How a new drug gets approved

alarm clock boyPity the poor schmuck who has no trouble falling asleep at bedtime, but is then wide awake in the middle of the night, staring bleakly at those evil green numbers on the clock radio for the next four hours. Have you been there yourself?  What if there were a magical pill we could take in the middle of those nights that would help us drift off to sleep again for just a few more hours until morning?

Enter the drug Intermezzo, a potential treatment for people suffering from this specific form of insomnia that involves difficulty falling asleep after waking up in the middle of the night. 

The drug’s manufacturer, California-based Transcept Pharmaceuticals, originally filed for approval from the U.S. Food and Drug Administration to market Intermezzo (also known as zolpidem, and better known as Ambien at its higher bedtime dose).

But last week, shares of Transcept tumbled by nearly 50% on the stock market after the FDA issued the biotech company a Complete Response Letter, meaning that the FDA had completed its initial review of its application to approve Intermezzo, but would not approve the application until specified changes were made.

And the FDA asked these very tough questions. They demanded additional data demonstrating that Intermezzo, when taken as directed in the middle of the night, would not present an unacceptable risk of residual effects, particularly on next-day driving ability. The FDA also expressed two concerns about the possibility of sleep-deprived patients making dosing errors in the middle of the night that could lead to next-day residual effects. The agency told Transcept to address methods to avoid inadvertent dosing with less than four hours of bedtime remaining, and also inadvertent re-dosing in a single night.

Transcept responded that, based on the content of the FDA letter, it is possible that it will need to conduct additional safety studies. UPDATE: After the FDA had twice previously refused to approve Intermezzo citing those safety concerns,  the drug was finally approved by the agency in November 2011. Because the drug was shown to badly impair driving, and that this effect lasts longer in some people than in others, the manufacturer agreed to change the Intermezzo label to state that the drug should only be taken when people have at least four hours of sleep time remaining, and that people should not drive for at least one hour after waking and at least five hours after taking the drug. Moreover, people should not take Intermezzo if they’ve been drinking alcohol or if they’ve taken other sleep aids.

Most pharmaceutical companies claim that it can be a long and expensive journey taking an average of 12 years and over $350 million to get a new drug like Intermezzo from the pharmaceutical lab to your medicine cabinet.

This dollar value claim, incidentally, is vigorously disputed by many analysts, including medical ethicist Harriet Washington who claims that number’s far closer to $100 million, as she describes in her book Deadly Monopolies: The Shocking Corporate Takeover of Life Itself—And the Consequences for Your Health and Our Medical Future:

“The pharmaceutical industry doesn’t deny that it charges high prices for our drugs, but what it says is:  ‘We have to charge high prices because it costs up to $2 billion to develop every new drug. So we have to recoup our research and development costs, and also make sure that the money is there for the next development, the next innovation.’

“Well, it’s not true. I did a thorough analysis with the help of economist Merrill Goozner. Basically, what Big Pharma has done is to look at a very narrow swathe of drugs that are extraordinarily rare and expensive. If they had not, they would have come up with a figure more like $100 million. As Merrill Goozner said: ‘It’s not chump change, but it’s not $800 million either, it’s not $2 billion!’ 

“And a lot of the innovation is fueled by government support of research. And who pays for government support of research? You and I do with our tax dollars. So, it’s almost entirely a fiction.”

Money quibbling aside, drug companies explain that this drug development process basically includes this journey:

  • a company develops the drug
  • 3-4 years of laboratory and animal testing
  • application to a government regulating agency (for example, the FDA in the U.S. or Health Canada here, or the European Regulatory Authorities) to begin testing the drug in humans (only one in 1,000 of the compounds that enter laboratory testing will ever make it to human testing)
  • if approved, a Phase 1 clinical trial uses 20-80 healthy volunteers to establish a drug’s safety and profile over one year
  • Phase 2 uses 100-300 patient volunteers to assess the drug’s effectiveness over about two years
  • Phase 3 uses 1,000-3,000 patients in clinics and hospitals who are monitored to determine effectiveness and identify adverse reactions, over about three years
  • application submitted (usually about 100,000 pages) to the regulatory agency for approval – may take over two years
  • after final approval, the drug becomes available for physicians to prescribe during the post-marketing stage
  • drug company is required to report all cases of adverse reactions and other clinical data to regulators

Sounds simple enough.

When a drug is approved by a government regulating agency, the available evidence is based on data presented to them at that time. That information can be based either on clinical trials, or real world trials, or both.

So patients being prescribed a new drug cannot know the full scope or nature or quality of the evidence of this newly licensed medication.

The American Food & Drug Administration is a regulatory agency that has been criticized for not asking enough tough questions, as well as for the quality of its drug approvals and post-marketing surveillance systems in recent years.

But in its early history, the agency approved new prescription medicines at a grudging snail’s pace, paying daily homage to the physician’s creed, “First, do no harm”.

Then in the early 1990s, the demand for AIDS drugs changed the political climate worldwide.

