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

The Main Objective:

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

Presentation ObjectivesAt the conclusion of this discussion, participants will be

able to:– Define standard operating procedures (SOPs) as

they pertain to the clinical trial environment– Describe key components of an SOP– List SOPs that exist in your institution and

department that pertain to clinical research– Understand what additional SOPs will aid in

performing high quality clinical research– View SOPs from the perspective of the sponsor

What are SOPs?• Standard Operating Procedures (SOP) are:

– a set of instructions with the force of a directive that defines or standardizes a procedure or specific function

– an effective catalyst to drive performance improvement and improve organizational results

– create the level of quality and accepted practice for a specific procedure

– the foundation of every good quality system

Clinical research SOPs are an important way to help you follow

Good Clinical Practices (GCPs)

SOPs for Clinical Research

What are GCPs?

• Good Clinical Practices are guidelines for conducting sponsored clinical research

• Published by the International Conference on Harmonization (ICH)

ICH

• International Conference on Harmonization• ICH consists of regulatory authorities from

Europe, Japan and the United States and experts from the pharmaceutical industry in the three regions to discuss scientific and technical aspects of clinical research.

• ICH is considered the authority on clinical research theory and principles.

www.ICH.org

ICH Principles

• The guiding principles of ICH are to:– develop scientific consensus through

discussions between regulatory and industry experts

– assure wide consultation of draft consensus documents through normal regulatory channels before a harmonized text is adopted

– secure commitment by regulatory parties to implement the ICH harmonized text

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

• Publications of the ICH include:– Safety management in clinical trials, including

periodic safety updates of research and marketed drugs

– Dose response data collection– Statistical principles for clinical trials– Publication of the final study report– Choice of control groups in clinical trials– Pediatric clinical trials– Good Clinical Practices

ICH

ICH E6: Good Clinical Practice

• Contents:1. Glossary2. The Principles of ICH GCP3. Institutional Review Boards4. Investigator5. Sponsor6. Clinical Trial Protocol(s)7. Investigator Brochure8. Essential Documents for the Conduct of a

Clinical Trial

• Get to know this document!

US regs vs. ICH?

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

• 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 regulations– HOWEVER there is guidance and regulations

that infer responsibility and SOPs formalize investigator responsibilities.

– 21 CFR312.53 mandates that the investigator will “ensure that all associates, colleagues, and employees assisting in the conduct of the study are informed of their obligations in meeting the above commitments.”

• 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 and/or fellows

SOPs for Imaging: Benefits

• Image standardization – All technologists doing the same task in the

same way – Reproducible camera performance– Documentation of deviations

• Standardization of patient data– Blood and urine samples– Vital signs– ECGs

Key Components of SOPs• Description of the purpose of the procedure/task• Background information and definitions • Specific components to successfully perform the

task/procedure– Required personnel to perform all aspects of

the procedure– Appropriate patient population (as applicable)– Required equipment, supplies, information

and/or data

– Equipment settings, as appropriate and/or necessary to acquire/process data

– Quality control procedures to assure optimal results

– Interpretation and reporting criteria, as necessary for consistent and uniform review of data

• Effective date and expiration date

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 radioactive materials

– ALARA protocols– Personnel monitoring– Pregnancy protocols (patient/employee)– Radioactive spills– Quality control procedures– Safety training (ie, CPR, fire extinguisher, patient

transfers)

SOPs: Nuclear Medicine (cont.)

• Examples of SOPs in Nuclear Medicine:– Specific imaging/non-imaging protocols

• Quality control• Patient assessment• Patient education/preparation/discharge • Acquisition• Processing• Data storage/transfer

– Adverse drug events/misadministrations

Patient Privacy SOPs

• Sometimes these get complicated with nuclear medicine data –– Can data go to PACs with a research code

number?– Is the data sent to the sponsor with the

identifiers stripped?– Is there a backup copy of identifiable data in

the department?– Who has access to the images or biologic

data?

• 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 21CFR312 guidelines

ICH E6 : Investigational Product

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

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

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

questionnaires?• Radiopharmacy dosing records – integrated into

medical records?

Documentation SOPs• 21CFR312.62 (b) Case histories. An investigator is required

to prepare and maintain adequate and accurate case histories that record all observations and other data pertinent to the investigation on each individual administered the investigational drug or employed as a control in the investigation. Case histories include the case report forms and supporting data including, for example, signed and dated consent forms and medical records including, for example, progress notes of the physician, the individual's hospital chart(s), and the nurses' notes. The case history for each individual shall document that informed consent was obtained prior to participation in the study.

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

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

Documentation SOPs

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 consistent• Acquisition protocols must be per sponsor’s/clinical

investigator’s specifications• Gamma camera must meet software and QC

specifications• Data transfer must meet sponsor’s specifications• Patient information (demographics) must be

stripped from the final study prior to transfer; essential acquisition/processing data must be retained

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

Summary

• Sponsors expect you to be familiar with ICH GCP and the federal regulations

• Gather or develop SOPs that will provide clear, precise instructions/directions for tasks and conditions that are covered in the GCPs– Institutional and departmental SOPs will be

useful– Create documentation SOP as a way to train

all employees about appropriate record-keeping methods

• SOPs to cover aspects of GCP are sponsor confidence boosters

• Don’t stop at being a GOOD research site – become a GREAT research site!

Summary

Acknowledgements

Presentation writers:

Rebecca Sajdak

Kathy Thomas

Presentation Editor:

Aileen Carey

Knowledge Assessment Writer:

xxx

VOICE application:

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