The U.S. Food and Drug Administration (FDA) expects clinical researchers to abide by standards of Good Clinical Practice (GCP), and when they are not in compliance, investigators are subject to receiving a Warning Letter from the FDA. Between January 2005 and December 2010, 129 Warning Letters were issued to investigators, with the most common deviations at study sites being noncompliance with the investigational plan, failure to maintain accurate and adequate case histories, and informed consent issues.1 The frequency of these deviations and, consequently, the receipt of Warning Letters can be greatly minimized if standard operating procedures (SOPs) are in place for all study-related activities at research sites.
In clinical research, SOPs are detailed instructions that help define and standardize how and by whom a unit’s procedures are conducted to assure execution of research tasks in accordance with institutional, state, and federal guidances. According to the International Council for Harmonization (ICH) Guideline for GCP E6 2.13, “Systems with procedures that assure the quality of every aspect of the trial should be implemented.” This is generally accomplished through the implementation of an SOP program.2 The ICH GCP guideline is upheld by regulatory authorities in the U.S., Canada, European Union, Japan, and Switzerland.
Quality in clinical research starts with a systems approach.3 In this context, “systems” include training programs, role definition, organizational structure, responsibilities and accountability, SOPs, and metrics. All clinical research sites should have quality systems to ensure that the clinical trials conducted are of the highest quality and in compliance with the tenets of GCP, study protocols, and local and federal requirements. In essence, SOPs answer the who, what, when, where, and how questions of all clinical trial activities and its management.
Thus, SOPs serve the following objectives:
- Improve and maintain quality of operations
- Standardize working practices
- Ensure high-quality, consistent, and reproducible results
- Define best practices
- Define roles and responsibilities of the individuals involved
- Ensure compliance with GCP guidance and regulatory guidelines
- Save time
A key part of quality is consistent performance of procedures producing a consistent result. A critical part of these quality actions is developing SOPs, so that anyone performing the procedure will complete it in the same way and produce the same result. In addition to providing a standard for procedures, SOPs provide training information for new hires on what kinds of clinical trial activities are ongoing at their new workplace.
Further, SOPs set the measure for quality results so staff performance can be measured to the standard required.4 Establishing and improving quality of clinical trials requires the use of the systems approach, tools, and models. In this regard, FDA recommends a four-step systems approach5: (a) Say what you do (b) Do what you say (c) Prove it (d) Improve it.
Say What You Do
The site should have a qualified and responsible management team to provide governance of the clinical trial process in its entirety. SOPs should define procedures and responsibilities for all key clinical trial processes, from site qualification to site close out.
Do What You Say
This step largely describes uniform education and training of all site staff regarding the trial protocol, study requirements, policies, and procedures. All site staff need in-depth training in regulatory requirements, ethics, consent process, and protocol compliance.6 Needless to say, it is imperative that site staff are aware of their responsibilities.
This step utilizes risk-based monitoring and trend analysis, which would be functions of an institution’s internal quality assurance unit.7 Risk-based monitoring focuses on process management and verification of critical activities, including quality control, to ensure that they are carried out as planned.4 Trend analysis looks at data as compliance intelligence, and employs such approaches as statistical monitoring to assess data trends across the sites and trials with an objective of proactively identifying and evaluating compliance signals and unanticipated risks.4
Improving quality will require actions— namely, effective corrective and preventive actions (CAPAs). For a CAPA plan to be effective, there should be an in-depth analysis of the root cause of any issue that is degrading quality at a site, and a search for an action plan that can provide long-term and sustainable solutions.5 The system and processes should be reassessed to ascertain how the problem occurred in the first place.6,8
Get Your Studies Off to the Right Start
Take control of your processes and ensure compliance with your organization’s SOPs and study regulatory requirements. The central feature of mapping out the required SOPs is a list of the steps or activities that constitute the required task. One way to do this is to begin by creating a flowchart of the clinical research process (cradle to grave); identify the individual steps (what to do) and place them in logical order.9
Based on the author’s perspective, here are the three most important SOPs that any site should develop and apply to the conduct of clinical research:
- SOP for Preparing and Maintaining SOPs—This is the primary SOP, as it helps in preparing, maintaining, numbering, and formatting SOPs. It helps the research team to prepare SOPs that comply with the guidelines set by ICH GCP and regulatory authorities.
