The Importance of Following the PROTOCOL in Clinical Trials

The Importance of Following the PROTOCOL in Clinical Trials
CTN Workshop February 1-2, 2010 The Importance of Following the PROTOCOL in Clinical Trials This talk, “The Importance of Following the Protocol in Clinical Research”, is part of a series of presentations designed by the Clinical Trials Network and for imaging site personnel who may already be doing and/or starting a research study, but have not necessarily been formally trained on some of the expectations that pharmaceutical companies hold when choosing an imaging site. As a member of the audience, you may have already heard some of this information, but it is probable that not everyone in your department is aware of everything in this presentation. And from reports of pharmaceutical companies, we know that in general, imaging studies are very problematic in terms of protocol compliance. A recent speaker at a seminar sponsored by the Clinical Trials Network said that “50% of the imaging studies were acceptable, and we thought that was pretty good!” As imaging research sites, and as the Clinical Trials Network, we strive to do much better than that, and by doing so, becoming a positive agents for change in improving the lives of patients who will someday benefit from the drugs and/or protocols being testing. All of us want to make a difference for our patients; this presentation is intended to teach imaging personnel what a drug company sponsor is expecting from an imaging site, and how assumptions from both sides (the imagers and the sponsors) can get in the way of optimal research study success. This presentation is focused on sponsored research, meaning sponsored by a pharmaceutical or device company. Many of the same principles could very well be applied to cooperative group studies, NIH studies, investigator-initiated studies, and other non-corporately-sponsored research. 1

CTN Workshop February 1-2, 2010
What would you do if… A study patient arrives two hours late for an image that is supposed to occur 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? These are not-so-unrealistic hypothetical situations in clinical research. So often the protocol that we receive is a one-page synopsis of what scans should be done, or when the scans should be done. The protocol synopsis may contain very little information on which to base your scanning parameters. Alternatively, it may be extremely detailed and call for things that your site does not and can not provide with your level of staffing and equipment. These are not intended to be trick questions, but examples of what can really happen in the real life of imaging research protocols. Have any of you ever been in one of these situations before? 2

To be a GREAT clinical research site, the answer must always be one of the following: 1. Follow the Protocol. 2. If you can’t do #1, call the sponsor. To be a GREAT site, not just an adequate site or a participating site, this is the formula: Always follow the protocol. If you can’t follow the protocol for some legitimate reason, you must call the sponsor to have a discussion about how to proceed. And with the exception of patient safety, believe it or not, following the protocol supersedes your imaging experience and clinical judgment! There are regulations that state exactly this, and the sponsors who hire us to be imaging sites live by those regulations. They expect that you do, too. 3

The Main Objective: Be a GREAT clinical research site For the sponsor For your patients For your organization For your own professional development So this presentation, along with all of the other presentations in the “CTN” series, is about being a GREAT site. You may be already doing a good job, but it is the belief of the CTN that teaching these important concepts to all study personnel in the imaging department will raise the quality of research at your site, and in the imaging community. If this happens, The sponsor will be very happy with the quality and standardization of data from site to site, will complete the study sooner and with much less time and money spent on data clarifications; Our patients will benefit from research that moves faster through the regulatory process and sooner to market; and they will not be wasting the most precious gift they offer –their time; (imagine being a patient in a cancer study and finding out that your study was not able to be analyzed because the imaging site decided to change the scan parameters and the data had to be thrown out….) Your organization will be pleased to advertise a great reputation for high quality imaging research and believe me, they will be happy with the number of sponsors knocking on the door to do studies with you; And you have access to professional development opportunities in this new environment of molecular imaging, where pharmaceutical companies are hungry for people who know how to do this type of work.

Upon completion of this presentation, participants will be able to:
CTN Workshop February 1-2, 2010 Presentation Objectives: Upon completion of this presentation, participants will be able to: 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. During this presentation, we will go over some seemingly basic definitions and explain what the sponsor means when they use these terms. Every one of these terms is linked to a specific federal regulation, and we will inform you about those. We will discuss the impact of not following the protocol – the consequences of which can be dire for the pharmaceutical company in terms of time loss (= money loss), regulatory issues, and data quality. And we will also discuss some types of questions that really should be in protocols but often are not, and how you as a GREAT imaging site can get those questions answered before it is too late to impair the progress of the study.

