. Imaging procedure is conducted as a measure of
  therapeutic efficacy of the investigational
  product
• C. Both the imaging procedure and the therapeutic
  pharmaceutical are investigational.

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Types of Sponsored Protocols

• A. Studies in which the radiopharmaceutical is
  the IP
• Examples
• I-131 radiopharmaceutical for cancer therapy
• Tc-99m labeled agent for infection imaging
• All regulations governing the distribution and
  accountability of IP apply to the
  radiopharmaceutical
• Sponsor may or may not be familiar with
  radiopharmacy SOPs, distribution of radioactive
  products, record-keeping for RAM
• Nuclear medicine MD may or may not be the PI

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• Types of Sponsored Protocols

• B. Studies in which the imaging procedure is
  conducted as a measure of therapeutic efficacy of
  the investigational product (IP)
• Imaging is one of many clinical measures of
  safety and efficacy
• Examples
• Myocardial perfusion imaging to study the effect
  of anti-ischemic therapy
• Nuclear medicine MD is usually a subinvestigator

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Types of Sponsored Protocols

• C. Both the imaging procedure and the therapeutic
  pharmaceutical are investigational.
• Example F-18 FLT to measure the response of an
  investigational chemotherapy
• Investigator is subject to the same drug
  accountability for F-18 FLT as for the
  investigational chemotherapy
• Investigator is subject to the same regulations
  for informed consent for F-18 FLT as for the
  investigational chemotherapy

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Control of Investigational Drug

• 21 CFR 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
  subinvestigator responsible to the investigator.
  The investigator shall not supply the
  investigational drug to any person not authorized
  to receive it.
• Sec. 312.60 General responsibilities of
  investigators.
• An investigator is responsible for the control
  of drugs under investigation.

http//www.accessdata.fda.gov/scripts/cdrh/cfdocs/
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Control of Investigational Drug

• Sec. 312.62 Investigator recordkeeping and record
  retention.
• 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.

http//www.accessdata.fda.gov/scripts/cdrh/cfdocs/
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General Investigator Responsibilities

• 21 CFR 312.60 General responsibilities of
  investigators
• Ensuring that an investigation is conducted
  according to the signed investigator statement,
  the investigational plan, and applicable
  regulations
• Protecting the rights, safety, and welfare of
  subjects under the investigator's care
• Obtain the informed consent of each human subject
  to whom the drug is administered.

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Signed Investigator Statement

• Form FDA-1572
• Statement of the investigator
• Submitted to FDA by the sponsor
• Must be signed by the investigator
• Contains the name and address of the IRB, all
  clinical labs and locations at which the study
  will be conducted
• Lists subinvestigators who are under the
  supervision of the primary (principal)
  investigator

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Signed Investigator Statement

• I agree to conduct the study(ies) in
  accordance with the relevant, current protocol(s)
  and will only make changes in a protocol after
  notifying the sponsor, except when necessary to
  protect the safety, rights, or welfare of
  subject.

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Form FDA-1572
http//www.fda.gov/downloads/AboutFDA/ReportsManua
lsForms/Forms/UCM074728.pdf
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Sponsor Responsibilities

• 21 CFR 312.53 Selecting investigators and
  monitors
• Select only investigators qualified by training
  and experience as appropriate experts to
  investigate the drug.
• Ship investigational new drugs only to
  investigators participating in the investigation.
• Ensure the investigation is in accordance with
  the IND

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• Protocol DEVIATION Definition

• Variation from processes or procedures defined in
  a protocol.
• Does not preclude the overall evaluability of
  subject
• Does not affect the safety of subject

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Protocol DEVIATION Examples

• Examples of a protocol deviation.
• Patient has lab values out side the range listed
  in the protocol for eligibility
• Protocol says images must begin 15 /- 5 minutes
  post injection but begins at 22 minutes.

