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International Clinical Trials
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Sponsors need to ensure that their product’s knowledge store is
complete, searchable, traceable and accurate in a changing environment –
a task that brings both challenges and benefits.
Traceability can be defined in various ways, depending on the
environment and process under consideration. It describes the ability to
verify the origin, location or application of an item by means of
documented, recorded identification. Traceability facilitates
transparency, which is an essential component in building confidence in a
result or conclusion (1).
With regard to clinical information, traceability means knowing where
data are located, as well as how information is derived and from which
data. At a higher level, it also applies to the information that was
used for a decision that led to a label being submitted for approval to
the authorities. At the point of regulatory submission, it is important
to recognise ‘the one version of the truth’ in support of a label.
Centralising and standardising the process from first trials in man
through to the submission, approval, label extension and marketing
phases of the product will also ensure that whenever a question is asked
about a label, the response will be fast, traceable and above all,
accurate.
Why Is Traceability Important for Clinical Information?
The way in which a company creates, stores and retrieves clinical
information has a significant impact on its reputation, efficiency and
ability to keep products on the market. Therefore it is essential that
the traceability of planned information (clinical trial data) is
considered at a very early stage of a product’s clinical development
life cycle.
It is only natural for clinical teams to focus on the information
required for submission and approval, whereas the product’s entire
clinical life cycle needs to be considered from a traceability and
information storage perspective. At any point in time, authorities may
ask for a product’s total trial profile, and this is where traceability
becomes paramount.
Key considerations in this respect include:
- Regulations governing the conduct and management of clinical
trials in a given country (10). For example, in the UK, ‘all clinical
trial information shall be recorded, handled and stored in a way that
allows its accurate reporting, interpretation and verification’ (2)
- Timescales – many years will pass from first-in-man testing,
through submission, approval and marketing, to eventual product death.
During this time, there are many occasions when the product’s
information may be required for efficacy and safety profiling
- Changing environment – standards are never standard for long;
regulations evolve and technology improves, often becoming more complex.
During the product’s life cycle, a sponsor may change technology
provider, collaborate with a new CRO, in-license, partner or perhaps
even merge with another company
Traceability of Information from a Clinical Development Perspective
Traceability means that every unique piece of clinical data can be
traced through the entire software flow of all relevant application
programmes, from data capture to final submission documents. Documents
and files at any point in the system can be audited for accuracy and
completeness against the raw data.
As a starting point, sponsors could ask the question ‘where is our
clinical information?’ Across a portfolio of studies that may span years
from Phase 1 to Phase 4, across various countries, companies and
systems, has there been sufficient upfront planning and management to
recognise the one version of the truth at the time it is needed? That is
traceability in itself.
At another level, a sponsor may be looking for traceability across the
information trail within a study for a particular product. For example,
information in the statistical analysis plan (SAP) that also appears in
the Clinical Study Report (CSR) and Common Technical Document (CTD)
summaries, can become traceable and reusable (from a metadata
perspective the Clinical Data Interchange Standards Consortium (CDISC)
analysis data model (ADaM) is a good example of this). Storing that
piece of information once and referencing it from the documents or
summary tables provides a centralised, reusable piece of information.
Think about where you store one of the most important information points
for your study, the p-value. Is it stored in a reusable information
store for future use, or is it buried in a table generated from your
in-house reporting environment and copied numerous times across numerous
text documents?
One final aspect to consider is the decision-making process during the
life cycle of the product. Information and decisions made during the
course of a submission need to be traceable back to the raw data. Under
the tight timelines during submission, it may not seem efficient to
record the reasons for taking a particular approach. These captured gems
of information, if preserved for future reference, will save time,
credibility and perhaps the label.
Managing Standards from the Beginning
The biggest problem in managing data is time: a product’s life cycle can
last for many years. The clinical data from a single portfolio can end
up being stored in multiple locations with different technology
providers, utilising different systems and formats. Technology is now
available to manage the vast amounts of information created during a
clinical trial, and companies and vendors are investing heavily in this
area. However, technology alone cannot solve the problem; it is critical
to get stakeholder buy-in from the governance and functional teams, to
consider what communications and behavioural changes are required, and
to ensure that the process is auditable.
Clinical Information Principles
In general, this article will use ‘information’ as a term applying to
all aspects and all levels. However, it can be useful to think of four
different levels of clinical information that contribute to a product’s
label:
- Raw data collected during the conduct of the clinical trials
- Summarised and reported, the derived data become ‘information’
- Apply expertise to that ‘information’ and it becomes the ‘knowledge/conclusions’
- That overall knowledge then forms the basis for the label of a product or ‘wisdom’
A label submitted for approval is done so on the basis that the sponsor
has proven that a product intended for use in a certain population is
safe, is effective in its defined use, and is manufactured to an
acceptable quality. A vast amount of information goes into a submission,
in the preclinical and clinical research areas, chemistry,
manufacturing and controls and, of course, the regulatory area. In fact,
the majority of regulatory knowledge is generated outside of the
regulatory affairs function.
In order to be readily available for the right audience at the right
time, the information generated from a clinical programme needs to be
structured in the correct way. The inclusion of metadata (‘data about
data’) to surround the information provides the opportunity to create
and maintain the one version of the truth. It also provides the user of
the information with a common store referenced from many different types
of media, hence becoming more efficient.
Clinical Information Storage and Traceability
During the conduct of a clinical study, many information points are
created using various methods and computer systems. Information gets
diluted as data is drawn from the raw data into the CSR and other
regulatory documents.
