2014 Jan-Feb Issue

R ESEARCH
PRACTITIONER
VOLUME 15, NUMBER 1
January–February 2014
4
10
Computer Simulations Take Their Place
in Clinical Trial Design
Sue Coons, MA
Creating a Standard Practice
for Communicating Lay Language
Trial Results to Study Volunteers
Ken Getz and Zach Hallinan
16
Continuing Education
18
Regulatory Update
EARN 3 CONTACT HOURS IN THIS ISSUE
R ESEARCH
PRACTITIONER
AUTHORS
Sue Coons, MA
Science Writer, Columbus, OH
Ken Getz
Director, Sponsored Research Programs, Tufts CSDD; Founder and Board Chair,
CISCRP, Boston, MA
Zach Hallinan
Director, Patient Communication and Engagement Programs, CISCRP, Boston,
MA
EDITORIAL BOARD
Anna J. DeMarinis, MA, CQA(ASQ), MTA(ASCP)SBB
Principal, The DeMarinis Group, North Attleborough, MA
Lee Ferrell, CCRA, CCRP
NA Head, Regulatory and Start Up (RSU), Integrated Site Services, Quintiles,
Inc., Research Triangle Park, NC
Terry Hartnett
Medical Writer, Pittsburgh, PA
Carolynn Thomas Jones, DNP, MSPH, RN
Faculty Instructor, University of Alabama Birmingham, School of Nursing, AL
Nancy A. Olson, JD
Director, Institutional Review Boards/Human Research Office,
University of Mississippi Medical Center, Jackson, MS
Dónal P. O’Mathúna, BS (Pharm), MA, PhD
Senior Lecturer in Ethics, Decision-Making, and Evidence,
School of Nursing Academic Member, Biomedical Diagnostics
Institute, Dublin City University, Dublin, Ireland
Mark Parascandola, PhD, MPH
Staff Writer, Washington, DC
Sandra M. Sanford, RN, MSN, CIP
Nurse Planner
Education and Training Specialist, Human Research Protections
Armed Forces Services Corporation, Arlington, VA
Barbara S. Turner, RN, DNSc, FAAN
Chairperson, Doctor of Nursing Program, Professor, Duke University School of
Nursing and General Clinical Research Center, Durham, NC
Janet F. Zimmerman, MS, RN
Assistant Clinical Professor, Coordinator, Clinical Trials Research MSN Track,
Drexel University College of Nursing and Health Professions, Philadelphia, PA
Lynn D. Van Dermark, RN, BSN, MBA, CCRA, RAC
CEO, MedTrials, Inc., Dallas, TX
MANAGING EDITOR
Leslie Coplin
EDITOR-IN-CHIEF, CENTERWATCH
Cheryl Rosenfeld
GRAPHIC DESIGN
Holly Rose
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Volunteering for a Clinical Trial
Computer
Simulations Take
Their Place in
Clinical Trial Design
By Sue Coons, MA
Key words: computer simulation,
Critical Path, data standards
Learning Objectives:
1. List the benefits of using computer simulators in
clinical trials.
2.Discuss the need to move more scientific discoveries into improved treatment options.
3.Identif y FDA’s role in encouraging computer
simulations in clinical trial design.
4.Define clinical data standards.
A
November 17, 2013, Wall Street Journal article
brought to the nation’s attention the concept of using computer simulators to design better drug trials,
particularly in the area of Alzheimer’s disease.1 The simulators, the article says, can cut the cost and time of a trial by
showing researchers whether a certain set of variables such as
dosing and length of study will yield a result that is statistically significant for the treatment in question. Computer
simulations have been part of the clinical research world for
some time, however, and recent developments indicate that
they may become a vital part of determining a trial design in
the future.
“This modeling idea has been around since the 1980s, but
it really hasn’t been implemented effectively until the last 5
years or so,” says Nathan Teuscher, founder and president
of PK/PD Associates in the Dallas/Fort Worth, Texas, area.
Teuscher provides teaching and consulting services to the
pharmaceutical industry in the area of pharmacokinetics.
“Even over the last 5 years, the modeling has been useful but
not 100% predictive. People are using it to better understand
how a drug works, but they are not using it to simulate a full
clinical trial like you might do simulating flying an airplane.
[The simulators] aren’t that good yet.”
The Basics of Simulation
The information needed for a computer simulation in a
clinical trial includes population of subjects — such as age
and demographics, chemical composition of drug dosage
variations, and potential interactions, says Tim Lynch, CEO
of Psychsoftpc. Psychsoftpc has designed artificial intelligence software for AIDS research for the National Institutes
of Health (NIH). The complexity of the simulation depends
on whether some of the programming pieces already exist,
he says. “Modern programming involves using, reusing, and
adapting pre-existing code or classes. Modular programming
is the word.”
A 2004 article in the French journal Thérapie spoke of the
early promise of computer simulation in clinical trials.2
[The modeling approaches] have various uses, such as
proof of concept, decision analysis or experimental design
optimization. Also, the effect of departures from protocol on clinical trial results can easily be evaluated by the
use of simulation. This technique is now implemented
by the pharmaceutical industry for optimizing phase II
and III experimental designs when a good biomarker or
a clinical outcome model is available, but the use of an in
silico therapeutic model as a proof of concept is only just
beginning. In order to see such methodologies used more
widely in drug development, multidisciplinary efforts
4
Research Practitioner
need to be initiated, new modeling and simulation tools
developed, and sound modeling and simulation practice
documents need to be adopted. A reduction in the number of failed clinical development projects, the number of
negative phase II and III clinical trials, or in just their cost
and duration, are among the expected benefits of modeling and simulation in clinical drug development.
The Critical Path Initiative
Computer simulations in clinical trials became part of the
discussion at FDA as part of the Critical Path Initiative
in 2004. Launched by former FDA Commissioner Mark
McClellan, the independent,
nonprofit Critical Path Institute
(C-Path) was created “to drive innovation in the scientific processes
through which medical products
are developed, evaluated, and
manufactured.”3 FDA began talking about the “critical path” —
the path of a product’s discovery
or design concept to commercial
marketing — in March 2004
with the release of the white paper
Innovation/Stagnation: Challenge
and Opportunity on the Critical
Path to New Medical Products.4
The report highlighted the
slowdown between scientific discoveries that could cure medical
“killers” such as diabetes, cancer,
and Alzheimer’s and the translation of these discoveries into
innovative medical treatments.
According to the report, FDA
believes that the sciences needed
for medical product development
have not kept pace with advances
in the basic sciences.4 The report called for a national effort
to “identify specific activities all along the critical path of
medical product development and use, which, if undertaken,
would help transform the critical path sciences.”3 consulted about it with various stakeholders. Two years
later, FDA released the Critical Path Opportunities List,5 in
which the agency listed 76 examples where new scientific
discoveries could be applied during development “to improve
the accuracy of tests that predict the safety and efficacy of
potential medical products.”5 Number 51 of these examples
described clinical trial simulation:
Clinical trial simulation — using in silico modeling —
can predict efficient designs for development programs
that reduce the number of trials and patients, improve
decisions on dosing, and increase informativeness. Clinical trial simulation requires the development of a disease
model, with subsequent integration of information on
the investigational product. Such models could also help
refine some of the innovative
trial designs described in Topic
#2 [Streamling Clinical Trials],
above. Stakeholders are looking
for first steps, such as identification of tools and best practices.
The Critical Path
Institute was created
A 2008 article in the Annual Review of Medicine talked about CPath and its purpose. “FDA’s mission is to protect and promote the
health of the public. With respect
to drugs, biological products, and
medical devices, this translates
into ensuring reasonable product
safety while also facilitating the
translation of scientific innovations into commercial products,”
wrote Janet Woodcock, director of
FDA’s Center for Drug Evaluation and Research, and Raymond
Woosley, former C-Path president.
“The ongoing tension between
these two objectives results in
assertions that FDA requirements are stifling innovation, and
simultaneously that FDA standards are too low. The thesis
of the Critical Path Initiative is that scientific advances in
the development process are the best way to resolve these
conflicts to the satisfaction of most parties and to the benefit
of the public.”6
”to drive innovation
in the scientific pro -
cesses through which
medical products are
developed, evaluated,
and manufactured.”
“[The paper] was asking the pharmaceutical industry to
develop models that would better explain the phenomenon
that we see in clinical trials and hopefully those models
would be beneficial in future drug development,” Teuscher
says. Along with trying to encourage the development of the
models, FDA hired associates who had the expertise needed
to understand that type of mathematical analysis, he says.
