Almost There: Risks and Failures in Phase 3 Clinical Trials
Thadomal Shahani Engineering College
Every drug goes through a series of tests and trials to achieve an FDA approval before it can reach the market. These trials commonly start with small subsets of animal testing before moving on to human clinical trials. Clinical trials usually consist of five phases-four of which are needed for their final approval while the fifth one is for further research purposes. Over the years, it has been observed that some of these drugs work fluently till the first few phases, but things start going south during phase 3 clinical trial which goes on for several years in most cases. It’s a massive risk, with the potential of millions of dollars and years of effort invested in that particular drug by the pharmaceutical company going for a toss.
Phase three trials includes over 3000 participants. The most evident reason accounting for the failure of new drug candidates in this phase is the mere fact that this is the very first phase wherein the drug is used on real patients- who actually suffer from the condition that the drug is meant to treat. Another obvious reason is that phase three trials last for years which provides enough time for long-term side effects of the drug to surface. Being unable to fulfil the efficacy and safety parameters in this phase is often what leads to rejection of the drug. This failure not only diminishes the financial status and future of the company, but also delays and demotivates the potential of obtaining a treatment method for that condition.
Torcetrapib was one such drug sponsored by Pfizer which was meant to decrease LDL-C cholesterol level in patients with underlying heart conditions and hence reduce the risk of adverse cardiovascular events. Up until phase 2 trials, Torcetrapib showed a considerable decrease in LDL-C levels in the bloodstream even though there was a slight increase in blood pressure. Analysing the promising results in phase 2, Pfizer had already invested up to $800 million on the production and testing of the drug when an unexpected dead-end occurred. During the phase 3 trials randomised on 15000 people with various heart conditions, the expected outcome was an increase in the time to first occurrence of a major cardiovascular event along with a decrease in the amount of LDL-C and reduced blood pressure.
During the measurement of these parameters, it was found that the patients treated with torcetrapib were more likely to suffer from adverse cardiac events and die from the same. Not only was the drug ineffective, but also proved to be dangerous. The trials were put to a halt three years earlier than expected due to safety concerns. There have been several other similar cases associated with critical conditions like Alzheimer’s and allergic asthma wherein the drug candidate was either seen to be inefficient or worse, it led to worsening of the condition that it was meant to treat.
In order to prepare an improvised, adequate structure for clinical trials so as to reduce drug failures in phase 3, it is important to figure out the cause and parts of the process which ultimately lead to a nightmare in terms of investment as well as health. Ongoing studies for optimizing phase 3 trials include reviewing and possibly increasing the participation in phase 2 trials along with modelling and simulation procedures. The only downside to the above alterations is the huge investment to be made in the R & D sector so that the flaws of the drug can be put under a finer microscope for better understanding of the basic mechanism followed by the components of the drug. Even though the investment must seem enormous, when compared to the risk reduction associated with its impact it would appear to be more than worth it.