An Innovative Drug Industry? Well, No

[Guest guest]

For those who think (like me) that the reason why there are so few

treatment options in MS is the overregulation of the industry. A bit

long but worth reading it.

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washingtonpost.com

An Innovative Drug Industry? Well, No

By Lansbury

Sunday, November 16, 2003; Page B02

CAMBRIDGE, Mass.

My friend Jim Cordy was 40 when he was diagnosed with Parkinson's

disease. That was 16 years ago. There is no medicine to slow the

inexorable neurodegeneration that is the underlying cause of Jim's

condition, only drugs that provide short-term symptomatic relief.

Since I met Jim four years ago, the effectiveness of this medication

has faded, and he has become increasingly debilitated; in 10 years,

he may be virtually paralyzed. But Jim is hopeful: Surely a

breakthrough drug is just around the corner. Hasn't the federal

government doubled its spending on biomedical research in the past

five years? And what about the scientific revolution spawned by the

sequencing of the human genome?

Jim's hopefulness is understandable. I guarantee he'll see

tremendous advances in our scientific understanding of Parkinson's

in the near future. But when it comes to new medicines, I fear he

may have to settle for new versions of existing drugs for more

prevalent conditions such as allergies and heartburn.

The popular image of America's productive and innovative

pharmaceutical industry is a historical myth. The truth is that the

system that currently regulates the development and approval of new

drugs discourages innovation. Unless it's significantly reformed,

there are likely to be few breakthrough medicines for Jim or

millions like him who suffer from life-threatening or debilitating

diseases.

Unfortunately, rational discussion of this dire situation has been

overshadowed by the simplistic debate over prescription drug prices.

Despite their pronouncements to the contrary, neither the

politicians nor the pharmaceutical companies are acting in the

public's best interest.

The politicians who support reimporting drugs from Canada are

sacrificing future medical advances to save money and win votes in

the short term. It's disingenuous to claim that reimportation is

consistent with a free-market economy, since Canada's lower prices

result from government-mandated price controls. Such controls, while

lowering the price of existing drugs, would make it impossible for

the pharmaceutical industry to engage in the type of innovative

research necessary to produce breakthrough medicines.

Rather than advance this reasonable argument and call for reform,

the pharmaceutical industry, for its part, has raised dubious claims

about the safety of Canadian drugs. This transparently self-serving

campaign has added to the feeling that the industry is not entirely

trustworthy. It is difficult to sympathize with an industry that has

the highest profit margin in the country, especially when, to

protect those profits, it has increasingly turned away from its

history of innovation to focus on producing and aggressively

marketing modified versions of existing drugs for big-market

conditions, known in the industry as " me-too " drugs.

The trend away from innovative drugs started years ago. The FDA

classified 53 percent of the drugs approved between 1982 and 1991 as

offering " little or no therapeutic gain. " Between 1996 and 2001,

things got worse: The pharmaceutical companies' spending on research

and development increased by 40 percent, but the number of new drugs

reaching the market decreased by 50 percent. Of 31 " blockbuster "

drugs (those with annual sales of $1 billion or more) launched

between 1992 and 2001, 23 were me-too drugs for common conditions

such as allergies and inflammation. Now, get ready for an influx of

Viagra mimics. But do we really need five indistinguishable versions

of Viagra, when they divert resources that could be used to develop

innovative drugs for life-threatening diseases?

The Orphan Drug Act of 1983 was intended to promote the development

of drugs for diseases that affect fewer than 200,000 Americans by

offering incentives such as market exclusivity and tax credits.

Unfortunately, this legislation has been only moderately successful,

as its incentives are dwarfed by the profitability of me-too drugs.

This is because the legal system that regulates our pharmaceutical

industry forces manufacturers to choose between maximizing profits

and improving public health. This system, rather than the surface

issue of drug prices, should be the real focus of legislative

concern.

Take the patent law. A drug patent gives a company the exclusive

right to sell that drug for 20 years; after that, generic

competitors may enter the market and provide the same drug at lower

prices. This system was created to reward the innovator, but today,

it rewards the imitator. That's because the requirements for

patenting a particular drug have not significantly changed for 50

years. The science of drug discovery, though, has changed

dramatically, from a trial-and-error process to one targeting a

particular mechanism of action. Drugs that mimic the mechanism of

action of Viagra, Vioxx or Lipitor may be patented even though they

are not innovative, do not serve an unmet medical need, and are

often no more effective than the " trailblazers " on which they are

based.

