Wednesday, April 06, 2005

SOP Writing for Clinical Trials: Staff Training Aspects

By: Akanksha Saxena ,

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Write down what you do, do what is written down! The European Clinical Trial Directive 2001/20/EC put the magnifying glass onto the suitability of investigators, their supporting staff, and the quality of facilities when conducting clinical trials across European Member States. With this, the directive also entailed the awareness and importance of the critical conditions in which clinical trials are conducted and managed at investigative sites. It is well known that there are big differences in standards of facilities, which vary in size, expertise, and organization.
Every good quality system is based on its Standard Operating Procedures (SOPs). SOPs are defined by ICH as “detailed, written instructions to achieve uniformity of the performance of a specific function.” SOPs are necessary for a clinical research organization – whether it concerns a pharmaceutical company, a sponsor, a contract research organization, an investigator site, an ethics Committee or any other party involved in clinical research – to achieve maximum safety and efficiency of the performed clinical research operations.
It is therefore a must that all people and sites involved in Clinical Studies (both at the sponsor and at the investigative sites) have appropriate SOPs in place in order to conduct clinical research and to assure compliance with the current regulations. The ICH GCP Step 5 Guideline (Section 3.2.2) also hints on IRB to have their own SOPs or written standard procedures .This itself proves that presence of SOPs are the integral part of the Clinical trial at all levels.
The presence of these quality documents is essential when inspections take place since the most frequent reported deficiencies during inspections are the lack of written SOPs and/or the failure to adhere to them. The risk of GCP non-compliance is high at organizations with a poor availability of clinical research specific SOPs and also if at all they are available the staff or the people for whom they were written are not either aware of them or their need.
It therefore becomes very important for the staff to train them on these SOPs so that they are actually aware of why and how SOPs can play important role in fulfilling the ICH and other regulatory requirements. This article will cover the importance and value of SOPs, as well as present an approach for the development and training of SOPs at staff levels


Performing clinical trials is a complicated business. It is bound by regulations and good clinical practice, with the overriding concern of protecting the safety and welfare of study subjects. Sites must follow each protocol exactly and meet other sponsor demands. One of the best ways to ensure that all these conditions are met is to formulate and follow standard operating procedures (SOPs). Standard operating procedures are just that: the “procedures” and processes that are used and “operate” under that have been “standardized” to ensure that we do them the same way each time. An SOP is nothing more than a clearly written description of how a particular task is to be performed. SOPs are critical tools in successful business operations for all those involved in doing clinical trials, including investigative sites, sponsors and IRBs. They are essential for standardizing processes, for ensuring that regulatory and organizational policy requirements are met, for training new personnel and for managing workload. Following pages shall cover the importance and value of SOPs, as well as present an approach for the development of SOPs at investigative sites.

The regulations do not require that investigative sites have SOPs. However, the regulations do state that “A sponsor shall select only investigators qualified by training and experience...” (21 CFR 312.53) and that “[The investigator] will ensure that all [staff] are informed about their obligations...” (21CFR312.53). What does this mean? It means that investigators must be qualified to do trials, as well as qualified in the disease area. It also means that investigators must ensure that all others assisting in trials are knowledgeable about the obligations and responsibilities. One of the best ways to ensure this is to have SOPs that cover clinical trial procedures and responsibilities.

SOPs have several purposes. They ensure that the site has consistent processes that meet or exceed regulatory and good clinical practice (GCP) standards and that all employees are familiar with the processes. They also ensure that processes are reviewed and updated on a regular basis. Having and adhering to good SOPs helps to ensure that audits by sponsors or by the FDA do not result in detrimental findings, and may also afford the site some legal protection.

Writing SOPs is not an easy process. It is very time-consuming and involves analysis of processes. However, it pays big dividends when complete.

There are many ways to approach the formulation of SOPs. It’s foremost important to train the staff with the various aspects of SOPs and to explain their importance within the Clinical Trial.

Definition and Importance of SOPs:

The ICH defines SOPs as ‘detailed ‘written instructions to achieve uniformity of the performance of a specific function’. Consistency and control are fundamental components of a clinical research protocol; they also are necessary for any organization, institution, company to achieve maximum effectiveness of its clinical research operations.
SOPs help to ensure this consistency and control.