The white paper generated much discussion, and FDA
Research Practitioner
The article also looked at the progress of the C-Path projects:
One of the greatest scientific flaws in the current process
of medical product development is its failure to produce
generalized knowledge despite a huge investment in data
generation.… One important use of such data will be
to construct quantitative models of disease processes,
incorporating what is known about biomarkers, clinical
5
outcomes, and the effects of various interventions. These
models can then be used for trial simulations, to better
design appropriate trials and clinical outcome measures.
Although the FDA has constructed several disease models, this work is in its early stages and will require extensive partnerships. However, there is little doubt that such
quantitative approaches constitute the future of product
development and assessment.6
Some observers, however, thought the project had begun
to lose momentum a few years after its launch, one reason
being its lack of funding. “Science progresses at its own rate,
and medical science is necessarily more cautious than other
branches. But it feels like the lack of money and mindshare
are turning [C-Path] into just
another umbrella project. Without a committed voice of stature
constantly rallying the project
onward, the Critical Path Initiative has lost any sense of urgency,”
wrote John Russell, executive editor, Bio-IT World, at Cambridge
Healthtech Institute in Needham,
Massachusetts, in 2007.7
One of CAMD’s initial courses of action was to “establish
a common research support infrastructure for using pooled
control or placebo patient data from clinical trials to create
quantitative disease-progression models for both Alzheimer’s
disease and Parkinson’s disease.”10
“The more real-world data that can be applied, the better
the [computer] simulation,” Lynch says. “If good simulations
can be devised by inclusion of real-world data, a researcher
could run what amounts to hundreds or even thousands of
clinical trials virtually before attempting to run a real-world
trial.” CAMD had a head start on the real-world data when
it announced the release of a database of more than 4,000
Alzheimer’s patients who have participated in industry-sponsored trials. Seven of CAMD’s
member organizations agreed to
share their data from 11 Alzheimer’s disease clinical studies. The
data were standardized, pooled,
and made available to qualified researchers around the world. These
organizations included Abbott
Laboratories, Alzheimer’s Disease
Cooperative Study, AstraZeneca
Pharmaceuticals LP, GlaxoSmithKline, Johnson & Johnson, Pfizer,
and Sanofi Aventis. Ephibian,
based in Tucson, Arizona, built a
secure online data repository for
the information.11 CAMD called
the database the “first effort of its
kind to create a voluntary industry data standard that will help
accelerate new treatment research
on brain disease.”12 Patient identifiers have been removed to ensure
patient privacy.
“If good simulations
can be devised by inclusion of real world
data, a researcher
Modeling
Alzheimer’s
Disease
could run hundreds or
thousands of clinical
trials virtually before
C-Path ended up with about $9
million in public and private
donations during its first 5 years.
Science Foundation Arizona also
provided C-Path with $14 million over several years. Despite
its early challenges, C-Path has
formed seven global consortia,
one of which is the Coalition
Against Major Diseases (CAMD).
CAMD’s goal is to bring together major pharmaceutical
companies, FDA, the European Medicines Agency (EMA),
the National Institute on Aging, the National Institute of
Neurological Disorders and Stroke, and patient groups in “a
collaboration to develop new knowledge that will enhance
the industry’s ability to develop innovative new therapies.”8
The Coalition now includes more than 150 scientists.
CAMD set out to focus on accelerating drug development
for patients with chronic neurodegenerative diseases, such
as Alzheimer’s disease and Parkinson’s disease, by “advancing drug development tools for evaluating drug efficacy,
conducting clinical trials, and streamlining the process of
regulatory review.”9
attempting to run a
real-world trial.”
6
In addition to sharing data,
CAMD says its pharmaceutical
members have agreed to use the
new common data standard established for Alzheimer’s disease by the Clinical Data Interchange Standards Consortium
(CDISC), a global multidisciplinary, nonprofit organization. CDISC’s standards are developed to be vendor-neutral
and platform-independent and can be freely accessed on the
CDISC website. (See Figure 1.) “This unprecedented datasharing is game-changing for companies that are developing
new therapies for neurodegenerative diseases,” says Woosley
in CAMD’s press release. “Scientists around the world will
be able to analyze these new combined data from pharmaceutical companies, add their own data, and consequently
better understand the course of these diseases.”
Research Practitioner
Fig ure 1: CDISC Sta nda rds
For those interested in learning more about CAMD’s
Alzheimer’s Disease Clinical Trial Simulation tool, C-Path
provides this information:1
Intended Applications
■■ Sample size calculations
■■ Determination of optimal trial durations and treatment
effect measurement times
■■ Comparison of the sensitivity of competing trial designs
to assumptions about the types of expected treatment
effects (time to maximal effect, effects that increase or
decrease over time)
■■ Determination of the most appropriate data analytic
methods for novel trial designs
Basic Requirements
For the proper application of this clinical trial simulation
tool, the following background expertise and resources are
recommended:
■■ Advanced-level knowledge of the statistical and
methodological background behind drug-disease-trial
models
■■ Advanced-level knowledge of the R programming
language for statistical analysis
■■ Minimum system requirements:
–– Operating System: Microsoft Windows XP SP3, 7,
8/Mac OS X
–– Processor: 2 gigahertz (GHz) Dual Core
–– RAM: 2 gigabyte (GB) (32-bit) or 4 GB (64-bit)
–– Hard disk space: 150 megabytes (MB)
–– Graphics card: Microsoft DirectX 9 graphics device
■■ Please take the time to explore the Read Me file
Basic Components (R scripts)
Patient recruitment acRecruit()
■■ Generates patients, their demographics, APOE4 distri-
bution, and baseline MMSE distribution
Patient randomization acRandomize()
■■ Assigns patients to treatment arms, time intervals, and
drug effects
ADAS-cog simulation acRun()
■■ Given previous conditions, simulates ADAS-cog scores
(may include inter-study variability or dropouts)
Source: AD trial simulation. Critical Path Institute. Available at:
http://c-path.org/programs/camd/simulation-tool/.
Research Practitioner
CAMD continued to work on its computer simulator models
to be used in the treatment of mild-to-moderate Alzheimer’s
disease. On June 12, 2013, C-Path announced that both
FDA and EMA had independently reached favorable decisions on the value of the disease simulation tool.13 The FDAdesignated “fit-for-purpose” tool, which applies computerized
models to simulate “what-if” scenarios, is the first of its
kind to receive this regulatory designation. The tools will be
offered as a public resource for sponsors who are designing
trials of new therapies. “This model provides valuable insight
into the relatively slow rate of disease progression in a mild
patient population — a critical area of focus for drug development — and guidance for designing an effective study in
multiple populations, while emphasizing the need to refine
the model as we work to treat patients earlier in the disease
process and as new data emerges,” says Richard Mohs, vice
president, early-phase neuroscience clinical research at Eli
Lilly and a member of the CAMD coordinating committee.
The computer simulator models caught the attention of the
Wall Street Journal (WSJ), which talked about how stakeholders hope the models can help prevent high-risk drug
failures. Pfizer told the WSJ it was using the simulator to
help design trials for four Alzheimer’s drug-development
programs. Richard Lalonde, Pfizer’s global head of clinical pharmacology, told the WSJ that the company uses the
simulator to see how long a trial must last. To evaluate test
designs, the simulator incorporates data from previous trials
of Alzheimer’s treatments as well as findings from a NIH
neuroimaging study of Alzheimer’s patients and published
academic paper.1
Pfizer also has used computer simulators in clinical trial
design in the testing of gabapentin, a mood-stabilizing
anticonvulsant. In a July 1998 article in Epilepsy Research,
researchers spoke of using a computer-simulated pharmacokinetic model as one part of a two-part study.14 The other part
consisted of a clinical pharmacokinetic study in nine adult
epileptic patients. In the discussion of the study, the authors
said, “Good agreement was observed between values from
this study and predicted values based on the pharmacokinetic model.” Fast forward to a 2013 article in the American
Journal of Therapeutics in which pharmacokinetic simulations
assessed different dosage regimens to help guide clinicians in
moving patients from gabapentin to pregabalin therapy when
warranted.15
Pfizer used this modeling work to gain approval for gabapentin, Teuscher says. “The general public thinks that simulations occur where there is no human testing and then you
approve a drug. That’s not what was done.” Drug approval
required two clinical studies of the drug at the same dose
level, he explains. “If both studies show that the drug is
effective, then the drug can be approved. In the gabapentin
7
The Importance of Standards
I
f students in a classroom each wrote a paper in a different language, their teacher would spend much of
her time trying to understand them. So it is with data
standards. If the data from different health care institutions are formatted using the same rules, then communication and efficiency are greatly increased.