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 I have to believe that some of you in the audience are thinking, “for heaven’s sake, I know what a protocol is. When is lunch?” Except that, in all the situations that we use the word protocol in our daily lives, to the sponsor, “Protocol” means something extremely specific: it has a specific title, a unique number, has a version number and date, and is registered with the FDA and reviewed by the IRB. It would be desirable if there were different terms (like how many words the Eskimos have for snow!) but that does not exist. For now, as site researchers, we always have to understand that when the sponsor talks about the word spelled p-r-o-t-o-c-o-l they usually mean THE PROTOCOL unless otherwise specified. 6

PROTOCOL: Definition ICH Guidelines, E6: Good Clinical Practice A document that describes the objective(s), design, methodology, statistical considerations, and organization of a trial. The ICH guideline number E6, which covers good clinical practice, contains the definition you see printed here: the protocol is a document which describes the objective(s), design, methodology, statistical considerations, and organization of a trial. 7

PROTOCOL: Definition 21 CFR Part 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. The US Federal Code Title 21, Part 312, contains a more detailed description of what a protocol must contain: A statement of of the objectives and purpose of the study The criteria for patient inclusion/exclusion An estimate of the number of patients to be studied (this is determined by statistical methods) A description of the design of the study, which must include a description of the control group (if one is being used) and methods to minimize bias of subjects, investigators, and analysts.

PROTOCOL: Definition (cont)
CTN Workshop February 1-2, 2010 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. The description continues: A protocol must contain The method for determining the dose(s) to be administered The planned maximum dosage The duration of individual patient exposure to the drug With isotope studies, the maximum, minimum dosage and patient exposure will be determined by the characteristics of the isotope used and the biodistribution of the pharmaceutical being used. The protocol must also contain Description of the observations and measurements to be made to fulfill the objectives of the study. Description of all clinical procedures, laboratory tests, or other measures is used to monitor the effects of the drug to minimize risk. Nuclear medicine and PET are usually included in this section of the protocols You can see why pharmaceutical company protocols can be very large documents – pages long at times.

Types of Sponsored Protocols
CTN Workshop February 1-2, 2010 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. As a way to better describe sponsored studies, they could be described as being in three categories: those in which the radiopharmaceutical is the investigational product under study, those in which the imaging procedure is conducted as a measure of therapeutic efficacy of the investigational product, and those in which both the imaging agent and the therapeutic agent are investigational.

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 This first category, those studies in which the radiopharmaceutical is the investigational drug under study, are typically conducted by companies which have a primary interest in imaging and/or radioisotope therapy. This has been the most common type of sponsored research with which nuclear medicine technologists and physicians have experience. Often the sponsoring company has at least some in-house experience with imaging, and the imaging or therapy procedure is described in detail in the clinical protocol. Some examples are listed here. Many of the radiopharmaceuticals that we use in clinical nuclear medicine today have gone through this process – Cardiolite, Myoview, ProstaScint, OctreoScan, to name a few. All of the FDA regulations that apply to any investigational drug apply to an investigational radiopharmaceutical, even if it is being developed for diagnostic scanning only. The sponsor of these projects is likely to be familiar with imaging and handling of radioactive materials, but not necessarily. Often a nuclear medicine physician is the principal investigator for these trials.

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 The second major subtype of sponsored protocols in imaging are those in which the imaging procedure is part of the evaluation of a therapeutic product under investigation. A classic example of this is seen in cardiology, where myocardial perfusion imaging can be used to test the efficacy of cardiac medications. In these types of studies, the nuclear medicine physician is often a subinvestigator, and the principal investigator is a physician with expertise in the disease state of the therapeutic intervention (such as an oncologist, cardiologist, or neurologist.) Imaging is a sub-part of the overall clinical procedure but it doesn’t minimize its importance to the study. 12

Types of Sponsored Protocols
CTN Workshop February 1-2, 2010 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 The CTN will be working with sponsors who are testing investigational drugs with molecular imaging tracers that are themselves investigational. For example, a new oncology therapy may be tested by looking at before and after treatment with F-18-FLT PET images. FLT is investigational, and so the sponsors and clinical trial sites have to treat both the therapeutic drug and the imaging drug as investigational. They are covered under the same FDA and ICH GCP guidelines. When this situation happens, the sponsoring drug company will work with the CTN to cross-reference the IND application for the F-18 FLT. The SNM is, in some ways, the sponsor of the F-18 FLT study because they hold the IND. At the site level, though, it is important to remember that both drugs, the therapeutic and the FLT, are investigational and have to be treated as such. The protocol still must be followed as completely as is possible.

