Arthur Hecht

This article aims to define guiding principles and to establish a framework to set up an ideal standard operating procedure (SOP) system. Only a few articles dealing with what constitutes ideal SOPs have been published.

 Rather than examining a few SOPs in a certain area or just the documents that carry such titles, it may be advantageous to take the entirety of all documents that describe relevant processes and call this an “SOP system.” SOPs are not usually standalone documents, but they are linked to each other and to other systems, such as policies, handbooks, guidance papers, or instruction documents. The definition of those items unfortunately varies and are used by different companies or institutions in different ways. In some cases, policies are above SOPs in hierarchy, which, in turn, are above guidance documents and, lastly, instruction papers. Common to all is a hierarchical structure of governing and dependent documents. An SOP system is described as the entirety of all above-mentioned documents that include the processes to generate and alter, distribute, train, implement, and maintain them. One publicly available example is The European Medicines Agency’s Integrated Quality Management System, which consists of six hierarchical levels, starting with the quality policy and the mission statement on level 1 down to “documents resulting from the process and needing to be controlled and stored in accordance with relevant agency policies and SOPs.”

 conducted by a subgroup of the German Association of Research–Based Pharmaceutical Manufacturers (Verband Forschender Arzneimittelhersteller, vfa) has shown that in the pharmaceutical environment, the number of SOPs and related documents is increasing. There is no indication that the objectives, such as quality or efficiency of underlying processes, are achieved or improved this way. Also, there is a large variety both in size and structure of the SOP system across companies. The survey revealed that there are major deviations between what the SOPs describe and how processes are implemented in real life. Several hypotheses/questions should therefore be explored:

		Is there a lack of knowledge due to the large amount of SOPs that are produced and changed frequently?

		Is there a lack of discipline to adhere to SOPs?

		Are the SOPs simply inadequate, leading to the need for deviations?

		Are deviations tolerated actions to avoid major problems in these situations?

		Are SOPs too complicated to allow timely reactions to problem, thus procedural shortcuts are implemented?

		Are decisions not taken, although the process to arrive at them has been described in the SOP?

		Does management not care about supervising the execution and adherence of SOPs?

	Within this survey, we learned that an ideal SOP system does not exist. Ways of thinking, expectations, and need for guidance differ considerably between functions. 

Experienced people require broader margins for individual decisions while those with limited experience ask for more and stricter guidance.

	The survey consisted of two sets of questions, one of which was directed to the management of clinical research, the other to the operations staff conducting the clinical trials (see charts at left and below; click on each to enlarge). In summary, the answers showed that this survey is a good starting point to generate ideas on how an ideal SOP system could look.

	While we shall briefly discuss the characteristics of

 ideal processes, the focus will be on the ideal SOP system-which requires that the individual processes are efficient by themselves. Regarding optimality, the requirements were, in summary, as follows ahead. It should be considered that there was a wide range of opinions, and this summary simply constitutes their majority. Our ideas on how to create an “ideal” SOP system are also vindicated by the results of the survey. The SOP system should cover all regulated processes, but only in a degree that allows optimization of processes easily.

	The definition of ideal processes is taken from business process excellence (e.g. ASQ

). There, an ideal business process is seen both from the outcome and the necessary inputs.

	Efficiency is defined as the optimal ratio of input vs. output. SOPs should reach their aim without the need to consume many resources. In fact, they should, through standardization, lead to fewer resources being consumed when achieving the same level of quality. Such questions could be answered by benchmarking with other organizations, or by consensus processes. It will be difficult in practice to find the minimum level of effort needed to achieve the necessary quality. In site monitoring, thresholds can be given; however, to transform this into an SOP is difficult, as there may be several different routes to arrive at this goal, and not all of them can be described in detail. Effort must be taken to measure efficiency in a reliable way in order to follow up on progress.

	However, other criteria such as simplicity and adaptability have also been quoted. The following paragraph attempts, on the basis of experience, to develop a set of guiding principles. These will not be hierarchically ordered, however, some may carry more weight than others depending on the circumstances.

	SOPs should only be defined where necessary. If they focus on rare situations, or situations which are not important for the quality of the study, they remain useless. Such situations should be managed depending on the circumstances of the individual case.

		How often is it executed? Does it bear a significant risk?

		What would happen without regulated process?

	An analysis should be performed as to which processes need detailed description and standardization for legal or regulatory reasons, which guides risks that need to be managed and to what degree, and whether SOPs are an adequate tool to do so. In some instances, the risks are minimal in comparison to the effort needed to avoid them.

