Welcome to this presentation by the Clinical Trials Network. This presentation has been created to provide insight into how SOPs in your imaging department can be extremely valuable in making your department a high quality research site. Many of the principles in this talk will be familiar, but our goal is to present this information from the point of view of a pharmaceutical or device sponsor. We also understand that you are probably already doing research protocols, and doing a good job. The function of the Clinical Trials Network is to help you go from being a GOOD research site, to being a GREAT research site!
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.
The objectives of this talk are to define SOPs as they relate to clinical research, and help you create a collection of SOPs that will aid your department in conducting clinical research at the highest quality. You will learn that while SOPs are not a requirement of the regulations, they will assist greatly in being a research site that is compliant with regulations.
SOPs are everywhere in medicine, and you have certainly used them for many aspects of your clinical practice. As you can see by this formal definition, SOPs are a set of instructions with the force of a directive that defines or standardizes a procedure of specific function.
For clinical research, however, the best use of SOPs is to help you and your department stay in compliance with Good Clinical Practices.
Good Clinical Practices are guidelines for conducting sponsored clinical research (and are often used in an institution for non-sponsored research, as well.) These guidelines cover all aspects of clinical trials, from the IRB to data management. You will hear your sponsor colleagues refer to the ICH GCPs – they are talking about this particular set of guidelines.
Medicine is global, and so is clinical research. The ICH is an international organization recognizes the importance of standardizing methods of performing, analyzing, and regulating clinical trials across nations. Representatives from Europe, Japan, and the US make up the Conference, and they meet regularly to discuss clinical trials and publish guidance documents for their member countries. The ICH has published guidance documents about safety reporting, statistical principles and methods, pediatric clinical trials, and many other topics. ICH is considered the authority on clinical research, and their publications are available on the website.
The guiding principles of the ICH are to develop scientific consensus between regulatory authorities and industry, to widely circulate draft consensus papers before the ICH guideline is adopted, and to have the regulatory authorities in member countries adopt and implement the ICH recommendations.
The ICH develops publications that are consensus documents of research experts, and guidelines for sites and companies to follow when conducting research. The topics covered in some of their publications may be of interest to you and your investigator. They are all available on the ICH website.
The ICH publication that is most important for you as a clinical site is the Good Clinical Practice guideline, which is publication number E6. It is available on the ICH website (as are all of the publications) and it is a tremendous reference. You can see the main headings here from the table of contents. The section about the investigator’s responsibilities covers the following subtopics: Investigator&apos;s Qualifications and Agreements Adequate Resources Medical Care of Trial Subjects Communication with IRB Compliance with Protocol Investigational Product(s) Randomization Procedures and Unblinding Informed Consent of Trial Subjects Records and Reports Progress Reports Safety Reporting Premature Termination or Suspension of a Trial Final Report(s) by Investigator/Institution
You might be wondering how the ICH fits in with the FDA? Remember that representatives from the FDA are part of the ICH, and so the GCP guidance is complimentary to the US Code of Federal Regulations. The main US regulations that cover clinical research are listed here. Your pharmaceutical and device company colleagues know and work with these documents regularly.
Both the ICH guidelines and the federal regulations are essential for a sponsor to conduct a clinical trial in the US. Sponsors know and follow both, and expect great research sites to be familiar with both.
As far as SOPs go, the US Federal regulations do not require them per se. But, the regulations require that the investigator conducts the study in accordance with the written protocol, can provide accurate and reproducible data, and that anyone who assists in the conduct of the study is properly trained. SOPs are an excellent way for an investigator to accomplish these requirements.
Also, the ICH GCP mentions SOPs repeatedly as a way to implement quality processes that protect the safety and welfare of human subjects.
Protecting the rights and welfare of human subjects is the most important focus of clinical trials, secondary even to collecting important new scientific data. SOPs help with that, as well as helping with improving the quality of the collected data. SOPs help the sponsor know that you, as a site, are organized and ready to take on the task of a clinical trial with their investigational device or drug. And, as you have probably found with many of your departmental SOPs, they serve as good training materials for new employees.