“The benefit of encoding clinical data standards in software applications is that, once developed and adopted, they
can be followed reliably with a low error rate — allowing
automation of repetitive processes and consistency across
applications,” says the California Healthcare foundation
in its article “Clinical Data Standards Explained.”1 “Thus,
clinical information can have the same meaning and usability in a wide range of settings. The challenge, however,
is agreeing to and coding for every possible rule and exception to handle the enormous complexity and variability of
clinical processes.”
A groundbreaking data repository of more than 4,000
Alzheimer’s patients who had participated in recent clinical trials is not useful if no one can read the data. That is
why the Critical Path Institute in Tucson, Arizona, signed
a partnership agreement in 2012 with the Clinical Data
Interchange Standards Consortium (CDISC) in Austin,
Texas, to establish the Coalition For Accelerating Standards and Therapies. The purpose of this initiative is “to
accelerate clinical research and medical product development by creating and maintaining data standards, tools,
and methods for conducting research in therapeutic areas
that are important to public health.”2 CDISC posted Version 1.0 of an Alzheimer’s data standard, used to develop
the Alzheimer’s disease data repository, on its website in
October 2011.
Standards are also in development for tuberculosis, pain,
Parkinson’s disease, polycystic kidney disease, virology,
oncology, and cardiovascular disease therapeutic areas,
CDISC says. In January 2013, CDISC announced a theraexample, they had two studies, but they had different dose
levels. They used modeling to show that even though they
had different dose levels, the effect was similar or relatable.
They were able to get the drug approved even though they
didn’t have two studies at the exact same dose level.”
A Look to the Future
Since not everything about the human body is understood
or can be explained, all of the models are wrong but some
8
peutic area data standard for Parkinson’s disease. The standard will help researchers combine and evaluate data from
multiple studies, streamline the efficiencies of new clinical
trials, and aid the evaluation of new drugs and treatments
for Parkinson’s disease, CDISC says.3
As adoption of its standards increased, CDISC wished to
provide a “one-stop shopping” environment where CDISC
data models, standard data elements, and controlled
terminology could be aligned, linked, and published for
electronic access and download, according to the National
Center for Biomedical Ontology (NCBO).4 “This environment, known as CDISC SHARE, is envisioned as a globally accessible electronic library, which through advanced
technology, enables precise and standardized data element definitions to be used by applications and studies to
improve biomedical research and its link with healthcare.”
According to NCBO, stakeholders will achieve multiple
benefits from SHARE including: improved operational
efficiency around the collection, processing, exchanging
and reporting of data, evaluation of drug safety concerns
across traditional organizational boundaries, and enhanced
scientific capabilities and resulting patient benefits and
therapeutic efficacies. For a detailed discussion of SHARE,
see http://www.bioontology.org/cdisc-share.
References
1. Clinical Data Standards Explained. California HealthCare Foundation. November 2004. Available at: www.iha.org/pdfs_documents/calinx/FactSheetClinicalDataStandardsExplained.
pdf.
2. CDISC, C-Path, and FDA Collaborate to Develop Data Standards to Streamline Path to New
Therapies. CDISC. June 2012. Available at: www.cdisc.org/content5571.
3. Coalition for Accelerating Standards and Therapies (CFAST) Announces a Resource for
Parkinson’s Disease Clinical Development. CDISC. January 31, 2013. Available at: www.
cdisc.org/content6455.
4. CDISC SHARE – Pathway into the Future for Standards Development & Delivery. The
National Center for Biomedical Ontology. April 21, 2010. Avilable at www.bioontology.org/
cdisc-share.
are useful, says Teuscher. “We as a scientific group still don’t
understand how the body works 100%. As we gain more
data and more information, we begin to refine those models
and improve them. Each time we learn more about the human body and how it works, we improve the model,” he says.
“These models are not like models of physics because we don’t
understand all of factors in the biology that affect how they
work. Appreciating that models can change over time as we
get new information is exciting, but it can also be troubling
for people who want absolutes. But with biology, there are very
few absolutes. We don’t understand the system well enough.”
Research Practitioner
Authors in a 2012 issue of Statistica reviewed computer
simulation from a design standpoint.16 Several “burning
questions” need to be answered in relation to clinical trial
simulation, they say:
■■
Scientificity: Is this new discipline rigorous enough?
Can results obtained by computer experiments really be
trusted?
■■
Efficacy: Is it true that simulated clinical trials can speed
the drug development process? After all, the model development procedure too is associated with time and high
costs.
■■
Ethics: Is it safe for the patients? Is it to their best advantage? Or do these efforts only help the pharmaceutical
companies to reduce costs without any benefit for the
patient community? 9
The authors say the successful execution of a simulation
project requires a multidisciplinary approach from scientists
from various disciplines and institutions. “We stress that
simulations are not aimed at replacing real-life trials; rather,
physical and computer experiments are two complementary sources of information with distinct roles and different
degrees of cost, speed, and reliability. Simulation is usually
cheaper and faster, and, what is more important, avoids the
major ethical problems involved in clinical research, but
in order to be of use, simulation must be fairly close to the
physical set-up.”
The authors suggest that a virtual experiment may be part of
a sequence in which simulations and physical observations
alternate roles. They says the fundamental steps in designing
such a mixed trial would consist of:
■■
Designing actual (small) trials that provide the physical
data
■■
Designing the simulated ones, to be run in groups, one
after another, to improve knowledge of the process
■■
Choosing a “switching rule”: When do you change over
from a virtual experiment to a real one to acquire more
data, and vice-versa?
■■
Choosing a final stopping rule.
References
1. Rockoff JD. Simulators Help Build a Better Drug Trial. Wall Street Journal Nov. 17, 2003. Available at: http://online.wsj.com/news/articles/SB100014240527023039143045791920
33377938714. Accessed Jan. 10, 2014.
2. Girard P, Cucherat M, Guez D. Clinical trial simulation in drug development. Therapie
2004;59:287-295,297-304.
3. U.S. Food and Drug Administration. Science and Research. FDA’s Critical Path Initiative. Available
at: www.fda.gov/ScienceResearch/SpecialTopics/CriticalPathInitiative/ucm076689.htm.
Accessed Jan. 10, 2014.
4. U.S. Food and Drug Administration. Science and Research. Challenges and Opportunities Report
– March 2004. Available at: www.fda.gov/ScienceResearch/SpecialTopics/CriticalPathInitiative/CriticalPathOpportunitiesReports/ucm077262.html. Accessed Jan. 10, 2014.
5. U.S. Food and Drug Administration. Critical Path Opportunities List. Available at: www.fda.gov/
downloads/scienceresearch/specialtopics/criticalpathinitiative/criticalpathopportunitiesreports/
UCM077258.pdf. Accessed Jan. 10, 2014.
6. Woodcock J, Woosely R. The FDA Critical Path Initiative and its influence on new drug development. Annu Rev Med 2008;59:1-12.
7. Russell J. Whatever happened to the Critical Path? Bio-It World April 12, 2007. Available at:
www.bio-itworld.com/issues/2007/april/russell-transcript/. Accessed Jan. 10, 2014.
8. Coalition Against Major Diseases: Work Scope 1.1. Critical Path Institute. July 2009. Available
at: www.c-path.org/pdf/CAMDWorkScope.pdf. Accessed Jan. 10, 2014.
9. CAMD Overview. Critical Path Institute. Available at: http://c-path.org/programs/camd/camdoverview/#section-1782. Accessed Jan. 10, 2014.
10. Coalition Against Major Diseases (CAMD). Work scope 1.1, July 2009. Available at:
www.c-path.org/pdf/CAMDWorkScope.pdf. Accessed Jan. 10, 2014.
11. Critical Path Institute and Clinical Data Interchange Standards Consortium announce release
of data standards for Alzheimer’s Disease. Critical Path Institute. Oct. 17, 2011. Available at:
http://c-path.org/wp-content/uploads/2013/08/AlzDataStandard.pdf. Accessed Jan. 10,
2014.
12. Coalition Against Major Diseases. Critical Path Institute. First combined pharmaceutical trial data
on neuro-degenerative diseases; shared resource from unique public-private partnership will help
accelerate Alzheimer’s, Parkinson’s, and other brain disease research. June 11, 2010. Available
at: http://c-path.org/wp-content/uploads/2013/08/CAMDPressRelease62010.pdf. Accessed
Jan. 10, 2014.
13. U.S. Food and Drug Administration and European Medicines Agency reach landmark decisions
on Critical Path Institute’s clinical trial simulation tool for Alzheimer’s Disease. July 10, 2013.
Available at: http://c-path.org/wp-content/uploads/2013/09/CAMD-AD-Model-press-release.
pdf. Accessed Jan. 10, 2014.
