Editorial
Why are drug trials in Alzheimer’s disease failing?
Science Photo Library
For the Review on
drug development see
Lancet Neurol 2010; 9: 702–16
For the meta-analyses see
PLoS Med 2010; 7: e1000245 and
PLoS Biol 2010; 8: e1000344
For genetic predisposition see
Lancet Neurol 2010; 9: 850–51
For the biomarker study see
Arch Neurol 2010; 67: 949–56
The printed
journal
includes an
image merely
Press Association Images
for illustration
For Donald Barr’s essay see
Perspectives page 678
658
Last week, semagacestat added itself to the phase 3
scrapheap of other disease-modifying hopefuls for
Alzheimer’s disease. This drug is a γ-secretase inhibitor of
the final step in amyloid-β protein synthesis, aggregates
of which form plaques, the hallmark of the disease.
A recent review in The Lancet Neurology summarises the
problems for drug development in Alzheimer’s disease.
Other drugs also failed phase 3 trials. Hopes were high for
latrepirdine, but its CONNECTION study did not reveal
a significant difference from control in March this year.
Similarly, tramiprosate and tarenflurbil were abandoned.
These studies join trials for other neurological diseases,
including stroke, multiple sclerosis, and Parkinson’s
disease, which, while showing promise in animal studies
and early human trials, were discontinued at late stages.
How do these drugs manage to progress to this stage?
Meta-analysis suggested that some animal models
inaccurately predict drug efficacy. The failure of the
translation of research could be attributable to poor
methodology in animal studies, or the use of models
that do not accurately reflect human pathogenesis.
What makes a good doctor?
The attributes of a good doctor vary according to the
population surveyed. Patients value communication
and care, colleagues seek competence and camaraderie,
medical students prize cheerfulness. By contrast,
admission panels focus on chemistry grades, as if
knowledge of ionic bonds is somehow a proxy for the
complex human and organisational bonds between
doctors, their patients, and colleagues. As a result, most
people seeking a career in medicine must first master
chemistry; those who cannot do so are unlikely to
become doctors. This ritual was played out on Aug 19,
when university applicants in the UK, including those
aspiring to medicine, received examination results
and wondered breathlessly if their chemistry (or other)
grades would be satisfactory. In today’s The Art of
Medicine, Donald Barr questions whether medical
schools’ scientific bias actually selects the best doctors.
The tyranny of basic science over admissions dates from
the Flexner Report 100 years ago, which redefined medical
education in the USA. By emphasising the importance of
Another meta-analysis showed that neutral or non-
significant animal studies are less likely to be published—
such publication bias can overestimate efficacy.
Current treatment targets patients with symptomatic
Alzheimer’s disease. But perhaps the disease is being
treated too late, when damage is irreparable? The best
time to treat Alzheimer’s disease is likely to be before
memory loss and tissue destruction occurs, but this is
hard to model in animals. That means identifying people
at risk of developing the disease, perhaps because of a
genetic predisposition or by measuring biomarkers, such
as the recently reported cerebrospinal fluid measurement
of a mix of amyloid β1–42 and phosphorylated τ protein.
Drug-industry scientists are failing themselves if
their animal studies are poorly done or use the wrong
model, and their companies are failing academics who
do their phase 3 trials with them, trial participants, and
shareholders. Perhaps the problem is “translational
research” itself: a phrase much bandied around, but
does anyone know what it really means, let alone how
to do it? ■ The Lancet
scientific study before medical school, and then a science-
based medical curriculum, Abraham Flexner improved the
quality of medical education, practice, and research. But
at what cost? The measures transformed medical schools
into the exclusive and expensive institutions they remain
today, and by 1925, Flexner himself worried that the
pendulum had swung too far towards science and away
from the humanitarian aspects of medicine.
To their credit, many medical schools seek balanced
intakes from a diverse pool of highly talented applicants.
But at a time when universities prefer to be known for
their research rather than their education, there is a
danger that scientific in-breeding will produce cadres
of doctors who are neither content nor emotionally
competent to provide the daily clinical care that
underpins health systems. To get the chemistry right for
future generations, a more holistic and sophisticated
approach to selection—based on predictors of care
that are both valid and patient-relevant—needs to be
developed and applied. ■ The Lancet
www.thelancet.com Vol 376 August 28, 2010