Part II: The Innovation Conundrum

Lost in Translation

Every analyst seeking an answer to the declining medical innovation conundrum recognizes the crucial role that scientific understanding plays in coming up with new therapeutic approaches to chronic disease. In its report last year on the declining output of drug industry research and development, the Government Accountability Office noted that the public and private sectors have done a poor job in translating the nation’s massive public investment in basic science and private sector investment in translational science into new therapies.

Think about the remarkable “breakthroughs” of recent years. University and government scientists have mapped the genome, identified key receptors on numerous cancers, and uncovered parts of the biological cascade behind chronic conditions like arthritis, Alzheimer’s and arteriosclerosis. Industry scientists have developed extraordinary tools for discovering new drugs like mass screening of new molecules using computer-chip bioassays and rational drug design based on x-ray crystallography.

There’s growing public investment in new fields like gene therapy and stem cell research, which hold out the promise of curing genetic disorders and degenerative diseases like Parkinson’s and diabetes. Barely a week goes by where a news magazine or the nation’s leading papers do not herald the alluring promise of some new biomedical breakthrough percolating in some company’s lab for one of the many forms of heart disease, one of the more than 200 forms of cancer, one of the numerous neurological disorders, or one of the musculoskeletal disorders that contribute to the frailty and infirmities of old age.

Yet years go by without significant advances against any of these chronic diseases, which are the primary causes of ill-health in an aging society. Something clearly is amiss, the report concluded, in translating basic science into usable products.

The report then critiqued the drug industry’s corporate culture, framed by the demands of Wall Street. The financial incentives formed by the stock market force R&D decision-makers to focus most of their attention on developing blockbuster drugs for proven mass markets. Minor aches and pains, allergies, depression, cholesterol management, acid indigestion – the rewards for a successful new entry in one of these categories, whether or not it represents a significant new advance over previous therapies, are measured in the billions of dollars in sales.

However, the cost of developing new drugs in these categories is high and major contributor to growing R&D costs since showing superiority to placebo for these products often requires clinical trials that enroll thousands if not tens of thousands of patients. Why? Since the drug itself has marginal utility, consumers, regulators and the companies themselves require larger trials to allay concerns that the new, unproven product may be less safe than readily available, proven alternatives. The additional expense of the larger trials inevitably inflates research costs and deflects scientific talent from investigating fields where the risk of failure is far greater.

To be sure, there are some areas where the evolution of scientific understanding has reached the point where successful therapeutic intervention is not only possible, but the likelihood of success is high. Yet industry ignores or under-invests in these areas because they only affect a few thousand or tens of thousands of people. The National Organization for Rare Diseases maintains a database that tracks more than 1,000 diseases, most of which receive scant attention from commercial drug developers. Yet the Pharmaceutical Research and Manufacturers Association – the trade group for the U.S.-based pharmaceutical industry – reports only 300 drugs in development for these conditions.

The blockbuster mentality also leads to a proliferation of so-called me-too drugs, which replicate the action of drugs already on the market and add little or nothing to physicians’ armamentarium for fighting disease. Besides the wastefulness of this activity, it also contributes to the high cost of developing drugs. lt is conceivable, of course, for a company developing a new acid indigestion pill to improve on the 90 percent effectiveness of those already on the market. But it’s not likely. And it’s hard to imagine that the medical benefit would ever justify the cost of enrolling ten thousand or more patients in a clinical trial capable of showing superiority in a statistically significant way. Yet the tests go on. Why? The sad truth is that the upward spiral of drug development costs in recent years in intimately tied to the drug industry’s desperation to replace blockbuster drugs coming off patent with comparable drugs that may provide another 20 years of market exclusivity (and thus marketability), but not much else.

This trend, noted in the GAO report, led the auditors to conclude that the nation’s patent laws were one of areas in need of reform if industry was going to refocus its attention on medically significant products. A series of laws and court rulings have given manufacturers the right to obtain new patents for minor changes in chemical structure, changes in routes of administration, and new uses for old products. These patent extenders provide substantial financial rewards to firms that focus their research attention on extending the marketability of their existing products instead of focusing on the truly new and innovative – always an inherently risky proposition.

Finally, the GAO’s panel endorsed the views of those who partly attribute the slowdown in new drug approvals to regulatory uncertainty, lamenting the fact that the FDA does not have precise standards for measuring the safety or effectiveness of new drugs. Moreover, those standards are constantly shifting, they alleged. In this view, regulatory standards have become progressively tougher in recent years due to a number of high profile safety scandals that led to pulling popular drugs from the market like the fenfluramine/dexfenfluramine combination (1997), Propulsid (2000), Rezulin (2000), Baycol (2001), Vioxx (2004), and Trasylol (2007). With tougher standards have come fewer new drug approvals.

FDA officials vigorously rejects that charge. "I've been at the FDA for 15 years and we've never changed the standards for drug approval," John Jenkins, director of the FDA's Office of New Drugs, told the press when it became apparent that 2007 was shaping up as a very poor year for new drug approvals. Moreover, the rate of approvals has run roughly parallel with the rate of new drug applications, according to FDA statistics.

Tomorrow: Blaming the Messenger?

Posted by gooznews at December 12, 2007 08:14 AM