Control of Investigational Drug
CTN Workshop February 1-2, 2010 Control of Investigational Drug 21 CFR 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 General responsibilities of investigators. An investigator is responsible for the control of drugs under investigation. Part of following the protocol is maintaining proper control of the investigational drug. Control of the investigational drug, whether it is the imaging tracer or the therapeutic agent, is a critical focus of the FDA regulations. The code of federal regulations cites specific responsibilities of the investigator with regard to controlling access and dispensing of any investigational drug. Section states that the investigator will only adminster the drug under their personal supervision or under that of a subinvestigator. The investigator will not supply the investigational drug to anyone not authorized to receive it – which is language for “those who are eligible for the clinical trial and have provided informed consent.” Section makes a general statement that the investigator is responsible for control of the drugs under investigation.

Control of Investigational Drug
CTN Workshop February 1-2, 2010 Control of Investigational Drug Sec 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 As part of that control of the investigational drug, even if it’s the imaging tracer such as FLT, the investigator is required to keep careful logs of the disposition of the drug, including dates, quantity, and use by subjects/patients. If the investigation is terminated for any reason, the investigational product has to be returned to the sponsor or disposed of. For radiopharmaceuticals, the disposition would be most likely letting it decay to background, disposing of it, and documenting that disposal. Most sponsors will provide drug accountability logs as part of the study documentation. These logs require entries for when the drug is received at the clinical site, how much is received, how much is dispensed, to whom and what date, and what is done with the remaining product. Often these logs are created by a pharmacist for a traditional type of drug, and need to be revised somewhat for a radiopharmaceutical. A drug accountability log is in addition to all of the record keeping that you have to do for state and federal regulators of radioactive materials.

General Investigator Responsibilities
CTN Workshop February 1-2, 2010 General Investigator Responsibilities 21 CFR : 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. In addition to keeping close supervision of the investigational drug, this section of the regulations cites more responsibilities of the investigator: Ensuring that the investigation is done according to the protocol and regulations, and according to the signed investigator statement Protecting the rights, safety, and welfare of human subjects and making sure that informed consent is obtained from all subjects prior to administering the investigational product.

Signed Investigator Statement
CTN Workshop February 1-2, 2010 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 The signed investigator statement is a document that gets signed by the principal investigator and goes on file with the FDA. It is form number FDA-1572, and you will hear the sponsor refer to this form simply as “the 1572.” The 1572 is a binding agreement with the FDA that the investigator will follow the protocol set up by the sponsor. The form states that subjects rights of refusal and for treatment as well as their safety and welfare must be protected. The form also covers the following agreement: that all drugs must be used solely for the investigation and used in accordance to the procedural protocol. In addition to the regulations about properly performing the protocol, the site has signed a confidentiality agreement. The site is responsible to the sponsor to protect the sponsors protocol and can not duplicate, trade, or sell copies of the protocol.

Signed Investigator Statement
CTN Workshop February 1-2, 2010 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.” Most relevant to our discussion today is the fact that one of the agreed-upon statements on the form that the investigator has to agree to comply with is this: “I agree to conduct the studies in accordance with the relevant, current protocol and will only made changes in the protocol after notifying the sponsor, except when necessary to protect the safety, right, or welfare of the subject.” In very strong terms, this agreement with the FDA for a sponsored study says that the site personnel will not change the protocol unless the sponsor has been notified. That includes the imaging parameters as well as everything else. The safety caveat allows a nuclear medicine department to make a protocol change in a situation where the safety of the patient is paramount – such as an intervention due to an adverse event.

Form FDA-1572 This is what the Form FDA-1572 looks like, and you can download this form easily from the FDA website if you would like to read the complete form and instructions.

Sponsor Responsibilities
CTN Workshop February 1-2, 2010 Sponsor Responsibilities 21 CFR 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 The sponsor also has responsibilities that are carefully outlined in the regulations. One of those, pertinent to our discussion today, is that the sponsoring company is responsible for selecting only qualified investigators. Usually the choosing of investigators is done very carefully, by screening many names and institutions to find the most appropriate people to be involved. Part of the emphasis on getting every physician’s CV and medical license into the drug company is to provide documentation to the FDA that they are indeed qualified in their clinical expertise to be participating in the study. Any pharmaceutical company study that is using a molecular imaging tracer to study the effect of their drug on disease will then need to have a nuclear medicine physician selected to be part of the study, because they are the persons with the appropriate expertise. While several physicians in a nuclear medicine department may participate in the study by reading images or participating in case conferences, those that are listed on the 1572 as subinvestigators or as the principal investigator are considered by the FDA to be responsible for the trial.

