The Other Side of Drug Discovery, Part 2
By Jason Socrates Bardi
In
"The Other Side of Drug Discovery, Part
1", TSRI investigator Tamas Bartfai says, "If you make a truly original
drug that has a health benefit, people will eventually buy it."
However,
drug design is not all wine and roses.
Drug development is the single most regulated human activity. The mandate
of the FDA is to protect the public against dangerous drugs, and they
do this in a variety of ways, including monitoring approved drugs on the
market for unexpected health consequences, reviewing drug applications,
and mandating full disclosure in drug labels and advertisements.
Nevertheless, regulation limits the number of drugs that companies can
bring on the market, and forces the pharmaceutical companies to make tough
choices. Often these choices involve research and development, which sometimes
directly affects investigators at universities and institutions like TSRI
who partner and collaborate with scientists in industry.
Bringing a drug from the test tube to the prescription bottle costs
in excess of $500 million on the average. The amount of this spent on
initial research and development may be miniscule by comparison with the
clinical trials and the marketing expenses—perhaps only 1.5-5.0 percent
of the total.
"The marketing costs, for instance," says Bartfai, "are usually 15 to
20 times the cost of researching the drug."
For the most part, basic research is blind to this sort of decision
making because an equal amount of science goes into making a small drugs
and big drugs. "With equal ingenuity, you can make a drug that will sell
for $100 million or one that will sell for $100 billion by the end of
its lifetime," says Bartfai.
But when companies are selecting drug candidates for the proverbial
$500 million check, they make sure that the candidates make good economic
sense. A new anti-epileptic, for instance, poses formidable economic challenges
because of difficulty testing it. "If you cannot figure out how a drug
can be tested, you cannot make the drug," says Bartfai.
Consider that there are three types of epilepsy patients: those who
are not yet diagnosed and therefore not taking medication; those who are
diagnosed and currently taking approved medications; and those who are
diagnosed but who are resistant to current medicines.
The best population in which to test a new drug would be newly diagnosed
patients, but one would have an uphill battle overcoming doctors' bias
towards existing drugs. Why would a doctor put a patient on an experimental
drug when there are others that seem to work just fine? One would need
an extraordinary amount of data suggesting that the new compound is significantly
better.
And anyone who is currently taking an anti-epilepsy drug and doing just
fine would not stop to take a new, experimental drug and risk having a
seizure. Nor would a doctor recommend an experimental drug to a patient
who is responding well to an approved one.
That leaves only the group of people who are resistant to all existing
anti-epileptic drugs, who would not be the best test population
"Is a new anti-epilepsy drug a great discovery?" asks Bartfai. "Yes.
But does it have great commercial value? No."
"If you want to make a drug that acts on the brain," he adds, "if, then
the marketing and clinical development departments will suggest you make
a drug for Alzheimer's disease."
Commercial Accessibility
People will only switch to a new drug if the new drug is substantially
better—for instance if it is 10 times more powerful, if it can be
taken orally rather than injected, or taken once a day as opposed to once
every four hours.
In the same vein, there are many drugs that fail because of their side
effects, despite the fact that they actually work very well. For instance
fat absorption blockers should be a raging success story in the United
States, where according to Center for Disease Control and Prevention (CDC)
estimates, nearly a third of the adult population is obese. These drugs
should allow people to literally have their cake and eat it, but they
are one of the failures in the annals of drug design, because they prevent
the absorption of fat with the undesirable side effect of causing diarrhea.
However, says Bartfai, if a new drug were to be invented that had the
same effect without these side effects, it would be a huge success.
In addition to toxicity, bioavailability, synthesis, and efficacy, a
potential drug's commercial accessibility makes a big difference to pharmaceutical
companies. Doctors will choose whatever drugs they know to treat the symptoms
they see, and if there is not a compelling reason to switch to a new drug,
they won't.
"The rule of thumb is that any physician can remember three drugs for
any set of symptoms," says Bartfai. "If there are 17 drugs in your category,
and you are not in the top three, then forget it." That makes marketing
the decisive factor for success of the Pharma companies.
Novel compounds that elicit an existing effect may not be worth the
effort of developing into a licensed and approved drug.
"Once you make a human heart beta-receptor and a slightly better one
and a slightly better one, there's not much left," says Bartfai. "People
buy an effect—they don't buy a new mechanism. No physician or patient
is convinced by a new mechanism."
All of this adds up to a drug development landscape that is pock-marked
with pitfalls and chasms that can derail a potential drug's success even
after it has emerged as a highly successful candidate. Communicating how
to navigate this landscape is one of Bartfai's goals for the lectures.