In molecular imaging, one of the biggest concerns for pharmaceutical and device manufacturers is image standardization from site to site. Many a product has taken extra months, even years, to make it to market because data from sites that didn’t follow the protocol had to be thrown out and new patients had to be enrolled to make up for lost data; or worse yet, an additional study has to be performed. (Plus, can you imagine telling your patient who has donated hours of their time for research that their data is being discarded because you didn’t follow the instructions…?) SOPs in an imaging department are a starting point for clinical research because they create an environment where attention is paid to quality details, such as camera performance and task reproducibility. SOPs that cover how biologic data samples are collected, stored, and processed allow a sponsor to see your capabilities in handling trial data. The same can be said for ECGs and vital signs.
This lecture is not really intended to be a complete workshop on how to create a great SOP, but here are at least some guidelines. You will need to provide a background for the subject of the SOP, definitions of any terms that will be used in the SOP, and a breakdown of specific components. Here is a list of some of the components that may be covered in a clinical research SOP: the personnel that will be required, the appropriate patient population that the SOP is intended to cover, what equipment is required.
Continuing the list of potential components of a clinical research SOP: what equipment settings are used, what QC is done to ensure optimal results, what will the interpretation and reporting criteria be. Another key component of an SOP is the effective date, and if applicable, an expiration date. The date could be a timeline such as “2 years from the effective date.” This is a way to ensure that SOPs are reviewed regularly to keep them effective as useful, working documents.
The SOPs are good for general education in your department, but are also good for specific education to all research personnel. Your SOPs can be a foundation for training on a specific clinical protocol.
This is a list of SOPs that probably already exist in your hospital. These are universal in their application to clinical research projects as well. For example, if there is a specific piece of medical equipment that will be used in a clinical trial, the sponsor may request documentation of how that equipment is maintained and where the service logs are kept. Or, the sponsor may wish documentation of how patients are identified prior to undergoing procedures or being dispensed medication. If you don’t have a copy of these in your department, contact risk management in your institution for copies of these.
You already have many SOPs related to radioactive materials, as well. A sponsor may want to know how you will assure that a patient is not pregnant prior to injection of the investigational product; or what quality control procedures exist to make sure the patient dose is prepared properly (aseptic technique, appropriate labeling, etc.) For administration of an investigational product, especially in Phase I, the sponsor may wish to know your emergency safety SOPs.
If the sponsor has not defined the imaging parameters completely in the protocol, having your own SOPs that describe specific camera/isotope protocols might be very helpful. How you archive your data, how you back up the digital images, whether or not you use a PACs system – all of these SOPs will be of interest to the sponsor who knows that an FDA audit can take place years after the protocol is completed. While every sponsor will have a specific set of documentation instructions for adverse events, whether or not they are related to the investigational product, it will be useful to demonstrate via a departmental SOP that there is a set procedure in place to medically handle and officially document such incidences.
The sponsor may want to see what your procedures are for de-identifying research data. In some instances, the PACS system requires the patient’s hospital number and full patient name, but the sponsor only wants data that is anonymous. Having a defined procedure in place will be very helpful. There are also issues with regard to data transfer, as well. Many sponsors request that image data be sent with a secure file transfer protocol over the internet. Your institution probably has both a digital firewall as well as rules that say patient data cannot be sent out over the internet. A set of procedures that are in place prior to the beginning of the study will help make sure there are no crises when it comes time to sending data.
Electronic data transfer is often used in sponsored studies, and having your own SOPs for how to work with IT to deal with potential firewall and patient ID issues will be very helpful up front. An SOP that covers this area should identify who has authority to grant approval for the electronic data transfer.
Nuclear medicine departments have strict rules (either NRC or state) about how radioactive drugs are stored. But, the sponsor may or may not be familiar with radiation regulations, and will be pleased to know you have an SOP that documents every aspect of an investigational product received by the department to make sure that the process complies with ICH E6 and 21CFR312 guidelines
Control of the investigational product is a key focus of federal regulations and the ICH guidelines. Regarding the investigational product, nuclear medicine departments already have strict rules (either NRC or state) about how radioactive drugs are stored. But, the sponsor may or may not be familiar with radiation regulations, and will be pleased to know you have an SOP that documents who can access the drug and how it is stored when not in use. The shipping, receipt, storage, and documentation of how investigational products are dispensed is very important to a pharmaceutical sponsor, as is making sure that no one receives the investigational product who has not signed informed consent and is eligible for the study. As you can see from this excerpt from the GCPs, standard operating procedures around investigational product will be very helpful. The questions a sponsor will want to know is: Who is authorized to receive, handle, dispense, store, or dispose of the investigational product? Will it be kept in a location that is locked and not accessible to the public or non-authorized personnel? How will it be accounted for at the end of the study?