- SOP for Responsibilities of the Research Team—This SOP defines the responsibilities of the research team, such that all conditions defined by the relevant regulatory authority on the use of investigational articles are followed. The principal investigator acts as the head of the team and is responsible for implementing the guidelines. This in turn will help in preparing SOPs detailing each of the tasks under site staff responsibility. For example, it is the responsibility of the investigator to assess adverse events. This will help in preparing an SOP detailing toxicity evaluations, as just one example.
- SOP for Training and Education—This SOP defines the standard training procedures that must be adopted to ensure that clinical research is carried out in a responsible manner. The purpose of the SOP is to define guidelines for GCP at the site in compliance with regulatory expectations.
Accordingly, the most common SOPs present at research sites in the author’s experience are:
- GCP Training
- Authority and Delegations of Responsibilities of Research Staff
- Subject Screening and Recruitment
- Informed Consent Process and Documentation
- Eligibility Confirmation
- Source Documentation
- Data Management
- Protocol Deviations
- Adverse Events and Serious Adverse Events Reporting
- Drug/Device Storage, Accountability, and Management
- Regulatory Document Submission Process (Initial Submissions, Amendments, and Continuing Reviews)
- Sample Processing and Shipping Procedure and its Training
- Monitoring Visits
- Sponsor, Contract Research Organization, and Internal Audits
- FDA Audits
- Writing SOPs
- Record Organization and Retention
- Sub-Site/Ancillary Site Management
Indeed, FDA’s 2009 guidance on investigator responsibilities10 recommends that sites have procedures for many study activities, including ones to ensure high-quality source data, protocol compliance, and proper adverse event reporting.
Who Writes SOPs and How Should They be Written?
The process of developing an effective SOP is critical to its successful implementation, and the process should be inclusive.11 Highly successful managers actively engage their teams, and it is human nature that people support what they help create. Thus, managers who write SOPs without input from workers run the risk of upsetting them, while those who enlist the talents of their workers increase buy-in.
Apparently, the most convincing reason to involve others is that individuals who participate in the process are positive about generating ideas, accept the SOPs, and feel a sense of ownership in them, which is not the case when workers feel that management is imposing an SOP without regard to their input.12
As suggested above, start with an overall view. Once the process is mapped, improvisations, revisions, and edits must be expected. Then, turn the flowchart into a narrative that assigns process steps to roles (who will do it) and includes details as necessary (how to do it).9
Zimmerman13 discusses an eight-step process for writing SOPs that involves the following:
- Process Mapping
- Formatting (includes language considerations)
- Revising and Archiving
During SOP development, start with an understanding of such sections of the Code of Federal Regulations as 45 CFR 46 (pertaining to research overseen by the Office for Human Research Protections [OHRP]) and 21 CFR 50, 56, and 312 (pertaining to research overseen by FDA); the ICH GCP guidelines and other pertinent guidance from OHRP and FDA; and applicable institutional policies. As written previously, include representatives from every impacted institutional area in the process.
SOPs should not merely duplicate regulations or guidelines; rather, they should be instructive as to how the regulations and guidelines will be followed in a consistent manner. Each procedure should be clearly and concisely written with little room for interpretation, while ensuring that the procedure is compliant with applicable laws and regulations. A good SOP should clearly identify the scope, be separated into easily identifiable sections, and include responsibilities for specific tasks, detailed procedures to perform tasks, and any associated documents/forms/tools to support the work governed by the SOP, such as checklists and templates.14
The benefits of SOPs are obvious, in that they provide a level of formal accountability for team members and prevent noncompliance on a systemic level. They help to ensure that all research conducted as part of the clinical trial follows federal regulations, ICH GCP, and institutional policies. They ensure processes have been examined, optimized, and standardized.
If used right, SOPs can provide valuable sustenance to new employees in need of details on how activities are required to be performed. Most importantly, SOPs allow for continued operations if a key staff member is unavailable. By referring to the SOP, someone can handle an urgent task and do it correctly the first time. This becomes necessary especially if research sites are experiencing high turnover rate.
Further, SOPs may in some cases support institutional practices that sponsors may dispute.15 Last, but not the least, SOPs help reduce errors or variations and improve the quality of the data collected.9 Thus, an effective SOP should:
- Be written in a simple, easy-to-understand language
- Be a comprehensive document
- Differentiate between instructions and general information
- Describe procedures thoroughly
- Contain a descriptive title
- Contain an indication of the SOP’s position among other SOPs
Writing SOPs Isn’t Enough: Challenges Ahead
Although SOPs are invaluable, they can be burdensome—especially when one considers the elaborate steps involved in such tasks as document control, revision, review, and training, and the high levels of scrutiny for strict adherence that come with established SOPs. It would be wise to consider the following before writing an SOP:
- Can the SOP be consistently followed?
