PDUFA Follies

Important reporting from today’s edition of the Wall Street Journal:

“An unusual clinical trial involving four different drugs offered promise that guiding treatment based on the molecular traits of a tumor can improve survival from lung cancer. Researchers said the study amounted to "proof of concept" for a new approach to clinical trials that could improve the efficiency of cancer-drug development and eventually shorten the time it takes to get new treatments to market.”

The “Battle” study involved 255 patients with advanced lung cancer.

According to Edward S. Kim, a cancer researcher at M.D. Anderson and principal investigator of the Battle study, "This is a first step to find biomarkers that may help supplant existing toxic therapies and to find the right population for a particular drug," said.

The WSJ writes, “The adaptive design is gaining interest among researchers and drug companies because it could help identify drugs that don't work sooner, and identify biomarkers that would be used to enroll patients in late-stage studies required for market approval.”

Currently large clinical trials typically take all comers without evaluating their biomarker status. "The problem is that when you take a drug that has a specific target, but you treat everybody, you dilute the effect" of the drug, said Dr. Kim.

Researchers say that is why many targeted cancer drugs fail in late-stage or Phase III studies.

"This is the future," Tyler Jacks, a cancer researcher at Massachusetts Institute of Technology and president of the AACR, said of the Battle trial. "This is how drugs will be developed and clinical trials organized."

Important news.  Good news. Potentially life-saving news.  And interesting news considering that some are using the current PDUFA reauthorization debate to suggest the FDA demand comparative effectiveness studies as part of the agency’s drug approval process – something that no other drug licensing agency in the world does.

If the Battle study proves nothing else – it’s that we don’t know enough about how new medicines work once approved ("in the real world"). And that’s particularly true for cancer drugs. So what does “comparative effectiveness” really mean?  And should it be applied to the global gold standard of safety/efficacy or, if you prefer, risk/benefit.  Lung cancer is a good example, considering that average survival on chemotherapy is about eight months. What’s the value in asking about pre-approval “comparative effectiveness? Compared to what? "Best practice" treatment? And compared how?

Those who call for such a third leg are on a price jihad (cost effectiveness). That’s their privilege – but they had better understand the consequences such a move inside the FDA process would have on pharmaceutical  innovation.

But first, there are some things they should understand, more generally about innovation itself:

Innovation is slow.  As any medical scientist will tell you, there are few "Eureka!" moments in health research. Progress comes step-by-step, one incremental innovation at a time. Companies more often profit by improving existing chemicals and making processes more efficient than by revolutionizing the whole field with new products.

Innovation is hard.  Today it takes about 10,000 new molecules to produce 1 FDA-approved medicine. And if that's not frightening enough, only 3 out of 10 new medicines earn back their research and development costs. And here's the kicker -- unlike other R&D-intensive industries, pharmaceutical investments generally must be sustained for over two decades before the few that make it can generate any profit.

Innovation is expensive.  In 2003, researchers at TuftsCenter for the Study of Drug Development estimated the costs to bring a new medicine to market to be $802 million, and others suggest that the total cost is closer to $1.7 billion

Innovation is under attack.  From accusations of the “me-too” variety, to crackpot schemes to replace pharmaceutical patents with a “prize” system, life for innovator pharmaceutical companies is rough and tough.  Israel Makov (formerly the Big Abba of generics giant Teva) once told me that he wasn’t really in the pharmaceutical business, but rather “in the litigation business.”

But innovation is important – and not just for pharmaceutical industry profits. Increases in life expectancy resulting from better treatment of cardiovascular disease from 1970 to 1990 have been conservatively estimated as bringing benefits worth more than $500 billion a year. In 1974, cardiovascular disease was the cause of 39 percent of all deaths. Today it is about 25 percent. Cerebrovascular diseases were responsible for 11 percent of deaths back then. In 2004 they caused 6.3 percent of deaths. Kidney diseases were linked to 10.4 percent of deaths and now they are associated with 1.8 percent. And that’s just for the United States.

As Harvard University health economist (and Obama healthcare advisor) David Cutler has noted: "The average person aged 45 will live three years longer than he used to solely because medical care for cardiovascular disease has improved. Virtually every study of medical innovation suggests that changes in the nature of medical care over time are clearly worth the cost."

Comparative effectiveness is an interesting health policy issue -- but the PDUFA reauthorization process is the wrong place for the conversation.