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International Clinical Trials
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Commercially confidential information (CCI) is defined by the EMA as
meaning any information which is not in the public domain or publicly
available, and where disclosure may undermine the economic interest or
competitive position of the owner of the information.
However,
publishing information about the development and authorisation of
medicines in the public domain is critical to generate trust and build
confidence in the regulatory process, and to provide the knowledge
required for decision-makers. As described by the EMA, it is important
to strike the right balance between “respecting patients’ and doctors’
needs and the public’s entitlement to extensive and timely information
about clinical trials, and developers’ and researchers’ need to protect
their investments. A balanced approach is needed to protect public
health and also foster the innovation capacity of European medical
research”(1).
There are various ongoing regulatory procedures regarding clinical trial transparency, relating particularly to:
- The
introduction of the EU clinical trial portal and database as provided
for in the new EU Clinical Trial Regulation No 536/2014 (2)
- The publication of clinical data as described in the EMA policy 0070 (3)
Policy 0070 is composed of two phases:
- Phase 1 of Policy 0070 entered into force on 1 January 2015. This pertains to publication of clinical reports only
- Phase 2 will be implemented at a later stage, which pertains to the publishing of individual patient data (4)
With
the aim of ensuring that clinical trials are conducted in the EU with
the highest standards of safety for participants, the new EU Clinical
Trial Regulation No 536/2014 will come into force in mid-2016. The
regulation will substantially increase transparency of information, with
details of the major characteristics of the trial and their results
becoming publicly available. It will also harmonise the rules that
govern clinical trials across the EU member states, thereby simplifying
the clinical trial application process.
Clinical Trial Portal
A
key part of this simplification process is the introduction of a new
portal and database system that will be used as the single point of
submission and maintenance of clinical trial applications within the EU,
and also serve as the source of the publicly available information.
Once the decision on a clinical trial application has been made, the
public will be able to access extensive details of the study through
this database.
Timeframes
In accordance with Article
82(1) of the new Clinical Trial Regulation (EU) No 536/2014, the Agency
shall, in collaboration with the member states and the European
Commission, draw up the functional specifications for the EU portal and
the EU database, together with the timeframe for their implementation.
The auditing of the database should be complete and endorsed by December
2017, with the production version scheduled to go live in September
2018 (5).
Public Access
In March 2016, the EMA
published detailed guidance for companies on the requirements to comply
with policy 0070. The EMA expects to make continuing updates to this
guidance (6).
It is currently proposed that the information to
be made publicly available at the time of the decision on the trial will
include: the start date; the main characteristics of the trial; the
protocol summary; the conclusion on the assessment of part one of the
trial; and the decision on the trial including reasons for refusal if
the trial is not authorised (1).
Information released during the
trial will include: the end date of the trial; the first visit of the
first subject in the trial in each member state concerned; any
substantial modification, temporary halt, or early termination of the
trial; and notification on the end of recruitment in each member state
(1).
Additionally, 12 months after the end of a trial, a summary
of the results and a lay summary will be published. Then, 30 days after
completion of the marketing authorisation process – regardless of
whether this is an approval or rejection – the clinical study report for
those trials authorised under the new regulation, and included
thereafter in a marketing authorisation dossier, will also be published.
The Regulation requires that the information is made publicly
available via the clinical trial database, unless one or more of the
following exceptions apply:
- Protection of personal data
- Protection
of CCI, in particular taking into account the marketing authorisation
status of the medicine – unless there is an overriding public interest
- Protection of confidential communication between member states in the preparation of their assessment
- Protection of the supervision of clinical trials by member states
While
the review and approval of clinical trials will remain within the
individual EU member states, the portal and database will be the
responsibility of the EMA.
Redaction of Clinical Reports
A
recent EMA webinar explained how the Agency intends to implement policy
0070 on the proactive release of clinical trial data and the principles
for the submission of redacted clinical reports (7). The EMA is looking
at both a short-term and long-term solution, with the short-term option
being the redacted clinical reports presented as read-through text,
whereby the EMA can see what the proposed redactions are. The long-term
option is to explore if a format change in the electronic common
technical document (eCTD) could be achievable. An amendment to the eCTD
would need to go through the ICH procedures – which would require
international agreement.
