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International Clinical Trials
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Standard operating procedures (SOPs) rarely grab the spotlight like
transformational technologies or newer strategies, such as risk-based
monitoring or Quality by Design. But SOPs deserve some love. With their
coveted goal of improving operational efficiency, they have long been
fundamental to many industries, and the clinical trials sector is no
exception.
Sponsors are motivated to develop SOPs, not only as a
standard business practice, but also in support of regulatory
compliance. For example, Good Clinical Practice (GCP) guidelines state
that audits generally involve a systematic review of trial-related
activities and documents, including SOPs (1). However, just because a
company has invested significant time and resources in creating SOPs
does not mean they are always being followed. They may even be avoided.
But this is where technology can help.
This article describes
how automating SOPs for a key element of clinical trial conduct – study
start-up (SSU) – can guide sponsors and CROs to comply with
organisational standards and country-specific regulatory workflows.
Other automated SSU features include facilitating document collection
and handoffs across the globe, version control and status reporting.
Using this approach, bottlenecks that typically occur throughout the
start-up phase of clinical studies are reduced, bringing greater
efficiency to the critical path and tighter adherence to timeline and
budget.
Clinical Research
Conducting clinical
trials is justifiably a highly regulated activity. Encouraging
volunteers to participate in the testing of investigational products has
inherent risks, so ethics dictate that carefully defined SOPs are to be
utilised – along with intense safeguards and protection – to enhance
patient safety. These include an array of regulations from the ICH
(ICH-GCP) (2), the FDA (3), the EMA (4) (see full PDF for Box 1) and
other regulatory bodies across the globe. Collectively, they carefully
detail how studies are to take place, ranging from the responsibilities
of investigators to how and when serious adverse events are to be
reported.
On the manufacturing side, regulations note that SOPs
must be supplied in writing and distributed to employees in a timely
manner (5); furthermore, it is a requirement to set up and maintain
quality control systems supported by written SOPs (2). Interestingly,
there is virtually no guidance on SOP system design, whether for
manufacturing or clinical research (6,7). Failure to comply with them,
however, can result in violations during regulatory audits.
In
2015, the FDA Office of Bioresearch Monitoring issued 283 violations
known as ‘483s’, which are delivered when inspectors notify management
of objectionable conditions (8). Specifically, failure to follow written
procedures, conduct clinical trials in accordance with signed documents
or SOPs (9), or failure to keep accurate records and establish and
maintain SOPs appear frequently in Form 483 violations and warning
letters issued by the FDA. These findings reflect the fact that
companies may not have procedures that support operational processes
(10); employees do not understand their job responsibilities (5); they
lack access to the SOPs; or are not aware of them (9).
Definition of SOPs
What
exactly are SOPs? According to the ICH-GCP, they are defined as
detailed written instructions meant to achieve uniformity of performance
of a specific function (2). They describe who does what, where, when,
why and how (11). Literature suggests that an SOP document should be
created by the lead employee responsible for the task being described,
and should include sufficient details. Diagrams and flowcharts are
helpful to define the sequence of steps (12).
SOPs are also
living documents meant to evolve with time and experience (12). In
addition, for new as well as experienced employees, they serve as a
resource for conducting clinical trials in a consistent manner. In
simple terms, SOPs entail writing down what is to be done, and doing
what is written down. They are an effective catalyst to drive
performance improvement and organisational results.
The importance of SOPs in clinical trials cannot be overstated (12). Specifically, they:
- Manage compliance obligations in accordance with regulatory guidelines and institutional policies
- Create operational efficiency by ensuring that processes have been examined, optimised and standardised amongst all studies
- Reduce the learning curve and training of staff
- Ensure
business continuity: SOPs allow for continued operations in the event
that a key staff member is unavailable. By referring to the SOP, someone
can handle an urgent task and do it correctly the first time
- Improve
quality control by reducing errors or variations. They enhance the
quality of the data collected, thereby improving the science of the
study
These benefits provide a level of formal accountability
for team members, and they prevent non-compliance on a systemic level.
But they cannot help if they are not used. Some explanations as to why
they are not used consistently include difficulty in locating the total
collection of SOPs, being written in a foreign language, and more (see
full PDF for Box 2) (9). These findings are similar to those from a
survey regarding SOPs for clinical trials, in which 18 German
pharmaceutical companies participated (6). Results showed that only 19%
of respondents were fully satisfied with the SOP system in their
respective organisations, and that the main complaints were the
complexity, length and lack of clarity of individual documents, which
made it difficult for users to rapidly locate the relevant sections of
SOPs or instructions required for day-to-day work or in a specific
onsite situation.
SOP Workflow
As suggested in
the German survey, stakeholders have long recognised the value of SOPs –
but until recently, SOP manuals were only renowned for their unwieldy
size and length, and sometimes incomprehensible material. They took up a
lot of space and may have been relegated to a forgotten but secured
closet visited occasionally, maybe in anticipation of an upcoming audit.
Fortunately, cloud-based technology accessed through a user-friendly
dashboard now offers a meaningful alternative to the infamous SOP
manual. It automates workflows according to how a particular SOP is to
be followed. This is a vast improvement over traditional attempts at
following often confusing SOPs, with deviations sometimes resulting in
violations (5).