A clinical research organization – whether a sponsor, CRO, site management organization (SMO), institutional review board (IRB) - that has well written, comprehensive and practical clinical research specific SOPs, is an organization that has distinct advantage over those that do not.

The advantage is that writing SOPs prompts an organization to take the critical step of interpreting and applying GCP regulations and guidelines to its unique clinical research operations. SOPs ensure consistency, compliance and accountability of personnel all levels of clinical research. Organizations without clinical research specific – SOPs run a high risk of GCP non-compliance and poor productivity.

SOP and Training:

In addition to the aforementioned GCP regulations and guidelines, development of a GCP training program should include review of the organization’s current clinical research SOPs. Because SOPs include who, what, where, how and why of clinical research operations, it is important for the trainer to become familiar with the SOPs and integrate them into the training program.

When a trainer applies and explains GCP regulations and guidelines with the examples of the organization’s clinical research specific SOPs, it ensures a more practical and meaningful interpretation of GCP documents and enhances learning. It also demonstrates that the organization is committed to implementing its clinical research SOPs and not have them languish on a shelf and go unused.

Objective of SOPs:

The sponsor, Investigator and all the Clinical Trial’s staff should be very clear on the objectives of the SOPs while writing them .They can be broadly described as objectives / performance goals
· Define the FDA’ s expectations and ICH principles regarding content and format of SOPs
· Understand why SOPs are needed, who uses them and how they are used
· Determine SOP needs and assign local responsibility for management and review
· Distinguish between SOPs, guidelines, policy statements, and work instructions and learn how each may work for area of responsibility
· Implement appropriate SOP training programs
· Integrate SOPs into a comprehensive document management system
· Implement change control systems and improve management of SOPs
· Understand the role of Quality Assurance in SOP systems.

Production of SOPs:

The primary purpose of the SOPs is to guide and standardize working procedures in order to ensure data reliability and integrity. It is therefore crucial that staff read and follow the SOPs. If this is not the case, not only will the SOPs fail in fulfilling their goal but will also lull staff and management into sense of false security. Often the failure of an SOP or a collection of SOPs originates from the technical shortcomings of the SOPs and the following depressing list shows why staff might resist using SOPs-

· The required SOP is difficult to locate in the total collection of SOPs
· The SOP is written in foreign language
· The SOP is written in language difficult to follow
· Instructions and general information are mixed
· The procedure is described in an unfamiliar way
· The user knows another (better) method, or can do the procedure in ‘his sleep’.

What should SOP cover?

The number of SOPs the arrangement of material in SOPs and the level of detail in the SOPs depend upon entirely on the organization and its related role in the Clinical Trial. e.g., the SOPs at the sponsor’s site will be different than those at the Trial Site. It depends upon the requirement and role of the staff members executing their work.
Following can be considered the brief outline which in general all the SOPs must cover-
· A descriptive title and indication of the SOP’s position in the total collection.
· Date when the SOP became operative
· The edition number and a statement that this edition replaces an earlier edition from an earlier date
· The exact distribution of SOPs
· The signature of the person responsible for writing the SOP
· The signature of the person responsible for authorising the SOP
· In some contexts the purpose of the SOP

The title should contain sufficient information about the SOP’s contents and be placed prominently on the page, to allow the user to identify and find it easily.

The distribution list directs the SOP to the place where it will be used. It should be distributed at all the related places of its function. A strict check should be kept for the numbers of SOPs issued and distributed at each working area.

The signature of the person responsible for writing the SOP shows that the SOP is complete and correct, Should an auditor or for matter any one else have a query about the content of SOP, this would be the person in contact. The signature of the person responsible for authorizing the SOP also shows that the SOP is operative.

Who writes SOPs?

The SOP must convey a clear instruction. Not only must the user understand the instruction, the must also be prepared to carry it out. The logical step is to let the user, as far as possible, write the SOP, in collaboration with the Trial Manager / Investigator or Clinical Research Associate.