14. Gidal BE, DeCerce J, Bockbrader HN, et al. Gabapentin bioavailability: Effect of dose and
frequency of administration in adult patients with epilepsy. Epilepsy Res 1998;31:91-99.
15. Bockbrader HN, Budhwani MN, Wesche DL. Gabapentin to pregabalin therapy transition:
A pharmacokinetic simulation. Am J Ther 2013;20:32-36.
16. Giovagnoli A, Zagoraiou M. Simulation of clinical trials: A review with emphasis on the design
issues. Statistica 2012;72:63-80.
Giovagnoli and Zagoraiou conclude:
To the best of our knowledge, the best strategy of integrating real and simulated trials to build actual knowledge while dynamically modifying the computer code to
get closer and closer approximations to the reality, has not
yet been the object of theoretical investigation in a clinical
research context.
Research Practitioner
9
Creating a Standard
Practice for
Communicating
Lay Language
Trial Results
to Study Volunteers
By Ken Getz and Zach Hallinan
Key words: communicating trial results, delivering
results, standard practices, study volunteers
Learning Objectives:
1. Discuss the current conditions for disclosing
lay- language clinical trial results summaries to
study volunteers.
2.Describe a tested and feasible approach to
delivering lay language trial results to study
volunteers.
3.Identif y barriers and challenges research
sponsors face in implementing trial results
communication programs.
S
ince its onset, the “patient centricity” movement has
prompted a growing number of research sponsors to
develop and implement new initiatives intended to
acknowledge and amplify the important role that patients
play as participants and partners in clinical trials. Among
these new initiatives are programs designed to deliver clinical trial results in lay language, non-technical summaries to
study volunteers. This article provides context for the critical
obligation to provide lay language results to study volunteers,
discusses efforts underway to establish standard practices to
routinely deliver these results, and describes the anticipated
impact of these programs.
Background
Clinical research volunteers want to know that their participation mattered and that it was appreciated. But historical
industry practice among clinical research professionals has
sent a very different message to study volunteers. Although
clinical trial results are routinely posted online, in compliance with federal law when the drug/device is approved
or within a year of study completion, the routine communication of those results is not occurring. Survey research
reviewed in the literature shows that, on average, more than
90% of study participants in any given trial report that they
never learned about their specific results from study staff or
the research sponsor.1
In a global survey of more than 5,600 study volunteers
conducted in late 2013, the prospect of receiving their trial
results was one of the top five reasons for choosing to participate. Among study volunteers from South America and AsiaPacific countries, the prospect of receiving trial results was
rated the most important factor in their enrollment decision,
above even quality medical care.2
The Declaration of Helsinki has long treated the dissemination of clinical trial results as a moral obligation of the
research community to its study subjects, and in the most
recent revision states: “All medical research subjects should
be given the option of being informed about the general
outcome and results of the study.”3 In March 2011, FDA
adopted final amended informed consent regulations requiring informed consent forms to include a statement indicating
that data from the clinical trial has been or will be entered
into the ClinicalTrials.gov registry.4 But posting clinical trial
results on this public forum does not go far enough.
Assessments on the use of the ClinicalTrials.gov registry
show that study volunteers, patients, and the general public
are not the primary audience for this information.5 Not all
study volunteers have access to the Internet or the ability to
locate their specific trial. Among those who are able to find
10
Research Practitioner
their specific clinical trial, interpreting the technical trial
results summaries is very difficult.6 The parties primarily
accessing the highly technical information on ClinicalTrials.
gov are professional researchers, policymakers, and analysts
monitoring data trends.6
Recently, European regulators and lawmakers have been
especially active in ensuring even greater transparency. In
October 2013, the European Medicines Agency (EMA) announced progress upgrading the EudraCT system to allow
for the public release of clinical trial results summaries in
technical format, with full implementation expected before
the end of 2014.7 The European Parliament will vote in
March 2014 on a revised clinical trials directive, including
a widely supported provision to require that trial results be
provided in lay language, nontechnical summaries within a year
after the trial ends, regardless of
marketing authorization.8
so that clinical research professionals can perform their work
and public health can advance.
Failure to communicate trial results is also a substantial
missed opportunity for the research community to rebuild
public trust, and establish and nurture relationships with
study volunteers. An overwhelming majority of investigative
sites (98%) also want to provide trial results to their study volunteers.11 They feel that it is not only their moral obligation to
do so, but also an essential way to strengthen the relationship
with study volunteers and an opportunity to maintain contact
with patients who have completed participation.
Study staff feels that patient relationships are compromised
when they are unable to provide results. Investigative sites
note that they too feel valued as
partners when research sponsors
share trial results with them. For
these reasons, there is a strong
business imperative for research
sponsors to proactively and routinely communicate trial results.
The Declaration of
Trade associations are also weighing in. In 2013, the Pharmaceutical
Research and Manufacturers of
America and the European Federation of Pharmaceutical Industries
and Associations issued a joint
statement expressing the commitment of their members to share
“clinical trial results with patients
who participate in clinical trials” as
one of five Principles for Responsible Clinical Trial Data Sharing.9
This commitment is intended to
begin as of January 2014, and at
least one industry sponsor already
has committed to release of trial
results in lay language for all Phase
IIb and III studies starting in 2014
and going forward.10
Helsinki has long
treated the
dissemination of
clinical trial results as
a moral obligation
of the research
communit y to its
study subjects.
A Winning Initiative
Clinical research volunteers deserve our full commitment
and best efforts to communicate their trial results. Even
more, they shouldn’t have to search for their trial results on
their own, they should receive them directly from their primary partner-in-research — the study staff. Moreover, study
volunteers should receive them in a reasonable time frame
and in a form that is easy to understand. Although disconcerting for some sponsors, there is no ethical justification for
withholding lay language results until marketing authorization has been received. This is the ultimate act of appreciation to those who have given the gift of their participation
Research Practitioner
Ultimately, routinely and systematically communicating trial
results summaries in lay language
to study volunteers is the right
thing to do. Since 2010, the
Center for Information and Study
on Clinical Research Participation
(CISCRP) — in collaboration
with research sponsors — has
found that communicating lay
language trial results summaries
can be easily, feasibly, and affordably established as a standard
practice within organizations and
industry-wide.
CISCRP began piloting programs
with Pfizer in 2010 and with Lilly
in 2011. Results of some of these early pilots are published
in Applied Clinical Trials and Expert Review in Clinical
Pharmacology.1,12 Although early adoption rates were slow,
CISCRP has seen the number of sponsors communicating
trial results to their volunteers doubling each of the past 2
years, bringing the total to 24 research sponsors piloting or
broadly implementing programs at the time of this article’s
authorship.
The program is designed to integrate easily into established
clinical trial practices and the research sponsor’s internal
clinical trial results publishing practices. The program also
engages study staff throughout the process. Study staff
initially discusses when clinical trial results will be made
11
Fig ure 1: Process for Commu nicating Tria l Resu lts to Study Volu nteers
Discuss
during
informed
consent
Set Expectations
Review
process at
volunteer’s
last visit
Thank Volunteers
Send
reminders
every 6
months
Share trial results when
they are posted on registries
and published in peer-reviewed
journals
Ongoing Updates
Communicate Study
Findings
Ambassador
– Educator
Establishing a cycle
of education, trust,
and engagement
Public
Study
Volunteer
Source: CISCRP
available during the informed consent process. Next, study
volunteers receive a reminder and a thank-you note during
their last study visit. Generally every 6 months after the trial
has ended, volunteers receive a reminder that their study
results are being analyzed. An institutional review board or
an institutional ethics committee approves all communications that are received by the study volunteers while they are
actively participating in the study.
The research sponsor notifies CISCRP once the sponsor
has prepared and published a technical summary on www.
ClinicalTrials.gov, the EudraCT system, or in a recognized
peer-reviewed journal. CISCRP’s editorial panel — made up
of consumer science and medical communication experts,
health care providers, and patient advocates — translate the
technical/scientific study results into easy-to-understand lay
language summaries at a validated sixth- to eighth-grade
reading level. CISCRP also manages the translation of the
non-technical summaries into patient’s native languages. The
sponsor’s researchers and staff then review the lay language
trial results summary for accuracy and consistency with the
technical/scientific summary. Next, CISCRP professionally
produces printed reports and ships them to study staff to be
disseminated to study volunteers.
