Biopharmaceutical
Statistical, Data Management Issues
Addressed by PhRMA Working Groups
Catherine Celingant, Millennium; Dave Christopher, Schering-Plough; Christy Chuang-Stein, Pfizer;
Jose Pinheiro, Novartis; Walt Offen, Eli Lilly; and Steve Snapinn, Amgen
T
he Pharmaceutical Research and partially responsible for the recent decline web site is not connected to PhRMA, nor is
Manufacturers Association of in the success rate of drug development it overseen or sanctioned by PhRMA.)
America (PhRMA) represents the programs. This spawned the formation of a
country’s leading research-based pharma- number of cross-functional teams to address
Adaptive Dose-Ranging Studies
ceutical and biotechnology companies pre-competitive issues in drug development. Adaptive dose-ranging studies (ADRS) are a
devoted to inventing medicines that allow Some teams include a single statistician, while type of response-adaptive design that focus-
patients to lead longer, healthier, and more others are mostly made up of statisticians. es on adapting the allocation of patients to
productive lives. Although there are many Several of these cross-functional teams are led doses as information becomes available in
full-time employees at PhRMA, much of or co-led by statisticians. BDMTG members the trial. The adaptive allocation rule is
the work that involves interacting with regu- and others from PhRMA-member companies aimed at optimizing a quantitative char-
latory agencies, such as the U.S. Food and have excellent leadership opportunities and acteristic of the trial, such as the precision
Drug Administration, is conducted by are making important progress. of the estimated target dose. A practical
employees of PhRMA-member companies. appeal of ADRS is that they allow the use
PhRMA hosts a number of commit-
Adaptive Designs
of more initial doses than traditional dose-
tees, technical groups, working groups, and Adaptive designs use accumulating data to finding trials, adaptively focusing on fewer
other teams comprised mostly of employ- modify certain aspects of a trial according doses in the “most informative” range as the
ees of PhRMA-member companies, with a to a pre-specified plan. For an adaptive study unfolds. The Adaptive Dose-Ranging
PhRMA staff member serving as a liaison. trial to be credible, the adaptations must Studies Working Group (ADRSWG)
The purpose of these groups is to advocate not undermine the validity and integrity was formed with the goals of evaluating
for improved regulatory processes for drug of the trial. potential benefits of adaptive dose-ranging
development and approval by reaching out After the successful Adaptive Designs methods in clinical development and mak-
to academicians and regulatory agencies. Workshop in 2006, the Adaptive Designs ing recommendations about their practical
The Biostatistics and Data Management Working Group (ADWG)—led by Mike use, with the intention of influencing their
Technical Group (BDMTG) is one such Krams (clinician at Wyeth) and Brenda acceptance by regulators. From its start,
group. Active members of BDMTG are Gaydos (statistician at Eli Lilly)—kicked ADRSWG has worked in close collabora-
selected in annual elections to a three-year off nine subteams to focus advocacy efforts tion with ADWG.
term. Six are from clinical statistics, three regarding education, ICH harmonization, The initial focus of ADRSWG was the
are from nonclinical statistics, and three are data monitoring issues and processes, good quantitative evaluation of adaptive and
from data management. adaptive practices, case studies, software nonadaptive dose-ranging designs and
BDMTG is mostly focused on advocacy user requirements, clinical trial material, analysis methods, via a comprehensive
relating to scientific/methodological topics communications/outreach, and key simulation study. The results of this evalu-
in drug development. The group works on opinion leaders’ relationships. A core group ation, together with key recommendations
problems that are current with regulatory of ADWG participated in a face-to-face from the group, were published in a discus-
expectations or requirements and tries to meeting with senior leaders of the FDA in sion paper that appeared in the Journal of
influence the regulatory agencies, with a pri- August 2007. ADWG held a face-to-face Biopharmaceutical Statistics in 2007. The
mary focus on FDA. Teams can be comprised meeting with its members in September, conclusions and recommendations from
of all statisticians, all data management pro- reconfirming the 2008 directions. In the simulation study were also the focus
fessionals, or a combination of professions. addition, select members of the working of discussion at a face-to-face meeting the
These efforts generally result in PhRMA group participated in a December workshop working group had in May 2007 with
position papers published in peer-reviewed on adaptive designs for confirmatory trials senior leaders of the Office of Translational
journals. Often, the FDA helps choose the cosponsored by the European Medicines Sciences at FDA. Following suggestions of
topics in which the group engages and offers Agency and the European Federation of topics for further investigation made by
input to solutions and opinions. Pharmaceutical Industries and Associations. FDA at this meeting, the group reorganized
In March 2004, the FDA published what The next milestone for the group is to itself into four work streams: evaluation of
is referred to as “Critical Path: Innovation or share case studies with the FDA. Some of additional adaptive dose-ranging methods,
Stagnation,” which can be found at www.fda. the working group’s output can be found impact of ADRS on overall probability of
gov/oc/initiatives/criticalpath/whitepaper.html, at the BioPharmNet web site at www. success of a clinical development program,
highlighting critical issues considered to be biopharmnet.com/doc/doc12004.html. (This impact of exposure-response modeling,
APRIL 2008 AMSTAT NEWS 37
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