“Eroom’s Law: the cost of developing a new drug doubles every nine years”

Arnst Drug Approval 610x408

Eroom’s Law is Moore’s Law spelled backwards. Sadly it describes the reality of declining drug approval rates. Diagnosing the decline in pharmaceutical R&D efficiency was published in Nature Reviews Drug Discovery March 2012. The abstract: 

The past 60 years have seen huge advances in many of the scientific, technological and managerial factors that should tend to raise the efficiency of commercial drug research and development (R&D). Yet the number of new drugs approved per billion US dollars spent on R&D has halved roughly every 9 years since 1950, falling around 80-fold in inflation-adjusted terms. There have been many proposed solutions to the problem of declining R&D efficiency. However, their apparent lack of impact so far and the contrast between improving inputs and declining output in terms of the number of new drugs make it sensible to ask whether the underlying problems have been correctly diagnosed. Here, we discuss four factors that we consider to be primary causes, which we call the ‘better than the Beatles’ problem; the ‘cautious regulator’ problem; the ‘throw money at it’ tendency; and the ‘basic research–brute force’ bias. Our aim is to provoke a more systematic analysis of the causes of the decline in R&D efficiency.

For some commentary on the Scannell et al paper, this is useful Why Drug Development is Failing – and How to Fix It. BTW Derek Lowe is my favorite observer of pharma research – I highly recommend In the Pipeline.

The new drug drought was highlighted in January by Derek Lowe, a pharmaceutical scientist who writes the influential blog In the Pipeline. He asked his readers to name the most worthwhile new drug that had been introduced since 1990. Of the many candidates nominated, the vast majority were brought to market in the first half of that 20-year span.

One reason for the industry’s meager R&D productivity is the sheer complexity of the human body, argue four analysts at Sanford C. Bernstein, led by Jack W. Scannell. In their article in Nature Reviews Drug Discovery, “Diagnosing the Decline in Pharmaceutical R&D Efficiency,” they examined R&D projects for more than 28,000 compounds investigated since 1990. During that 20 year period the pharma industry increasingly concentrated its R&D investments on drugs that address unmet therapeutics needs and untargeted biological mechanisms—areas where the need is great but the risk of failure highest. This is the widely-held “low hanging fruit” theory of the drug drought: the easier disease targets, such as high cholesterol, asthmatic airway passages, migraines, and ulcerous digestive systems, have been met. Complex diseases such as cancer and neuro-degenerative conditions are much harder to solve.

But Scannell and his colleagues also laid out four additional, interlocking arguments that may explain the decline in R&D output:

  • The ‘better than the Beatles’ problem: Imagine how hard it would be to come up with a successful pop song if any new song had to be better than the Beatles . Unlike cars, or electronics, with drugs there’s no interest in novelty for its own sake. And there’s no point in creating something that’s only just as good as what’s already available, especially since today’s hit drug is tomorrow’s inexpensive generic.
  • The ‘cautious regulator’ problem: The progressive lowering of risk tolerance, particularly after the pain treatment Vioxx was removed from the market in 2004 for safety reasons, raises the bar on safety for new drugs, which makes R&D both costlier and harder.
  • The ‘throw money at it’ tendency: The tendency to just keep pouring more money and resources into a research project or a widely-held theory until something sticks. Could also be called throwing good money after bad.
  • The ‘basic research-brute force’ bias: The industry’s tendency to overestimate the probability that advances in basic research and large scale screening processes will show a molecule safe and effective in clinical trials.

As an outsider I find it easy to place a lot of the blame on the ‘cautious regulator’ problem. A similar disease afflicts the US nuclear power industry. A standout example of the impact on drug development is the near impossibility of gaining approval of new drug “cocktails”. The ‘personalized medicine’ concept exploits our ability to combine very fast sequencing of the patient’s DNA with exploding ‘big data’ containing detailed cases of patients-symptoms-drugs-outcomes. Sadly it’s nearly impossible to get such drug-combinations approved. 

Scannell and his fellow authors throw water on the personalized medicine theory by pointing out that despite the shift to targeted drugs and high tech screening tools, the probability that a small-molecule drug will successfully complete clinical trials has remained almost constant for the past 50 years. And those treatments that do succeed can cost patients and insurers hundreds of thousands of dollars per year, because they will by definition only work on the small number that have the cellular target. Physicians who prescribe drugs and the scientists who invent them are increasingly embracing a more nuanced view of drug discovery, the idea that most diseases require a combination of targeted drugs, often called a cocktail, to be held in check. The cocktail approach proved effective against AIDS, and medical experts believe the same approach may be necessary for cancer, Alzheimer’s, and a range of other diseases.