In evaluations of the program through surveys, interviews,
12
and focus groups, study volunteers have been very receptive
to the program. They have expressed high levels of satisfaction with the lay language summaries. In pre- and postprogram comparisons, study volunteers have demonstrated
statistically significant improvements in their comprehension
of the purpose of their clinical trial and the summary findings of the study.1
Investigative site staff also has been very receptive to the
program. Since the launch of the program, CISCRP has
gathered feedback from more than 50 investigators, study
coordinators, and clinical research directors. Only one investigator was opposed to providing lay language clinical trial
results summaries, citing his belief that research professionals
“know what is best for their patients.”11
All other study staff felt that there is a substantial and essential need for a program to communicate trial results in nontechnical language, and they appreciated the opportunity to
disseminate results to their patients. As one study coordinator put it: “In my 25 years of conducting clinical trials, I have
never been able to let subjects know how the study turned
out.” Many study staff echoed this sentiment and felt that a
program to communicate trial results to study volunteers has
the additional benefit of ensuring that site staff is informed
of the results.
Research Practitioner
Lessons and Insights
the lay-language summary of results by email, but volunteers
report that receiving a printed, hard copy is preferred.1
During the past several years, CISCRP has learned from
working with research sponsors in implementing clinical trial
results communication programs. Several key themes are
described below:
It is critical to keep communications to study volunteers
unbiased and strictly non-promotional. The FDA Amendments Act of 2007 provisionally requires sponsors to post a
“summary of the clinical trial and its results that is written
in non-technical, understandable language for patients” to
ClinicalTrials.gov. As of late 2013, however, no final ruling on this provision has been made. This delay is in large
part associated with the government’s challenge in ensuring
that the trial results summary not
be misleading or promotional as
required under the law.13
Clearly it is essential that clinical
trial results summaries be completely free from bias or promotional
language. To address this issue, the
independent, non-profit CISCRP
convenes an objective editorial
panel to “translate” the technical
findings. The sponsor’s research
staff then provides a final review
for accuracy. This approach creates
multiple checks against misleading
and biased communication, with
the sponsor separated from patients
by both investigative sites and a
patient-focused third party with no
vested interest in the study outcome.
Based on qualitative feedback from site personnel, study
staff estimate that their time commitment to support the
CISCRP program ranges from an additional 30 minutes to
2 hours per study, with the largest time commitments coming not
when sites have high numbers of
patients — even sites with 40 or
more patients report half-hour time
commitments — but when patient
records have been moved off-site
into archival storage.
It is essential that
clinical trial results
summaries be
completely free from
bias or promotional
language.
Study staff is a partner in the
process. Study coordinators and investigators consistently say
that they are ultimately responsible for any communications
to their patients. This ensures not only patient privacy on
the one hand, but also provides an opportunity to strengthen
the relationship between study volunteers and study staff.
Study volunteers view their relationship with site personnel
as a fundamental determinant of a successful clinical trial
experience.14
As more sponsors begin regularly communicating trial results
to their volunteers, it is critical that the central role of the
investigative site be recognized and leveraged while minimizing any added burden on study staff. In CISCRP’s program,
this is accomplished by providing all patient materials to sites
in mail-ready envelopes, so that sharing results with their
study volunteers can be as simple as adding an address and
a stamp. In certain cases, it may be appropriate to provide
Research Practitioner
Some investigative sites choose to further personalize each
report sent to study volunteers. Handwritten notes and evening events during which the investigator discusses the results
with his or her patients using the written lay-language report
as a jumping-off point are two examples of these personal
approaches that sites have implemented. Even when staff resources do not allow for these additional steps, almost all sites
are able to mail a printed report to their study volunteers.
It is best to introduce trial results
communication programs during
the study planning stage. During
a pilot rollout, the CISCRP trial
results communication program
typically represents an unplanned
expense. As a result, it often
requires an inordinate amount of
time to approve that unplanned
expense and to determine what
function will cover that expense.
Many research sponsors begin
pilot efforts to communicate trial
results by identifying a handful of studies that are soon to
be or have already been completed. CISCRP has found that
the ideal process plans for and integrates trial results communication from study initiation onward. Doing so ensures
that the communications process is integrated into the study
planning and budgeting process and that study staff are
engaged at the outset of the trial.
Committing to communicate trial results at the start of
the study also optimizes the value of the program. Among
other benefits, study volunteers are reassured that sponsors
intend to disclose the trial results regardless of the study
outcome (and volunteers are clear that they want to know
the results whether positive or negative). For study volunteers, the prospect of learning how the study contributed to
the advancement of medical knowledge may also engender a
higher sense of commitment to stay in a clinical trial and may
13
Fig ure 2 : Grow t h in t he Number of Sponsors Actively Pla nning a nd E xecuting
Tria l Resu lts Commu nication Progra ms
30
Number of Major and Mid-Sized
Pharmaceutical and Biotechnology Companies
21
15
4
1
2010
2011
2012
2013
2014E
Source: CISCRP
help to foster altruistic motivations that are among the most
important factors leading to the decision to enroll in a clinical
research study. Engagement of study volunteers can be further
strengthened with ongoing communication to bridge the gap
between their last study visit and the time that trial results are
ready to be shared.
Programs are more easily embraced and supported when
they are tied to broader organizational initiatives. Most
research sponsors who have successfully executed trial results
communication programs did so as part of broader, enterprise-wide initiatives to support patient-centricity, patient
retention initiatives, or sponsor-site relationship improvement.
In many cases, resources are more easily found when the CISCRP program is tied to broader initiatives that have already
received organizational buy-in and support. Enterprise-wide
initiatives also tend to have more visibility, making it easier to
raise initial and ongoing awareness among clinical teams.
Creating a New Standard
The research enterprise is taking steps to improve transparency of clinical study results for the scientific community
(e.g., FDA’s proposed TEST Act of 2012; the EMA’s planned
release of trial data sets, and the AllTrials Campaign call for
open data). And more is being done to ensure that clinical
trial results are given to study volunteers. To them we owe
14
not only our sincerest gratitude, but also our respect reflected
in our commitment to ensure that they are among the first to
learn about the results of studies to which they gave the gift
of their participation. A growing number of research sponsors are implementing trial results communication programs.
But they are largely doing so voluntarily to honor and thank
their study volunteers and in anticipation of regulatory
changes requiring them to do so.
Within 5 years, pharmaceutical and biotechnology companies will be routinely providing clinical trial results to
study volunteers around the world in response to regulatory
mandate, public pressure, and a desire to build stronger relationships with clinical research volunteers. Although at this
time clinical trial results are provided a year or so after the
clinical trial has ended, within 5 years we anticipate that the
duration between study completion and communication of
clinical trial results will be compressed. The growing impact
of data management technology solutions and patient preference for timely information will prevail.
High levels of study volunteer and investigative site receptivity to this initiative suggest that the communication of
clinical trial results may become a means to differentiate the
clinical trials experience for participants and may assist in
improving volunteer retention rates and study staff morale.
During the next several years, research sponsors will primarily focus on providing general clinical trial results to study
volunteers. But within 5 years, as the patient centricity move-
Research Practitioner
ment continues to gain traction and this standard practice
evolves, it is conceivable that many sponsors will be piloting
and implementing efforts to communicate more detailed,
customized, patient-specific study findings.
References
1. Getz K, Hallinan Z, Simmons D, et al. Meeting the obligation to communicate clinical trial results
to study volunteers. Exp Rev Clin Pharmacol 2012;5:149-156.
2. CISCRP 2013 Perceptions and Insights Study. Available at: www.ciscrp.org. Accessed Jan. 15,
2014.
3. World Medical Association. 2013. World Medical Association Declaration of Helsinki: Ethical
Principles for Medical Research Involving Human Subjects. JAMA 2013; doi:10.1001/
jama.2013.281053.
4. Food and Drug Administration Amendments Act (“FDAAA”) § 801(b)(3)(A) 21 C.F.R. §
50.25.
5. Zarin D, Tse T, Williams Ret al. The ClinicalTrials.gov results database – update and key issues.
N Engl J Med 2011;364:852-860.
6. Getz K. Public and Patient Usage and Expectations of Clinical Trial Registries. Clinical Trial
Registries. Boston: Birkhauser Verlag; 2006: 47-58.
7. European Medicines Agency. European Medicines Agency launches a new version of EudraCT.
2013. Available at: www.ema.europa.eu/docs/en_GB/document_library/Press_release/2013/10/WC500151974.pdf. Accessed Jan. 15, 2014.
8. European Parliament. 2012/0192(COD) - 10/06/2013 Committee report tabled for plenary,
1st reading/single reading. 2013. Available at: www.europarl.europa.eu/oeil/popups/summary.do?id=1274291&t=d&l=en. Accessed Jan. 15, 2014.
