The pipeline in Pharma is drying up. The number of new chemical entities being released is at an all time low, the cost to develop a new drug is increasing, and more drugs are failing in Phase II and III clinical trials. Things do not look good for the pharmaceutical industry. All this despite an explosion of knowledge from basic science research. The number of new drugs for psychiatric disorders is even lower.
Drugs are theoretically supposed to hone in on a specific single target/molecule and leave all other targets alone. The problem is often this more true in theory than practice. 6.7% of hospitalized patients suffer severe adverse drug reactions (Lazarou, Pomeranz, and Corey 1998). Serious being defined as an event that prolongs hospitalization or results in death or disability. William Bains, then-chief scientific officer of Amedis Pharmaceuticals in the UK estimates that 50% of all drugs in development fail to progress to the market because of problems associated with ADMET (absorption, distribution, metabolism, elimination and toxicity) and 50% of all drugs that do make it to market have problems associated with ADMET. 80% of new chemical entities (NCEs) fail after Phase I clinical trials. Hepatotoxicity is the most common reason for the failure. Barry Selick, formerly with Glaxo believes that for every drug that is withdrawn from the market, 10 remain available to people even though they have ADMET-associated problems. He also says that for every drug that is on the market with ADMET-associated problems, there is an additional 10-50 that will fail before they reach the general public (Hodgson 2001). ADMET testing has traditionally been animal-based although other methods are also used.
When a drug enters clinical trials, the company has very little idea if it will damage humans. Because ADMET studies in animals are so unreliable, Tom Patterson, chief scientific officer at Entelos, likens the current practice of drug testing in humans during clinical trials to making airplanes, trying to fly them, and marketing the one that does not crash. (Hodgson 2001)
In part the above is due to the fact that different species react so differently to the same drug. Ganellin and Duncan:
Strangely, in [James] Black's bioassays DCI was as powerful a stimulant as isoprenaline. He set up other assays and was astonished to find that, depending on the tissue preparation, DCI could be a full agonist, activating the β-receptors, or an antagonist that bound to the receptors but failed to activate them. As Black stated later, “as analytical pharmacologists, what we see of the properties of a new molecule is totally dependent on the bioassay we use”. (Ganellin and Duncan 2010)
In 2009, the Innovative Medicines Initiative announced a collaboration between drug companies called NEWMEDS. NEWMEDS stands for Novel Methods leading to NeW MEdications in Depression and Schizophrenia. NEWMEDS has pooled data from 23,401 patients in 67 trials of 11 compounds in over 25 countries. It is composed of 9 major pharmaceutical companies (including Pfizer, AstraZeneca, Eli Lilly and Roche), 7 academic institutions, and other smaller companies.
One reason for the lack of NCEs is, as the coalition acknowledges, the lack of predictive animal models. By using human data and pooling their data, the coalition hopes to improve the success rate.
Peter McGuffin (Institute of Psychiatry, King's College London) stated:
NEWMEDS has facilitated an unprecedented collaboration between academia and industry on the pharmacogenetics of depression that finally gives us a big enough, powerful enough sample to address how genetics influences antidepressant response. This could lead to changes in the way we select patients for trials, and in the long run how we select treatments for individuals.
Kapur, the academic leader stated:
The landscape of drug development and scientific discovery is changing. After pioneering examples in the field of genetics where sharing data has led to new discoveries – we wanted to see how this could be done in the clinical arena. NEWMEDS is the first large scale example of such collaboration between industry and academia in this field in psychiatry. Hopefully, this will be one step that will help reverse the drought of new medications in psychiatry.
Hopefully there will be more efforts like this one.
Ganellin, Robin, and William Duncan. 2010. Obituary: James Black (1924-2010). Nature 464 (7293):1292-1292.
Hodgson, J. 2001. ADMET--turning chemicals into drugs. Nat Biotechnol 19 (8):722-6.
Lazarou, J., B. H. Pomeranz, and P. N. Corey. 1998. Incidence of adverse drug reactions in hospitalized patients: a meta-analysis of prospective studies. JAMA 279 (15):1200-5.