To make matters worse, the me-too drugs, when aggressively marketed,

typically become bigger sellers than the trailblazers. Me-too drugs

are much more likely to win approval than novel drugs and are more

easily developed than trailblazers. Eliminating undeserved patent

protection for them would encourage development of breakthrough

medicines.

Then there's the expensive, time-consuming approval process. To win

approval from the FDA, a drug must be demonstrated as safe and

effective against a particular condition through three stages of

clinical trials. In Phase 1, safety is evaluated for six months in a

group of up to 100 healthy volunteers. In Phase 2, safety and

efficacy are evaluated in a group of approximately 200 patients, who

suffer from the condition in question, for approximately two years.

Finally, Phase 3 trials test safety and efficacy in thousands of

patients for up to four years. Phase 3 trials account for roughly 50

percent of the total cost of bringing a drug to market. Replacing

the Phase 3 requirement with a conditional approval, based on

successful completion of Phase 1 and Phase 2, would reduce the price

of new drugs while making them available to patients more rapidly.

There are also scientific reasons to replace Phase 3. The reasoning

behind the Phase 3 requirement -- that the average efficacy of a

drug is relevant to an individual patient -- flies in the face of

what we now know about drug responsiveness. Very few drugs are

effective in all individuals. In fact, most are not effective in

large portions of the population, for reasons that we are just

beginning to understand.

It's much easier to get approval for drugs that are marginally

effective in, say, half the population than drugs that are very

effective in a small fraction of patients. This statistical barrier

discourages the pharmaceutical industry from even beginning to

attack diseases, such as Parkinson's, that are likely to have

several subtypes, each of which may respond to a different drug.

These drugs are the underappreciated casualties of the Phase 3

requirement; they will never be developed because the risk of

failure at Phase 3 is simply too great.

The irony of the Phase 3 requirement is that physicians can

prescribe a drug even if it hasn't been shown to be clinically

effective. Once the FDA has approved a drug based on its

effectiveness against one condition, it can be prescribed for any

other condition. This practice recognizes that your physician is

best equipped to evaluate all the available information and advise

whether you could benefit from a particular drug. About 40 to 50

percent of all drug use is for such unapproved, or " off-label, "

uses. Some drugs that " failed " in Phase 3 trials for one condition,

but were approved for another, are still widely prescribed for the

first because physicians agree that the evidence shows they can be

effective.

Then there are drugs like Neurontin, an off-label blockbuster, with

more than 80 percent of its sales being for unapproved uses. Though

approved by the FDA for refractory epilepsy and pain related to

shingles, Neurontin is more widely used for bipolar disorder, social

phobia, panic and neuropathic pain. Even though its effectiveness

against these prevalent conditions has not been tested in FDA-

approved Phase 3 trials, encouraging data from small academic

clinical trials and anecdotal reports of its effectiveness have

convinced physicians that Neurontin can work.

If expensive Phase 3 trials were eliminated, patients using

conditionally approved drugs could be closely monitored by their

physicians and the FDA. This kind of public trial system would

guarantee that patients would be rapidly informed of all clinical

findings. After two to three years of carefully documented clinical

use, full approval could be granted. This way, all patients, many of

whom would not meet the strict requirements for inclusion in a Phase

3 trial, would have access to new drugs, and drug companies could

take more risks on innovative ideas, since development costs would

be cut in half.

As Jim Cordy's Parkinson's disease progresses, he will have the

right to weigh for himself the risks and benefits of several

experimental brain surgeries that could improve his symptoms. These

procedures do not work for everyone, and they do involve risk. Drugs

are no different. Surgeons are rightly encouraged to develop new

breakthrough procedures. So why do we support a system that

discourages pharmaceutical companies from even attempting to find a

cure for Jim and others like him?

Author's e-mail:

plansbury@...

Lansbury is associate professor of neurology at Harvard

Medical School and a founder of the school's nonprofit Laboratory

for Drug Discovery in Neurodegeneration.