	Such a risk analysis describes the magnitude of risk, its probability of occurring, and the risk reduction through SOPs (and other measures) in two key dimensions: patient safety and data integrity.

	In practice, the identification of processes without a need for an SOP is challenging. This is also reflected in the results of the survey that showed that “the vast majority was unable to identify SOPs that could be done without.” In consequence, the focus should be on how detailed a process must be covered by an SOP and/or which process steps can be eliminated in order to achieve the needs of the different users/user groups.

	Does this regulated process do what it is intended to do? This may also be called functional reliability or effectiveness. SOPs should be written in such a way that the objective of the underlying process is supported. One needs to avoid formal hurdles that hinder the objectives of the process being reached. One example is the reporting of serious adverse events (SAEs), where the need to report is more than obvious and the SOP, including any templates/forms, needs to provide an easy way as to how to best support the reporting. Every element, the SOP itself, the forms and the templates, needs to support a smooth reporting process and should not add problems to it.

	Effective SOPs describe the processes in a way that their efficiency is not impaired by lack of clarity or understanding, and that they achieve the deliverables with a minimum of effort. Implementation of a new SOP, or SOP revisions should follow a pragmatic approach. If the need is there, implementation is more accepted by the users.

Simplification, transparency, and ease of acquiring

	KISS-“keep it short and simple.” An SOP should describe the standard situation of a process. Therefore, special rules and exceptions should be avoided. SOPs need not consider all imaginable situations. SOPs and associated workflows should be kept as simple as possible. As a rule, an employee should be able to easily memorize the relevant processes. Critical processes such as safety reporting should be easily available for everybody and everywhere. For less important processes or areas, an overview should be easily accessible for staff on where to find the respective SOPs. To support easy access a logical and easy to remember numbering system can be of great help.

	As an example, the EMA groups together documents according to their scope,

		1000-1999 PDM (Product data management)

	“Less is more.” Changes to SOPs should only be made for two reasons: if legal or regulatory changes mandate it or if major process improvements can be gained. Therefore, it may help to avoid detailed information, which are not process relevant but subject to frequent changes, for example, version numbers of supporting documents. In addition, highly variable elements, such as templates, may be attached to an SOP to be adapted without changing the SOP itself.

	A regular review cycle of the SOPs (we suggest two to three years) should be established in order to evaluate whether modifications of processes or changes in the organization have taken place and are not covered by the SOPs.

	As almost all registration studies are multinational, SOPs need to be globally usable. Therefore, global SOPs should describe all globally defined processes to ensure harmonization and efficiency across the whole organization. However, regional or local amendments to global SOPs need to be possible but should only be introduced if required by regional/local law/regulations or organizational structures of affiliates.

	There is an ongoing misconception that the size of SOPs is critical for the acceptance of the user. As we learned from the survey, more important than the size of an SOP or SOP system is how to navigate within and how the connections between them can be highlighted. This may explain why the satisfaction with the SOP system is not associated to its size.

	Simplification of SOP systems often aims to reduce the number of SOPs based on the misbelief that the number is an important indicator of the quality and usability of the system. Respective activities are merging several SOPs into one document, renaming of SOPs to, e.g., working instructions, best practice documents, functional guidelines, and monitoring manuals. This is not the way to handle the problem, as the results of the survey pointed out that the number of SOPs does not matter at all.

	There is a strong tendency to have, e.g., best practice documents outside of the official SOP system. This is born out of the misbelief that these documents are not in the scope of audits and/or inspections. According to ICH GCP, chapter 1.29,7 the inspector can review every document deemed relevant.

	SOP improvement projects almost always build on an existing system. They are adding further requirements and restrictions to already overregulated processes, with the aim of coming as close as possible to a perfect solution. Very often the current system is not questioned and, therefore, complexity is increased, slowing down changes, e.g., prolonged update cycles. PARETO rule (80:20)

	It is a misconception that distributing SOPs to a broader audience allows them to understand the big picture. This leads to an information overload, which can lead to frustration and resistance. The risk may be that relevant items are diluted by the vast amount of information.

	The assumption that following the SOP ensures quality in itself is dangerous. The processes described in the SOPs need to be transferred into the individual daily business activities. It still requires lateral thinking and does not replace interactions and communications in specific situations.

	The assumption that the SOP describes the perfect solution is misleading. The aim of an SOP is to provide a reliable, robust, and standardized way of reaching a defined outcome. “All roads lead to Rome.”