For SSUs – including country selection, site
selection and initiation, regulatory document submission, contract and
budget execution and more – countless country requirements must be
factored in, reflecting the global nature of clinical trials. An
automated workflow is effective for conforming to those varied demands,
particularly related to the volume of document exchange inherent in SSU:
a frequent bottleneck. This works by integrating SOPs into an
out-of-the-box solution that provides real time study status and
standardised processes.
Becoming Global
The
standardisation aspect is of growing importance as clinical trials are
increasingly global. A report from the EMA notes that the number of
investigative sites involved in pivotal studies submitted in marketing
authorisation applications to the EMA changed dramatically over a six
year period (13). According to the report, in 2011, 71.9% of sites
conducting those trials were located either in North America or the EU.
This is a big drop from the 2005 figure of 89.5%. As a result,
technology needs to accommodate this continuing trend, including how
SOPs can be used to better manage global study conduct. They need to
address factors such as country-specific regulatory document flow among
stakeholders, version control, status update, and ability to spot
bottlenecks – a difficult task when SOPs for these factors remain
paper-based, or are not readily available.
Jeff Kasher,
President of Patients Can’t Wait, and formerly Vice President of
Clinical Innovation and Implementation at Eli Lilly and Company,
comments: “With globalisation expanding its footprint, improved study
start-up is essential for building speed into the clinical development
process. Conducting clinical trials in places with unfamiliar regulatory
pathways and limited infrastructure is highlighting the value of study
start-up technology that allows for better SOP and regulatory
compliance.”
The automated workflow operates by configuring
settings in real time to accommodate changes in country-specific
regulations or organisational SOPs. Authorised team members, as defined
in the SOP, can view and manage existing configurations and then edit
them to create the settings needed for tracking documents, submissions
and milestones. Figure 1 (see full PDF) shows a step-by-step automated
workflow for documents needed to start a study in the UK.
SOP Compliance
With
the advent of intelligent document routing technology, stakeholders
have the ability to support country-specific document regulatory
workflows. This functionality allows for better compliance with SOPs,
which, in conjunction with regulatory guidelines, help improve the
operational efficiency of clinical trials – particularly in the SSU
phase. Historically, regulations have not provided specific guidance on
the format or content of SOPs, allowing companies to design SOPs that
best conform to their unique practices (12). But the long history of
them being confusing, overly complex or existing in paper format has led
to their lessthan- consistent use, or even avoidance. Fortunately,
there is now a more sustainable method that walks users through an
easy-to-follow workflow, enhancing SOP compliance and adherence to
clinical timelines and budgets.
References
1. ICH-GCP
Guidelines for Industry, E6 Good Clinical Practice: Consolidated
Guidance, April 1996. Available at:
www.fda.gov/downloads/Drugs/.../Guidances/ ucm073122.pdf
2. ICH-GCP, Guidelines, 5.1.1. Visit: www.ichgcp.net/5-sponsor
3.
21 Code of Federal Regulations Part 312, Investigational New Drug
Application, US Government Publishing Office. Visit: www.ecfr.gov/
cgi-bin/text-idx?SID=29bce88cdf8ce294019da4ab281ff014&mc=
true&node=pt21.5.312&rgn=div5
4. Regulation (EU) No 536/2014
of the European Parliament and of the Council of 16 April 2014 on
clinical trials on medicinal products for human use, and repealing
Directive 2001/20/EC, Official Journal of the European Union. Visit: www.ec.europa.eu/health/files/eudralex/ vol-1/reg_2014_536/reg_2014_536_en.pdf
5. Peterson DC, Assuring the effective use of standard operating procedures (SOPs) in today's workforce, BioPharm International,
September 2006. Visit: www.biopharminternational.com/assuringeffective-
use-standard-operating-procedures-sops-todaysworkforce?
id=&sk=&date=&pageID=3
6. Schmidt GB, SOPs in clinical research, Applied Clinical Trials, August 2013. Visit: www.appliedclinicaltrialsonline.com/sopsclinical- research?pageID=1
7.
Anderson C, FDA and EMA: Differences in approach, SOP Writing, April
2011. Visit: www.sopwriting.wordpress.com/2011/04/05/
regulatory-requirements-differences-between-fda-and-ema
8. FY 2015
Inspectional Observation Summaries, FDA, January 2016. Visit:
www.fda.gov/ICECI/Inspections/ucm481432. htm#bioresearch monitoring
9. Saxena A, SOP writing for clinical trials: Staff training aspects, 2005. Visit: www.sopwriting.blogspot.com
10.
Pickett JM, Reading for a US FDA inspection, Expert briefings, May
2013. Visit: www.expertbriefings.com/tips/readying-for-aus-
fda-inspection
11. Applied Clinical Trials Editors, SOPs: A must for sites, Applied Clinical Trials, March 2010. Visit: www.appliedclinicaltrialsonline. com/sops-must-sites
12. Kumar M, SOPs: Least understood, most important tool to ensure regulatory compliance, Regulatory Focus, October 2011. Visit: www.amarexcro.com/articles/docs/RAPS_Focus_SOPs_Oct2011.pdf
13.
Clinical trials submitted in marketing-authorisation applications to
the EMA: Overview of patient recruitment and the geographical location
of investigator sites containing data from 2005 to 2011, EMA, 2013.
Visit: www.ema.europa.eu/docs/en_GB/document_
library/Other/2009/12/WC500016819.pdf
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