WHEN LESS IS MORE in Drug Development
clinical therapy development is moving beyond the classical clinical
research trial paradigm used to develop new oncology treatments.
This paradigm was based upon the sequential use of Phase I trials to define
toxicity and tolerable doses and schedules. Phase II trials then
search for signals of efficacy in particular disease types. Phase III
trials complete the paradigm and are designed to test new therapies against
the current standards of care. Therapies successfully completing the Phase
I, II, and III trials are presented to regulatory agencies for approval as
widely available cancer treatments.
Although there will always be a role for some drugs to be developed using
the classic Phase I-III mechanism for development, many newer cancer
treatments will be targeted not against a cancer type but rather against
specific molecular targets that may be identified in
cancers arising in various different organs. Therefore it doesn't make
sense to do Phase I- III clinical trials in large number of patients with a
histologically defined cancer (lung cancer, breast cancer, renal cancer,
for example). Rather one needs to test the efficacy of a targeted therapy
in tumors that carry the target of interest.
example of this scenario is the HER2 target. HER2 was
originally identified in breast cancer and a monoclonal antibody targeting
HER2 (Herceptin) was developed and shown to be efficacious in HER2+
breast cancer. More recently HER2 was identified in about 20% of stomach
cancers. Herceptin was shown to be active in HER2+ gastric cancer but not
in the roughly 80% of tumors that were HER2-.
gastric cancer HER2 story illustrates important points about targeted
therapy development. First, clinical trials taking
all comers with a histologically defined cancer like stomach cancer makes
no sense. The patient population chosen must be from the 20% of patients
whose stomach cancers express HER2. Also full toxicity evaluations and dose
finding studies do not need to be done since we have much of these data
from the experience with Herceptin in breast cancer.
bottom line here is that as we get increasingly more
sophisticated in defining molecular targets in cancer, we will be dealing
with smaller clinical trials performed in carefully defined patient
populations. The molecular biology of the cancer and the targeted therapy
will be come increasingly more important in cancer therapy development.
Dr. John S.
Senior Consultant for The Academic GI Cancer Consultant
Consortium (AGICC) & The Academic Myeloma Consortium (AMyC) of The
Oncology Consortia of CRITERIUM, INC. Global CRO
John S. Macdonald, MD, is Senior Medical Advisor for Criterium
Inc. He served as Medical Director and Chief of Gastrointestinal Oncology
at St. Vincent's Comprehensive Cancer Center in New York City from
1998-2007. Dr Macdonald is Board certified in internal medicine and
oncology. In addition to his responsibilities at the Saint Vincent's Cancer
Center from 1998 to 2007, Dr. Macdonald served as Chief of Medical Oncology
at St. Vincent's Hospital and Medical Center, and Professor of Medicine at
the New York Medical College.
Dr. Macdonald was named
as the first recipient of an endowed professorship, the Lynn Wood Neag
Distinguished Professor of Gastrointestinal Oncology, in 1999. He is
recognized as a leading educator in Medical Oncology and has received
numerous forms of recognition for his skills in medical education.
A leader in his field
and a specialist in gastrointestinal cancer, Dr. Macdonald has authored
more than 400 articles, abstracts and book chapters and has been published
in many medical journals, including The New England Journal of Medicine,