9. Pharmaceutical Research and Manufacturers of America. European Federation of Pharmaceutical
Industries and Associations. 2013. Available at: http://phrma.org/sites/default/files/pdf/
PhRMAPrinciplesForResponsibleClinicalTrialDataSharing.pdf. Accessed Nov. 15, 2013.
10. Pfizer. Returning Clinical Trial Data to Patients. 2013. Available at: www.pfizer.com/research/
clinical_trials/trial_data_and_results/data_to_patients/. Accessed Jan. 15, 2014.
11. Center for Information and Study on Clinical Research Participation (CISCRP). Presented
December 4, 2013 at Harvard MRCT Center Annual Meeting, Boston, MA.
12. Getz K. The imperative to provide trial results to study volunteers. Appl Clin Trials 2010;19:52-9.
13. FDA Amendments Act of 2007 Sec. 801(J)(3)(D)(i). Available at: www.gpo.gov/fdsys/pkg/
PLAW-110publ85/html/PLAW-110publ85.htm. Accessed Nov. 15, 2013.
14. Getz KA. Conversations with study volunteers. Appl Clin Trials 2010;19:32-34.
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Continuing Education
Requirements for Successful Completion
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Exam for Continuing Education
Research Practitioner 15.1
3 Contact Hours
Computer Simulations Take Their Place
in Clinical Trial Design
1. Computer simulations of a clinical trial are as predictive as
a simulator for flying an airplane.
A. True
B. False
2. What was NOT listed as information that is often needed
for a computer simulation of a clinical trial?
A. Age and demographics
B. Sponsor contacts
C. Chemical composition of drug dosage variations
D. Potential interactions
5. What do Janet Woodcock and Raymond Woosley say is
one of the greatest scientific flaws in the current process of
medical product development?
A. The growing length and complexity of the consent form
B. An ever-growing mass of confusing federal legislation
C. A huge investment in data failing to produce generalizable knowledge
D. Deviations from the established protocol
6. What was one concern that supporters had of C-Path in the
early years?
A. Lack of funding
B. Conflict of interest
C. Outdated technical standards
D. Uncertainties about safety and effectiveness
7.
C-Path’s Coalition Against Major Diseases (CAMD) released a database of more than 4,000 patients in clinical
trials testing treatment options for what disease?
A. Parkinson’s
B. Diabetes
C. Alzheimer’s
D. Epilepsy
8. An article in Statistica says several burning questions need
to be answered when looking at computer simulations from
a design standpoint. Which of the following is NOT one of
them?
A. Ethics
B. Scientificity
C. Efficiency
D. Efficacy
3. According to an article in Therapie, what is one of the
expected benefits of using computer simulations in clinical
trials?
A. An increased number of trial subjects
B. A faster way to get products to market
C. A way to reduce price of drug products
D. A reduced number of failed clinical trials
9. What is one of the challenges of encoding clinical data
standards?
A. Coding for every possible rule and exception
B. Estimating subject dropout rate
C. Finding experienced technical personnel
D. Automating the evaluation of eligibility criteria
4. According to FDA, what is the critical path for product
development?
A. The path of creating predictive biomarkers to identify
safety problems and designing clinical trials
B. The path of a product’s discovery/design concept to
commercial marketing
C. The time to develop and revise the trial protocol
D. The path of recruiting subjects and following them to
the trial end
10. Clinical Data Interchange Standards Consortium’s SHARE
is:
A. a website where technical personnel present standards
they created.
B. a website where health care professionals rate the
ease of using data standards.
C. a globally accessible electronic library of standardized
data elements.
D. an interactive electronic library of adverse events.
16
Research Practitioner
Creating a Standard Practice
for Communicating Lay Language Trial
Results to Study Volunteers
11. What percent of study participants report learning about
specific results from the study in which they participated?
A. 10%
B. 25%
C. 60%
D. 90%
12. Among study volunteers in South America and Asia-Pacific
countries, what was the most important factor in their enrollment decision?
A. Receiving quality medical care
B. The prospect of receiving trial results
C. Receiving financial compensation
D. Receiving a detailed explanation of the study design
18. When should sponsors begin discussing the trial results
communication program?
A. During the planning stage
B. During the pilot rollout
C. Once the study is underway
D. After the study is complete
19. For study volunteers, the prospect of learning how the study
contributed to advancement of medical knowledge may
lead to a higher sense of commitment to staying in a clinical trial.
A. True
B. False
20. Communication of clinical trial results may lead to improving volunteer retention rates and study staff morale.
A. True
B. False
13. Which group is among the primary audience for the
www.ClinicalTrials.gov website?
A. Study volunteers
B. Patients
C. The general public
D. Professional researchers
14. According to research from the Center for Information and
Study on Clinical Research Participation, what percent of
investigative sites indicated a desire to provide trial results
to study volunteers?
A. 88%
B. 90%
C. 95%
D. 98%
15. The number of sponsors communicating trial results to
volunteers is declining each year.
A. True
B. False
16. It is acceptable for clinical trial results summaries to contain
promotional language.
A. True
B. False
17. What is the largest time commitment for study staff communicating results to study volunteers?
A. When studies have more than 40 patients
B. When trial results are mailed to study volunteers
C. When patient records are moved into offsite
archives
D. When trial results are sent to study volunteers via
e-mail
Research Practitioner
17
Regulatory Update
Final Guidance on Design
Considerations for Pivotal
Clinical Investigations
for Medical Devices
In the November 7, 2013, Federal Register, FDA announced
the availability of a guidance document titled Design Considerations for Pivotal Clinical Investigations for Medical Devices.
This document is intended to provide guidance to those
involved in designing clinical studies intended to support
premarket submissions for medical devices and for FDA staff
who review those submissions. This guidance document
describes different study design principles relevant to the
development of medical device clinical studies that can be
used to fulfill premarket clinical data requirements.
Although FDA has articulated policies related to design
of studies intended to support specific device types, and
a general policy of tailoring the evidentiary burden to the
regulatory requirement, FDA has not attempted to describe
the different clinical study designs that may be appropriate
to support a device premarket submission, or to define how
a sponsor should decide which pivotal clinical study design
should be used to support a submission for a particular
device. The guidance document describes different study design principles relevant to the development of medical device
clinical studies that can be used to fulfill premarket clinical
data requirements. The guidance is not intended to provide
a comprehensive tutorial on the best clinical and statistical
practices for investigational medical device studies.
A medical device pivotal study is a definitive study in which
evidence is gathered to support the safety and effectiveness evaluation of the medical device for its intended use.
Evidence from one or more pivotal clinical studies generally
serves as the primary basis for the determination of reasonable assurance of safety and effectiveness of the medical
device of a premarket approval application (PMA) and FDA’s
overall risk-benefit assessment. In some cases, a PMA may
include multiple studies designed to answer different scientific questions.
The guidance describes principles that should be followed
for the design of premarket clinical studies that are pivotal in
establishing the safety and effectiveness of a medical device.
Practical issues and pitfalls in pivotal clinical study design are
18
discussed, along with their effects on the conclusions that can
be drawn from the studies concerning safety and effectiveness.
In the August 15, 2011, Federal Register, FDA announced the
availability of the draft version of this guidance. There were 19
comments received from the public, and FDA considered the
comments and revised the guidance, as appropriate.
Interested persons may submit either electronic or written comments regarding final FDA guidance at any time.
Submit electronic comments on the guidance to http://www.
regulations.gov/. Submit written comments to the Division
of Dockets Management (HFA-305), FDA, 5630 Fishers
Lane, Room 1061, Rockville, MD 20852. Identify comments
with Docket Number FDA-2011-D-0567.
Final Guidance
on Qualification Process
for Drug Development Tools
In the January 7, 2014, Federal Register, FDA announced
the availability of a guidance document titled Qualification
Process for Drug Development Tools. This guidance describes
the qualification process for drug development tools (DDT)
intended for potential use over time in multiple drug development programs. The guidance provides a framework for
interactions between FDA and sponsors to support work
toward qualification of an identified DDT and creates a
mechanism for formal review of data to qualify the tool and
ensure that the evaluation is comprehensive and reliable.
In March 2006, FDA issued the “Critical Path Opportunities Report and List,” in which FDA described six key areas
along the critical path to improved therapies and listed specific opportunities for advancement within these topic areas.
The report noted that a new product development toolkit
containing new scientific and technical methods was needed
to improve the efficiency of drug development. Too often,
attention to a needed DDT is delayed until the time when
study protocols are under development and the available
DDTs are inadequate. Innovative and improved DDTs can
help streamline the drug development process, improve the
chances for clinical trial success, and yield more information
about a treatment and/or disease. DDTs include, but are not
limited to, biomarkers and patient-reported outcome instruments. This guidance describes a formal process that FDA
will use in working with sponsors of these tools to guide
them as they refine the tools and rigorously evaluate them for
use in the regulatory process.
