We are currently on the verge of the most pronounced growth in the
geriatric population ever experienced. By 2050, the United Nations
estimates that the elderly population of the world (persons 65 and over) will double,
from 7.6% to 16.2%. The fastest increase will be of those 85 and
older. What is so critical to the healthcare industry is that with
increasing age comes greater comorbidity and likelihood of an adverse drug
reaction or interaction. Aging impacts the pharmacokinetics and
pharmacodynamics of many drugs by reducing hepatic metabolism (as low as
30-50%) and renal function while increasing the volume of distribution of lipid
soluble drugs. Consequently this extends a drug’s elimination
half-life.
Thus, there has been an ongoing call to action by experts in aging
to the therapeutics industry to modify the way we do business, particularly in
the area of drug therapy development. In fact, as far back as 20
years ago, experts raised concern regarding the lack of consideration for the geriatric
population during the planning and development of drug therapies, even those
specifically targeted for use by older individuals. A summary from a
workshop piloted by the Institute of Medicine (IOM) focused on Drug Development for the
Geriatric Population published in 1990 expressed the need for significant changes
in the effort to address this demographic shift.
As it has been 20 plus years since this document was written, I
thought would be important to determine how much progress the industry and
related stakeholders have made. I have chosen to focus this post as
well as the next on three of the key recommendations offered by this expert
panel with an assessment of any developments that may have taken place. The
final three will be covered in a subsequent article.
1. Design drugs specifically
for older people. The experts suggested that drugs destined
for the geriatric population should be developed so that they ideally fit the
needs of the aging body. They would produce effects at a pace which
maintains physiological balance. This would be slow enough to reduce shock to
the system yet as quickly as possible to relieve symptoms at minimal
doses.
While such products do not yet appear to be available, there is
evidence of developments which if applied effectively could
eventually accomplish this goal. For example, personalized medicine
such as intelligent dosing uses computer models. It takes into
consideration a multitude of factors to determine the ideal medication dose for
a given patient. In the area of drug delivery, innovations such as a
multi-unit particulate system may allow drugs to be dosed in a highly precise
and individualized manner by allowing a combination different pellets within a
capsule or tablet to take effect at different times and at varying strengths.
More appropriate drug formulation is also being examined; possibly greater
availability of liquid formulations, rapidly dissolving tablets, and even
drug-impregnated film that may be placed on the tongue. Additionally,
there has been interest among some researchers to address deficits in visual
and tactile ability which result in difficulty of patients to differentiate one
pill from the other.
While the number is still relatively low, companies have been taking
interest in therapies for diseases of aging and those for frailty itself. In
particular, for a few years now, Sanofi has had the Aging Therapeutic
Strategic Unit. This department is charged with
rethinking how treatments to the aging population should be developed and
delivered. According to an article discussing the Unit, there is
concentration in detecting, preventing and reversal of age-related
dysfunctions, disorders, and diseases including Alzheimer’s, chronic pain,
osteoarthritis, hearing disorders, sarcopenia/frailty. More
recently, Abbvie and Google have paired up with the goal of spending up to $1.5
billion to research and commercialize novel drug treatments for diseases common
in aging individuals. This ranges from cancer
to Alzheimer's disease.
2. Increase training in geriatrics, pharmacology, and
pharmacoepidemiology. The report
commented that in the late 1980’s there were few geriatric trained faculty in
medical schools. They blamed those circumstances on the lack of
“drive to develop a geriatric research environment”.
As of 2013, there were 137 Liaison Committee on Medical Education
(LCME)-accredited medical schools in the US. The encouraging news is
that the vast majority of schools offer in some form, geriatric education or
training. Still, the majority of the faculty who lead these programs
do not have formal geriatric training; as of 2005, only 44% of directors of
geriatric academic programs underwent either geriatric fellowship or earned a
Certificate of Added Qualifications in geriatric medicine. Furthermore,
of schools awarding a degree of MD, in 2005 only seven reported
having a full-fledged “department”. Instead, they tend to be
divisions or sections of other departments such as internal medicine. As
expressed in a 2009 article by Bernard, et al., a department provides for “a seat at the table” with respect
to budgeting, strategic planning and allocation of resources within an academic
institution. Such status may indeed enhance research program
development. It should also be noted that as of this posting,
unlike pediatrics, geriatrics is still considered a subspecialty. In contrast,
in 16 countries within the EU, geriatrics is indeed a specialty; the differences
between the US and the EU will be discussed in a future posting.
3. Study very old – get results to physicians. The experts commented on the paucity of clinical trial
data at the time in the very old and “oldest old”. This includes
patients over 75 and older and 85, respectively. Furthermore, this included the
proposal to create a method of dissemination for such data to the wider group
of clinicians who manage these patients. This database would include
the latest information on pharmacodynamics, pharmacokinetics, and interactions.
The number of older patients enrolled in clinical trials has
somewhat increased since the IOM document, however there is still not adequate
data available so that providers can be confident that the medications they use
in their geriatric patients are safe and effective in this population. For
example, in a 2007 study sponsored by the Robert
Wood Johnson Foundation which reviewed 109 clinical trials, it was revealed that a fifth of them
excluded patients above a specified age, and that almost half of the remaining
studies used criteria likely to exclude the elderly disproportionately—frailty
or impaired cognition.
These
results are echoed in a 2013 article by Hamaker and colleagues who reviewed
1207 clinical trials in hematological malignancies and found that patient-centered outcome measures such as
quality of life, health care utilization and functional capacity were only
incorporated in a small number of trials. Even in trials developed exclusively
for older patients, the primary focus lies on standard end points such as toxicity,
efficacy and survival, while patient-centered outcome measures are included in
less than one-fifth of studies. In other
words, the data from these studies are inadequate in their ability to provide
effective guidance to clinicians on these therapies’ effect on the very old.
In
1993, the FDA released guidelines focused on increasing the amount of
geriatric information available in the label for drugs which will be
predominantly used in this population. By 1997, a “Geriatric Use” section was added to the label in order to
report any pharmacokinetic or pharmacodynamic differences between the geriatric
and overall populations. Recently there has been a greater push by
regulatory agencies both in the US and Europe with the release of ICH E7, guidelines driving toward the goal of
ensuring that “real world” geriatric patients including “oldest old”, those
with comorbidities, and receiving concomitant therapies are well-represented
in clinical trials of new therapies or formulations. At
current time, these remain only guidelines. The FDA is currently
holding meetings with experts on how to improve the data coming out of trials
of therapies designed to treat diseases of aging.
The EU
seems to be taking a more aggressive role as the EMA as part of the Agency’s
Road Map to 2015, has devised a “Geriatric Medicines Strategy ” and
has even put together a Geriatric Expert Group that is charged with providing
scientific advice to CHMP and the EMA on issues related to the elderly.
The next post will outline and discuss key recommendations offered
by the expert panel with respect to cost-containment, geriatric-specific
endpoints, and with an assessment of any developments that may have taken
place. In the meantime, I look forward to your thoughts.
