Once the initial safety of the drug candidate has been confirmed in Phase I trials, Phase II trials are performed on larger groups (20 to 300), this time of patients. Phase II trials are designed to assess how well the drug works on the disease in question, as well as to continue Phase I safety assessments in a larger group of volunteers and patients. Phase II studies are sometimes divided into Phase IIA and Phase IIB, where Phase IIA is specifically designed to assess dosing requirements (how much drug should be given) in patients, and Phase IIB is specifically designed to study efficacy (how well the drug works at the prescribed dose(s)).
"...after years of research and hundreds of millions of dollars, the majority of drugs that never get to market fail because they do not show efficacy in the disease they were intended for."
Phase III studies are randomized, controlled, multicenter trials on large patient groups (usually 300 to 3,000 or more depending upon the disease/medical condition studied) and are aimed at being the definitive assessment of how effective the drug is in comparison with current "gold standard" treatment for the disease. Because of their size and comparatively long duration, Phase III trials are the most expensive, time-consuming and difficult trials to design and run, especially in therapies for chronic medical conditions. While not required in all cases, it is typically expected that there be at least two successful Phase III trials in order to obtain approval from the appropriate regulatory agencies such as the Food and Drug Administration (in the United States), or the European Medicines Agency (in the European Union), for example. Once a drug has proved satisfactory after Phase III trials, the trial results are usually combined into a large document containing a comprehensive description of the methods and results of all human and animal studies, the manufacturing procedures, formulation details and shelf life. This collection of information makes up the "regulatory submission" that is provided for review to the regulatory agencies. They will review the submission and make the final decision on whether to grant the pharmaceutical or biotechnology company approval to market the drug. However, many drugs undergoing Phase III clinical trials can be marketed under FDA norms with proper recommendations and guidelines (after all, they have been shown to be both safe and effective in the Phase I and Phase II studies), but in case of any adverse effects being reported anywhere, the drugs will be recalled. While most pharmaceutical companies refrain from this practice, it is possible to see drugs that are still undergoing Phase III clinical trials being used in the clinic.
So, given that the failure rate for small-molecule therapeutics is about 19 out of 20 once clinical trials commence (and 4 out of 5 for biologicals), where do you think the major roadblock is to approval? If you said Phase I, because that is where toxicity (and side-effects) are first assessed, you said what I once thought, and you’re wrong. It’s not in Phase III either; in fact, although failures in Phase III do occur (and often engender a lot of publicity), most drugs that enter Phase III trials are eventually approved. The bottleneck is in Phase II.
That’s right: after years of research and hundreds of millions of dollars, the majority of drugs that never get to market fail because they do not show efficacy in the disease they were intended for. That’s a staggering fact, and it has a number of important implications. One of the implications is that our animal models for toxicity are pretty good (after all, the Phase II failures passed Phase I, which looked for toxicity), but our animal and cell-culture models for disease are very poor for many diseases. In other words, we lack good models that would allow us to validate targets and fail compounds much earlier in the drug-development pipeline, when the cost would be much lower. If I were the pharmaceutical and biotech companies, I would be funding a lot of research in academic labs on the development of better disease models (induced pluripotent stem cells (iPS cells) may be a big advance here, but it’s too early to tell), and I would be working more closely with academic labs for longer periods of time to validate targets and find additional targets deeper into the development process.
But that isn’t my main point. My main point is that the Phase II failures represent an enormous, untapped resource for the biomedical sciences - a resource that could go a long way towards solving the problem of low productivity, in terms of cures, that plagues both industry and academic medicine.
You see, the Phase II failures have all passed Phase I, so they have been shown to be safe in humans. They failed for efficacy. They failed because they did not effectively treat the disease they were intended to treat, even though they showed biological activity in assays and model systems. There are hundreds of them - perhaps more than a thousand. I don’t know the number because drug companies bury those failures. They don’t want to release a lot of information about the molecules in question because, among other things, they fear that will give their competitors too much of an insight into what they are working on. But here’s the question I would like you - and them - to ponder. What if those drugs were not tried on the right disease?