Regulatory Feature
How to Make Electronic Submission
a Business Benefit
Jesper Bendtsen, Niels Buch Leander and Thomas Hornbæk
Svendsen describe how companies can gain business benefits
from implementing an electronic submission system.
Many companies think of the electronic common technical document for submissions as a mere
electronification of the CTD. They believe that implementing the eCTD essentially removes the
printing processes while adding new processes for PDF rendition, bookmarking, hyperlinking
and generation of the XML backbone. While this conception is not mistaken, it ignores
important business potentials that the eCTD can offer a pharmaceutical company. Substantial
business benefits such as reductions in submission times and costs could be achieved by
companies if they approached the implementation of the eCTD as an opportunity to rethink
their entire process hierarchy.
Due to the specific nature of regulatory legislation and guidelines, a given process hierarchy
quickly grows complex. New requirements lead to the continuous implementation of new
processes on top of existing ones. Meanwhile, because legislation seldom becomes less restrictive,
existing processes are rarely removed. Confronted with this growth in complexity, organisations
rarely get an opportunity to restructure their processes.
The implementation of the eCTD could provide companies with an opportunity to evaluate
their existing process hierarchy with the purpose of optimising or adjusting the processes to fit the
purpose of the current organisation. A firm could, for example, ask the following questions: How
do the new processes depend upon previous processes? How are the processes interdependent?
Which content does each process deliver?
With the eCTD life-cycle concept, processes throughout the product life-cycle can be included
in a transition towards the eCTD. By focusing on detailed eCTD requirements, formatting
requirements, for example, provide an opportunity to look at template documents. Similarly, the
hyperlink requirements provide an opportunity to look at the authoring process and the requirements
for keeping everything in an electronic format provide an opportunity to consider how data and
content could be captured, stored and prepared for submission across the organisation.
eCTD can offer
pharmaceutical
companies important
business potentials
Implementation of
eCTD is an opportunity
to restructure the
process hierarchy
Establishing the right process hierarchy
When looking at the content generation for regulatory paper submissions, companies tend to focus
on three main processes – authoring, reviewing and printing. When introducing the eCTD, the
approach is often simply to add two new processes – rendition and publishing – and then revise
the existing printing process into a publishing process. This approach typically leaves the company
with five main processes to support the eCTD, as illustrated in Figure 1.
Figure 1. The five main processes typically considered for eCTD submission purposes
Companies tend to focus
on five main processes
Author
Review
Render
Compile
Publish
The specific sequence of processes may vary from company to company. But regardless of the
variation in process hierarchy, the following recommendations can help companies achieve the
business benefits of eCTD implementation:
•
document reviewing and control of document quality should not be perceived as distinct
steps in the submission process. Instead, they should be perceived as parallel processes
Jesper Bendtsen, Niels Buch Leander and Thomas Hornbæk Svendsen are business consultants specialising in regulatory
submissions at NNIT A/S, a Danish consultancy in IT implementation and services for life sciences.
© Informa UK Ltd 2009
www.rajpharma.com
RAJ Pharma September 2009
587
Regulatory Feature
•
Hyperlinking should
be introduced as a
separate process
•
that must be performed continuously, as electronic content is generated and updated;
processes should reflect the fact that document formatting becomes even more critical
with the eCTD and the submission process is different from the one used for paper
publishing. As such, companies should consider adding two new processes. Firstly, they
should introduce a “decision on content” process prior to the authoring process that
forces authors to begin by considering the template and the layout of the document.
Secondly, they should introduce a “finalise and submit” process that deals with the
activities regarding the finalisation of the submission; and
hyperlinking, because of its critical nature and complexity, should be introduced as a
separate process (more advice on hyperlinking can be found below).
These recommendations on process hierarchy are illustrated in Figure 2.
Figure 2. The main processes that should be considered for eCTD submission purposes
Decision on
content
Author
Render
Compile
Link
Publish
Finalise
and submit
Figure 3, meanwhile, illustrates the need to review the deliverables of some of the processes, either
by content review or by technical review (for example, proper rendition and hyperlinking).
Figure 3. Content review and technical review of deliverables
Decision on
content
Author
Render
Content
review
Review
technical
quality
Compile
Link
Publish
Review
of link
destinations
Test publish
and quality
control
Finalise
and submit
Control
There is a need to review
the deliverables of some
of the processes
Optimising the hierarchy
Based on these recommendations and observations, the following sections describe five concrete
recommendations on how to optimise the process hierarchy.
Companies should use
a phased approach to
implement eCTD processes
588
Clarify vision and scope
Companies should use a phased approach to implement eCTD processes. Firms often equate the
implementation of eCTD processes with a full eCTD submission. This does not necessarily have to
be the case. It is important to keep in mind that the implementation of eCTD processes is as much
a question of working with electronic content as a question of planning and submitting an eCTD.
The initial processes are more or less similar to a single file electronic submission, for example, a
periodic safety update report or a minor variation. The scope of the relevant departments involved
with a PSUR is admittedly smaller than that involved with a full eCTD, but the smaller PSUR
submission can provide a company with an ideal occasion to test the process setup and evaluate
the efficiency on a smaller scale than would otherwise be possible. As illustrated in Figure 4, most
companies will discover that the majority of the processes involved in submitting an electronic PSUR
or a minor variation are identical to the processes involved when submitting a complete eCTD.