The user-author practice prevents the working procedure appearing unfamiliar or awkward in the SOP, it is unlikely that the user would resist using it on the grounds that ‘he could do his job in his sleep’-even if this were the case. It is much likely that the user –author practice will result in an improved sense of responsibility for the obligation to use and comply with the SOP.
SOP’s Eight Fold Steps:

Step 1 - Mapping SOPs
Process mapping is a procedure of laying out all the steps in a currently used process and analyzing the process with the goal of making it more efficient and easier to follow. It involves taking each step in the process and “mapping” it into a process chart. All the people who are involved in doing the task should be involved in mapping it into a process chart, and there should be free and open discussion. It is often discovered during this process that all involved people do not do things the same way and have very different ideas about how the current process works and how it should be done in the future.
The SOPs cover all aspects of a clinical trial, including:
protocol preparation
ethical approval
assessing and monitoring trial sites
safety data reporting
checking data integrity
clinical report writing
database preparation
validating computer systems.
This is the computer age and therefore all the records are generally created electronically. SOPs are no exception and are therefore treated as electronic records. Therefore, it’s important to create them according to the Guidelines by FDA or other applicable regulatory Body. FDA’s Draft Guideline - ‘Computerized System used in Clinical Trials’ recommends following SOPs on site
· System Setup/Installation
· Data Collection and Handling
· System Maintenance
· Data Backup, Recovery, and Contingency Plans
· Security
· Change Control
· Alternative Recording Methods (in the case of system unavailability)

SOPs do not have to “fit into a box”. Formats can vary. Presentation techniques such as flow charts, diagrams, narratives, tables and bulleted lists should be considered in addition to the traditional text and paragraph formats. Presentation might vary, and should address conditions pertinent to the individual environment. Procedures should be presented in a format that will work for the institution and address specific needs in various ways. The goal is to have an easily understood procedure that the Clinical Research Staff will clearly understand and utilize.

Step 2 - Use of Language and Scripting the SOP
The SOP must be written in the language which is understandable by the staff or people dealing with it. If for regulatory purposes or for the foreign auditors the language of SOP has to be in a foreign language, an authorized translation of the SOP in the local language which is understandable by its users must be readily available at the working area.

Authorities, clients and colleagues must be prepared to accept translations; however after all, they are not the primary target of the SOPs.

The SOP must communicate their message effectively. They must be crystal clear on who is to do what. This almost seems too obvious to write, but many SOPs are difficult to read. The rule of thumb for writing instructions in SOPs is these-
· Use short active sentences
· Use simple words and terms where possible
· Write the sentences as instructions:’ do this, do that’
· Write the instructions in the right order, so the operator knows when to do the appropriate task
· Separate the instructions from general information ,either typographically or by putting the general information in a foot note
· Limit the amount of information per page-maximum ten different actions
· Use diagrams wherever appropriate
· Give sources and references at the end

Step 3 - Editorial Responsibilities of SOPs
It is possible for each department or section to write, authorize and produce SOP’s in isolation. For the company or the sponsor, however, it is advantageous to give someone editorial responsibilities.

Management decides whether or not to edit the SOP’s. Suitable editors might be an interdepartmental GCP committee or some of the QAU (Quality Assurance Unit) personnel.
Their duties would include checking a new SOP for-
Style and format
The edition number
Consistency of content in context with relevant SOPs from other departments
Compliance with policy, ICH GCP and other regulatory requirements

Step 4 - Authorizing the SOPs
No SOP is a SOP without its proper authorization. The purpose of the authorization is to decide on an appropriate method for a given procedure, standardize the performance of the procedure and communicate these decisions to everyone involved. The most effective authorization is done by someone with organizational influence, specialist insight and knowledge of ICH GCP.

The rational approach is to let management, in its policy, mandate the use and production of SOPs. In the same policy it can delegate the responsibility for authorization to the person in charge of each specialist area. These people are defined as ‘management ’in this special context. Departmental SOPs then specify which named individuals are empowered to authorize SOP’s in their area.

Step 5 - Distributing and Archiving the SOPs
Each department or for that matter section (e .g sponsor ’site or Trial site) administers its own collection of SOPs and must identify (by the management) who is responsible for their distribution and withdrawal.

Responsibility for typing and copying of SOPs will depend on capacity in the different departments. When the requisite number of SOPs have been produced, before distribution, they should be stamped ‘DO NOT COPY’ and ‘CONTROLLED COPY’ with coloured stamp, or some other technique to distinguish between the original from photocopied versions. The original SOP should be kept by the QAU or a responsible management representative in a secure place.