Locating the information point in an information store and referencing
it using metadata is an elegant solution to this issue. This approach
ensures that documents do not simply become the creation and storage
mechanisms of information, but the users of the information. Information
that is tagged through metadata can then be traced right back to the
raw data. This ability may be critical in certain situations, such as in
defence of a product label.
Working in this way means that information also becomes traceable back
to the raw data. This will enable faster access, and improve response
times to regulatory authorities as a result.
Providing the Constant in a Variable Environment
Many different factors influence the decision-making process when a
sponsor considers where to conduct their clinical studies. For example:
- Specific therapeutic experience or knowledge
- History of success
- Access to specific populations
- Location
- Cost-effectiveness
- Expertise with certain phases of development
It is unlikely that one unit/CRO will be the optimum choice for every
study in a portfolio and therefore, studies for any individual compound
will continue to be performed across several different units/companies.
Since the cost of actually conducting the trial is the largest part of
the overall study budget, it is understandable that the focus is on this
aspect. However, these units/CROs are not necessarily the best choice
for housing and reporting the data.
Taking the approach of including the data collection, storage and
reporting for a study with a full service CRO means that programme
information becomes scattered across various companies and systems using
a variation on a standard with little or no traceability. This
compromises on the quality of the input and output from a biometrics
perspective and loses the vital consistency required at a later stage of
the product’s life cycle.
Why Not Make the Information Traceability the Constant?
Solution providers can supply not only the technology and the
standardisation, but also, and most importantly, knowledge of the
clinical trial process and therapy area. Consider the advantages of
having the same medical writer provide input to a Phase 1 protocol,
prepare a CSR, and eventually prepare the publications that are created
for the marketing of the product. The saving in terms of the reuse of
intellectual property across a brand is obvious from a data management
perspective and output generation perspective. Combine that with the
consultancy input from a knowledgeable statistician across the
development programme – a study can be designed so that the data fit
together seamlessly if required for submission.
Think of it as a bank of information. When selecting a bank to support a
business, organisations often look for one that can provide a secure
place for money, with accessible interfaces to work on a global scale;
in other words, one that will turn foreign currency transactions into
the currency of choice. They will help companies do business with many
different companies but will always provide the applications and
interfaces to standardise the money and ability to pay out in different
currencies to your customers. A centralised biometrics organisation will
do the same for you with your clinical information.
With data collected from all sources – the company’s own records,
partners such as CROs, laboratories, research institutes – and over the
life cycle of a product, a centralised clinical data specialist will be
able to supply the information that is needed, in the right format, at
the right time and to different regulatory customers.
Generating the Traceability Up Front
Creating a standard to follow can be difficult to do within an
organisation, but maintaining it is even harder. The introduction of
standards such as CDISC has given companies major challenges to
implement and uphold. Standards then need to be maintained through new
versions and the task of traceability becomes progressively more
complicated. Systems driven by metadata are becoming increasingly
important in delivering long-term benefits.
Metadata control the way that standards are managed and the traceability
between your data and information. These types of tools provide great
advantages in terms of traceability, although they do require
maintenance and governance, which can be resource-heavy.
Traceability of an information point can start to make use of such
environments. It is possible to identify the data used in the generation
of such information when a query is raised. The one version of the
truth is found with confidence and in a timely manner.
Through some environments, it is possible to use a reverse-impact
analysis across a mapped workflow in order to show visually how a
summarised piece of information was generated, from what data points and
using which algorithms. Managing this internally as part of your
ongoing submission timescales can be daunting if you are using multiple
partners. It is possible, however, if you are relying on one CRO to
manage your data. Centralising this process becomes your constant and
customers of the data are provided with access to the information they
need, when they need it. This model also reduces your technology burden
internally and compliance with 21 CFR Part 11 is all handled for you.
There are many different systems offering such functionality. Sponsors
spend a great deal of time and effort choosing the environment and then
need to implement and maintain the system. They also have to re-train or
recruit resources to manage the process. All of this happens during the
same time that they are delivering on the requirements of the clinical
trials. Companies that provide access to the best-ofbreed industry tools
and have trained resources for these environments will obtain great
benefits.
Conclusion
Centralising clinical data services provides sponsors with a constant
within their clinical trial submission process. The traceability of that
information over time is managed from day one of a product’s life cycle
and information points along the timeline are stored once, progressed
to stay inline with the evolution of the standard, and are always
accessible.
When questions are asked about the product, the responses are managed
through the information trail that has been generated, and sponsors can
be reassured that they have the one version of the truth. Every life
science company faces the same challenges in the management of their
clinical information. To be more effective in the management of clinical
knowledge and information, it is important to consider the basic
principles of how data, information, knowledge and wisdom are generated
and how these can be traced throughout the life cycle of a product.
Additionally, knowing how information flows across and within functions
is important to gain a true understanding of what information is in
place to support the label of a product and the speed and accuracy at
which it will be accessed.
The ultimate metrics around the submission relates to the approval
timeframe and the quality. In essence, if by providing data of real
quality our response times are kept to a minimum, this is a true measure
of the quality of information supporting the statements in the label.
References
- CDISC Analysis Data Model (ADaM) Team, CDISC Analysis Data Model, Version 2.1, 2009, available at www.cdisc.org/standards
- www.legislation.gov.uk/uksi/2004/1031/schedule/12/made Schedule 1, Part 2
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