 There are always several potential routes to getting a result. The SOP defines one route for which we know how to manage hurdles and challenges.

	To ensure commitment and acceptance of SOPs, often all concerned line managers are included in the sign-off of the SOP during the release cycle. This is based on the assumption that signing an SOP increases acceptance and commitment of the user. Finally, it prolongs the release cycle and slows down the update of SOPs. Thus, the number of signatures should be minimized. Nevertheless, process modifications always have to be aligned with the relevant functions.

	Writing an SOP is challenging and requires deep insight into how to analyze processes and how to describe and visualize them. The SOP system in its entirety should appear in a harmonized and standardized format. Preferably an SOP writer is recommended, who acts as moderator and even as change manager during the SOP generation process.

	An SOP should follow the logical flow of a process and describe the associated roles and responsibilities. Flow chart(s) could be of added value to provide an easy and quick overview. This can be implemented using business process modeling software tools, which can help identify shortcomings in the underlying process.

	Any process step should have one responsible role that performs the activity. Further contributors can be visualized using a RACI matrix (R=responsible, this function does the actual work, A=accountable, this function supervises and decides; C=to be consulted; I=to be informed).

	If further governing or dependent documents are associated with SOPs, e.g., forms, templates, standard letters, related SOPs, checklists, or literature references, they need to be clearly referenced. Interfaces to other SOPs should also be mentioned. The interfaces may transgress the boundaries of a department, and may, therefore, have to be aligned with processes in other departments. Preferably a process should be described in one SOP only (end to end). If hyperlinks are used, the selection of the current version should be ensured to avoid outdated links. In addition, the SOP must contain transition rules, and version change details.

	SOPs should be written by specialized/professional SOP writers who interview the process owners to translate the steps into a well-arranged process flow. Clarity, simplicity, and intuitive logic should guide them.

	As alternative, specialized SOP facilitators (i.e., experts who support the subject matter experts) can be used when the process owners try to write the SOPs as they do it. In any case, the overall responsibility for the appropriateness of the business processes resides with the operating functions.

Articles

A "can’t live with them, can’t live without them" attitude is revealed in survey of standard operating procedures in the management and conduct of clinical trials.

An Ideal SOP System

 unanimously request effective and efficient quality management systems (QMS). However, 

 demonstrate the need for continuous improvement.

	Therefore, development of a strategic organizational structure focusing on the subject of quality management has become a top priority in many pharmaceutical companies. Since clinical quality assurance (CQA) plays an integral role within the QMS, this makes it all the more important that up-to-date benchmarking information on CQA systems is evaluated.

 provided an overview of CQA best practices within the pharmaceutical industry 10 years ago. A recently conducted comprehensive literature review did not reveal relevant updates on the subject. Therefore, a follow-up benchmarking survey was conducted to assess current practices. The survey among global pharmaceutical companies of different sizes focused on the organization, resources, strategies, and activities of CQA.

	In this article, we critically review the changes over the past 10 years and provide recommendations on how to shape the future.

	Benchmarking information regarding organizational structure, capacities, and strategies is difficult to obtain in a highly competitive environment. In 2004, we managed to receive information from 19 global companies. In our current survey, we received feedback from 12 global pharma companies, which also reflects mergers that took place in the past 10 years.

	Organizational structures of the participating companies differ substantially. Compared to the results in 2004, there is a shift of CQA reporting to a higher management level. Also, the current results are showing no instances where CQA reports into the clinical development team. This finding perfectly reflects the necessity of independent CQA units in the spirit of 

 (refer to section 2.13, 5.1, and 5.19). This is also in alignment with guidelines such as 

Guideline on Good Pharmacovigilance Practices (GVP) – Module IV

 where a harmonized and independent “quality unit” is requested.

	Ten years ago, the results showed a clear relationship between R&D budget and CQA capacity. This reflected the obvious relationship between R&D activities and the required quality management (QM) support. We did not find this relationship replicated in the present results. Whereas, in 2004 most elements of QM support were provided by centralized CQA, today this is much more heterogeneous. In some companies, quality and compliance functions are implemented in a decentralized model within business units with less increase of CQA staff. In addition, the much higher level of outsourcing of clinical research activities, either including QM support (fully outsourced models) or keeping QM support in-house, contribute to the heterogeneity seen in the current survey.