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 We’ve now covered the protocol, what it is and who is responsible for it. Now, let’s talk about what happens when the protocol is not followed. A protocol deviation is when there is a variation from the processes or procedures defined in a protocol. Typically, a protocol deviation does not make the data ineligible for analysis. A protocol deviation also does not affect the safety of the human subject. A protocol deviation is usually defined after an event occurs, such as a blood sample is missed or a vital sign is taken outside of the window prescribed in the protocol. Sometimes an investigator will ask a sponsor prior to the event for permission to alter the protocol in a minor way. When permission is granted, that is sometimes called a protocol “exception.” Just like a deviation, a protocol exception does not make the subject unevaluable, and does not affect the safety of the subject. If you are requesting a protocol exception, you must receive permission in writing for it to be considered granted. 21

Protocol DEVIATION: Examples
CTN Workshop February 1-2, 2010 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. Here are some examples of protocol deviations: The study says that a patient’s platelets must be at least 150K to enroll in the study. The patient has platelets of 149K, and no other clinical issues. The investigator, sponsor, and medical monitor agree that the lab values do not constitute a clinical risk or a risk to data integrity. The investigator can request a protocol exception, and the drug company can grant the exception to enroll the patient on study. That patient’s data will still be evaluable, and the medical monitor has determined that there is no additional risk to the patient’s safety and well being. Here is another example: you are preparing to start the images at the prescribed time period of 15 minutes plus or minus 5 minutes, and the nurse has to repeat the patient’s ECG due to some artifact. Because of the delay, you have to start the study at 23 minutes post injection. This is outside the protocol-specified window of 15 plus or minus 5 minutes. This is a protocol deviation, and will be documented as such by the sponsor. You must document on the source document why the scan started late. The patient’s data can still be evaluated on the study, and there is no additional risk to the patient’s safety and well being.

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 In general, you want to keep the number of protocol deviations as small as possible. They are acceptable when the clinical or technical situation varies beyond your control. Many IRBs require that you report all protocol deviations when a safety measurement is missed. For example, if the patient is supposed to have blood tests done and does not show up for the appointment, that is a safety parameter that has to be reported to the IRB. Don’t use protocol deviations as a way to change the protocol to make it easier, more routine, or even to get “better” images. 23

Protocol VIOLATION: Definition A significant departure from processes or procedure May affect the evaluability of the data A protocol violation is more serious than a deviation. A violation is described as a significant departure from the processes or procedure outlined in the protocol. Protocol violations risk making the patient’s data not ineligible for analysis. For the sponsor, a protocol violation represents a potential loss of patient data. It also will usually lead to additional time and money spent in retraining the site to prevent further violations. 24

Protocol VIOLATION: Examples
CTN Workshop February 1-2, 2010 Protocol VIOLATION: Examples Some examples of Protocol Violation Changing technical parameters of the acquisition Enrolling an ineligible subject Improper informed consent Here are some examples of protocol violations: Changing the technical parameters of the acquisition Why is this so important? Because most studies that use imaging are attempting to have standardization from site to site, so that results can be generalized to all patients with the disease. When images are not standardized due to varying acquisition or processing parameters, that data has to be thrown out. Enrolling an ineligible subject If an investigational drug is dispensed to a noneligible subject, it is a serious violation of the investigator statement and of the protocol. The exposure of a noneligible patient to the risks of the investigational product is seen as a serious issue by the IRB and the FDA. That patient data cannot be used in the analysis. Improper informed consent can result in all of that patient’s data being dismissed. The informed consent process is the foundation for ethical research practices, and a practice of performing research on patients who are not properly given the opportunity to provide consent is a serious problem in the eyes of the IRB and the FDA. You might be thinking, who would do research on a patient without getting informed consent? Not many people, intentionally. But if care is not taken to document consent properly, or if an outdated version of the consent form is used, or there is not a record in the patient’s medical history that they consented to the study – these things count as improper consent procedures and can trigger audits by the IRB and FDA, with the worst case scenario being shut down of a trial, a site, a company.

