Part III: The Innovation Conundrum

Blaming the Messenger

Contrary to popular belief, the regulatory environment for new drug development has grown less stringent over the past two decades, not more so. A succession of changes in food and drug laws plus new rules propagated by the FDA itself, which began when an alarmed HIV/AIDS patient community began clamoring for new drugs to treat that deadly disease, substantially liberalized the rules under which new drug development takes place.

The Prescription Drug User Fee Act of 1992 sharply reduced the amount of time that FDA reviewers may take to evaluate new drugs once all the data from confirmatory clinical trials have been submitted to the agency. Regulations put in place the same year allowed new drug applicants to measure surrogate markers, not clinical endpoints, to get new drugs approved.

For instance, patients with AIDS saw their white blood cell counts dwindle to near zero. The agency began approving drugs based on a temporary improvement in those white blood cell counts, even though it didn’t substantially increase the likelihood that patients suffering from the disease would survive. It was only when a number of marginally useful drugs were used in combination with each other that clinicians finally figured out how to control the disease in a way that actually saved lives.

The industry also won relaxation of the rules governing industry marketing with passage of the Food and Drug Modernization Act of 1997. Direct-to-consumer electronic advertising began flooding the airwaves. Policing of print advertising and detailing materials (the handouts and gifts used by salespersons who routinely visit physician offices) declined as the number of inspectors on the FDA payroll plummeted. The industry also won strengthened intellectual property protection in the form of extended patent life for conducting pediatric clinical trials or additional market exclusivity for drugs that treat rare diseases.

The FDA Amendments Act of 2007, signed by President Bush in October, passed in large part because of the Vioxx scandal where an estimated 40,000 people died from heart attacks, strokes and other cardiovascular complications that were the unwanted side effect of a painkiller that was no better than many others already on the market. It was the first reversal of the deregulatory trend since the 1970s.

Opponents of the new law at first claimed its passage would slow the pace of innovation. This allowed industry lobbyists to succeed in eliminating most of its more stringent proposals, such as forbidding direct-to-consumer ads for the first three years a new drug is on the market. By the time it passed, even industry applauded the bill.

Why is there any reason to think that this modest bill will slow the pace of innovation, even if it had included the tougher measures?

If anything, history shows that the tougher the rules, the greater likelihood that industry will pursue innovative therapies. The number of new drugs and biologics approved by the agency fell consistently over the past 15 years, a period when the legal and regulatory environment was becoming substantially more hospitable to winning approval of new technologies.

On the other hand, the greatest tightening of standards in the history of drug regulation – the 1938 passage of the safety requirement and the 1962 passage of the efficacy requirement – ushered in eras of rapid medical progress and an explosion of new therapeutics as companies adapted to the higher, more scientific standards. It’s unlikely the 2007 law, which focuses primarily on post-marketing safety issues, will have a comparable positive effect. But there’s no reason to think its impact will be negative.

Clearly, something else is at work to slow the pace of innovation. And that something, in my view, is intimately related to the maturity of the drug industry, and its biotechnology offshoot. It’s been a little more than a century since the German histological chemist Paul Ehrlich developed the “magic bullet” theory of medicinal chemistry. He subsequently developed the first antibiotic for treating syphilis. Today, the FDA has more than 2,400 different approved drugs listed in its so-called Orange Book, covering nearly every imaginable disease (and some that are near to being imagined like restless legs syndrome).

A common ailment like hypertension, where there is a clear correlation between reducing its incidence and curbing heart disease, today has at least six classes of molecules and multiple molecules in each class competing for the large patient population requiring the medicines. In the anti-acid field (an age-old affliction; Alexander the Great is said to have died from a burst peptic ulcer after an all-nighter of binge drinking), acid binders like calcium carbonate (the active ingredient in Tums) begat H2 antagonists like Zantac (now over-the-counter), which begat proton pump inhibitors like Prilosec (now over-the-counter), which begat Nexium (the enantiomer half of the Prilosec racemate mixture, which means when you’re taking Prilosec, half of the pill is made up of the chemical in Nexium). Despite its lack of additional efficacy compared to the OTC medications that could be obtained at a fraction of its price, Nexium was the second best-selling drug in the world in 2006 with $6.7 billion in sales and a 16.9 percent annual growth rate.

A similar analysis could be conducted for many serious ailments like cancer, arthritis, diabetes and asthma. It’s not that these diseases have been cured by the pharmaceutical revolution. Many drugs that exist today only mask symptoms or provide very inadequate relief. Other drugs, such as many of the new antidepressants, are not much better than placebo in treating the disease. Many cancer drugs only extend life for a few months or years, and even then at a frightful cost in terms of caustic and sometimes harmful side effects. The need for better drugs is clear. But after a century of concerted research and development by tens of thousands of scientists and physicians working in the public and private sectors, the low-hanging fruit of medical progress has been picked.

Tomorrow: The Challenges Ahead

Posted by gooznews at December 13, 2007 07:32 AM