	In 2004, CQA capacity was spent relatively homogenously; besides the core activity of auditing (~70%) consultancy, SOPs, and training accounted for about 5% to 10% each. Today, auditing, including audit conduct and management of contracted audits, still reflects the highest share of CQA capacity, but has decreased to about 50%. Whereas, capacity spent for consultancy and training remained the same, it increased from about 5% to 10% for SOP management.

	Today, CQA departments take over a broader variety of tasks. In particular, inspection management; non-compliance investigations, including root cause analysis; and involvement in process improvement projects are now typical activities of CQA and account for 5% to 10% each. This matches the decrease of capacity spent for auditing. Another new activity is vendor oversight other than audits (e.g., vendor selection) by CQA, which is performed by more than half of the pharmaceutical companies surveyed.

Figure 1: Distribution of CQA activities in 2014 displayed by minimum and maximum values, upper and lower quartile, and median (%). Count [n] reflects the number of companies (total n =12) performing a certain activity.

	The CQA of one company performs quality control for other departments. In the view of the authors, this is not in line with the independence of CQA and furthermore undermines the accountability of the individual departments in regards to Quality Control steps.

	Outsourcing of certain tasks is very common in pharmaceutical companies. The number of organizations outsourcing CQA activities increased from 63% in 2004 to 75% in 2014.

	Investigator site audits are outsourced most frequently. The in-house capacity necessary for handling and supervising outsourced audits is still about 30%. The outsourced audit activities are budgeted for by CQA in about 75% of the companies. All this did not change in the past 10 years.

	Although outsourcing of vendor and system audits increased, it is still a lesscommon practice. Because vendor audits are primarily performed by internal auditors, this helps assure the company’s own quality standards are fostered and knowledge about the vendors is maintained within the company.

	The majority of companies outsource audits either to specialized audit CROs or individual independent auditors. In this benchmarking survey, 25% of the companies stated that they outsource audit activities to the CRO that is also in charge of conducting/monitoring the respective trial. This increased from about 5% in 2004 and might be a consequence of full package outsourcing. Due to potential conflict of interest, the authors strongly recommend to separate out CQA outsourcing that better reflects ICH GCP 5.19.2: “The sponsor should appoint individuals who are independent of the clinical trials/systems to conduct audits.”

	In the current survey, we also explored outsourcing of activities other than auditing. Except for SOP management and vendor oversight, all other activities are outsourced to some extent, most prominently internal training and training/education of CQA staff. This provides the advantage of getting input from third parties (e.g., external trainers).

	In contrast, outsourcing of SOP management and vendor oversight is not commonly done, as it requires that external consultants are contracted on a long-term basis. This is conducted as such so the consultants can acquire sufficient knowledge of the company’s processes and responsibilities in order to provide beneficial support.

	Today, nearly all companies (with one exception) establish an annual audit program. Out of these, the great majority apply a risk-based approach, most of them using a formal scoring system for risk factors.

	A variety of risk factors are taken into consideration for establishing the audit program and the most common risk factors named are as follows:

				Trial type/importance (pivotal, dose-finding, proof-of-concept, supporting safety, bio-equivalence, post-approval, etc.)

				Special populations /vulnerable subjects

				Novelty of design, indication, or technology

				Registration intent (e.g., first registration [NCE] vs. line extension vs. publication)

				Previous compliance history (monitoring / site management)

				Product portfolio (importance/properties of projects)

				Workload/volume of activities (e.g., number of PV cases or Phase I trials)

				Prior compliance record (audit and inspection history)

	Based on the audit strategy, audit coverage for trials, systems, and vendors (CROs) is determined. While risk factors already played a role in 2004, today the use of a risk-based strategy is much more pronounced and formalized with explicitly defined criteria, scoring rules, and associated tools.

	Regarding trial audits, about one-third of the companies focus their audit activity on pivotal trials; about one-third state they have all trials from Phase I to IV in scope; the remaining companies determine audit coverage according to the risk level assigned to the trials. One company does not target trials, instead focusing on systems and, therefore, certain studies within the scope of their system audits. Compared to 2004, the sample of audited sites per trial selected for audits has decreased: typically, it now lies in the range of 5% to 10%, whereas 10 years ago, samples were in the range of 10% to 20%.

	Regarding document audits, about half of the companies do not perform them at all; the other half select clinically important documents (protocol, IB, TMF, trial report, submission dossier)-mostly on a sample basis. There is a clear decrease in selecting documents for audits in comparison to the practices in 2004.

	For system and vendor audits, the approach is relatively homogeneous across companies. Risk levels assigned to systems/vendors guide the selection for audit and also determine the audit cycle times, which range from two to five years.

