Transcript Capital Committee Meeting

Clinical Trial Development: A Focus on
Publication of Trial Information
at
The Sixth Annual Pharmaceutical Compliance
Congress and Best Practices Forum
Mark S. Brown
Margaret K. Feltz
November 7-9, 2005
Washington, D.C.
*The comments and opinions expressed herein are the authors’ only and
should not be attributed to King and Spaulding or Purdue Pharma L.P.
Clinical Trial Development: A Focus on Publication of Trial Information
November 8, 2005
Agenda
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Why is this such a hot topic now?
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What is required? What is suggested?
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Why is this harder than it seems?
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Roadblocks and Challenges
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Questions and Answers
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Clinical Trial Development: A Focus on Publication of Trial Information
November 8, 2005
Goals – Conducting Research
vs. Reporting Research Results
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The goal of research is: To generate scientific
and clinical knowledge
The goal of reporting is: To ensure that
scientific and clinical knowledge gained from
research will be listed and shared from study
initiation to conclusion to ensure that positive
and negative findings can be evaluated in the
broad context of outcome possibilities
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Both positive and negative results have intrinsic
value
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Clinical Trial Development: A Focus on Publication of Trial Information
November 8, 2005
Clinical Trial Registry vs.
Clinical Trial Results Database
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Clinical Trials Registry
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“Provides patients and physicians with information
about ongoing clinical trials that are open and
recruiting patients.”
Clinical Study Results Database
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“Designed to improve accessibility to, and
transparency of, the results of clinical studies.
This electronic database is a central standardized
repository for published and unpublished clinical
studies that have already been completed. This
industry-sponsored registry will provide access to
the results of all hypothesis-testing clinical studies
of marketed drugs – regardless of outcomes.” 4
Clinical Trial Development: A Focus on Publication of Trial Information
November 8, 2005
Pop Quiz! – Who Said It?
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“Results! Why, man, I have gotten a lot of results. I know
several thousand things that won't work.”
“Just because something doesn't do what you planned it to
do doesn't mean it's useless.”
“I have not failed. I've just found 10,000 ways that won't
work.”
Thomas A. Edison
(US inventor, 1847-1931)
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Clinical Trial Development: A Focus on Publication of Trial Information
November 8, 2005
NY AG Paxil Case - Background
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June 2004 – NY Attorney General Eliot Spitzer sued
GlaxoSmithKline alleging that the company failed to
disclose certain clinical data that suggested that Paxil
was no better than a placebo in treating depression
in pediatric populations and could lead to suicidal
ideation.
Suit based on NY consumer protection law making
“any deception, misrepresentation, concealment or
suppression” of a material fact illegal.
Paxil is not approved for use in pediatric populations.
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Clinical Trial Development: A Focus on Publication of Trial Information
November 8, 2005
NY AG Paxil Case - Settlement
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GSK required to post summaries of clinical
studies on all GSK drugs marketed in the
United States
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Must maintain a clinical trial registry on a website
Free and unrestricted access
For 10 years
“Clinical studies” are defined to include:
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Any “research investigation on human subjects to
answer specific questions about a GSK drug.”
Definition is not limited to randomized, controlled,
or blinded studies.
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Clinical Trial Development: A Focus on Publication of Trial Information
November 8, 2005
NY AG Paxil Case - Settlement
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By the end of 2005, GSK required to post
summaries of studies that were completed
after the merger of Glaxo Wellcome and
SmithKline Beecham.
For ongoing studies of marketed products,
GSK has 10 months from completion of trial
to post data.
GSK may seek to delay posting of summaries
of studies where required to protect
intellectual property or to comply with policies
of journals to which manuscripts have been
submitted.
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Clinical Trial Development: A Focus on Publication of Trial Information
November 8, 2005
NY AG Paxil Case - Settlement
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GSK shall make a “reasonable effort” to
encourage the publication of studies in which
GSK was a significant participant.
In future studies, GSK will make a
“reasonable effort” to exclude contractual
provisions that may limit the publication of
clinical study reports.
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Clinical Trial Development: A Focus on Publication of Trial Information
November 8, 2005
NY AG Paxil Case - Settlement
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GSK to ensure that all Medical Information
letters and other communications to
physicians concerning a GSK drug “shall fairly
and accurately reflect the safety and efficacy
data from clinical studies concerning the offlabel use.”