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• Protocol DEVIATION

• The number of protocol deviations should be
  minimal
• Where clinical or technical situation varies from
  the protocol due to circumstances beyond your
  control
• Protocol deviations that involve safety
  measurements should be reported to the IRB
• Protocol deviations should not take place in
  situations where you simply want to do things
  differently

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Protocol VIOLATION Definition

• A significant departure from processes or
  procedure
• May affect the evaluability of the data

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Protocol VIOLATION Examples

• Some examples of Protocol Violation
• Changing technical parameters of the acquisition
• Enrolling an ineligible subject
• Improper informed consent

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Example 1

• You are supposed to inject 10 mCi per protocol,
  and due to the radiopharmacy processing you only
  have 7.5 mCi in the syringe. What do you do?
• Depending upon the study, the sponsor may provide
  a protocol exception, or may instruct you to not
  use that dose because it is too low.
• Do not simply inject just because the patient is
  on the table!
• If the sponsor allows the exception, make sure
  you have the sponsor provide official
  documentation stating that it was ok to inject
  the lesser amount.

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Avoiding Deviations Violations

• If a technical glitch causes a protocol
  deviation that is out of your control, document
  the situation in writing (note to file) what
  happened, what you did, and why you did it.
  Always include your signature and the date.

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Example 2

• You are supposed to collect all urine for 24
  hours after the injection, but the patient
  reports that he forgot in the middle of the
  night. What do you do?
• Document the situation for the sponsor. Be sure
  to sign and date the note.
• This is a protocol deviation.

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Example 3

• A study specific quality control procedure that
  was supposed to be performed within one week of
  the participants imaging session was instead
  performed at ten days. What do you do?
• Even if the calibration value was normal, the
  sponsor must be notified since it will be
  considered a protocol deviation.
• Document the situation for the sponsor, and
  initial and date the note.
• Create a plan within the department to make sure
  the QC is performed with the study specific
  guidelines.

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Avoiding Deviations Violations

• Provide education and written information to all
  imaging technologists that may be participating
  in the scanning of a research patient.
• This will help reduce deviations and violations
  of the protocol.
• Source documentation will be standardized
• Sponsors expectations will be met

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Avoiding Deviations Violations

• Provide a copy of the protocol and technical
  manual to the technologists in addition to
  keeping a copy in the department.
• Reinforce the importance of quality imaging data.
• Worksheets and checklists are recommended

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Avoiding Deviations Violations

• There may be a long period of time between
  scanning study participants.
• Prepare prior to the participants arrival.

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Avoiding Deviations Violations

• If the study protocol is standard of care
  imaging
• It is still important to identify the patient as
  a study participant.
• If the study protocol is not standard of care
  imaging
• Review the protocol and the imaging manual.
• Have all case report forms that need to be filled
  out at the time of the scan readily available.
• Confirm the participants appointment and the time
  of the delivery of the radiopharmaceutical.

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• Protocol AMENDMENT Definition

• ICH Guidelines, E6 Good Clinical Practice
• Protocol Amendment A written description of a
  change(s) to, or formal clarification of a
  protocol.

http//www.ich.org/cache/compo/276-254-1.html
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Protocol AMENDMENT Definition

• 21 CFR 312.30 Protocol Amendments
• A sponsor shall submit a protocol amendment
  describing any change in a Phase 1 protocol that
  significantly affects the safety of subjects or
  any change in a Phase 2 or 3 protocol that
  significantly affects the safety of subjects, the
  scope of the investigation, or the scientific
  quality of the study

http//www.accessdata.fda.gov/scripts/cdrh/cfdocs/
cfcfr/CFRSearch.cfm?CFRPart312
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Protocol AMENDMENT Definition

• Examples of changes requiring an amendment under
  21 CFR 312.30
• Any increase in drug dosage or duration of
  exposure of individual subjects to the drug
  beyond that in the current protocol, or any
  significant increase in the number of subjects
  under study.
• Any significant change in the design of a
  protocol (such as the addition or dropping of a
  control group).

http//www.accessdata.fda.gov/scripts/cdrh/cfdocs/
cfcfr/CFRSearch.cfm?CFRPart312
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Protocol AMENDMENT Definition

• The addition of a new test or procedure that is
  intended to improve monitoring for, or reduce the
  risk of, a side effect or adverse event or the
  dropping of a test intended to monitor safety.

