Why is There a Shortage of Neuroscience Drug Approvals for the Market?

    18/01/2015

    Despite a recent upsurge in the number of new drug chemicals (New Molecular Entities or NMEs) approved by the Food and Drug Administration (FDA), there remains a lack of drugs for the treatment of central nervous system and psychiatric diseases, otherwise known as CNS diseases. The most well known CNS diseases currently being targeted for therapy include depression, psychosis, epilepsy and Alzheimer's disease. As of 2014, 41 New Drug Applications have been approved in the US - a major improvement compared with the downward trend of previous years and almost as good as the last approval boom of 1996 (53). However, the number of NMEs designed to treat neurological disorders has been lacking. Why is this? To understand the issue, one needs to look back at the role of the FDA and the regulation of drug development by pharmaceutical companies.

    In 1937 a scandal broke out in which an elixir of sulfanilamide, used to treat bacterial infections, caused the deaths of over 100 patients in 15 states across the US. The drug was dissolved in diethylene glycol which had not been tested for toxicity and was ultimately found to be fatal. In the immediate aftermath the Food and Drug Cosmetic Act was introduced by President Theodore Roosevelt to ensure all manufactured drugs were tested for dangerous effects before being placed on the market. Since then, every drug that has ever been legally sold in the US has gone through a rigorous safety/toxicity testing process and a thorough critical review processes to satisfy FDA approval. Every drug must be tested for a variety of effects in the laboratory, then in animals, then in human patients (Phase I to III clinical trials) and then during postmarketing surveillance. Many potential drug compounds are dropped during these stages of development from which only one may or may not be selected for final review. Similar processes hold true for Europe and Japan, who also have agencies equivalent to the FDA. Over the years this process of drug testing has taken longer and review processes have become increasingly complicated in order to keep up with modern medicine. The entire timeline for developing one single drug usually takes over 10 years, amounting to over $100 million in costs. In recognition of this burden, both the FDA and the pharmaceutical industry have undergone structural reforms to ensure more urgent new drugs can be expedited to the market approval stage. Thus, it is in the interest of companies to develop a drug that will make big financial returns to cover the exorbitant costs of innovation and development, especially before the 20 year patent cliff expires.

    A simplified cartoon of the drug discovery process:

    However, a study last year by Tufts concluded that only 6% of new drugs for CNS disorders entered into Phase I clinical trials are ever able to make it through the pipeline to FDA approval. CNS drugs are 10% less likely to pass from Phase II to the all-important Phase III clinical trials stage compared with a drug that treats other indications such as cancer. The time taken for the FDA to review neurological drug applications also takes up to 5 months longer than for other types of drug. In Europe, the statistics are no better - the number of new active substances approved by the European Medical Agency decreased from 15 between 2004-2008 down to 9 between 2009-2013.

    Study from Tufts shows a lower probability of CNS drugs to advancement through clinical testing and longer time frames for development (from the Regulatory Affairs Professional Society):

    Part of the problem with developing CNS drugs is that pathologies vary so widely and so little is know about measuring their progress objectively. While neuroscience discoveries in these fields have advanced quickly, the translation into clinical treatment is hindered by the lack of solid end-points (ie. at what point should the treatment be stopped) and also by unknown adverse effects (such as the tendency for suicide after a prolonged dose of certain anti-depressants). Furthermore, many brain disorders are triggered by genetic inheritance, epigenetic factors, or as yet unknown causes for which the the mechanisms are not well defined.

    The other issue is simply economics. The number of deaths worldwide that can be attributed to neurological disorders alone (excluding stroke) are less common than the number of deaths due to cardiovascular diseases, respiratory tract disorders and cancer. An estimate by the World Economic Forum in 2011 showed that 30% of deaths worldwide were caused by cardiovascular disease and 13% caused by cancer, while the WHO estimated in 2012 that global deaths due to neurological disorders amount to around 11%. However, of that proportion, only 15% of brain disorder deaths are due to damage other than cerebrovascular disease. Funding for heart disease and cancer research, both in academia and in industry, has traditionally been better than for neuroscience research. On the other hand, compared to all other chronic diseases, neurological and neuropsychiatric illnesses account for up to 6% of financial and years lost by a patient who would otherwise be healthy - that was a cost of over $2.5 trillion as of 2010.

    In order to stimulate a growth in drug approvals for CNS disorders it is up to the pharmaceutical industry and regulatory agencies to shift their emphasis towards long-term impacts of chronic diseases rather than on shorter term diseases that result in high mortality. Furthermore, it appears that smaller biotech, pharma and startup companies would have the edge on pushing neuroscience drugs towards market development compared to large traditional pharmaceutical companies, weighed down by bureaucracy and steak holders demanding profits. In the age of personalized medicine and epigenetic innovations, it should be easy to see a turn around in a few years time for CNS drug treatments to gain more widespread approval. The question now is whether there is a will to do so in industry.