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. Here is an example from the beginning of the talk. You may have knowledge that 7.5 mCi will be enough to get a good clinical image. But, that is not the only consideration mCi will be a protocol deviation, because it differs from the dose that is described in the protocol. You should contact the sponsor, and ask for a protocol exception. Get the response in writing before injecting the dose, even if it is approved over the phone. (As a second best, and if timing is critical to do the injection, get the documentation at your first opportunity.)

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. 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.

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. 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? Be sure to document the situation for the sponsor. Sign and date the documentation. This is a protocol deviation, but not within your control and documentation is the key.

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. Example 3: You did not complete a specific quality control procedure within one week of the images (for example, a COR correction, or a high count uniformity flood). What do you do? As in the previous examples, documentation is the key. This is a protocol deviation, but with proper documentation the study can still be acceptable. Make sure you record: What happened Why it happened What you did How you will make sure it doesn’t happen again Date, with your signature. Remember: if you deviate from the protocol, the imaging data may not be able to be used for the final analysis.

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 Sponsor’s expectations will be met 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 (trial protocol is most likely different than your institutions standard of care). The sponsor will usually provide source documentation worksheets that are standardized from patient to patient and from site to site. Always keep a copy for your records. Sponsor’s expectations will be met if you provide documentation for each protocol deviation. Everyone takes vacations, and most everyone has a sick day now and again. Your best protection for preventing protocol violations and deviations is to have multiple people trained on what to do for protocol patients.

Avoiding Deviations & Violations
CTN Workshop February 1-2, 2010 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 A good way to minimize deviations is to 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 (remember – if the images are not done according to the protocol, that data may not be able to be used in the final analysis). If the sponsor does not provide a worksheet or checklist, create your own flowsheet or whatever documentation will help to keep everyone organized.

Avoiding Deviations & Violations There may be a long period of time between scanning study participants. Prepare prior to the participants arrival. There may be a long period of time between scanning study participants. If the patient population under study has a rare condition, or if the study entry criteria are very strict, you may have months in between individual patients on a study. You can’t rely on memory for details about how to perform the protocol. Prevent deviations and violations by reviewing all study documentation prior to the patient’s arrival.

Avoiding Deviations & Violations
CTN Workshop February 1-2, 2010 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. If the study protocol is standard of care imaging (meaning, the parameters for imaging are the same as what you do for clinical patients): It is still important to identify the patient as a study participant, and to document in the patient medical record that they provided informed consent to participate in the study. The drug accountability records still have to be kept, and the source documentation still must be completed per protocol. 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.

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. Frequently a protocol will get underway at multiple sites and the sponsor will find it necessary to revise the protocol – either for new scientific data that has come in, or because the practical implementation of the protocol requires some changes. In that case, a protocol amendment is issued. The ICH guidelines define a protocol amendment as “a written description of a change(s) to, or formal clarification of a protocol.” Amendments are intentional, prospective changes to a protocol. 34

Protocol AMENDMENT: Definition
CTN Workshop February 1-2, 2010 Protocol AMENDMENT: Definition 21 CFR 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 The Federal code provides some additional detail about amendments as seen here on this slide: The sponsor must submit amendments describing any change that affects the safety of subjects in a Phase I trial, or that which affects safety, scope, or quality of the study in a Phase 2 or 3 protocol. Since a Phase I study is primarily done for safety data, essentially any change to the protocol requires an amendment.

Protocol AMENDMENT: Definition Examples of changes requiring an amendment under 21 CFR : 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). Here are some examples of changes in a protocol that require amendments: Increase of drug dose or change in duration of exposure of any individual subject to the drug Any significant increase in the number of subjects under study Any significant change in the design of the protocol

Protocol AMENDMENT: Definition
CTN Workshop February 1-2, 2010 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. Continuing from the previous slide, an amendment is required for the addition of a new test or procedure that is intended to monitor safety, or the dropping of a test intended to monitor safety. From a practical level, a pharmaceutical protocol will be amended formally when there is any change to it.

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 All protocol amendments must be submitted to the IRB and approved prior to implementation. Amendments are submitted to the FDA by the sponsoring company, and must be submitted to the investigator in writing. If the amendment requires a change in consent form, the IRB-approved consent form must be given to all subsequent patients, and all patients currently on study. If the amendment is administrative or clerical in nature, approval by IRB is not required, however, notification must be on file.