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Protocol AMENDMENT Definition

• Amendments (and revised consent forms) must be
  approved by the IRB prior to implementation
• Exception administrative or clerical amendments
  can be submitted to the IRB as informational only
• Amendments are submitted to the FDA by the
  sponsor
• Amendments are submitted to the investigator in
  writing

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Site Participation

• Prior to a site participating in a sponsored
  clinical trial, a general discussion should take
  place between the sponsor and the imaging
  personnel.
• The aim of this discussion is to assess whether
  the site is capable (i.e. equipment and/or
  personnel) of properly conducting the study
  procedures.

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Site Participation

• This discussion (or questionnaire) may include
  information regarding
• Site information (address, email, fax, phone)
• Site equipment (scanner, radiopharmacy, phantoms,
  collimators)
• Investigator/personnel
• Regulatory requirements (lab certifications, CVs
  and medical licenses)
• Research experience (Phase 1, 2, 3)
• HIPPA compliance
• Medical records policies

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Feasibility Examination

• Imaging personnel should carefully review the
  protocol for details on technical procedures.
• Does the protocol detail the
• Scanning parameters
• Quality control procedures (e.g., calibration)
• Imaging and radiopharmacy equipment required
• Specimen handling required (e.g., blood samples)
• Specialized equipment required (e.g. well
  counter, centrifuge)

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Feasibility Examination

• Questions to consider
• Does your site have the proper personnel and
  equipment to participate in the clinical trial?
• It is not enough to simply say yes, we do
  PET/CT in response to a question about whether
  you can do a sponsored clinical trial!

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What questions do I ask?

• Do I have to qualify my PET or PET/CT scanner?
• Can my site receive or produce the
  radiopharmaceutical used in the study?
• How long will the scans and QC take?
• Is there any specialized equipment (such as a
  biohazard freezer, centrifuge, well counter)
  required for the study?
• Who is responsible for labwork, ECGs, urine
  collection, or other study parameters?

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What questions do I ask?

• How will I be transferring the image data and
  when does it need to be transferred (i.e. sFTP
  and within what time period)?
• What imaging data needs to be submitted (e.g.,
  raw data or reconstructions)?
• What are the file naming procedures (i.e. PET AC,
  PET NAC, CTAC, etc.)
• What are the dose ordering procedures?
• What forms do I use to record data?

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Sponsor-Provided Materials

• Protocol
• Technical manual(s)
• Forms/worksheets for source documentation and
  image transfer
• The advantages of a technical manual are
• Protocol amendments not required for changes
• Ease of distributing a specialized document
• Can be modified based on site-specific needs

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Sponsored-Provided Materials

• Who writes the manual?
• Scrutiny of details may provide a benefit to the
  sponsor.
• After all, the sponsor presumably came to you
  for your expertise in imaging!

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Implementing the Protocol

• Reviewing the sponsors imaging protocol and/or
  manual is important to determine whether the
  scanning protocol makes clinical sense.
• The imaging data should provide information to
  support or answer the primary goals or the
  imaging endpoints of the study.
• If the principle investigator (PI) is not in the
  imaging department, such as oncology, close
  communication between department staff is
  required.

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Implementing the Protocol

• What do you do if you have not been given ample
  opportunity to perform a thorough review of the
  imaging, QC, or radiopharmacy procedures?
• Contact the sponsor, CRO, or imaging core lab.
• Document all communication.
• Emails
• Memos
• Telephone conversation
• Keep the study coordinator in the loop.