To address this gap in knowledge between the academic and corporate worlds
,"[Bartfai] offered to give these lectures as a primer," says Skaggs Institute
Director Julius Rebek.
"Since I came here, I have [had] about five colleagues each week asking
me something about drug development," Bartfai says. "People have asked
me questions like, 'Why did they stop the development of this drug that
we have worked on?'"
He has been asked to look at their business plans or to clear up confusion
over a decision by a large company with which they collaborate, for instance,
or to help make sense of a new request.
The Sociological Imperative
Another perspective Bartfai hopes to address during the upcoming lectures
is how the pharmaceutical industry is highly sensitive to the social context
in which it exists.
Drug development follows trends and these trends are informed by the
public's actual and perceived wants and needs. In America today, that
does not simply mean demands from patients and from doctors tending to
their patients' needs, but also pressure from patients' interest groups
and health maintenance organizations and other large demographic forces.
We are an aging society. The CDC estimates that by the year 2030, there
will be 70 million elderly Americans—more than twice the current
number. And the United Nations recently estimated that population of people
in the world over the age of 60 will reach two billion within 50 years.
This aging of America and the rest of the world means an increased demand
for better compounds to combat those diseases and indications specific
to the elderly, and the pharmaceutical companies are a weathervane of
this demand.
For instance Alzheimer's disease, which is believed to afflict four
million Americans, is now a major area of research. Our aging society
has recognized and understood the need to confront the problem of Alzheimer's
disease, and today, according to Bartfai, there is no self-respecting
pharmaceutical company that does not have 5-15 Alzheimer's programs. Yet
this has not always been the case.
"If somebody stood up in 1970 and said, 'I want to make an Alzheimer's
drug,' he would not only have not got any support within a drug company,
but he would also not have gotten a grant from the NIH [National Institutes
of Health]," says Bartfai.
Similarly, other targets of pharmaceutical research are aimed at an
aging America.
Osteoporosis drugs are needed to combat the deterioration of bones in
the elderly, one of the leading causes of loss of quality of life in later
years. Some 44 million Americans—most of whom are women—have
already developed osteoporosis or the early signs of bone density loss
that lead to it. As our population ages, this number will only increase,
and osteoporosis blockers are a major target for pharmaceutical companies.
Many companies are also taking aim at other age-related ailments like
arthritis, Parkinson's disease, and urinary incontinence.
Besides being an aging society, we are a society that is increasingly
aware of mental illness and increasingly more willing to medicate it.
Antidepressants already make up one of the largest markets in the United
States, amounting for around $15 billion annually. However, there is still
a great need for a fast acting antidepressant. Normal antidepressants
take two or three weeks to take effect, and as many as a third of patients
do not respond to the drugs. This is problematic because the core symptom
of serious depression is suicidal tendencies. In 1997, for instance, 30,535
Americans committed suicide, making it the eighth leading cause of death
in the United States that year. One of Bartfai's own longstanding goals
is to develop a quick-acting compound for the treatment of depression.
"We just don't know how to make such a tablet yet," he says.
Some of the other drug targets today are high-profile diseases, like
AIDS and various types of cancer. From a global perspective, there is
a need for vaccines for tuberculosis and malaria, both major health problems
worldwide.
"People would like to have vaccines [against TB and malaria] without
a shadow of a doubt," says Bartfai, "Even the rich countries have come
to realize that helping to eradicated these diseases would be a formidable
form of aid, not only to third world, but also to countries such as Russia
with 26 million tuberculosis cases."
Other drug targets are not so obvious to those outside the field, such
as drugs to control asthma and other respiratory infections and constrictions,
preventative migraine medicine, or a decent (safe, less side-effect prone,
but efficacious) acne drug—the market for which, Bartfai insists,
should not be underestimated.
"If someone came up with [a decent acne drug], it would sell for billions,"
says Bartfai.
Upcoming Lectures:
TARGET-BASED DRUG DISCOVERY, on Thursday, May 2. Topics to be discussed
include validated drug targets: what they are and for whom, a determination
of their value, and comparison of targets for the same clinical indication.
SELECTION OF CLINICAL CANDIDATES: MULTIPLE PRESSURES, on Thursday, May
9. The presentation will focus on the key milestones of preclinical drug
development—timing, expenditures, backup strategies, outside validations,
and orphan drugs—as these factors play out in big Pharma decision
making.
Lectures will be held from 5 to 6:30 PM in the Neurosciences Institute
Auditorium, 10640 John Jay Hopkins Drive.
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