- How will all staff be trained on the SOP initially, as new staff are added, and as the SOP is revised?
- How will compliance to SOPs be assessed?
- What are the added regulatory burdens and costs of compliance?
Thus, writing SOPs is simply the beginning in achieving quality results. As written previously, everyone must be trained on the SOPs, and performance must be measured against the standard to ensure the correct results. Metrics must be collected on a regular basis to ensure staff are following the SOPs; if metrics and performance measurements are not undertaken, SOP compliance, standardization, and quality will inevitably decrease and the efforts taken in designing and writing the SOPs will prove to be futile.
In short, for standard processes leading to quality to be effective, there must be written SOPs, training on the SOPs, and metrics and measurement on the compliance to the SOPs—this, in effect, is the trifecta for quality in clinical research.
The Future of SOPs
Traditionally, SOPs are documented in unwieldy manuals; however, this need not be the case if resources permit the use of documentation applications to build a database of information. Most software systems will not only be able to support creation and maintenance of SOPs, but can manage organizational charts, instructions, and checklists in a centralized domain.
SOPs make it simpler for the research team to carry out trials in compliance with the standards set by regulatory authorities, sponsors, and institutions. The twin objectives of quality—data integrity and subject projection—can be met by a systematic approach to the conduct of clinical trial process.
Research relies on repeatable, reliable, accurate data; a breach or compromise in any of these facets can be disastrous to the research study. Compliance to quality requirements is the foundation of a scientifically valid and ethically sound clinical trial. The recent regulatory approaches of risk-based inspections and real-time oversight, combined with a specific focus on quality systems, demand continuous vigilance and continuous process improvement, from scientific and operational design to the conduct and monitoring of clinical trials.
- Gogtay N, et al. 2011. A study of warning letters issued to clinical investigators and institutional review boards by the United States Food and Drug Administration. Indian J Med Ethics 8(4):211– 4.
- U.S. Department of Health and Human Services. 1996. Guidance for Industry—E6 Good Clinical Practice: Consolidated Guidance. https://www.fda.gov/downloads/drugs/guidances/ucm073122.pdf
- Zon R, et al. 2008. American Society of Clinical Oncology Statement on Minimum Standards and Exemplary Attributes of Clinical Trial Sites. J Clin Oncol 26(15):2562–7.
- Bhatt A. 2011. Quality of clinical trials: a moving target. Persp Clin Res 2(4)124.
- Meeker-O’Connell A. Enhancing clinical trial quality: CDER perspective. (referenced in Bhatt A., above, at https://www.researchgate.net/publication/51856119_Quality_of_clinical_trials_A_moving_target/fulltext/57ebb0a008ae66664093116e/51856119_Quality_of_clinical_trials_A_moving_target.pdf)
- Kleppinger CF, Ball LK. 2010. Building quality in clinical trials with use of a quality systems approach. Clin Infec Dis 51(Supplement 1):S111–6.
- Niranjan SJ. 2016. Building an internal quality assurance program: from the ground up. Clin Res 30(6):52–3.
- Niranjan SJ, Saleh M. 2014. Lessons learned from audits past. Clin Res 28(4)54–8.
- Manghani K. 2011. Quality assurance: importance of systems and standard operating procedures. Persp Clin Res 2(1):34.
- U.S. Food and Drug Administration. 2009. Information Sheet Guidance for IRBs, Clinical Investigators, and Sponsors—FDA Inspections of Clinical Investigators. www.fda.gov/downloads/RegulatoryInformation/Guidances/UCM126553.pdf
- Amare G. 2012. Reviewing the values of a standard operating procedure. Ethiopian J Hlth Sci 22(3).
- Stup R. 2001. Standard Operating Procedures: A Writing Guide. Dairy Alliance, Penn State University.
- Zimmerman JF. 1999. The importance of standard operating procedures for investigators. SoCRA Source. www.readbag.com/impactcg-docs-socra-11-99-sops
- Sajdak R, Trembath L, Thomas KS. 2013. The importance of standard operating procedures in clinical trials. J Nuc Med Tech 41(3):231–3.
- Goldfarb NM. 2005. Something for everyone: standard operating procedure products for the investigative site. J Clin Res Best Pract Vol. 1, No. 4.
Soumya J. Niranjan, BPharm, MS, CCRP, (email@example.com) is a quality assurance manager with the University of Alabama at Birmingham’s Comprehensive Cancer Center.