GSK required to submit to the NY AG Medical
Information Letters or other communications
to physician regarding Paxil or depression in
pediatrics.
$2.5 million fee for disgorgement and costs
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Clinical Trial Development: A Focus on Publication of Trial Information
November 8, 2005
NY AG Paxil Case - Ramifications
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Spitzer contends failure to report negative
clinical trial data a problem that “runs
throughout the industry” and is “an area of
continuing interest.”
Motivating states to investigate drug
advertising and promotion based on
consumer protection laws.
States intruding in FDA’s jurisdiction and
comprehensive regulation of drug advertising
and promotion.
Copycat actions brought in state courts.
Preemption anyone?
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Clinical Trial Development: A Focus on Publication of Trial Information
November 8, 2005
FDA Clinical Reporting Obligations
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IND Annual Reports must include for each
study:
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Brief Summary of Study Status (e.g., completed,
ongoing, number of subjects entered, dropouts,
etc.)
If study completed or interim results known, brief
summary shall also include a brief description of
results.
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Clinical Trial Development: A Focus on Publication of Trial Information
November 8, 2005
FDA Clinical Reporting Obligations
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NDA Annual Report must include clinical data:
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Copies/abstracts of published clinical trials of the
drug
Summaries of completed, unpublished clinical
trials or pre-publication manuscripts, if available,
conducted by or otherwise obtained by the
company.
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A study is considered completed one year after its
conclusion.
No affirmative obligation to prepare or submit final
report on study of an approved drug.
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Clinical Trial Development: A Focus on Publication of Trial Information
November 8, 2005
FDA Clinical Reporting Obligations
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NDA Annual Report must also include:
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Analysis of available pediatric safety and efficacy
data, regardless of whether manufacturer is
proposing revisions to the product labeling.
Status report of each post-marketing study of the
drug undertaken by or on behalf of the sponsor,
including pediatric studies required by FDA or that
the sponsor has agreed to undertake.
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Clinical Trial Development: A Focus on Publication of Trial Information
November 8, 2005
Clinical Trial Registry:
www.clinicaltrials.gov
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Clinical trial registry launched in Feb. 2000,
pursuant to FDAMA.
Administered by NIH and National Library of
Medicine in conjunction with FDA.
Includes all Phase II-IV studies for products
to treat serious or life-threatening diseases.
Does not require posting of results.
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Clinical Trial Development: A Focus on Publication of Trial Information
November 8, 2005
PhRMA Principles
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Pharmaceutical Research & Manufacturers of
America (PhRMA) Principles of Conduct of
Clinical Trials and Communication of Clinical
Trial Results (the “Principles”)
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www.ClinicalStudyResults.org
Standardized format, including:
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Results from all hypothesis testing clinical studies
Mainly Phase III and Phase IV studies
October 1, 2002 forward
For all drug products approved in the United States
Regardless of publication status
Companies urged to post unpublished study summaries
within one year of study completion
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Clinical Trial Development: A Focus on Publication of Trial Information
November 8, 2005
Clinical Trial Registries –
Publication Standards set by ICMJE
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ICMJE member journals* require as a
condition of consideration for publication,
registration in a public clinical trials registry
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*
Must register on or before onset of patient
enrollment;
Applies to all trials enrolling after 7/1/05.
