August 2010

Using Phase II Failures

ASBMB Past-president Gregory A. Petsko explains why Phase II drug failures from pharmaceutical companies are the perfect subjects for academic research. (Originally titled "When Failure Should Be the Option".)


Phase IIGive me your tired, your poor, your Phase II failures… Well, OK, to be honest, I’m not sure I want your tired or your poor, and besides, the Statue of Liberty has that pretty well covered. But I am sure that I want your Phase II failures. I REALLY want your Phase II failures.

Before I explain what I mean, I should review the progress in making drugs to treat serious human illnesses in the first decade of the 21st century – or, more accurately, the lack of progress. While it’s been true for a long time that about the hardest thing human beings have ever tried to do is to make a drug, it seems as though lately it's got even harder. The number of new therapeutics approved for use on humans, per year, has been essentially flat for more than two decades. During this time, new technologies such as structure-based drug discovery have been created, pharmaceutical companies have merged to form giant entities and hundreds of biotechnology companies have been launched to rival them, the research expenditure of the National Institutes of Health has more than doubled and the R&D budget of the drugs industry has shot up. Yet, despite all that, we are not developing new drugs any faster than we did before. Why not?

One reason is that the diseases we are now trying to treat, such as cancer and Alzheimer’s, are harder than many of the infectious diseases that dominated our efforts 50 years ago. But another reason lies in the nature of the drug development process itself.

For every drug that is used clinically to treat a disease, more than 6,000 completely new chemical compounds are synthesized. On average, about 20 drug candidates are tested in people for every one that gets to market. (The failure rate for biopharmaceuticals, which are macromolecules rather than small organic compounds, is a lot better, but still very high: about one in five of those candidates tested in humans make it to the clinic.) For chemical drugs, the process takes, on average, about 12 years from target identification to drug approval and costs close to $1 billion (the timeline is shorter for biopharmaceuticals and the overall cost is only about a third of this, in part because there are fewer failures). More than half the cost comes from the clinical trials that must be undertaken once a drug candidate has been approved for human testing. This approval comes at the end of an extensive period of preclinical testing, which involves in vitro (test tube) and in vivo (animal or cell culture) experiments using wide-ranging doses of the study drug to obtain preliminary efficacy, toxicity and pharmacokinetic data (data on absorption, distribution, metabolism and excretion, popularly known as ADME) in animal models of the disease in question. Such tests allow pharmaceutical companies to decide whether a drug candidate warrants further development as an investigational new drug.

In the United States, which is both the largest drug maker and the largest single drug market in the world, the next step is the clinical trial process, which has three main phases. Phase I trials are the first stage of testing in human subjects. Normally, a small (20 to 100) group of healthy volunteers is selected. They are given the drug to assess its safety, tolerability, pharmacokinetics and pharmacodynamics in people. These trials are often conducted in an in-patient clinic, where the subject can be observed by full-time staff. Phase I trials also include dose-ranging, also called dose escalation, studies so that the appropriate dose for therapeutic use can be estimated. The tested range of doses will usually be a fraction of the dose that caused harm in the preclinical animal testing. Although Phase I trials typically use healthy human volunteers, there are circumstances in which real patients are used, such as patients who have terminal cancer or are infected with HIV and lack other treatment options.

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