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. Prior to your site agreeing to participate in a clinical trial, it is important that a general discussion take place between the sponsor and all of the imaging personnel in your department that will be directly involved with the trial. Note that in this slide and in the rest of this talk, I’ll use the term “sponsor” for the sponsoring company as well as any of the sponsor’s representatives, which could be a CRO, an imaging core lab, or a data management company. The FDA says that any agent of the sponsor has the same responsibilities as the sponsor for ensuring compliance with the federal regulations. Before your site is allowed to accrue a participant and or scan that participant for the trial, you and the sponsor will have to assess whether your site has the capability of properly conducting the study procedures.

Site Participation This discussion (or questionnaire) may include information regarding: Site information (address, , 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 You may be asked to complete a protocol specific application which will include information regarding your research experience, site information (i.e., equipment and/or personnel), provide regulatory documents, describe your research experience, etc. The most important factor is that you and your site want to participate in the trial and that you have the resources and the capability to do so. The timeline of these discussions varies widely, but a typical scenario is that you have an initial discussion and then don’t hear anything for 6 months to a year. In a case like that, the protocol may be in revision, the FDA may be awaiting data before giving the authorization to start, or the protocol may be under review by the IRB. The financial aspects of the trial such as contracts and payments also take a long time to accomplish, and usually cause a delay from the initial discussions to the actual implementation of the study.

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) After your initial meeting with the sponsor, all of the imaging personnel from your site should carefully review the trial protocol for details on all of the technical procedures that you will be responsible for completing. It is important that you review the protocol to make sure it clearly identifies all of the scanning parameters (e.g., acquisition and reconstruction parameters), quality control measures (e.g., phantom imaging and cross-calibration with your well counter and PET scanner). It is also important to make sure you have the capability to perform these trial specific tasks or ask the sponsor to provide training for some of the procedures that you may never have had to perform (e.g. brain phantom, cross-calibration). In addition to the imaging parameters, you may be responsible for obtaining specimens from the patient (e.g., blood sampling). The blood sampling procedure may need to be performed during the participants scan. All of these are trial specific details that the sponsor needs to provide your lab/department.

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! So, you have now met with the sponsor and internally reviewed the protocol with the imaging department. You now need to consider: Does your site have the proper personnel and equipment to participate in the trial? The personnel not only includes the imaging technologists, it may include nurses and schedulers from your department and other departments within your institution. You may need to determine if you have an adequate number of staff that can handle a clinical trial in addition to your daily clinical workload. Your department may not have access to protocol specific equipment or have the proper training to perform the tasks. It is NOT enough to simply say “yes, we do PET/CT” in response to a questions about whether you can do a sponsored clinical trial. One reason why it is not enough to simply say “yes” is because the majority of the time a clinical trial protocol is different than routine clinical imaging protocols. Review the entire protocol before agreeing to participate in the study.

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? You should have some questions prepared for the sponsor, either at an initial meeting or after reviewing the protocol in detail. Do I have to qualify my scanner? Some sponsors require a site to qualify their scanner prior to accruing a patient on the trial. The procedures may include the acquisition of a phantom using the protocol specific acquisition and reconstruction parameters to confirm that the scanner being used in the trial is calibrated properly. This takes extra time and resources on the part of the department, and can be a prerequisite to even being allowed to participate in the study. Can my site receive (or produce) the radiopharmaceutical used in the study? Depending on the radiopharmaceutical being used, it may be a requirement that you have an on-site cyclotron or be in close proximity to a commercial radiopharmacy. Perhaps the requirements of the protocol depend upon a staff radiopharmacist, and you don’t have one in your department. How long will the scans and QC take? Due to the amount of clinical patients being scanned on a daily basis, is there adequate scanner time that can be scheduled specifically for research patients? Maybe the scan only takes one hour but the measurement of vital signs and post injection assessments will take three hours. Is there any specialized equipment required for the study? Often sponsored studies require blood and urine collections. You should know the procedures that will be required for handling of those specimens, and if your department has the appropriate equipment. Who is responsible for lab work, ECGs, urine collection, or other study parameters? Make sure that you review the protocol to see if a nurse or additional study coordinator will be required to accomplish all of the tasks involved in the study.