	The following is a typical response regarding system audits: 

“Selected based on risk. Various risk rating tools employed. Cycle time determined by risk, typically every three to five years.”

	Another response regarding vendor audits: 

“Volume and importance of work. Time since last audit with identified issues. Preferred providers are audited every two years.”

	In contrast to 2004, risk-based approaches are now widely applied to trial, vendor, and system audits.

	The number of trial, system, and vendor audits performed per year and audit type varies considerably across companies (e.g., for investigator site audits the number varies from nine to 600). The number of investigator site audits is nearly perfectly correlated to the number of trials (r=0.99).

	The majority of audits still focus on trials (investigator sites and trial documents) but their proportion decreased in favor of system and vendor audits. This clear trend is in line with the reduction of sample size for investigator site audits reported above.

Figure 2: Distribution of trial, vendor and system audits compared 2004 (n = 3310, total audits performed across 19 companies) and 2014 (n = 2592 total audits performed in 12 companies)

	The shift from trial to vendor and system audits surely reflects the increase of outsourcing and the use of additional technologies. In our view, however, the main driver of this change is the paradigm shift towards a holistic QM system with focus on processes and systems. This interpretation is also supported by the regulatory agencies’ views (e.g., the 

Report on the Pilot EMA-FDA GCP Initiative

’s conclusion: “To focus the joint inspections on sponsors and CROs instead of investigator sites in order to work towards developing a truly harmonized quality-systems approach to sponsor/CRO inspections.”

	The trend seen is very likely to continue to achieve a healthy balance between focusing the audit strategy on processes and systems supported by trial audits (

ISO9001:2008 – Guidance in the concept and use of the process approach for management systems

	In addition to audits, we asked for the number of pre-inspection visits performed per year. Again, this varies considerably across companies (range 0 and 20 visits).

	Resource assumptions for the different audit types have been collected and analyzed. In general, more capacity is spent on system and vendor than on trial audits. This is also reflected in the median number of man-days spent for an audit:

	Compared to 2004, the capacity spent for an investigator site audit increased by about 50% (2004: 8 man-days, 2014: 12 man-days).

	In summary, compared to practices in place 10 years ago:

		Risk-based approaches are currently more formalized and applied to all types of audits

		More capacity is allocated to individual audits, but fewer sites tend to be audited per trial

		Fewer document audits tend to be performed; it is rather the exception than the rule

		Finally, the proportion of system and vendor audits clearly increased reflecting a possible paradigm shift in the audit approach

	The process of audit reporting is quite standardized amongst companies and did not significantly change compared to 2004:

		Evaluation of significance of audit findings (e.g., critical, major, minor/other)

		Content-related categorization (e.g., study medication, monitoring, etc.)

		QC-steps for reporting of audit findings (e.g., peer review of audit reports)

A follow-up survey on clinical quality assurance (CQA) assesses current industry best practices compared to a decade ago, and provides recommendations on this key component of quality management for the future.

Critical Appraisal of Clinical Quality Assurance Based on Benchmarking Results: Past - Present - Future

Clinical project managers, monitors and assistants in the pharmaceutical industry involved in conducting clinical trials are experiencing increasing regulation. This seems to be more of a hindrance than a help in their daily work. As well as being expected to be aware of the manifold legal requirements and international regulations such as the German Drug Law (AMG), GCP Regulation, ICH GCP, various European directives, and FDA guidelines to boot, in the case of global trials, employees are also confronted with an array of sponsor-generated quality management documents which frequently seem to consist of a tangled web of rules and regulations. The result is employee dissatisfaction and demands for improvement of the content, a reduction in the number of SOPs, and improvement in the way the content is presented. This situation is due in no small measure to the fact that there has been little or no debate to date on what constitutes "adequate quality" of an SOP system. 

The literature has comparatively little to say about what an optimal SOP system can and should look like. Most authors limit themselves to very basic suggestions (e.g., short, meaningful sentences, clarity, use of illustrations)

  or alternatively very detailed instructions,

  which are ignoring basic elements of instructional design. GCP requires "the setting up and maintenance of quality control systems supported by written SOPs,

  but provides virtually no guidance on SOP system design.  

Only a few articles looked into the complex regulatory environment of the pharmaceutical industry

  and the resulting principles of writing effective SOPs.

