Transcript Clinical Trial Disclosure and Redaction

at
6th Asia-Pacific Pharma Congress
July 11-13, 2016 Kuala Lumpur, Malaysia
Clinical Trial Disclosure and Redaction:
The Balance from
A Medical Communicator’s Perspective
Dr.Namrata Singh
Director - Medical Services
Turcaoz Health Care Solutions
Table of Content
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Clinical trials Disclosures
Evolution of Disclosure
Gap and challenges in clinical trial disclosure
Clinical trial disclosure regulations
Impact of clinical trial disclosure on medical documents
CSR and CORE reference
Redaction
Way forward
Conclusion
Why Clinical Trial Disclosures in Asia Pacific?
Asia Pacific an important region for clinical trial industry
US and Europe have formulated guidelines for clinical trial disclosures
All regions and companies are moving towards clinical trial disclosures
Asia-Pacific trial numbers to grow 10%–15% annually, compared to just 7%
in the Group of 7 countries (US, UK, France, Germany, Italy, Canada, and
Japan)
• Asia pacific hosts 60% of world population
– Largest patient pool
– Treatment naïve
– Urbanization
– Lower operational cost
– Emerging healthcare infrastructures
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Clinical Trial Disclosures: Current Requirements
• Increased regulations/guidances
– Current guidelines
• Acceleration of disclosures
– Evolution of clinical disclosures
• Increased volume of disclosures: how can technology help
– Artificial intelligence
– Automated authoring
Clinical trial disclosure
• Compliance requirement across the globe
• Balances health authority requirements and dynamic clinical trial data
• Disclosure also referred as
– Transparency
– Public disclosure
– Clinical trial disclosure
• Other disclosures
– Financial disclosures
– Public disclosure of clinical research
– Patients/subjects data confidentiality
Why Disclosure?
Legal requirement
Ethical responsibility
Industry commitment
Impacts ability to publish
Supports research
– Learn from what is posted by other companies
– Use shared information to optimize your trial designs / development
plans
– Use clinical trial data sharing to support a positive company image
– Use clinical trial data sharing as a vehicle to influence / foster research
• Avoids duplication of research
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Evolution of disclosure
• Clinical trial disclosure evolution is driven by an increasing desire for
transparency of drug development
– Public
– Regulators
– Pharma
Voluntary
public
disclosure
Mandatory
trial
registration
Summary
results
disclosure
Document
disclosure
Data
disclosure
Gap: Clinical Trial Results not Disclosed
• 1/3rd of clinical trials conducted at US major universities and academic
hospitals never got published in peer reviewed journals or government
registry online
• Between 2007-2010, out of 4,347 trials conducted, only 29% got published
within 2 years of finishing data collection, and 13 % were posted on the
government database clinicaltrials.gov within the same period
• Overall, about 67 % of the studies disclosed their results by July 2014
• Pharmaceutical companies, the government and foundations invest a lot
of money in clinical trials and not disclosing the results is a waste
http://www.bloomberg.com/news/articles/2016-02-17/one-third-of-clinical-trial-results-never-disclosed-study-finds
Challenges in Clinical Trial Disclosure?
• How to balance the risks to patient privacy in the context of
maintaining document transparency when redacting
commercially confidential information and personal protected
data?
• How will it effect the clinical trial disclosure regulatory
framework on protocol design and clinical study report content
and structure?
Privacy vs closure
• Disclosure requires us to share documents and data
• Company commercial information and patient confidentiality requires us
to protect certain information
• How do we balance these opposing objectives ?
Privacy
Disclosure
Clinical Trial Disclosure Regulations
Clinical trail disclosure in the US
FDA Modernization Act
(FDAMA) 113 (1997) mandates
registry for Phase II-IV trials
Maine law (2005)
requires posting of
trial info and result
FDA Amendment Act (FDAA)
801 requires posting of result
after a positive NDA (2007)
ClinicalTrials.gov
launched (2000)
1995
2000
Next FDA
updated
expected 2017
2005
2010
2015
Trial disclosure in US
• Trial registration
– FDAAA requires registration not later than 21 days after the first patient is
enrolled
– For maintenance of registered trials, the recruitment status changes
must be disclosed within 30 days and other changes must be disclosed
within 12 months
– According to ICMJE policy, trials must be registered at or before the
onset of patient enrolment
– World Medical Association (WMA) requires disclosure before recruitment
of the first subject
Trial disclosure in US (Contd.)