In 1988, AIDS activists paralyzed operations for a full day at the FDA’s headquarters, demanding immediate approval of experimental drugs that offered at least a ray of hope to those patients otherwise facing death.

Politicians ordered the FDA to work closely with pharmaceutical companies in getting new medicines to market more swiftly. President Bill Clinton urged FDA leaders to trust industry as “partners, not adversaries.”

Well, regulators did start moving more swiftly, and there have been heavy costs for that speed ever since. “It’s shocking,” warns Dr. Brian L. Strom, chairman of epidemiology at the University of Pennsylvania.

“How can you say, ‘Release drugs to the market sooner,’ and not know if they’re killing people?  It really is a dramatic statement of public priorities.”

For example, back in 2005 following problems involving rofecoxib, an anti-inflammatory pain drug known by its brand name Vioxx, criticisms of the FDA intensifed when a senior drug reviewer at the FDA accused his employer of ignoring his warnings about the deadly dangers of the now-discredited Vioxx and five other new drug submissions,an accusation that prompted a federal government inquiry.

Dr. David Graham, Associate Director for Science and Medicine in the FDA’s Office for Drug Safety, told the inquiry in November of that year:

“Rofecoxib is a terrible tragedy and a profound regulatory failure. I would argue that the FDA is incapable of protecting us against another rofecoxib. We are virtually defenceless.”

Dr. Graham cited what he termed the “inherent conflict of interest” in having the same office within the FDA that approves a new drug also responsible for taking post-market surveillance and regulatory action against it.

“When a serious safety issue arises post-marketing, their immediate reaction is almost always one of denial and rejection. They approved the drug so there can’t possibly be anything wrong with it.”

In 2004, controversy had erupted over the FDA advisory hearing reviewing Vioxx – when it became clear that FDA advisors with financial conflicts of interest were more likely than those without conflicts to vote that Vioxx was safe and should be allowed to stay on the market.

The drug was ultimately withdrawn after a study showed it was associated with approximately 60,000 deaths. In 2008, partly in response to this uproar, the FDA issued new guidelines on how to handle conflicts of interest among its advisors, stating that it wanted to “reduce bias” and to be “more transparent.”

The Canadian Medical Association Journal reported in  2005 that a survey of almost 400 FDA scientists indicates that almost one-fifth of scientists have been pressured to approve a new drug despite their reservations about its safety. Most of the scientists surveyed also said they doubted the FDA’s ability to monitor prescription drugs once they were on the market.

“In Canada, treating the pharmaceutical industry as the regulatory agent’s client can be detrimental to the public interest. When companies become the regulator’s customers, the government regulators want to be able to help them, because they realize the enormous research and the resources that have gone into the clinical trials. So they want to be able to deliver a positive message for them.”

Dr. Wiktorowicz added that the expert advisory committees that review drug companies’ data are rife with individual conflicts of interest.

“There is a small pool of experts on particular drugs, and it’s difficult to find any who have not been involved in the clinical trials under review,or who have not been paid by the same pharmaceutical company for other trials.

Besides the deadly Vioxx, we’ve also seen recalls of other dangerous yet previously approved drugs like:

  • painkiller Bextra
  • Cylertfor Attention Deficit Hyperactive Disorder
  • Baycol – cholesterol-lowering drug
  • Lotronex – for Irritable Bowel Syndrome
  • diet pill Redux
  • antibiotic Raxar
  • blood pressure medication Posicor
  • painkiller Duract (approved despite FDA’s own scientists’ repeated warnings of the drug’s liver toxicity)
  • diabetes medication Rezulin (recalled in North America two years after its recall in Britain)
  • heartburn drug Propulsid

True, it is a long and expensive journey between lab and medicine cabinet.

But sometimes, it’s not long enough.


See also:

© 2009 The Ethical Nag – Carolyn Thomas

6 thoughts on “How a new drug gets approved

  1. I found this step by step explanation very helpful. It also makes me more sympathetic to drug companies who do all this research and development on a product that may or may not even make it to the market. It’s an incredibly expensive process – no wonder companies have to resort to questionable marketing practices like medical ghostwriting or hiring doctors to push their product for them. Do they have any choice? It’s all about money and keeping thier shareholders happy.

  2. Hahaha. Nutrition Biz you almost had me believing you there. You’re a stringer for The Onion, right? Way good.

    Tucked into research and development totals are some actual research bills. The rest is what most people call advertising, graft, speechifying, expert buying.

    Hello Carolyn – where did
    u get that little boy picture? Just the best.

    • Not sure what your point is Riv. It’s illuminating to learn as much as we can about the basic process behind the approval of what ends up in our medicine cabinets. I for one had no idea of the exact procedure/timeline of drug testing. Appreciate this overview.

      • I agree James – the more informed we are about this process, the better our credibility when we make sweeping generalizations like Riv’s….

  3. I this this approval process is very interesting and I will surely forward this to my friends online. Thanks for sharing this.

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