For trials enrolling before 7/1/05, registration
required by 9/13/05 before journal will consider
publishing trial data
JAMA, NEJM, New Zealand Medical Journal, Norwegian Med. J., CMAJ, The Lancet, National Library of
Medicine, Annals of Internal Med, Croatian Med. J., Dutch Journal of Med., J. of the Danish Med. Assoc.,
Annals of Internal Med., The Med. J. of Australia
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Clinical Trial Development: A Focus on Publication of Trial Information
November 8, 2005
Clinical Trial Registries –
Publication Standards set by ICMJE
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ICMJE does not advocate a particular registry
but requires that the registry be:
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Accessible to the public
Free of charge
Open to all prospective registrants
Managed by a non-profit organization
Valid
Electronically searchable
Contain standardized entries
www.clinicaltrials.gov meets the ICMJE
criteria
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Clinical Trial Development: A Focus on Publication of Trial Information
November 8, 2005
Joint Position* on the
Disclosure of Clinical Trial Information
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Desire to balance public health benefits associated
with clinical trial publication with protections of
individual privacy, intellectual property and contract
rights
Committed to transparency via vehicles of clinical
trials registry and clinical trials results databases
Implementation Dates:
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*
Trials initiated on/after 7/1/05 should be included in registry
Ongoing trials should be included by 9/13/05
Industry groups include European Federation of Pharmaceutical Industries & Associations,
International Federation of Pharmaceutical Manufacturers and Associations, Japanese Pharmaceutical
Manufacturers Association and Pharmaceutical Research & Manufacturers of America
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Clinical Trial Development: A Focus on Publication of Trial Information
November 8, 2005
Joint Position (cont.) –
Clinical Trials Registry
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Clinical Trials Registry – a repository of information
on ongoing clinical trials
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All non-exploratory clinical trials submitted for listing in a
free publicly accessible registry within 21 days of initiation of
patient enrollment, unless there are alternative national
requirements
Registry contains basic information sufficient to inform
interested subjects and practitioners about how to enroll in
trial
Trials identified by unique identifier that permits users to
track a trial through multiple databases, including results
databases
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Clinical Trial Development: A Focus on Publication of Trial Information
November 8, 2005
Joint Position (cont.) –
Clinical Trials Results Database
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Clinical Trials Results Database – a repository for the summary
results of completed clinical trials
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Results of all non-exploratory clinical trials conducted on a drug
that is approved for marketing and is commercially available in at
least one country should be disclosed on a free, publicly accessible
clinical trial results database, regardless of outcome
Exploratory study results should be publicly disclosed if they have
significant medical importance and may impact labeling
If results are published in a peer-reviewed medical journal, the
database should include a citation or link to article or summary of
results, posted in standardized format
All results should include the trial’s unique identifier
Results should be posted within one year after drug is first
approved and commercially available within a country or, for trials
completed after this initial phase, within one year of trial
completion unless such posting would compromise publication in a
peer-reviewed medical journal.
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Clinical Trial Development: A Focus on Publication of Trial Information
November 8, 2005
Fair Access to Clinical Trials Act
(“FACT Act”)
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Introduced in both the House (HR 5252)
and Senate (S 2933).
Would require sponsors of clinical trials to
register and publish information about
drugs, devices, and biologics.
Would expand www.clinicaltrials.gov to
create a publicly accessible national data
bank of clinical trial information – both a
registry and results database.
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Clinical Trial Development: A Focus on Publication of Trial Information
November 8, 2005
FACT Act
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The legislation would:
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Foster transparency and accountability in healthrelated treatment research and development.
Maintain a registry for ongoing clinical trials for
serious or life-threatening diseases.
Establish a clinical trials results database of all
publicly and privately funded trials, regardless of
outcome.
Be accessible to scientific community, health care
professionals, and the public.
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Clinical Trial Development: A Focus on Publication of Trial Information
November 8, 2005
FACT Act
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The legislation would:
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Apply to clinical trials for drugs, biologics, and
medical devices.
Require that foreign trials submitted to FDA or
used in advertising to U.S. physicians be
registered in the database at the time of
submission.
Exempt Phase I trials conducted only to test safety
of unapproved products.
Impose penalties and fines for non-compliance.
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Clinical Trial Development: A Focus on Publication of Trial Information
November 8, 2005
Maine Clinical Trial Disclosure Law
LD 1618 (22 M.S.R.A. §2700-A)
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Manufacturers or labelers that are required to report
marketing costs under 22 M.R.S.A. §2698-A are also
required to post clinical trial data on a publicly
accessible internet website beginning on October 15,
2005
Posting requirement applies to:
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Any “clinical investigation” (as defined by the FDA)*
conducted on or after October 15, 2002 that is intended to
test the safety or efficacy of a drug or biologic in humans
and intended to be submitted to the FDA in support of a
marketing application
This includes Phase I, II, III and IV trials
* FDA defines a clinical investigation as “any experiment in which a drug is administered or dispensed to,
or used involving, one ore more human subjects. … [A]n experiment is any use of a drug except for the
use of a marketed drug in the course of medical practice.” 21 C.F.R. § 312.3(b).