The historical or expired SOPs whose new versions have been issued should be properly archived with ‘ARCHIVED’ stamp on the original SOP. They should be kept in a designated place with controlled entry called ‘Archives’. These SOPs can be retrieved from the ‘Archives’ for the purpose of reference or audit whenever required with a proper documentation and the SOPs should be re-archived after the job is finished. A management designated person called ‘Archivist’ should be responsible for managing the archives.

All the photocopies of expired SOP must be destroyed immediately after its new version comes in effect. This is to reduce the confusion for the staff in working by existence of two different methods floating simultaneously.

Step 6 - Training of the SOPs
Training on SOPs is often the last thing that people think about once the SOP is written. When the SOP goes into effect there is often a great sense of relief. However, it is frequently the case that staff does not receive adequate training on the SOPs. The purpose of the SOPs thus, remains unfulfilled.

The QAU/ Monitors / Clinical Research Managers and the management should see to it that there is continuous training of SOPs among the staff. The trainings should be documented properly and all records in form of training log must be maintained in the staff training record. Generally, the effective date for a SOP must be two to three days after it is authorized. This is to give sufficient time for staff to read and understand the SOP before it is actually implemented in the system. The effective date should be clearly specified on the SOP so that the staff is aware of it. Also staff training on FDA’s 21 CFR Part 11 and related guidelines on electronic records should be undertaken.

Formal and continuous training sessions should be taken by the QAU, Clinical Research Associate and Clinical Research Managers. Thus would increase the SOP awareness among the staff and also the continuous review will help in amending the SOP, if required.

Step 7 - Alterations in SOPs
When a mistake in an SOP is found, it is tempting to alter the text by hand. It is especially tempting when the SOP is newly issued or if the change is only in the distribution list. Such alterations are dangerous as no one knows whether the comments appear in all SOPs of that edition, how long they have existed there, whether anyone has modified their working routine as a result, or whether data has been compromised .The detection of such actions must prompt inquiry, and if alteration is necessary, the SOP will need updating.

In case of electronic SOPs, there must be a secured system of change control and rights to modify SOPs should be properly reflected in audit trail.

The procedure of updating a SOP must reflect in the appropriate SOP both electronically and manually (if practiced).

Step 8 - Reviews of SOPs
Standard Operating Procedures should be regularly reviewed and updated to ensure that they encourage efficient working practices that comply with the ever increasing requirements, improvements and government regulatory framework that have to operate within.

It is prudent for the management to introduce a scheme for automatic review of SOPs. This date of next review should be reflected on the SOP itself so that everybody is aware of the next review date for the SOP and are ready with their suggestions and improvements.

If no changes are necessary this decision should be recorded but still the version number of the SOP should be changed to reflect that review did happen.

The Use of SOPs:

Deviations from SOP
A deviation from SOP is a procedure that does not comply with the written instructions and where the non compliance is not described in the study protocol.

They can be both planned and unplanned and must be recorded as ‘SOP Deviations’. These deviations must be authorized by the Investigator or the Trial Manager at the sponsor’s side.
The Monitors, QAU are responsible for assuring management that working procedures comply with the SOPs and for reporting deviations.

The staff should know that the deviations always occur during the course of trial. Deviations show that the work was done and problem was solved but it is very important to get them documented and authorized. While deviations sometimes occur due to inattention, tiredness, pressure of work, sometimes the SOP itself is at fault .Perhaps the user has found a much superior way of doing the job. If the cause of deviation lies in the SOP, it is time for the SOP to be updated, since continued deviation is unacceptable.

Quality Assurance of the SOPs
Before any Inspection or audit starts, it is customary for the Inspector or the Auditor to read the current SOP’s for the relevant Trial. This is to judge the compliance of SOPs and the how sincerely they are used in the trial related activities and thereby following ICH GCP and other applicable regulatory guidelines.