The problem with cocktails, however, is that it can be difficult if not impossible for two different companies to test experimental drugs in concert, for both competitive and safety reasons. Companies are beginning to overcome those competitive challenges, however, and collaborate on some of the most difficult challenges in medicine, most notably Alzheimer’s disease, the only one of the top 10 causes of death in the U.S. with no known cause, cure or even a way of slowing its progression. In 2004 the National Institutes of Health, the FDA and 20 drug companies joined forces to start the Alzheimer’s Disease Neuroimaging Initiative (ADNI), a landmark public-private partnership tasked with mapping all the biological markers connected to Alzheimer’s. The ADNI’s defining principle is to publicly share and relinquish ownership of all data and findings as soon as possible. More than 57 sites are collecting data from thousands of patients, and the results to date have already been incorporated into research and trials by pharmaceutical companies.

Meningitis Outbreaks Call for FDA Leadership. Don’t Hold Your Breath

Henry Miller:

 

Vaccination is one of the most important advances in public health in recent centuries, and hundreds of vaccines have all but eradicated many of the infectious disease scourges of the past. But two recent college campus outbreaks of Meningitis B (MenB), which is caused by serotype B of a bacterium called Neisseria meningitidis, or meningococcus, show that more needs to be done. What we need right now is not scientific or technological ingenuity, but more enlightened and responsive government oversight.

Since the first MenB cases were reported at Princeton University nine months ago, the federal government has taken insufficient and piecemeal steps to stem the further spread of the highly contagious and potentially deadly disease. The second outbreak has occurred at the University of California, Santa Barbara over the past month. Twelve students in all have been infected. Worldwide, there are 20,000-80,000 cases of MenB annually, with a mortality rate of about 10 percent. Of those who survive, about one-fifth suffer from devastating permanent disabilities such as brain damage, deafness, or limb loss. One UCSB case is a freshman lacrosse player whose feet had to be amputated.

As students and administrators at UCSB have learned to their dismay, there is no approved MenB vaccine in the United States although one called Bexsero, manufactured by Novartis, has been approved by regulators in the European Union, Australia, and Canada, and is available in those countries. The same vaccine is in clinical trials in the United States, but characteristically, the FDA has slowed the testing and approval process, so officials at the affected campuses have been forced to appeal to the federal government for special permission to import and administer it.

 

Why not reciprocity?? Burned by the FDA

Alex Tabarrock asks why the US FDA has to duplicate drug approvals already completed by reliable nations – e.g.. Germany, Great Britain. Is there any explanation other than aggregation of power to the bureaucracy?

If you lived in Great Britain or Germany and your physician prescribed a pharmaceutical, would you ask them, ‘has this pharmaceutical been approved by the U.S. FDA?’ Probably not. At FDAReview.org Dan Klein and I argue that international reciprocity is a no-brainer:

If the United States and, say, Great Britain had drug-approval reciprocity, then drugs approved in Britain would gain immediate approval in the United States, and drugs approved in the United States would gain immediate approval in Great Britain. Some countries such as Australia and New Zealand already take into account U.S. approvals when making their own approval decisions. The U.S. government should establish reciprocity with countries that have a proven record of approving safe drugs—including most west European countries, Canada, Japan, and Australia. Such an arrangement would reduce delay and eliminate duplication and wasted resources. By relieving itself of having to review drugs already approved in partner countries, the FDA could review and investigate NDAs more quickly and thoroughly.

Unfortunately, even when they can, the US FDA does not take advantage of international knowledge as the WSJ notes in European Sunscreen Roadblock on U.S. Beaches:

Eight sunscreen ingredient applications have been pending before the U.S. Food and Drug Administration for years—some for up to a decade—for products available in many overseas countries. The applications were filed through the federal TEA process (time and extent application), which allows the FDA to approve the ingredients if they have been used for at least five years abroad and have proved effective and safe.

…Henry Lim, chairman of dermatology at Henry Ford Hospital in Detroit and a member of the American Academy of Dermatology, says multiple UVA filters still awaiting clearance in the U.S. have been used effectively outside the country for years.

‘The U.S. is an island by itself on this one,’ he said. ‘They’re available in Canada, available in Europe, available in Asia, available in Mexico, and available in South America.’

(…snip…)

Dr