For any new drug to be approved, it must be proven to be both safe and effective in large clinical trials in patients. Biopharmaceutical companies have been running these trials, known as randomized clinical trials (RCTs), for decades. RCTs are run in such a way that both the patients and doctors are “blinded” in that they don’t know if the patient is receiving the study drug, a comparator drug, or a placebo. Once the study has been completed, the “blind” is broken and the results are analyzed to determine the effects of the new drug with respect to the comparator.
RCTs are the cornerstone of drug R&D. Yet, despite spending 7 – 10 years in studying an experimental medicine to get it into these late stage studies, known as Phase 3, there is no guarantee that the drug is going to work. There are a number of reasons for this, but the fundamental problem that companies face is that it is VERY hard to come up with a single medicine that is equally safe and effective in the broad population: male/female, young/old, different ethnic groups, etc. Think about how people can have different reactions to foods. How many friends do you have whose stomachs can’t tolerate spicy food or those who break out into hives when eating certain types of fish? There are even those who can die due to peanut allergies. How can anyone think that a drug, which is specifically designed to modify a person’s biological processes, will be universally safe and effective?
The general public doesn’t have much of an understanding of what is involved in RCTs. Thus, when a front page op-ed by Clifton Leaf appeared in the NY Times Sunday Review
, it seemed to be a great opportunity to teach people about these issues. Leaf’s piece does do a little of this. Unfortunately, he also resorts to negativism in his discussion.
Here are some of the more provocative comments that appear:
“Companies spend billions on drug tests that often produce little information.”
“…despite the rigorous monitoring of clinical trials, 16 novel medicines were withdrawn from the market from 2000 through 2010, a figure equal to 6% of the total approved during the period.”
“The failures of the last 20 or so Phase 3 trials testing drugs for Alzheimer’s disease (AD)……could have been predicted based on the lackluster results from Phase 2. Still, the payoff for a successful Phase 3 can be so enormous that drug makers will often roll the dice – not on the prospect that the therapy will suddenly work, but on the chance the trial will suggest that it does.”
These comments all feed the frenzy that drug companies continue to look for devious ways to sell the public products that don’t work. Here, however, is some further background on the above comments. Yes, Phase 3 trials do fail. Let’s take the disappointments that have occurred in AD. The drugs that have been studied in Phase 3 all showed signals in earlier human trials that they either lowered markers of AD or improved cognition or both. However, this doesn’t mean that the drug will slow or reverse AD. For that, you need to study the drug in large groups of patients for months if not years. AD is a slowly progressing disease and it can’t be expected that a drug will miraculously stop AD overnight. As Leaf points out, these trials all failed. Yet, the negative trials taught scientists a variety of things; for example, patients may need to be treated at the earliest stages of disease and not when the disease is too far advanced.
No company embarks on Phase 3 trials frivolously. Long-term studies to prove the safety and efficacy of a new drug can cost hundreds of millions of dollars. Any company that runs such expensive clinical studies with the hope of “getting lucky” won’t be in business for very long. Yet, this sort of risk is encountered by drug companies daily. Such RCTs are important. It is these drug trials that prove or disprove medical hypotheses.
What about the 6% of drugs that were withdrawn from the market? As Leaf points out, in the past drugs have been approved for showing a beneficial effect – such as a new cancer drug that shrinks tumors. However, in recent years it has been shown that, while shrinking tumors, some drugs inexplicably don’t extend patients’ lives. Thus, the FDA is now requiring proof of survival benefits beyond tumor shrinkage. The same can be said for drugs for other diseases as well. Just because a drug lowers LDL, the “bad cholesterol”, it doesn’t mean that the drug will reduce heart attacks and strokes. Phase 3 studies also are needed to show that the LDL lowering lowers cardiovascular disease.
Drugs can also be withdrawn for safety reasons. As large as RTCs are, once a drug is on the market hundreds of thousands of people may take it. In all likelihood, more adverse events will be seen in real world usage of a new medicine for all the reasons discussed above. As a result, it is possible that a serious side effect can be found that can lead to a drug’s withdrawal.
The real key to improving the quality and success rate of Phase 3 is being able to select patients who have a better chance of benefiting from your specific drug. As Leaf points out with his example of the breast cancer drug, Herceptin, thanks to breakthroughs in molecular genetics, Genentech was able to prescreen breast cancer patients to determine if their disease was susceptible to its drug. As a result, it was able to run smaller, targeted RCTs to prove the safety and efficacy of this important medicine. This, however, is not a unique example. Pfizer PFE +0.62%
’s lung cancer drug, Xalkori, was also designed for a specific subpopulation of patients, rather than being broadly tested across all lung cancer patients. As a result, the Phase 3 program was relatively small, focused and successful. This type of oncology R&D is becoming routine.
These are examples of personalized medicine – identifying a specific biological approach to treat a particular subset of patients. Someday, all RCTs will be run in this fashion. Unfortunately, we do not yet understand enough about diseases to be able to attack them in such a personalized manner. Diseases like diabetes, depression, asthmas, etc. are not the same for everyone and different treatments may be needed for different patient subgroups.
So, do clinical trials work? Absolutely. Can they be done better? Yes. The more we understand about the fundamental cause of disease, the better we will be able to discover and develop new medicines. The progress in the last decade has been great. But hopefully in the next decade we will marvel at the greater progress that will be made. But let’s not trash the current system. It will evolve as the science advances.