Standard Operating Procedures in the Regulatory Framework
In the regulatory framework, following standard operating procedures (SOPs) can serve two chief purposes, i.e., compliance with regulatory guidelines and generating quality outputs from a big-budgeted clinical trial. However, negligence in following these SOPs can lead to fallbacks during FDA inspections. It has been observed from a cross-sectional analysis that the FDA inspections found significant evidence for problems with adverse events reporting, failure to follow the investigational plan, inadequate or inaccurate recordkeeping, failure to protect the safety, rights, and welfare of patients, or issues with informed consent.1 All these problems could have been avoided if the SOPs were followed.
A well-experienced Project Manager of a clinical trial will know the value of following SOPs in the regulatory framework. Therefore, we present all the critical information related to SOPs in this blog that you can implement during clinical trial conduct.
Importance of SOPs in Regulatory Framework
Standard operating procedures are utilized at every stage before, during, and after clinical trial conduct. The primary importance of SOPs in the regulatory framework is that SOPs provide a mode of compliance with various regulatory guidelines. Some of the below given regulatory guidelines clearly state the use of standards in clinical activities:
Good laboratory practices (GLP)
One of the GLP principles states that “the test facility should ensure that appropriate and technically valid SOPs are established and followed, and approve all original and revised SOPs.”2 Therefore, as the nonclinical laboratory studies are executed to support research as well as marketing approval of products from the FDA, these studies have to be conducted in compliance with GLP (as per 21 CFR Part 58),3 these should be executed based on valid SOPs.
Good manufacturing practices (GMP)
One of the GMP principles states that “SOPs and corresponding records, where required, should be available. These include equipment assembly and cleaning, personnel training, clothing and hygiene, maintenance, sampling, analytical apparatus and instrument calibration, testing, rejection, and pest control.” Additionally, “SOPs should be reviewed periodically and kept up to date.”4 Therefore, as the FDA enforces the current GMP regulations to confirm pharmaceutical quality,5 the manufacturing of investigational products used in phase 2 and phase 3 clinical trials (for human and animal) are recommended to be in compliance with the SOPs
Good Clinical Practice (GCP)
One of the GCP principles states that “systems with procedures that assure the quality of every aspect of the trial should be implemented.” According to the ICH E6(R1) guideline (which is based on GCP principles):
- The sponsor is responsible for implementing and maintaining quality assurance and quality control systems with written SOPs to ensure that trials are conducted and data are generated, documented (recorded), and reported in compliance with the protocol, GCP, and the applicable regulatory requirement(s).
When using electronic trial data handling and/or remote electronic trial data systems, the sponsor should maintain SOPs for using these systems.
- The monitor(s) should follow the sponsor’s established written SOPs as well as those procedures that are specified by the sponsor for monitoring a specific trial.
Code of Federal Regulations (CFR)
Some parts of Title 21 of the CFR describe the requirements of SOPs in regulatory processes. These include:
- 21 CFR Part 211
- 21 CFR Part 606
- 21 CFR Part 610
- 21 CFR Part 630
Besides the primary importance, SOPs help to provide consistent workflow at the clinical trial site. As every staff member follows the standard process defined in the SOP, a consistent workflow is certain. It also helps to generate consistent data from different studies conducted under the same sponsor’s roof.
Key Requirements in Regulatory SOPs
As per the ICH E6(R1) guideline, “The SOPs should cover system setup, installation, and use. The SOPs should describe system validation and functionality testing, data collection and handling, system maintenance, system security measures, change control, data backup, recovery, contingency planning, and decommissioning. The responsibilities of the sponsor, investigator, and other parties with respect to the use of these computerized systems should be clear, and the users should be provided with training in their use.”6
Considering the above guideline, an SOP should have detailed information about who will execute a specific process, how this process will be executed, and when this process will be executed for each clinical trial activity.
The U.S. Environmental Protection Agency (EPA) provided a very clear guidance document for preparing SOPs.7 Concisely written, step-by-step, and easy-to-read SOPs are more understandable by users. The information presented should not be overly complicated.
Implementing SOPs in the Regulatory Framework
Implementation of SOPs in clinical study activities is a crucial step. The errors found during the FDA inspections are mostly due to non-compliance with SOPs. Therefore, a strong system that keeps an eye on the implementation of SOPs is a necessity. Below are steps that can be followed to implement SOPs:
- Training: It is crucial to provide training to the clinical study personnel related to their respective responsibilities. This training is conducted before the distribution and implementation of SOPs. This training via SOPs serves two purposes: training the personnel for their responsibilities and live testing of the effectiveness of an SOP so that remedial actions can be taken, if any. Additionally, training records can be kept either in the SOP file or a personnel training file.8
- Implementation: SOPs should be available at the site where used. The master copy of an SOP can be retained with the quality manager or principal investigator and a controlled copy can be displayed.
Quality Control and Review Processes for Regulatory SOPs
To keep the SOPs updated, a review process is required. It is a systematic way of evaluating and revising SOPs on a regular basis. It involves checking SOPs for accuracy, clarity, completeness, and alignment with the latest regulatory processes.
For doing so, review criteria need to be defined first. This criteria can include steps that will be used to assess the relevance, accuracy, clarity, completeness, and compliance of SOPs with regulatory processes. During the review of SOPs, self-review, peer-review, or audits can be planned.
- Self-reviews involve the SOP owner or study sponsor/representative reviewing the SOP and noting any issues or areas for improvement.
Peer-reviews involve a subject matter expert providing feedback and suggestions.
- Audits involve an internal inspection or verification of the SOP and its implementation.
This review process is documented (date of review, reviewer, steps involved, feedback, and actions taken) along with the documentation involving updates in the SOP after review (updating SOP date,number, and version, updating reviewed procedure, and updating signature for approval of changes). The updated SOP comes into action and is archived simultaneously according to the sponsor’s retention and disposal policies.
Standard operating procedures are valuable documents in the regulatory framework. Conducting each process that is related to the approval of drugs for human use in compliance with SOPs can generate quality data. This data can ultimately help the regulatory authorities make fair decisions for the approval of drugs. Therefore, the preparation, implementation, management, review, and updating SOPs should be given more significance than ever.
Seife C. Research misconduct identified by the US Food and Drug Administration: out of sight, out of mind, out of the peer-reviewed literature. JAMA internal medicine. 2015 Apr 1;175(4):567-77.
Organisation for Economic Co-operation and Development (OECD). OECD Series on Principles of Good Laboratory Practice and Compliance Monitoring. Number 1. OECD Principles on Good Laboratory Practice (as revised in 1998) No. ENV/MC/CHEM (98) 17
International council for harmonisation of technical requirements for pharmaceuticals for human use (ICH). Integrated Addendum To ICH E6(R1): Guideline For Good Clinical Practice E6(R2). Updated on 09/11/2016.
Barbé B, Verdonck K, Mukendi D, Lejon V, Lilo Kalo JR, Alirol E, Gillet P, Horié N, Ravinetto R, Bottieau E, Yansouni C. The art of writing and implementing standard operating procedures (SOPs) for laboratories in low-resource settings: review of guidelines and best practices. PLoS neglected tropical diseases. 2016 Nov 3;10(11):e0005053.