• Results disclosure
– FDAAA requires trial results be published not later than 12 months after
study completion date
– Results must be disclosed for all interventional Phase II, III and IV trials of
FDA approved marketed products
• Consequences of non-compliance
– Fines start at $10,000 for the first event and $10,000 per day for every
day late
– Public notice of failure or violations in the registry/results data bank and
withholding of remaining or future grant funding where applicable
– FDA inspections may also results in the issuance of a public warning or a
corporate integrity agreement
Clinical trail disclosure in the EU
Treaty on the
functioning of the EU
(TFEU) Article 15
“gives right of
access to
documents” (1958)
POLICY/0043 Gives
access to documents
(related to medicinal
products for human
and veterinary use)
(2010)
Commission Guidelines
implementing EU Regs
1901/2006 & 726/2004Mandatory EudraCT
Submission of Phase I-III
trial results irrespective of
MAA status (2012)
EC Reg 1049/2001.
the Clin. Trial Reg.
“any person can
request access to
….docs” (2001)
1960
2000
POLICY/0070 on
publication of Phase II-IV
trial data in centralized
MAA irrespective of MAA
outcome (2014)
2005
2010
EU Reg 536/2014
(Clin. Trail. Reg) the
first legal basis for
disclosure of Phase I-III
trial results irrespective
Of MAA status 2014
Q & A on
POLICY/0070
(2015)
Guidance on
POLICY/0070
2015
WHO Statement on Public Disclosure of Clinical Trial
Results
• Clinical trial registry sites
– All clinical trials should be registered in a publicly available, free to access,
searchable clinical trial registry complying with WHO’s international agreed
standards
– Entry should be made before the first subject receives the first medical
intervention in the trial.
• On updating clinical trial registry entries
• On reporting timelines for clinical trials
– Main findings of clinical trials submitted for publication in a peer reviewed
journal within 12 months of study completion
– Published through an open access mechanism unless there is a specific reason
why open access cannot be used
– Or made available publicly at most within 24 months of study completion
– 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
WHO Statement on Public Disclosure of Clinical Trial
Results (Contd)
• Reporting of past clinical trials results
– Unreported clinical trials conducted in the past are to be disclosed in a
publicly available, free to access, searchable clinical trial registry
– Unreported clinical trials should also be published in a peer reviewed
journal
• On inclusion of Trial ID in clinical trial publication
• On data sharing initiatives
– WHO’s principle is to share research data for facilitation of research
through greater access to primary datasets
– Actively engaged with multiple initiatives related to data sharing, and
supports sharing of health research datasets whenever appropriate
Clinical Trial Disclosure Impact on Medical
Writing Documents
Documents impacted by Disclosure
• Pre-clinical trial (Clinical development plan)
– Trial registration and status reporting
– Protocol/ICF/CRF
• Trial conduct: SAP
• Post trial
– CSR/Expert summary/Lay summary
• Regulatory submission
– Redacted clinical reports
– Justification log for commercial confidential information (CCI)
– De-identification report
– Publications
Disclosed Reports Include
Clinical overviews (Module 2.5)
Clinical summaries (Module 2.7)
Clinical study reports (CSR, Module 5)
Appendixes to CSR no.
– 16.1.1 (protocol and protocol amendments)
– 16.1.2 (sample case report form)
– 16.1.9 (documentation of statistical methods)
• Commercially confidential information (CCI)
• Individual patient data (IPD)
• Personal data
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How is CSR Changing now?