This is a continuation of the ICH guideline, stating that the investigator is responsible for recordkeeping. Remember that an audit of a clinical trial can take place many years after the study is completed. Be sure that your records are kept in a specific location so they can be retrieved for review many years later without having to go through the records of every patient in nuclear medicine.
Storage of the investigational product for radioactive drugs is tightly controlled for purposes of radiation safety. But the sponsor may have additional requirements such as temperature or humidity control, exposure to light, etc. A departmental SOP that identifies where and how such sponsor-specific requirements will be met will be useful to convince a sponsor that you are capable of handling their request. Statement 4.6.6, about making sure the subject follows instructions properly, can include preparation instructions or radiation precautions for family members. An SOP that documents how PET patients are prepped, or how high-dose therapy patients are released and with what instructions will be very useful.
In addition to the GCPs around handling of the investigational product, the federal code of regulations offers some specific requirements. Obviously, control of the investigational product is extremely important to the agencies that are entrusted with protecting the rights and welfare of human subjects. The sponsor may or may not know how tightly radioactive material is controlled in a hospital setting, so you may think that their interest in how you store the product is overkill; but it comes from this imperative in the ICH guidelines and the federal regs.
In nuclear medicine, the control of the investigational product is usually delegated to a radiopharmacist or nuclear medicine technologist, but the investigator is always the one who is responsible.
Medical records SOPs are of interest to the sponsor, because the sponsor’s representative will be monitoring the patient’s progress through review of records. If your hospital system uses medical records, the sponsor will ask if they are 21CFRPart 11 compliant. 21CFR11 is the federal regulation that deals with electronic signatures and audit trails. Sometimes the hospital system uses electronic medical records, but the nuclear medicine department still keeps some paper records. Or, perhaps patient dosing records are kept in a radiopharmacy software program which is not integrated with electronic medical records. Keeping an SOP that describes where each data point is kept will be extremely helpful for the study monitor, as well as any potential auditors from the IRB, the FDA, or other regulatory agency.
The federal regulations require that the investigator keep a “case history” of the patient. For a study in nuclear medicine, this is sometimes an additional step that can be missed. The investigator must document in the medical record that the patient has provided written informed consent.
Documentation is a critical part of clinical research. The records must be clear, and changes to the record, even if not material (important), must be transparent. It would be good for your department to have an SOP about documentation. Such an SOP will be a way to assure that all technologists and other personnel in the department are trained in good documentation. This SOP should contain things such as: no white out can be used; records may not be erased or made illegible; changes to the record will be signed and dated by the person who made them; records will be transparent, meaning that the original entry and the changed entry will remain visible. These are good medical records policies, but are not often taught to the nuclear medicine staff. Think about being audited – what would make an auditor suspicious? The appearance of “falsified” documents creates a problem for the sponsor and any potential auditor.
In general, the sponsor is looking for a site that performs high quality procedures, in accordance with generally accepted standards of practice. Specifically, a sponsor wants to know that you know what you are doing and can handle the requirements of the study. Accuracy and standardization are usually more important to the sponsor than “creative” imaging – SOPs indicate to a sponsor that your site is organized and capable of the rigors of clinical research.
Here is the foundation of what the sponsor is looking for from a clinical site: Accurate and consistent data acquisition Following the protocols that are set forward by the sponsor Equipment that is maintained and performing to full capacity The ability to get data into the sponsor in a timely manner The ability to protect the patient’s privacy in accordance with applicable regulations
This is not an overwhelming task ahead of you – start by gathering existing SOPs that cover the areas mentioned in this talk from your institution and from your department. Analyze what you have, and where the gaps are. Then start creating additional SOPs for the needed areas. A sponsor is not going to walk in the door and demand to see your SOPs; rather, by offering the sponsor a chance to review your SOPs you will increase the sponsor’s confidence in your skill and capabilities to complete what is required by the protocol.