Clinical reports are proposed to be
provided between Day 181 and 220 of the marketing authorisation
application (MAA) procedure, or within 30 calendar days post-receipt of
the company’s letter notifying the withdrawal of the MAA. The
organisation should certify that the only difference between the
redacted clinical report and scientific review version are those
proposed redactions.
Companies will be required to make
proposals to the EMA for redaction to protect both personal data and
CCI. Businesses should, therefore, submit a justification table for
CCI-proposed redactions (this will be based on the tool used in the
EMA’s ‘access to documents’ policy), and an anonymisation report
explaining the company’s approach to the anonymisation of clinical
reports.
The organisation is free to choose the redaction
software tool they like best, as long as it adheres to the technical
requirements stipulated by the EMA. The Agency will support small- and
medium-sized enterprises (companies with fewer than 250 employees and an
annual turnover not exceeding €50 million) by obtaining a user’s
licence for a redaction tool, and through provision of training and the
creation of a helpdesk. This support will not be extended to large
businesses due to financial constraints.
The EMA will provide
guidance documents to assist with the anonymisation of clinical reports
for the purpose of publication on their website, and the redaction of
CCI in these reports. At the time of writing, these were still at a
draft stage. The EMA will adopt a risk-based approach concentrating on
the proposed CCI redactions, rather than reviewing personal data – it
will be the applicant’s responsibility for submitting clinical reports
that have been rendered anonymous. Redactions can be rejected if the
information is already in the public domain, does not bear any
innovative feature or does not, per se, constitute CCI.
They
foresee only one consultation round between themselves and the company,
ending with a definitive conclusion from the EMA rather than protracted
rounds of discussions. If the Agency and the applicant do not agree on
the confidential nature of parts of the reports, and the applicant has
sought a court injunction to prevent the publication of certain
information, then the published document will indicate that the
redaction of these parts is under dispute.
The EMA will only
publish the clinical report once the procedure has been finalised. This
will occur within 60 days following the European Commission’s decision
for approval/ refusal of the marketing authorisation or line extension,
or within 150 days of the company’s withdrawal letter. The European
public assessment report will be released ahead of clinical report
publication in order to give prior notification of the rationale for the
assessment decision.
The Agency does acknowledge that
redactions due to CCI will become less justified over the course of
time, as what was previously recognised as being CCI gets into the
public domain. A regular review of such published reports (14,000 per
annum) would not be feasible. Therefore, the redacted reports will
remain as such until, or unless, access is challenged under the access
to documents scheme (8).
Data Transparency
There
has been much publicity and many calls for the publication of all raw
clinical trial data. In May 2015, the British Medical Journal (BMJ)
announced that they will only publish trials that commit to sharing data
on request (9). This extension of the journal’s requirements applied to
all submitted clinical trials from 1 July 2015. In doing so, the BMJ
acknowledged that it was time for medical journals to play their part in
the movement to make clinical trial data widely accessible.
In
April 2015, the WHO and the Nordic Trial Alliance published declarations
regarding clinical trial transparency (10,11). The WHO have reiterated
their position that, before any clinical trial is initiated, the main
details have to be registered in a publicly available, free-to-access
website, which adheres to the WHO’s internationally agreed standards
(12). The WHO position is also a condition of a favourable ethical
opinion. All studies need to be registered before the first patient is
recruited. Examples of such websites available now are www.
clinicaltrials.gov (13) or www.controlled-trials.com (14). The
clinicaltrials.gov website is a service of the US National Institutes of
Health and was made available to the public in February 2000. It now
lists over 197,000 studies, with the number of studies listed increasing
year on year.
The WHO statement notes that: “Concerns have been
raised that there may be selective publication of trials dependent on
their results, with particular concern that trial results which may be
viewed as ‘negative’, are less likely to be submitted, or accepted, for
publication in the scientific literature or made public in other ways.”