September 2009 RAJ Pharma
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© Informa UK Ltd 2009
Regulatory Feature
Adjustments will have to be made when subsequently preparing a full eCTD, but it is easier to
revise processes for a few departments than for an entire organisation.
Of course, some firms may feel it makes sense to opt immediately for the full eCTD and test
all processes in one passage. However, it is much more likely that the transition towards electronic
submissions will be smoother if a phased approach is adopted, starting with a PSUR or a minor
variation.
Starting with a PSUR or
a minor variation may be
the best way to test the
submission process
Figure 4. Most PSUR processes are identical to those involved with a complete
eCTD submission
Decision on
content
Author
Print
Paper
Render
Compile
Publish
Link
CD publish
CD/DVD
publish
Single
electronic
files
Multiple
electronic
files (NEES)
with or
without
PDF ToC
Finalise
and submit
CD/DVD
publish
eCTD
submissions
To harvest the benefits of electronic document management, all authors, reviewers and approvers
must interact within the established infrastructure. This may prove extremely difficult and may
potentially necessitate a paradigm shift within the organisation. In order to locate a central starting
point for the adoption of the eCTD, a company must pose a number of important questions:
What is the vision? Who is the customer? Which benefits will it provide?
Moreover, it is vital to agree upon the scope in terms of people, processes and technology.
Although this may sound trivial, this point is often neglected. It is advisable to carry out an
assessment that will clarify the level of readiness in the relevant departments. Companies must
assess whether all their departments recognise that there is a need for a change towards the
eCTD. Moreover, it is important to ensure that the individuals responsible for activities within
each of the processes are aware of their role and ready to act and obtain the appropriate skills.
This awareness is crucial from the moment that the author creates the documents.
Remember that content begins with the author
Ideally, the author of a document should be the person most qualified to communicate the
intended message. In the case of regulatory submissions, however, the author of the content
is often a leading research scientist who ought to be free to work on valuable scientific
developments rather than be occupied extensively with inserting hyperlinks and quality
checking document renditions. It is important, therefore, to implement the processes in such
a way as to place as little burden on research scientists as possible, while ensuring that their
contribution as authors is optimised.
As such, organisations must help their research scientists to quickly obtain an understanding
of the processes to which they are contributing, whether rendition, hyperlinking or compilation. To
reduce rework, research scientists must learn to select and use the right template for the content and
be comfortable using the styles and formatting available in the template. If the template contains
embedded macros, these must be well described. The company should even consider embedding
macros into templates for common tasks, such as hyperlinking, indexing and formatting. This
will reduce the need for manual work and help limit the number of errors. Authors should be
instructed on how to write and format documents properly. The goal of each process should be to
minimise the number of iterations needed; every time that output from a process must be returned
to a previous process, the cost of keeping the overall process hierarchy in control increases.
© Informa UK Ltd 2009
www.rajpharma.com
Ask what the vision is,
who the customer is and
what the benefits to the
organisation are?
Avoid implementing
processes that burden
research scientists
RAJ Pharma September 2009
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Regulatory Feature
Administrative staff can
carry out hyperlinking
Change management
efforts involved with
eCTD transition should
not be underestimated
EDMS systems can often
accommodate the need for
document status tracking
590
It is advisable to identify processes in the hierarchy that could be handed over to administrative
staff or interns/trainees. For example, it makes little sense to use a scarce, and often expensive,
resource such as a research scientist to insert hyperlinks. With a well-written guideline on how
to indicate a hyperlink, administrative staff can carry out the actual hyperlinking based on the
research scientist’s input. To make the task as easy as possible for administrative staff, it is a good
idea to assign a unique document title or ID in the header of all documents, which the research
scientist can use when indicating a hyperlink.
Hyperlinking internally in the document can be done by using references that are automatically
converted to hyperlinks during the rendition process, for example, by always using “refer to” as
the first text in the link. Moreover, preliminary hyperlinks − such as a hyperlink to a destination
document that is not yet available − can be indicated by a specific colour in the document, and then
later changed to the required blue colour. One may also consider using available tools that suggest
the hyperlink target based on hyperlink text masks.
In summary, it is essential that authors understand to which process they contribute and
the reason for creating the content and how the content is subsequently used in other processes.
This insight will optimise the authors’ contribution according to the organisations’ needs.
Include people, processes and technology
A prerequisite to success in the transition to electronic submissions and the eCTD is that the
organisation understands the vision, challenges and advantages by adopting an electronic
paradigm. The organisation must also realise that it is impossible to prepare for electronic
submissions without having to revise existing processes and adding new ones.
