It only been a few hours since the FDA's warning on Spriva (an inhaler used for patients with Chronic Obstructive Pulmonary Disease or COPD) but there are already postings on the Wall Street Journal and AP ; and the night is still young.
As I warned when this initiative by the FDA was first announced:
Increasing public awareness about potential adverse reactions is a good thing, but please do not be alarmed every time you hear on the news that there is a new warning about a particular drug.
Though the Spiriva warning is not the first warning since this initiative, it is likely the first one that will get significant press. Specifically, the warning states that:
"ongoing safety monitoring has identified a possible increased risk of stroke in patients who take Spiriva (tiotropium)...... Boehringer Ingelheim reported to the FDA that it has conducted an analysis of the safety data from 29 placebo controlled clinical studies (“pooled analysis”)....(which showed) the preliminary estimates of the risk of stroke are 8 patients per 1000 patients treated for one year with Spiriva, and 6 patients per 1000 patients treated for one year with placebo. It is important to interpret these preliminary results with caution (my bold)."
Before further explanation, I want to point out that according to the FDA's statement:
-pooled analyses have inherent limitations and uncertainty
-Patients should not stop taking Spiriva
What's going on???
Once a drug gets approved, the company that makes it is required to report analysis of studies and determine if any potential risks exist. In the past, the communications stayed between the FDA and the drug company to determine if the risks were real, whether further investigation was needed or whether action should be taken. However in an effort to communicate to the public about early potential risks (or look like they were actually doing something to improve drug safety), the FDA decided to make these communications public.
What is a pooled analysis?
If a side effect occurs once in 10,000 patients taking a drug, you may need to give the drug to 30,000 patients before someone would have the side effect. Drug companies do many kinds of studies to investigate their drug before and after it is approved, but these studies are much smaller. By looking at all of these studies together, you might be able to see a rare side effect. The problem is that squishing all these studies together has its limitations, because the designs of the studies are quite different. Let's say that you were trying to prove that an apple a day keeps the doctor away. In 100 schools across the country, you gave half the students apples. In each school, there was no difference between the apple eaters and non apple eaters, but when pooled together, apple eaters were actually found to have more doctor visits. Apples must be harmful, correct? It depends on what schools (pre-schoolers are more likely to be sicker then high schoolers), when the study was done (fall worse than spring), number of students studied, and lenght of the study. If all things were pretty similar, then the study might have some merit. However, most of these pooled analysis do not use similarly designed studies, and can sometimes generate inconclusive data that scares people to death (see Avandia below). In this example, there could be more doctors visits in the apple eaters, but most of these visits could have been disproportionately represented by the one pre-school in the study that looked at doctor visits from September to December.
Does Spriva cause stroke?
It might. It might also cure cancer, but in both cases it just isn't clear. In 29 trials included data from about 13,500 COPD patients, there was a difference of 2 strokes per 1000 patients taking Spiriva for a year. This is a low number, and in a pooled analysis should be taken with a huge grain of salt. There is no biologically plausable reason for Spriva to cause a stroke. The best way to determine whether or not there is an issue is to do a large, controlled trial. This trial called UPLIFT (Understanding the Potential Long-Term Impacts on Function with Tiotropium) is actually underway, and the results are expected to be released in June. Why not wait a few months for the findings of this study before releasing data to the public? Though Spriva is not life saving (nothing but quitting cigarettes will save the lives of patients with COPD), but it does improve lung function and improves quality of life for patients.
If you have COPD, taking Spiriva, and it is helping you breathe then by all means continue to take it. The FDA release give such little information that your doctor will not likely be able to tell you much more, and may suggest stopping it simply because he or she is too worried about getting sued.
If this sounds familiar, it is. The same type of data was reported by GSK to the FDA on heart attacks with Avandia. GSK's large, randomized controlled trial to actually answer this question was ongoing, and so the FDA (correctly) chose to wait before alarming the public and drawing any incorrect conclusions. However, someone inside the FDA didn't like that idea and alerted Dr. Steve Nissen (of Vioxx fame, and now a frequent sound bite on any potential drug danger). Because of a settlement on another product, all of GSK's data was available online, so Dr. Nissen did his own analysis and got it published in the New England Journal of Medicine in a mere 3 weeks time (normal turnaround time is months). This created a media frenzy, which naturally scared doctors and patients (we recently looked at our own prescription data, and after this press release many of our patients stopped taking Avandia on their own, before speaking with their doctor). After several meetings and analysis, it turns out that in well done, large clinical trials, there is no risk of increased heart attacks with Avandia. Trying to determine what to do between the intial warning and subsquent findings, in November 2007 the updated Avandia's label and released a statment saying that:
FDA has concluded that there isn't enough evidence to indicate that the risks of heart attacks or death are different between Avandia and some other oral type 2 diabetes.
Of course this doesn't get nearly the press that the scary 5/07 release got.
My guess is that when UPLIFT shows no increase stroke with Spiriva, you won't here about that either.