The WHO expects that:
- The
main findings of clinical trials are to be submitted for publication in
a peer-reviewed journal within 12 months of study completion, and are
to be published through an open access mechanism – unless there is a
specific reason why open access cannot be used, or otherwise made
available publicly at most within 24 months of study completion
- In
addition, the key outcomes are to be made publicly available within 12
months of study completion by posting to the results section of the
primary clinical trial registry.Where a registry is used without a
results database available, the results should be posted on a
free-to-access, publicly available, searchable institutional website of
the regulatory sponsor, funder or principal investigator
Although
these criteria are not mandatory, the WHO encourages reporting in
shorter timelines. The new EU Clinical Trial Regulation and EMA policy
0070 go some way to addressing these calls in Europe.
Plan for the Future
In
December 2015, when outlining his five-year EMA vision, Executive
Director Guido Rasi highlighted transparency as a key aspect of the
EMA’s approach moving forward (15): “We have a pioneering approach to
transparency. We are the first regulator in the world to allow
researchers and academics, and the public as a whole, access to the
clinical data on which marketing authorisations are based.”
With
these new policies, the EMA aims to build trust and confidence in the
regulatory system, because it will allow the public to better understand
the Agency’s decision-making. The public disclosure of clinical trial
information will continue to be of major importance for the pharma and
healthcare sectors. These new regulatory procedures will make Europe a
leader in the publication of study data.
References
1. EMA, Clinical Trials Regulation EU No 536/2014: Provisions on transparency, DIA 27th Annual EuroMeeting, Paris 2015
2.
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. Visit: www.eur-lex.
europa.eu/legal-content/EN/TXT/PDF/?uri=CELEX:32014R0536&qid=
1430209172115&from=DE
3. EMA policy on publication of clinical
data for medicinal products for human use. Visit:
www.ema.europa.eu/docs/en_GB/document_
library/Other/2014/10/WC500174796.pdf
4. EMA, External guidance on
the implementation of the EMA policy on the publication of clinical data
for medicinal products for human use. Visit:
www.ema.europa.eu/docs/en_GB/document_library/
Presentation/2015/09/WC500194090.pdf
5. EMA, Delivery time frame for
the EU portal and EU database. Visit:
www.ema.europa.eu/docs/en_GB/document_library/Other/2015/12/
WC500199078.pdf
6. External guidance on the implementation of the
EMA policy on the publication of clinical data for medicinal products
for human use. Visit: www.ema.europa.eu/docs/en_GB/document_library/
Regulatory_and_procedural_guideline/2016/03/WC500202621.pdf
7. EMA,
Access to documents. Visit: www.ema.europa.eu/ema/index.
jsp?curl=pages/document_library/document_listing/document_
listing_000312.jsp&
8. Current status of EMA policy on
publication of clinical data, Stakeholder webinar. Visit:
www.ema.europa.eu/ema/index.
jsp?curl=pages/news_and_events/events/2015/06/event_
detail_001163.jsp&mid=WC0b01ac058004d5c3
9. The BMJ requires data sharing on request for all trials, British Medical Journal. Visit: www.bmj.com/content/350/bmj.h2373
10.
WHO statement on public disclosure of clinical trial results. Visit:
www.who.int/ictrp/results/WHO_Statement_results_reporting_
clinical_trials.pdf?ua=1
11. Nordic Trial Alliance Working Group,
Report on transparency and registration in clinical research in the
Nordic Countries, 2015. Visit:
www.nta.nordforsk.org/projects/nta_transparency_report.pdf
12. WHO International Clinical Trials Registry Platform. Visit: www.who.int/ictrp/about/en
13. Visit: www.clinicaltrials.gov
14. Visit: www.controlled-trials.com
15.
EMA, Press release: EMA ready to address challenges ahead. Visit:
www.ema.europa.eu/docs/en_GB/document_library/Press_
release/2015/12/WC500198366.pdf
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