The German Association of Research-Based Pharmaceutical Manufacturers—Verband Forschender Arzneimit-telhersteller (VFA)—appointed a taskforce from the Clinical Research and Quality Assurance subcommittee to look into the topic. The VFA is an organization of 45 research-based pharmaceutical companies whose studies, between them, make up a significant portion of clinical trial activity in Germany. Responses in this survey were obtained from several companies who belong to the leading pharmaceutical companies in Europe. The aim of the SOP Benchmarking project was to evaluate existing SOP systems on the basis of existing best practices and benchmarking, and to develop proposals for potential improvements. Existing SOP systems including the associated training were to be analyzed and improvement proposals were to be designed as appropriate on that basis. Another important issue was to determine whether specific SOP concepts were associated with higher "satisfaction" on the part of the parties concerned in their respective functions. The survey was conducted in late autumn of 2009 to determine the current state of affairs among VFA member companies, identify the mood/opinion of their employees with respect to the current situation, and present proposals as to what sponsors could do to change their SOP systems or remedy any deficiencies and inadequacies. 

The questions related only to SOP systems used to conduct Phase I to Phase IV clinical trials and did not cover health outcome studies or non-interventional studies.  

Two questionnaires were designed for the survey: Questionnaire 1 (Table 1) about the cost and benefit of SOPs looked at the existing structure and size/scope of the company's existing SOP system in terms of GCP, SOP management, and presentation of SOP content. The addressees were management and organizational employees (e.g., medical directors, directors of clinical investigation, and quality assurance directors).  

Questionnaire 2 was addressed at clinical research employees (i.e., monitors and project managers of the sponsor and freelancers/employees of CROs involved/in sourced by the sponsor for study projects). Questions were asked about handling and satisfaction with the existing SOP system/training methods, and respondents were asked to make proposals for possible future systems and methods. 

Replies from the two surveys were encrypted by VFA via company code so that it was possible to match management responses to employee responses, but without revealing the identity of individual companies and persons in the evaluation.  

A total of 18 companies took part in the survey, the majority of which is represented by a member in the already mentioned subcommittee. The results hence reflect relevant experience of SOP systems in the pharmaceutical industry. In nine cases the company was the local affiliate of a global corporation. Three to four responses per company were received from the employees invited to take part in the survey in the operative line departments (67 total); the majority were company project managers and/or clinical monitors with an average of 10 years of job experience.  

Estimation/user satisfaction with the currently established SOP system. 

Irrespective of their function or role in clinical research and time with the company, 19% of respondents were fully, 57% partly, 16% less, and 8% not at all satisfied with the current SOP system in their company. The main criticisms of existing SOP systems concerned the complexity and lack of clarity of individual documents/SOP systems, which made it more difficult for users to rapidly seek and find the relevant sections/instructions required for day-to-day work or in a specific on-site situation. In many cases, instructions concerning parts of processes (e.g., study initiation) are spread out among different sections of an SOP or even among a number of different documents (SOPs, instructions, appendices, etc.).  

SOPs with large numbers of pages did not necessarily receive poorer ratings. Instead, SOPs were criticized for being unclear and/or overloaded with abbreviations and jargon. Documents intended to be globally applicable were frequently mentioned in this context; respondents said global documents tend not to contain clear information/delimitations for each area (global/local functions). The associated need for additional material on local processes was seen to result in unreasonable multiplication of process descriptions. Users saw clear potential for improvement in implementing a level of document detail suited to the specific tasks and responsibilities, combined with a rapid and accurate search feature. Almost half of the respondents reported little or no personal involvement in the creation of SOPs. A mere 15% of those involved in document compilation said they were actual authors; most were involved only in the review/feedback process. Involvement in SOP compilation did however not correlate with level of satisfaction. 

Only 27% of respondents were happy with system size/scope and less than half (48%) were happy with the level of detail. Detailed evaluation showed that monitors tended to be more satisfied with lengthy SOPs than project managers. The same applied for satisfaction in relation to time spent working in the company. The SOP system was increasingly felt to be too lengthy with increasing time spent working in study management. In contrast to size/scope, there were no major differences in satisfaction between monitors and project managers in respect of level of detail. Here again, however, there was a trend toward dissatisfaction with overly detailed descriptions as a function of time spent working for the company (> 10 years of job experience).  

Twenty five percent of respondents said existing SOPs were not coherent and comprehensive. This opinion was more commonly expressed by project managers than by monitors. There was no correlation with time spent with the company. Thirty five percent of respondents said the SOPs were not clearly structured, monitors more so than project managers. Systems with fewer pages (in reference to monitoring) also tended to be rated more favorably.  