A draft version of this guidance was issued on October 25,
2010. FDA revised the draft after considering the comments
it received. Specifically, FDA provided general guidance on
Research Practitioner
the qualification process, samples of what should be included
in a qualification package, and examples of DDT. A new
DDT, Animal Models under the Animal Rule, has been
included and discussed in the final DDT guidance.
Interested persons may submit either written or electronic
comments at any time, as instructed above. Identify comments with Docket No. FDA-2010-D-0529.
Draft Guidance on
Qualification of Exacerbations
of Chronic Pulmonary Disease
Tool for Measuring Symptoms
of Acute Bacterial Exacerbation
of Chronic Bronchitis in
Patients with COPD
In the January 10, 2014, Federal Register, FDA announced the
availability of a draft guidance titled Qualification of Exacerbations of Chronic Pulmonary Disease Tool for Measurement of
Symptoms of Acute Bacterial Exacerbation of Chronic Bronchitis
in Patients with Chronic Obstructive Pulmonary Disease. This
draft provides a statement of qualification for the Exacerbations of Chronic Pulmonary Disease Tool (EXACT) patientreported outcome instrument and summarizes the concept
of interest and context of use (COU) for which the tool is
qualified through FDA’s Center for Drug Evaluation and
Research’s (CDER’s) drug development tool (DDT) qualification program. Qualification of the EXACT represents a
conclusion that, within the stated COU, the instrument can
be relied on to have a specific interpretation and application
in drug development and regulatory review. This draft guidance is an attachment to the aforementioned guidance titled
Qualification Process for Drug Development Tools.
CDER has developed a formal process, the DDT qualification process, to work with developers of these tools to guide
them as they refine the tools and rigorously evaluate them for
use in the regulatory context. Once qualified, DDTs will be
publicly available for use in any drug development program
for the qualified COU. COA DDTs are developed and reviewed using this process when they are intended ultimately
for use as primary or secondary endpoints in clinical trials
designed to provide substantial evidence of treatment benefit.
Upon qualification by CDER, a qualification statement is
provided describing the concept of interest and COU for
which the tool is qualified. This draft guidance describes the
qualification statement for the EXACT, a COA DDT.
Interested persons may submit either written or electronic
comments as instructed above. To ensure FDA considers
Research Practitioner
your comments on this draft guidance before it begins work
on the final version, submit either electronic or written comments by April 10, 2014. Identify comments with Docket
No. FDA-2013-D-1630.
Draft Guidance on Developing
Drugs for Pulmonary
Tuberculosis Treatment
In the November 6, 2013, Federal Register, FDA announced
the availability of a draft guidance document titled Pulmonary Tuberculosis: Developing Drugs for Treatment. The
purpose of the draft guidance is to assist sponsors in the
development of anti-mycobacterial drugs for the treatment
of pulmonary tuberculosis. This guidance applies to the development of a single investigational drug as well as development of two or more non-marketed investigational drugs for
use in combination.
Tuberculosis remains endemic in the United States and is
epidemic in many parts of the world. Current treatment
for tuberculosis involves administration of multiple-drug
regimens for a minimum of 6 months. The development of
new drugs for treatment of pulmonary tuberculosis remains
an important public health goal. Some of the public health
challenges to be addressed in the treatment of tuberculosis
include: 1) the administration of new drug regimens for
shorter periods of time, 2) new drugs that do not have drugdrug interactions with the drugs used to treat human immunodeficiency virus/acquired immunodeficiency syndrome,
and 3) new drugs that are active in the treatment of patients
with drug-resistant tuberculosis.
This draft guidance addresses these issues in the context of
clinical trial designs for new drugs. The draft addresses the
complexities of the superiority clinical trial design, where
an investigational drug is found to be superior on a clinical endpoint while ensuring that all patients in trials receive
appropriately active treatment regimens. The draft includes a
discussion of non-inferiority clinical trial designs, with justification for a non-inferiority margin in the setting of treatmentshortening regimens. The draft also discusses clinical trials
designed to include patients with drug-resistant tuberculosis.
Although comments on any guidance may be submitted at
any time, to ensure that FDA considers comments on this
draft before it begins work on the final version of the guidance, electronic or written comments on the draft guidance
should be submitted by February 4, 2014. Submit comments
as instructed above. Identify comments with Docket Number Docket No. FDA-2013-D-1319.
19
Draft Guidance on Developing
Drugs for Community-Acquired
Bacterial Pneumonia
In the January 10, 2014, Federal Register, FDA announced
the availability of a draft guidance titled CommunityAcquired Bacterial Pneumonia: Developing Drugs for Treatment. The purpose of this draft is to assist clinical trial
sponsors and investigators in the development of antibacterial drugs for the treatment of community-acquired bacterial
pneumonia (CABP). The science of clinical trial design and
understanding of this disease have advanced in recent years,
and this draft informs sponsors of FDA’s current recommendations for clinical development. FDA is requesting comment
on critical areas of scientific interest including the appropriate primary efficacy endpoints, the use of an intent-to-treat
(ITT) population for the primary analysis population, and
the use of antibacterial therapy by patients before participating in clinical trials.
Issues in CABP clinical trials were discussed at a 2008
workshop cosponsored by FDA and professional societies.
Recently, there have been additional discussions about clinical trial design and endpoints for CABP at several meetings
of FDA’s Anti-Infective Drugs Advisory Committee. As a
result of these public discussions, the science of clinical trial
design and the understanding of endpoints and approaches
to clinical development have advanced.
This revised draft supersedes the draft guidance published in
March 2009 and informs sponsors of the changes in FDA’s
recommendations. Although FDA acknowledges the challenges in conducting clinical trials of investigational antibacterial drugs in CABP, this revised draft incorporates changes
intended to attain a greater degree of balance between the
practicability of conducting CABP clinical trials and the trial
procedures needed for a scientifically sound and interpretable trial. FDA is requesting input from the public on these
changes for consideration before making the guidance final.
The changes from the 2009 draft guidance include:
■■
■■
■■
A description of two potential primary efficacy endpoints
for CABP clinical trials: 1) improvement in patient symptoms early in the course of therapy for CABP (at day 3 to
day 5) and 2) all-cause mortality.
A justification for a non-inferiority margin based on clinical responses observed early in the course of therapy, as
well as a justification for all-cause mortality as a primary
efficacy endpoint.
Suggestions for efficacy analyses based on: 1) an overall
ITT population and 2) a microbiological ITT population consisting of those patients who have a documented
20
bacterial pathogen known to cause CABP.
■■
An approach for accommodating enrollment of patients
who have received prior antibacterial therapy, provided
certain constraints are met.
Interested persons may submit either written or electronic
comments as instructed above. To ensure FDA considers
your comments on this draft guidance before it begins work
on the final version, submit either electronic or written comments by April 10, 2014. Identify comments with Docket
No. FDA-2009-D-0136.
Draft Guidance on
Bioequivalence Studies with PK
Endpoints for Drugs Submitted
Under an ANDA
In the December 5, 2013, Federal Register, FDA announced
the availability of a draft guidance titled Bioequivalence
Studies With Pharmacokinetic Endpoints for Drugs Submitted
Under an ANDA. This guidance provides recommendations to applicants planning to include bioequivalence (BE)
information in abbreviated new drug applications (ANDAs)
and ANDA supplements. The guidance describes how to
meet the BE requirements set forth in FDA regulations.
The guidance is applicable to dosage forms intended for oral
administration and to non-orally administered drug products
in which reliance on systemic exposure measures is suitable
for documenting BE. The guidance will be especially useful
when planning BE studies intended to be conducted during
the post-approval period for certain changes in an ANDA.
The guidance is applicable to dosage forms intended for
oral administration, including tablets, capsules, solutions,
suspensions, conventional/immediate release, and modified
(extended, delayed) release drug products, and to non-orally
administered drug products in which reliance on systemic
exposure measures is suitable for documenting BE (e.g.,
transdermal delivery systems and certain rectal and nasal
drug products).
This guidance revises parts of the guidance documents to
industry on Bioavailability and Bioequivalence Studies for
Orally Administered Drug Products—General Considerations,
and Food-Effect Bioavailability and Fed Bioequivalence Studies
Relating to BE studies in ANDAs.
Specifically, the draft guidance revises recommendations
related to 1) the use of systemic exposure measures and 2)
considerations for the conduct of BE studies. Revisions are
based primarily on experience gained with recommendations contained in prior guidance documents as well as on
Research Practitioner
scientific information that has become available to FDA. The
revisions will clarify guidance to applicants conducting BE
studies for systemically bioavailable generic drug products.