• Two-step process
– Submission-ready CSR that may contain data that must be removed
after submission
– Final disclosure-ready CSR
• CORE guidelines propose that the CSR should be as disclosure-ready as
possible from the outset
• Approach has the potential to save time, money and cost in the
development of CSRs
• CORE Reference should increase the quality of final CSRs and enhance
consistency
http://www.amwa.org/files/Events/AC2015/OS_Slides/OS02_BudapestWorkingGroup.pdf
Clarity and Openness in Reporting E3 Based: CORE
Reference
• Clinical study report ICH E3 1995
– Ambiguity in guidance
– Incomplete global and regional clarifications
– Last update was in 2012 Q and As
• Stakeholders from
– Global industry association
– Regulatory agency
– Patient advocate
– Academic and Principal Investigator representatives
CORE Reference
• Clarity: Medical writers should write CSRs
– ICH compliant
– Not ambiguous
• Openness: Must write CSRs that assure responsible clinical trial data
sharing
– Protect trial participant anonymity
– Protect identity of those involved in management, conduct, reporting
of clinical trials, as appropriate
– Appropriate language to safeguard Company Confidential Information
(CCI) in line with corporate policy
• Improve ‘public’ accessibility of referenced information
• Reporting E3-Based
– ICH E3 and 2012 Q and A compliant
What is Redaction?
– Redaction is a process to hide some information from the
readers which may be personal or of commercial interest
– Initiatives of US and European clinical trial data transparency
have created additional disclosure compliance requirements
for pharmaceutical companies
– To meet the compliance with mandates the pharmaceutical
companies are required to redact and de-identify the data sets
in their submission documents including clinical study reports
(CSRs) and publicly publish the clinical study information
Sensitive Information and Redaction
Sensitive information may fall in to one of three categories:
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Personally Identifiable Information (PII)
Patient Protected Data (PPD)
Company Confidential Information (CCI)
The information related to these three critical categories must be
identified and then redacted or removed before publishing the
documents to the public
Documents that require redaction
– Clinical trial protocol
– Statistical analysis plan
– Clinical study reports (CSRs)
– Clinical overviews and clinical summaries
– Documents meant for marketing application submission
(NDAs, MAAs, BLAs, etc.)
– Safety documents
– Annual reports
BLA: Biologics License Application; MAA: Marketing Authorization Applications; NDA: New Drug Application
What to Redact
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Names: Principle Investigator & the legal representatives of the Sponsor
Academic/organizational title
Addresses to all except the Sponsor
Authors of internal Sponsor reports
Subject identifiers (incl. medical record no, initials, case numbers, etc.)
Dates relating to individual subjects (incl dates of visit/treatment,
birthdates, etc)
Individual outcome/demographic characteristics (incl country, sex,
ethnicity, etc)
Extraordinary data range limits (case-by-case assessment)
Verbatim text (case-by-case assessment) – e.g. replaced by MedDRA
terms
Subject narratives & listings
What to Retain
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Study Roles of personnel
Academic qualifications of personnel
Country name in addresses
Published citations and references
Dates which are not related to study patients/volunteers
Study number or identification number
Register ID number of study (EudraCT, NCT no, etc.)
Future direction
Redaction
• Using manual or software redaction methods
• Low data utility
Proactive
authoring
De-identified
data sets
• Such as suggested in CORE reference
• Still likely to need redaction
• Grouping items in documents that require
removal
• Limited need for redaction
• High data utility
Way forward: Artificial Intelligence in Medical Writing
• Aim is to elevate the role of the medical writer
– Reduce menial tasks such as copy and paste and regurgitation of
previously written content
– Reduce effort spent on quantitative, data-based assertions
– Increase value of the medical writer by increasing available time,
allowing for initial drafting of qualitative clinical interpretations of the
data.
• Content reuse + Content generation
• Why automated authoring
– Manual process replicated often
– Simple process
– Natural progression to believe we can automate this simple process
What documents can be automated?
• All regulatory documents
– Protocol
– Statistical analysis plan
– Clinical study report
– Patient narratives
– Safety update report
– Submission documents
• Non-regulatory documents
– Redaction
How does AI authoring work?
• Artificial Intelligence uses the past to predict the future.
CSR
Template
Previous Report
Packages
Style
Guides
Neural
Analyzer
Sponsor Specific Data
Models and CSR Output
AI uses the same documents and process as a medical
writer would to create a CSR
Trial Protocol
Statistical Analysis Plan
(“SAP”)
Tables, Listings & Figures
(“TLFs”)
(Microsoft Word Document)
(Microsoft Word Document)
(Zip File)
5 Minute Upload to AI SaaS
Engine
AI Engine
First Draft CSR
• Automatically generated
• 80-90% complete
• Accurate non-interpretive text
Medical Writers Complete CSR
Conclusion
Thank You