SOPs were primarily found to be useful (approximately 85%), irrespective of duration of job experience, even more so by monitors than by project managers.  

Are SOPs more restrictive than the legislative framework? 

About two-thirds of respondents said internal company SOP systems were more restrictive than applicable law. Project managers tended to find them even more restrictive than monitors.  

There was a trend for a negative rating of all the sub-elements of scope/size, level of detail, comprehensibility, clarity, usefulness, and restrictiveness from employees who were dissatisfied with the SOP system overall. 

Existing SOP systems in clinical research. 

The global and/or local SOP systems for conducting trials that exist alongside legislative requirements differ greatly between companies. The survey shows that there is neither a uniform hierarchy/structure in respect to SOP documents, nor in terms of nomenclature of document types. To name just a few, the terms employed include SOP, policy, operating instruction, and working instruction. There is also a plethora of different annexes such as flow charts, tables, job aids, completion guides, etc. The reported estimated length of SOP systems ranged from a few pages to complex SOP constructions with an estimated number of up to 8,500 pages. 

Comparison of job areas and processes with a largely pre-dictated scope of regulation (e.g., monitoring, SAE reporting, audit conduct, and collaboration with third parties/CROs) gives a similar picture. Again, there are huge differences between SOP systems. For monitoring (site selection/pre study visits, study conduct, study completion, and close out visit), the scale ranged from one to 35 SOPs (Figure 1) and from 10 to 700 pages. The mean number of SOPs a study manager/project manager in clinical research had to be familiar with was approximately 50 SOPs/480 pages.  

Increase and overregulation of processes—potential for reductions. 

Whether and how subjective dissatisfaction in recent years correlates with SOP proliferation is evident from the following statements from management staff. About 40% said there had been no change regarding the estimated number of global or local SOPs. Thirty percent had an increase of less than a 10%; 30% of more than 10% increase per year. None had a reduction in the past 12 months. Respondents said processes were overregulated (not including those relating to clinical trials but not originating in clinical research) in about 5% (median) of all processes described.  

Few ways of streamlining processes or eliminating SOPs showed up. Half of the companies' management staff surveyed saw little or no potential for reductions (two SOPs on average). The vast majority was unable to identify SOPs that could be done without. In contrast, clinical operations staff felt that a median of 10% of SOPs they have to comply with in their day-to-day clinical trial performance were superfluous.  

Conversely, gap analysis revealed little or no need to extend the SOP system. Only two companies reported a specific need for regulation in particular areas. 

According to the respondents, corporate headquarters are responsible for SOP authorship in 60% of the surveyed companies. More than 70% of the surveyed companies involve the line departments and about 50% involve quality assurance in SOP compilation. One-quarter of the companies involve SOP writer specialists in drawing up SOPs. Affiliates and subsidiaries are involved in the generation of global SOPs in addition to corporate headquarters. Sixty five percent said they were included in discussions about new SOPs, and their feedback is adopted/integrated in documents in more than 70% of cases. The expertise of SOP authors was largely rated favorably; only 10% of respondents said SOP authors tended to be far removed from reality. 

In about 70% of companies, additional local processes and SOPs are generated to supplement the corporate regulations in order to reflect and implement local/regional needs and legislative requirements.  

Three-quarters of the surveyed monitors and project managers said they sometimes had to deviate from an SOP in their day-to-day work. The main reasons cited for necessary deviations were "unfeasibility," as well as (lack of) time, effort, and cost. About 45% of employees said they never deviated from an SOP. Almost the same number (about 42%) said they deviated one to two times per year, and only a few said they had to deviate more than three times or five times per year.  

Deviations resulting from a discrepancy between global SOPs and local legislation are handled in different ways. About 50% of companies draw up local modifications. About 30% put national laws ahead of company instructions and implement this policy without any formal modification/amendment of the global SOP. 

Respondents said one reason for violations and dissatisfaction among those working with SOP systems was the compilation process itself or the generation period/revision cycle. About 40% of management employees said that new or revised SOPs were often implemented unexpectedly and without "prior warning" by corporate headquarters. The SOP generation period from first draft through feedback periods to approval and release lasts 10 weeks on average. Lead times from announcement to enforcement of an SOP were four weeks on average. 

In addition to regular review of SOPs at intervals of two to three years, there are other important reasons for revision. In more than 80% of reported cases, a change in legislation was the reason for an SOP revision or creation of a new SOP. A similar situation applied (almost 90%) with respect to structural changes within companies that entailed adaptation of processes and responsibilities.  