During Inspection the Inspectors generally ascertain-
· Appropriate SOPs are available
· Edition numbers are correct and all obsolete editions have been withdrawn from circulation
· Distribution lists are still correct
· SOPs are effective, not leaving parts of the working procedures uncontrolled
· In case of transfer of Trial medication, CRFs, documents etc from one area to other, the SOPs follow the process the whole way and are consistent with SOPs in next area.
· Does the SOP convey a process that is effective in achieving compliance with requirements/standards?
· Is the process that is described in the SOP an efficient way of performing the task?
· Can the requirements of the SOP be enforced?
Audit trails or other appropriate security measures are needed to ensure electronic record integrity, it is recommended that personnel who create, modify, or delete electronic records (which also happen to be SOPs) not be able to modify the documents or security measures used to track electronic record changes. It is recommended in FDA Guideline that audit trials or other security methods should be used to capture electronic record activities document, who made the changes, when, and why changes were made to the electronic record. (Refer FDA’s Draft Guidance for Industry Computerized Systems Used in Clinical Trials)
The following are the danger signs-
· Unauthorized copies in use
· Unauthorized SOPs or drafts in use
· Sections of unauthorized copies, separated from edition number displayed on the notice board for easy reference.
· Unauthorized alterations written on the SOP
· Deviations.
· No or incomplete SOP training records for the staff

A file of all SOPs used throughout the study must be available. This may include archived SOPs if the inspection is conducted after the study is closed. Ensure all staff is familiar with their content and that relevant training has been provided and documented in the staff training records.

The Inspectors or auditors take a note of such findings and try to find out whether they affect a deeper failure, perhaps in training, understanding of the purpose of SOPs, management commitment, or a quite different cause. Then the findings can be used to optimize the SOPs effectiveness.

The limitations of the SOPs
GCP presents the tidy view of the world in which the implementation of a set of SOPs, combined with meticulous Monitors and Auditors attention to compliance will inevitably lead to set of reliable data. Unfortunately this comforting notion is a truth with many modifications. While SOPs are a powerful tool for controlling activities and assuring data reliability, like any other tools, they function best in the right hands; in untrained hand with malicious intent they can be dangerous. They do not replace trainings and the opportunity of dialogue.

Unexpected Interpretations
The first edition of any SOP usually contains ambiguous sections which seemed clear at the moment of writing but which produce unpredictable ways of working in the trial. The second edition usually replaces the first promptly, and the work is on the track. However the cleverest author will never be able to imagine the failures that even a good SOP cannot prevent.

Here is a real life incidence to prove this.

The SOP required the noting of exact time of dosing to the patient on the CRF (Case Record Forms).The nurse noted the time accurate to the minute required, having consulted an elegant watch whose face bore a golden disc for 12, and nothing more. The Monitor who was present queried the use of watch, to which the nurse replied (rightly) that it was more precise than the inferior digital contraption. The SOP did not specify what sort of watch to use, and the difficulty had to be resolved by recourse in other section in the guidelines, since the Monitor could not demonstrate non compliance.

Aspects not covered by SOPs
Controversies sometimes arise when Investigator considers a given procedure, such as procedure for physical examination of healthy volunteers too trivial to deserve an SOP. The justification for this point of view is that it is fair to assume a certain level of proficiency from a qualified Medico’s previous professional training and use this assumption to check the proliferation of SOP. However it is hard to draw a line between trivial and non–trivial operations. If there is no SOP, the Inspectors and Monitors cannot inspect the procedure for compliance.

The above SOP is not written because the Doctors considered the skill integral to the qualifications of anybody qualified to work in that area. Such an SOP would only add clutter without contributing to data quality. However, if such a process did go out of control, it would have to be formalized in an SOP.

Good SOPs are necessary-but not sufficient –for the production of quality data. Not only are the SOPs asset to the Trial and Sponsor, they also bring other advantages, such as the opportunity to clarify working routines an areas of responsibilities. A collection of good SOPs signals to outside world management’s commitment to GCP and production of quality and reliable documentation.

The SOPs are only useful if their user i.e. the staff involved in the Clinical Trial read understand and follow them. If the user is also authors, this purpose is usually fulfilled.
It’s very important to train the personnel involved in the Clinical Trial on SOP writing and its various important aspects for a successful and quality study.

· ICH Topic E6 Guidelines for Clinical Trial Step 5
· FDA’s Draft Guidance for Industry Computerized Systems Used in Clinical Trials
· OECD (1982) Principals of GLP
· Day, Ray How to Write and Publish a Scientific Paper(Philadelphia: ISI Press)
· Carson and Dent(1990), Good Laboratory and Clinical Practices(Pg67-82)
· Janet F. Zimmerman, Integrating Standard Operating Procedures into GCP Training