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? Information that you will need to ask the sponsor or the core lab are: How will you be transferring the image data and when does it need to be transferred in respect to the day of imaging. For example, you may need to send the images via sFTP within 24 hours of the scan. What imaging data needs to be submitted? Depending on what the sponsor and the core lab requires, you may need to send raw data and all of the protocol specific reconstructions. The data sets may need to be labeled a certain way – PET AC, PET NAC, CTAC You may also have specific dose ordering procedures that need to be followed. Inquiring about all of these details prior to imaging a participant will only make things easier for your department! Some of these details may not be in the protocol, but rather a protocol-specific technical manual.

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 A technical manual is often provided in addition to the protocol. This manual or image data plan includes trial specific details on scanning parameters that may not be specific in the protocol. This manual can be used as a teaching tool for the staff and a reference when needed throughout the trial. Sometimes you will not have a participant to scan for a significant amount of time - this is where the manual will be important to have in your lab. You may also have a new technologist perform the scan who is new or simply needs to be reminded of the study specific parameters. There is an additional advantage to providing the specific imaging protocol in the manual. If the sponsor would like to amend the imaging portion of the protocol after the trial is open and/or IRB (IRB or Institutional Review Board) approved it is acceptable to do so since the imaging specifications are in the manual and not in the protocol itself. This process is acceptable as long as the edits do not materially change the risk to the patient or potential outcome of the study. When a protocol is approved by the IRB, it’s too late make changes other than in the form of a protocol amendment. If an amendment is made to the protocol, any changes will have to be reviewed again by the IRB. If there are changes to the technical manual, they typically do not have to be reviewed by the IRB and can be implemented immediately.

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! A good question to ask is “who writes the manual”? Keep in mind that an imaging specialist may not have written the manual. Careful scrutiny of details may provide a key benefit to the sponsor. This will also ensure that the images are acquired and reconstructed properly. Due to the manual not being written by an imaging specialist, you and your lab may need to provide the specific patient preparation, acquisition, and reconstruction parameters for the manual. After all, the sponsor presumably came to you for your expertise in imaging! Keep in mind – any changes that you make to the manual, the sponsor will have give final approval. You will also need to have proper documentation that the sponsor has approved any changes.

Implementing the Protocol Reviewing the sponsor’s 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. Reviewing the sponsor’s 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. The sponsor is relying on each of the imaging centers that are participating in the trial to provide high quality images. It is not uncommon that the principle investigator (PI) is not in the imaging department or a radiologist/nuclear medicine physician. The PI may be an Oncologist. If this is the case, communication between the department staff is important. The PI is also relying on the imaging department’s expertise to image according to the protocol. If this is the case, it is imperative to keep good lines of communication between departments.

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. s Memos Telephone conversation Keep the study coordinator in the loop. In order to implement the protocol, you will need sufficient documentation (possible training) of the imaging procedures, QC, and radiopharmacy procedures. What do you do If you have not been given ample opportunity to perform a thorough review of the protocol? First, do not image a participant until you have resolved the problem. You will need to contact the sponsor and will also need to begin the process of working with the imaging core lab to obtain all of the needed details. When performing these tasks, remember to document all communication ( , memo, phone conversation) with the sponsor and the core laboratory. Throughout the trial, the study coordinator will need to be kept in the loop, especially any issues such as the need for information from the sponsor or the core lab. The coordinator will be able to help.

Implementing the Protocol In addition to reviewing the sponsor’s protocol and imaging manual, review any CRF’s 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. In addition to reviewing the sponsor’s protocol and imaging manual, you will need to review any CRF’s (Case Report Forms) or source document worksheets that you may be responsible for completing at the time of the scan. The CRF is a critical document and you will need to save a copy for your records. Source document worksheets are places where you record data for the first time, and should be signed, dated, and saved.

Implementing the Protocol
CTN Workshop February 1-2, 2010 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 The data that you may be required to provide is: date of scan, dose assay time (pre and post injection), net administered activity (possibly decay corrected), time of injection , and scan start time/end time. Depending upon the study, you may be asked to provide more details about the scanning equipment and parameters. The accuracy of this information is vital, and will be part of the quality control process at the sponsoring company or imaging core lab.

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. If any imaging data is found to be missing or if the data is inaccurate or inconsistent with the imaging protocol, a query or request for data clarification may be sent by sponsor or sponsor’s representative (such as an imaging core lab). A query may or may not be a protocol deviation or a protocol violation. If there has been a deviation from the protocol, a deviation form will be sent which will require an explanation for why the deviation occurred and the PI at the your site will need to both read and sign the form before it is sent back to the sponsor or their representative. A query is used to obtain missing information or to clarify a portion of the imaging data received.