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Implementing the Protocol

• In addition to reviewing the sponsors protocol
  and imaging manual, review any CRFs and source
  document worksheets that you may be responsible
  for completing at the time of the scan.
• A CFR (Case Report Form) is a paper or electronic
  set of questions that is used to collect data in
  a clinical trial.
• A source document worksheet is a place where you
  record raw data.

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Implementing the Protocol

• Data that you may be required to provide
• Date of scan
• Dose assay time (pre and post injection)
• Net administered activity
• Time of injection
• Scan start time, end time

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Queries and Data Clarification

• If any imaging data is found to be missing or if
  the data is inaccurate or inconsistent with the
  imaging protocol, a query or data clarification
  form may be sent by the sponsor.
• A query may or may not be a protocol deviation or
  a protocol violation.
• A query is used to obtain missing information or
  to clarify a portion of the imaging data
  received.

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Queries and Data Clarification

• A query may be sent due to
• Date of birth in the DICOM header does not match
  the CRF.
• Missing images or incomplete submission
• Time of scan does not match protocol requirements
• Data is not anonymized in all DICOM headers

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Documentation

• It is industry standard and imperative to
  document all correspondence between the site and
  the sponsor.
• It is also good to document all correspondence
  with the imaging core lab if one is used for the
  trial.
• Documentation includes
• Email
• Memo
• Phone conversation
• Note to file

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Communication

• It is important to include the study coordinator
  in all correspondence with the sponsor.
• Ways to keep the coordinator in the loop
• Courtesy copy on all emails
• Courtesy copy on paper correspondence
• Notify the coordinator of telephone conversations
  with the sponsor and the results
• Include the coordinator in all scheduled
  teleconferences and meetings with the sponsor

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Department Cooperation/Education

• Remember
• Research can disturb your schedule!

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Department Cooperation/Education

• Dont underestimate the time it will take for a
  research protocol.
• Schedule adequate time for any ancillary
  procedures that need to take place in the imaging
  room (vitals, ECG, blood draws, etc.)
• Inform front desk personnel about any specimen
  handling questions (such as a patient dropping
  off urine samples, questionnaires, etc.)

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Department Cooperation/Education

• Departmental staff may be required to alter
  standard department procedures to accommodate a
  research study.
• Staff may include
• Schedulers
• Transporters
• Nurses
• Administrative
• Radiation safety

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Department Cooperation/Education

• Taking the time to educate all departments that
  are involved with a research study.
• Education up front is always better than solving
  logistical problems on the fly!

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Department Cooperation/Education

• Design a procedure that will notify the nuclear
  medicine department when a trial participant is
  scheduled to have their scan.
• This will give the technologists enough time to
  perform any mandatory QC prior to the scan.
• The protocol may require the lab to perform a
  cross-calibration between the PET scanner and the
  well counter within a certain amount of days of
  the scan (blood sampling protocol).

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Interdepartmental Communication

• Attend research meetings
• Can answer imaging questions
• Can foresee problems
• Become a resource to study nurse
• For question from patient
• For any imaging issues that may occur
• Offer to provide radiation safety training
• Patient, family, staff
• Help others become familiar with the nuclear
  medicine procedures

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Summary

• The protocol is a specific document that
  describes the clinical trial in detail.
• Protocol amendments must be submitted to the IRB
  before they are implemented.
• The investigator is responsible for making sure
  all patients provide written informed consent.
• The investigator is responsible for control of
  the investigational product.

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Summary

• Imaging procedures may be included in the
  protocol or a technical manual.
• Avoid protocol deviations and violations.
• Dont change any protocol parameters without
  permission from the sponsor or the sponsors
  representative.
• Document everything, and communicate to everyone.

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Acknowledgements

• Presentation writers
• David Blea
• Adam Opanowski
• LisaAnn Trembath
• Presentation Editor
• Robert Pagnanelli
• Knowledge Assessment Writer
• Anthony Knight
• VOICE application
• Janet Gelbach

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The Main Objective

• Be a GREAT clinical research site
• For the sponsor
• For your patients
• For your organization
• For your own professional development