Two-thirds of the companies surveyed said learning SOP content was primarily the job of the individuals concerned. Nonetheless, formal learning was deemed the best method of learning (80% of companies that said this was mostly or occasionally the case). Two-thirds of companies rejected the prospect of ad-hoc training provided only to meet an acute need and if a particular process was specifically required. 

Seventy five percent of employees also said self-study was one of the most important ways of learning SOPs. Even more respondents (88%), however, said face-to-face training was the best learning method. Less than half of respondents (43%) said e-learning was the best method. However, acceptance of this method increased if it was linked with review of learning outcomes (58%). 

Despite significant variation among the surveyed clinical research management, self-study accounted for the major part of training effort, accounting for a median of 70% of total time required, followed by e-learning (median of 40%) and face-to-face/classroom training (median of 15%). Training with formal review of learning outcomes accounted only for a median of 7.5% of training events.  

Regardless of training events, the surveyed companies said the SOP competency of employees is not reviewed systematically. One-third do not regularly check competency, 15% only in isolated cases, if the manager notices deficits or an audit identifies any deficiency. Fifteen percent of companies check their employees' knowledge of the main SOPs at least once a year. Training units are repeated every one to two years in 56% of companies, and at intervals longer than two years in another third. 

The open-end answers clearly show that learning modalities cannot be viewed in isolation from the complexity or novelty of content, from the overall structure of the training system, or from the individual employee's level of experience: "The best setting to choose depends greatly on the content of the SOPs." Respondents also explicitly suggested combination with other learning modalities: self-study and online training for induction, face-to-face training to deepen understanding and for discussion. 

An average of 11 days per year is devoted to training, but this figure varied significantly among the respondents (Figure 2). The three-peak distribution shows peaks at five, 10, and 20 days. Monitors and project managers were asked which quantity of training they would consider to be the most appropriate. The answer was approximately nine days, again with significant variation. The breakdown here again shows systematic differences between the relevant user groups.  

In respect of cooperation with CROs, it emerged that sponsor SOPs were used as a basis for study conduct in approximately two-thirds of cases. CRO SOPs were used in less than one-third of cases. 

The baseline hypothesis (i.e., that SOP systems in GCP as they now exist would be rated inadequate by corporations and users) is not strongly supported. Although analysis of survey outcomes reveals deficiencies in the system and a need for improvement and change in some areas, the benefit of SOPs is nonetheless accepted. Nor did the survey results confirm the often cited suspected widespread overregulation of SOP systems.  

Not every SOP system is the same, and not every SOP is equally suitable for every organization. What works for one company need not be the best solution for another.  

Authors of SOPs tread a thin line in general, because user expectations and needs are as diverse as the spectrum of SOPs in existence. The needs of career starters differ from those of employees who have worked in the company or in clinical research for longer. Differences are also apparent in terms of the roles and responsibilities of respondents, for instance between monitors and project managers. Globally operating companies face the challenge of implementing global policies into local practice in a way that accommodates local legal requirements and best practice but at the same time does not violate global SOPs. 

The various aspects are looked at in greater depth in the following: 

SOPs are described overall as too lengthy. The subjective feeling of many respondents seems to be that "less is more." 

Many respondents cited the difficulty in finding individual process steps within an SOP system as being a key problem. "Details of a single process need to be searched for in multiple SOPs." "Search features in the electronic SOP repository are ineffective." "Sometimes it is not easy to find the right SOP you need for a particular process." 

The size/scope of SOP systems evidently differs greatly between companies indicating that SOP systems can display significant differences and may not always be directly comparable. The total number of SOPs and in particular the estimated number of pages—8,500 for one company—showed a wide range of variation. The only explanation is that SOPs may be written as no-frills "instructions" (who does what and how), as well as guidance (e.g., every single document, be it a simple letter to an investigating site, trial protocol template, or CRO communication plan). The latter policy may lead to a situation where important information and instructions for employees are hidden in a multiplicity of annexes/working instructions/templates to SOPs, which employees have to read and wade through even though they may not be immediately relevant to the specific (sub) task in hand. The former bears the risk of heterogeneous implementations. 

As already mentioned at the outset, existing regulations do not dictate the depth of regulation in SOPs. ICH GCP section 5.1.1 merely states that sponsors are obliged to implement an effective quality management system with written SOPs. Thus, the decision on depth of regulation is a task of the company.  

Survey appraises the use of SOPs in clinical research from the sponsors' point of view.

Arthur Hecht

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