This draft guidance contains recommendations for submission of BE studies for ANDAs only. A separate guidance titled
Bioavailability and Bioequivalence Studies Submitted in NDAs
or INDs—General Considerations to address investigational
new drugs (INDs), new drug applications (NDAs), and NDA
supplements will be published in the near future. FDA has
determined that separating guidance documents according to
application type will be beneficial to sponsors.
Interested persons may submit either written or electronic
comments as instructed above. To ensure FDA considers
comments on this draft guidance before it begins work on
the final version, submit either electronic or written comments by March 5, 2014. Identify comments with Docket
No. FDA-2013-D-1464.
Warning Letter to Investigator
FDA’s Center for Biologics Evaluation and Research (CBER)
issued a November 29, 2013, warning letter to Dr. George C.
Velmahos, at the Massachusetts General Hospital Division
of Trauma, Emergency Surgery, and Surgical Critical Care in
Boston, MA. CBER is responsible for the review and approval of vaccines, blood/blood products, allergenic products, and
cellular and gene therapies. The letter describes the result of
an FDA inspection concluded on July 25, 2013. At the end of
the inspection, a Form FDA 483, Inspectional Observations
was issued to Velmahos. Based on the inspection, FDA determined that there were violations of its regulations. Examples
extracted from the warning letter were:
1. You failed to ensure that the investigation was conducted
according to the signed investigator statement, the
investigational plan, and the applicable regulations, and
to protect the rights, safety, and welfare of subjects under
your care. [21 CFR 312.60].
There were four subjects who received an incorrect dose
of study drug. By permitting these incorrect doses to the
patients above, you failed to ensure that the investigation
was conducted according to the investigative plan. For
two subjects, study drug was ordered prior to randomization. Further, informed consent was obtained from (one
or more) subjects by physicians not included on the signed
Form FDA 1572. Finally, source documentation was inadequate according to protocol section 11.1. Protocol section
11.1, Source Data and Records, requires that “For each
subject enrolled, the investigator will indicate in the source
record(s) that the subject participates in this study.… The
Research Practitioner
investigator will record the following specific data which
are not part of routine documentation in the patient’s
file: study identification code (redacted), patient number
in the study, investigational drug details (including amount
and batch number, dates of administration), any adverse
events occurring during course of the study, laboratory
test results obtained locally, time and reason for premature
withdrawal, if appropriate.” The inspection revealed that
subject source records did not include documentation of the
study as required by protocol section 11.1. 2. You failed to administer the drug only to subjects under
the investigator’s personal supervision or under the supervision of a sub-investigator responsible to the investigator. [21 C.F.R. 312.61].
Personnel not included on the signed Form FDA 1572,
which lists sub-investigators who will assist in the conduct
of the investigation, or on the Site Responsibility Log
issued orders for (redacted) of the study drug to study
subjects. These personnel ordered study drugs for (one
or more) subjects. During the inspection, you explained
that the attending physician does not write orders. You explained that orders are written by surgical residents. This
practice constitutes a failure to administer a study drug
only to subjects under the investigator’s personal supervision or under the supervision of a sub-investigator responsible to the investigator. [Note: the practice of house
officers ordering study drug for subjects on a clinical trial
requiring in-patient hospitalization is common.]
3. You failed to prepare and maintain adequate and accurate
case histories that recorded all observations and other data
pertinent to the investigation on each individual administered the investigational drug. Case histories include case
report forms and supporting data. [21 CFR 312.62(b)].
Supporting data and documentation were missing from
or did not match case report forms (CRF) in numerous
instances. In particular, subject weight either was not
recorded in source documentation or did not match the
subject weight recorded in the CRF for (one or more)
subjects. During the inspection, you explained that there
were no bed scales in the emergency department and, as
a result, subject weight was estimated, self-reported, or
not recorded. Furthermore, source documentation was
inadequate to capture adequate and accurate case histories for subjects. Source data, including (redacted) times,
vital signs, and weight for the majority of subjects, was
captured on loose leaf paper maintained in the CRF
binder. This (sic) source data was not attributable and
incomplete. The inspection revealed that source documentation was inadequate to show that subjects were contacted and/or scheduled to complete the protocol-required
21-day, 3-month, and 6-month follow-up visits, resulting
21
in failure to capture and document adverse events.
4. 4. You failed to obtain the informed consent of each
human subject to whom the drug was administered in
accordance with the provisions of 21 CFR Part 50 and 21
CFR 312.60.
No documentation was located during the inspection to
show that informed consent was obtained from subject
(identity redacted). In your response letter, you acknowledge that the informed consent for (this) subject is missing. An outdated informed consent document was used to
obtain informed consent from subjects (identity redacted). (One) subject signed a version of the consent form
on June 3, 2010 that had expired on May 28, 2010. (Another) subject signed a version of the consent form on July
29, 2010 that had expired on May 28, 2010. This letter is not intended to be an all-inclusive list of
deficiencies with your clinical study of this investigational
product. It is your responsibility to ensure adherence to each
requirement of the law and relevant regulations.
Warning Letter to IRB
FDA’s Center for Drugs Evaluation and Research (CDER)
issued a November 27, 2013, warning letter to the Interim
Chief Executive Officer of St. Vincent Health in Indianapolis, IN. CDER is responsible for the review and approval of
prescription drugs (name brand and generic), over-the-counter drugs, and certain therapeutic biologic products that are
well characterized and used to treat oncology patients, e.g.,
monoclonal antibodies. The warning letter described objectionable conditions observed during an inspection of the
St. Vincent Hospital and Health Care Center Institutional
Review Board (IRB) conducted during August 12-26, 2013.
The inspection considered whether the IRB procedures for
the protection of human subjects complied with FDA regulations at 21 CFR parts 50 and 56. Based on the inspection,
FDA determined that there were violations of its regulations.
Examples extracted from the warning letter were:
1. The IRB failed to determine at the time of initial review
that clinical investigations involving children were in
compliance with 21 CFR part 50, subpart D, Additional
Safeguards for Children in Clinical Investigations [21
CFR 56.109(h)].
When some or all of the subjects in a clinical investigation
are children, the IRB must determine that the clinical investigation is in compliance with 21 CFR part 50,
subpart D (Additional Safeguards for Children in Clinical
Investigations) at the time of initial review. Under 21
22
CFR 50.50, an IRB must review the clinical investigation
and approve only those clinical investigations that satisfy
the criteria described in section 50.51 (clinical investigations not involving greater than minimal risk), section
50.52 (clinical investigations involving greater than
minimal risk but presenting the prospect of direct benefit
to individual subjects), or section 50.53 (clinical investigations involving greater than minimal risk and no prospect
of direct benefit to individual subjects, but likely to yield
generalizable knowledge about the subject’s disorder or
condition). To determine if a clinical trial involving children meets
subpart D criteria, the IRB must make certain types of
findings with respect to such investigations. In addition,
the IRB is required to document its activities, including actions taken during IRB meetings. Our inspection
revealed that in its review and approval of 31 active
clinical trials involving pediatric subjects, the IRB failed
to determine that the clinical trial satisfied the criteria
of subpart D. For example, on May 23, 2012, the IRB
reviewed and approved a pediatric clinical trial titled “(redacted).” However, there is no documentation, either in
the meeting minutes or in any other IRB materials, of the
IRB’s required determination at the time of initial review
that the clinical trial complied with subpart D. Failure to
determine that the additional safeguards for children in
research are met may expose this vulnerable population to
unnecessary risks, and may result in the child’s parent(s)
or guardian(s) not being fully informed about the proposed research. 2. The IRB failed to fulfill membership requirements (21
CFR 56.107).
The IRB allowed nonmembers to vote on clinical investigations. For example, the IRB meeting minutes from
March 28, 2012, show that an attendee identified as
(redacted) participated in voting. According to the IRB
membership roster, (redacted) was not a member of the
IRB when this meeting was conducted. IRB meeting
minutes from June 29, 2011, show an attendee identified
as (redacted) participated in voting. According to the IRB
membership roster, (redacted) was not a member of the
IRB when this meeting was conducted. Meeting minutes
from June 23, 2010, show an attendee identified as (redacted) participated in voting. According to the membership roster, (redacted) was not a member of the IRB when
this meeting was conducted. IRB membership requirements in 21 CFR 56.107 are in place to ensure the IRB is
qualified through its members’ experience, expertise, and
diversity to protect human subjects. Allowing nonmembers to vote calls into question the IRB’s ability to fulfill
this requirement.
Research Practitioner
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