Organisational change management involved with eCTD transition and the acceptance by
staff should not be underestimated – the company should expect the new and unknown to be met
by scepticism, maybe even with a negative attitude. The company should ensure, therefore, that
its implementation plans include dimensions of people, process and technology. Implementation
plans must take into consideration political, economic and social factors. They should include
measures to ensure that processes are described, approved and implemented; processes must
also be examined and evaluated frequently to make certain that they continuously support the
vision and scope. Implementation plans should also ensure that technology is implemented
and supported. This also includes the scope of the electronic submission system, including the
underlying electronic document management system, templates, editors, viewers, etc.
Consider existing tools before creating new ones
When moving towards electronic submissions, companies should consider whether to maintain
their existing IT tools. Firms that have been working with submissions for several years are likely
to have already implemented several IT-based tools that support a wide range of processes – for
example, for controlling the progress of documents that are to form part of a submission. Such tools
have often been developed on the basis of specific needs regarding the control and management of
information at a departmental level – and often Excel is used as the “platform”.
Where the Excel-based tool for controlling document progress has been used, the company
has most likely also implemented an electronic document management system (EDMS), which
has been adopted by numerous departments across the organisation. EDMSs offer a wide range
of functionality that supports the submission planning and assembly process. For example, they
support version labelling and document life-cycle management that can track document status,
which actually makes the Excel-based tool superfluous. A company may already perform some of
its document status tracking in an EDMS – but it often maintains spreadsheets simultaneously for
tracking content in the submission, for example, in order to control the table of contents. A saved
query can accommodate the company’s needs if the document types defined in the EDMS include
the metadata values for the CTD sections as well as submission number references and planned
CTD/eCTD sections, etc. The query result list may then serve as a list of documents to drag and
drop into the compilation software and provide a continuously updated status on the authoring
and reviewing progress. Empty placeholders for documents that are subsequently supplied, for
example, by external companies, can be inserted so that the search result also shows the status of
documents not yet in the EDMS. Metadata can also serve to track content or legacy documents that
need to be scanned, hyperlinked and reviewed for legibility and technical quality.
Wherever Excel has been used as the first choice of tracking system, companies should ask
whether their already implemented EDMS can achieve the same results. There may be some
information that the EDMS cannot track, but it is important to resist the temptation to introduce
yet another spreadsheet and consider instead the options available in the EDMS. The advantage
is not only that it saves time to maintain information in a single system; it also makes real-time
status information available to all relevant stakeholders and reduces the risk of making decisions
based on outdated information.
September 2009 RAJ Pharma
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© Informa UK Ltd 2009
Regulatory Feature
Remember that processes and deliverables are not always internal
When analysing processes with the aim of moving towards electronic submissions, it is a
common mistake only to pay attention to internal processes and deliverables. The starting point
should always be the content of the submission – and the recognition that content is typically
partly supplied by external companies such as clinical research organisations. Even though
pharmaceutical companies are not in charge of the processes in external organisations, they can
oblige external organisations to abide by a set of requirements regarding the formatting of relevant
documents. Many companies have established a written guide for corporate visual identity –
why not simply extend the guideline to encompass content delivered by external organisations?
The guidelines should also include requirements for bookmarks, margins, hyperlinks and the use
of colours, preferably in conjunction with a template for the external organisation.
It is a common mistake
to forget external
organisations when
defining processes
The optimal process hierarchy
Based on the above five recommendations, a company could optimise its process hierarchy.
Let us consider the case of, for example, a new drug product specification variation that must
be approved. Batches have already been manufactured as part of the development and quality
assurance approval process and the batch record and the specification already exist as PDF rendered
files. The regulatory affairs professional opens a variation template in the compilation software,
drags the documentation for the variation into the eCTD compilation software and uploads the
variation via a gateway for approval by the competent authorities. Upon approval, the status of the
variation sequence is set to ”effective” in the EDMS and the batch release software, and the QA can
release batches according to the new specification. In the regulatory status tracking application, the
sequence of the variation is automatically incorporated into the current and approved registration.
One cannot achieve this optimised chain of events unless everything is electronic and the input and
output of each process are mapped against each other.
Making electronic submission a business benefit
The prime incentive for moving towards electronic submissions is compliance. However, a rigid
focus on compliance may overlook potential long-term business benefits such as a reduction in
submission time and costs. At first glance, electronic submissions appear as extra work: legacy
paper reports must be scanned when used in submissions; and authors and reviewers must learn
how to format documents properly and insert bookmarks, hyperlinks, etc.
If, however, the implementation of the eCTD is seized as an opportunity to review the
processes, it may in fact reduce the submission time and workload in the long term. This is especially
important since companies often invest in EDMS systems because of the decision to adopt electronic
submissions – and this investment requires a strict focus on efficient processes if it is to pay off.
The predominant part of content in a submission today is created electronically in laboratory
systems, clinical trial systems and production management systems. Hence, to compile a paper
dossier requires transformation and consolidation of electronic information into a readable format.
If the benefit of moving to electronic submission is regarded simply as printing in PDF instead of
paper, potential business benefits of the move will be left unrealised – the transformation process
and the efforts involved will still be the same, if not increased, since bookmarks and hyperlinks
would need to be applied to most documents. Companies should instead focus on how to
minimise the human transformation effort of content. This will allow the move towards electronic
submissions to be a business benefit.
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RAJ Pharma September 2009
591