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 A query may be sent due to: Date of birth in the DICOM header does not match the CRF – this is a way for the core lab to confirm they have the correct scan for a particular trial participant. Missing images or incomplete submission – you may receive an image or forms due report from the core lab, this is a notice of the data that has not been submitted. Time of scan does not match protocol requirements – an example is the injection to scan time interval. The protocol may require a different interval than your institution’s standard of care.

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: Memo Phone conversation Note to file 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 or CRO if one is used for the trial. Documentation includes: Memo Phone conversation Note to file Your documentation must tell the story. When an audit is being performed, the auditor will need to be able to follow your documentation and understand what had happened without your verbally relaying the information. If you did not document – it did not happen!

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 s 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 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 s Courtesy copy on paper correspondence Notify the coordinator of telephone conversations with the sponsor and the results (it may be helpful to keep a telephone log) Include the coordinator in all scheduled teleconferences and meetings with the sponsor

Department Cooperation/Education Remember: Research can disturb your schedule! Remember: Research can mess up your schedule! Since research can easily mess up your schedule, you will need create a system within your department to handle both trial participants and daily clinical imaging studies without jeopardizing the quality of the scans performed.

Department Cooperation/Education Don’t 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.) Don’t 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.)

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 Departmental staff may be required to alter standard department procedures to accommodate a research study. Education up front is always better than solving logistical problems on the fly! 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, etc.) Radiation safety may need to be involved if radioactive blood, plasma, or urine is being stored for analysis.

Department Cooperation/Education
CTN Workshop February 1-2, 2010 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! Spending time in staff meetings to go over the details of a clinical trial protocol is never wasted time. Your colleagues may ask questions that you never thought to ask, about scheduling or technical issues. Solving problems before they occur is always easier!

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). 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). The procedure should also include a way of identifying the participant when they arrive the day of their scan. An example of why this is important to identify a trial participant prior to beginning their study – For FDG imaging, your departments standard of care may not require you to perform a blood glucose test, the trial may specifically mandate that a participants blood glucose be below 150 mg/dl. If you didn’t know the patient was a trial participant then you may not have performed the test prior to injection. If you didn’t perform the glucose test, it would be considered a protocol deviation and that participants scan may not be able to be used for the analysis of the study.

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 If nuclear medicine is not the primary department for the study, it is good to attend research meetings in other departments where the protocol will be discussed. An Imaging question may occur during a meeting and this would be a good forum for imaging problems to be alleviated early in study. It is important to answer all imaging questions that a patient may have; help a nurse explain what will occur in Nuclear medicine. Educate each patient and/or family , staff on what is radiation, how long they are radioactive, if they can be near other people, and any safety precaution needed. Whenever possible, arrange to attend research meeting where the protocol is being discussed by the clinical section (oncology, radiology, etc.). Providing technical expertise about imaging procedures may alleviate future problems. Schedule a radiation safety training session for anyone who may be interested in learning about how to handle specimens or in contact with participants that have been injected with an isotope. Comfort and familiarity with the nuclear medicine procedures will assist the protocol nurse/support staff in communicating with the nuclear medicine department and with participants in the trial.

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. In summary, here are the things that have been discussed today: The protocol is a specific, numbered and dated document that is provided by the sponsor and is filed with the FDA. It must be approved by the IRB before any procedures can be implemented. The investigator is responsible for making sure all patients have provided informed consent, and for control of the investigational drug.

Summary Imaging procedures may be included in the protocol or a technical manual. Avoid protocol deviations and violations. Don’t change any protocol parameters without permission from the sponsor or the sponsor’s representative. Document everything, and communicate to everyone. Imaging procedures may be included in the protocol or a technical manual. Make sure to carefully review all procedures prior to the beginning of the trial. Prepare questions for the sponsor about technical parameters and other details. Avoid protocol deviations and violations by following the protocol and technical manuals exactly as written. Don’t make any changes to the protocol without first contacting the sponsor. Document changes that are made due to situations out of your control, changes that you have been given permission by the sponsor to make, and all procedures performed on the patient. Keep the study coordinator in the communication loop when you talk with the sponsor. Keep copies of all correspondence. Train staff members on the protocol, and include ancillary staff who may have an impact on scheduling, sampling, etc.

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

The Main Objective: Be a GREAT clinical research site For the sponsor For your patients For your organization For your own professional development Thank you for your attention.

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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