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Clinical Trial Development: A Focus on Publication of Trial Information
November 8, 2005
Maine Clinical Trial Disclosure Law
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If the trial disclosure requirement
applies, the following information must
be posted:
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Name of entity conducting trial
Summary of purpose of trial
Dates trial occurred
Results of trial – including potential
adverse events
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Clinical Trial Development: A Focus on Publication of Trial Information
November 8, 2005
Transparency & Accountability
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With regard to the industry decision to publish
summaries of clinical trial results to a results
database, PhRMA president Billy Tauzin said
that:
“[The industry is] doing this because [it] recognizes
that sometimes what the law requires doesn’t give
patients all they need. Patients – both those with
manageable conditions and those who are gravely ill
– need information about new drugs that are being
tested.”
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Clinical Trial Development: A Focus on Publication of Trial Information
November 8, 2005
Why does this seem so difficult?
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Roadblocks and Challenges:
Ambiguity
 Intellectual Property Concerns
 Off Label Promotion Restrictions
 Ethical Considerations
 Burdens on Companies
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Clinical Trial Development: A Focus on Publication of Trial Information
November 8, 2005
Roadblocks – Ambiguity
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Registry vs. Results Database – where
is there crossover?
What does “within one year of trial
completion” mean?
What constitutes “publication”?
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Clinical Trial Development: A Focus on Publication of Trial Information
November 8, 2005
Roadblocks – IP Concerns
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Inclusion of Phase II or earlier data? Inclusion of
Phase III and IV trials of marketed products has
more wide-spread support.
“Hypothesis-generating” vs. “Hypothesis-testing”
trials
What is the impact of reporting clinical trial
information on competitive advantage when bringing
a new drug to market?
Would you expect that reporting clinical trial data in a
database or on a website would hamper an
investigator’s ability to publish findings in a medical
journal?
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Clinical Trial Development: A Focus on Publication of Trial Information
November 8, 2005
Roadblocks – IP Concerns
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“To put major information out about
particularly early-phase trials, their design
and how they are being done…would be
tantamount to disclosure of the regulatory
strategy, the timing and just enormous
disclosure of critical information that…[would]
prevent the ability of companies to gain an
appropriate return on their investment.”
Dr. Larry Hirsch
Merck Executive Director, Medical Communications
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Clinical Trial Development: A Focus on Publication of Trial Information
November 8, 2005
Roadblocks –
Off Label Promotion Restrictions
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If a clinical trial focuses on an off-label use or
is a head-to-head comparison with another
product, how should results be reported to
avoid being construed as promotion claims?
Clinical Trial data should be posted in a nonpromotional manner.
DDMAC will look at both the content and the
context of data posting.
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Distinction between data and conclusions.
Conclusions could turn data posting into
promotion.
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Clinical Trial Development: A Focus on Publication of Trial Information
November 8, 2005
Roadblocks – Ethical Considerations
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What are the risks created by making
available data that has not been published in
a peer-reviewed journal or otherwise been
validated?
By reporting both positive and negative
clinical trial results, are we flooding the
medical literature and websites with data that
is not necessarily useful?
Could providing positive and negative clinical
trial results on the internet negatively impact
the doctor/patient relationship?
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Clinical Trial Development: A Focus on Publication of Trial Information
November 8, 2005
Roadblocks – Burdens on Companies
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Will mandatory clinical trial reporting make
pharmaceutical companies more risk averse?
Will these requirements affect clinical trial
design for your company? If so, how?
What kind of constraints do these reporting
requirements place on your company?
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Time constraints?
Financial constraints?
Staffing constraints?
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Clinical Trial Development: A Focus on Publication of Trial Information
November 8, 2005
Our Contact Information
Mark S. Brown
Partner
King & Spaulding LLP
1700 Pennsylvania Avenue, N.W.
Washington, D.C. 20006
P: (202) 626-5443
F: (202) 626-3737
E: [email protected]
Web: http://www.kslaw.com
Margaret K. Feltz
Senior Manager
Purdue Pharma L. P.
One Stamford Forum
Stamford, CT 06901
P: (203) 588-8754
F: (203) 588-6269
E: [email protected]
Web: www.pharma.com
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