It is important to note that sponsors use SOPs to demonstrate to the FDA and other regulators that they are following the ICH GCP guidelines, as well as federal law. When a site has put thought and effort into conducting clinical research according to the regulations by instituting appropriate SOPs, it shows the sponsor that the data will more likely be standardized, reproducible, and accurate.
In summary, the CTN is asking you to put yourself in the shoes of the sponsor, and see how important attention to GCP details is to them. Of course, the proof is in the pudding – you have to produce good data!
If you are being evaluated as a potential site, the recommendations in this presentation will go a long way to be seen as a GREAT research site!
The Importance of Standard Operating Procedures (SOPs) in ...
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
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
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
– create the level of quality and accepted
practice for a specific procedure
– the foundation of every good quality system
Clinical research SOPs are an important way
to help you follow
Good Clinical Practices
SOPs for Clinical Research
What are GCPs?
• Good Clinical Practices are guidelines for
conducting sponsored clinical research
• Published by the International Conference on
• 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.
• The guiding principles of ICH are to:
– develop scientific consensus through
discussions between regulatory and industry
– 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
• Publications of the ICH include:
– Safety management in clinical trials, including
periodic safety updates of research and
– 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
2. The Principles of ICH GCP
3. Institutional Review Boards
6. Clinical Trial Protocol(s)
7. Investigator Brochure
8. Essential Documents for the Conduct of a
• Get to know this document!
US regs vs. ICH?
• The ICH does not override US regulations
governing clinical research; instead they are
– 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)
• 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
US regs and ICH
SOPs and Regulations
• SOPs are not specifically mentioned in the FDA
– HOWEVER there is guidance and regulations
that infer responsibility and SOPs formalize
– 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.”
• 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.”
SOPs and Regulations
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
SOPs for Imaging: Benefits
• Image standardization
– All technologists doing the same task in the
– Reproducible camera performance
– Documentation of deviations
• Standardization of patient data
– Blood and urine samples
– Vital signs
Key Components of SOPs
• Description of the purpose of the procedure/task
• Background information and definitions
• Specific components to successfully perform the
– Required personnel to perform all aspects of
– Appropriate patient population (as applicable)
– Required equipment, supplies, information
– Equipment settings, as appropriate and/or
necessary to acquire/process data
– Quality control procedures to assure optimal
– Interpretation and reporting criteria, as
necessary for consistent and uniform review
• Effective date and expiration date
Key Components of SOPs (cont.)
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
– ALARA protocols
– Personnel monitoring
– Pregnancy protocols (patient/employee)
– Radioactive spills
– Quality control procedures
– Safety training (ie, CPR, fire extinguisher, patient
SOPs: Nuclear Medicine (cont.)
• Examples of SOPs in Nuclear Medicine:
– Specific imaging/non-imaging protocols
• Quality control
• Patient assessment
• Patient education/preparation/discharge
• 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
– Is the data sent to the sponsor with the
– Is there a backup copy of identifiable data in
– Who has access to the images or biologic
• Electronic data transfer
– Firewall issues
– Patient ID issues
– May have to work with IT department
– May need administrative approval
Patient Privacy SOPs (cont.)
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
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
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
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.
• 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.
21CFR312: Investigational Product
Medical Records SOPs
• Electronic? Compliant with 21CFR 11?
• Nuclear medicine reports?
• Other documents – worksheets, H&P
• Radiopharmacy dosing records – integrated into
• 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
• 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
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
• Data acquisition must be accurate and
• Acquisition protocols must be per
sponsor’s/clinical investigator’s specifications
• Gamma camera must meet software and QC
• Data transfer must meet sponsor’s
• Patient information (demographics) must be
stripped from the final study prior to transfer;
essential acquisition/processing data must be
Conditions of Participation
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
• 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
– Create documentation SOP as a way to train
all employees about appropriate record-
• SOPs to cover aspects of GCP are sponsor
• Don’t stop at being a GOOD research site –
become a GREAT research site!