If you are a fan of Stephen King, you know how easy it is to get sucked into the strange and perverted worlds that he creates. It happens word by word, sentence by sentence. Sooner or later you find a general sense of uneasiness and then queasiness creeping into you. When this happens to me, I sometimes need to remind myself that this is just fiction and would never happen in reality. And with this mental safety line, I can pull myself to comfort. It’s fiction not reality, fiction, not reality….
Perhaps one of my favorite Stephen King stories is Quitter’s, Inc. The main character is Dick Morrison, a man who is suffering from overeating, working too hard and smoking. At a friend’s recommendation, he signs a contract with a company called Quitter’s Inc. which promises that he will never smoke again. He soon finds out that the company is run by a mobster and their strategy is simple: if Morrison is to smoke again, Quitter’s Inc. will do severe harm to those he loves most. Perhaps torture, maybe cutting off a loved one’s finger or worse. Reading this, I grabbed my mental safety line and left this disturbing story tucked neatly away in my subconscious, where it can do no harm.
That is until I stumbled upon the FDA and Vivitrol. A few days ago, I was emailed an article from the New England Journal of Medicine suggesting that the FDA needs to regulate organizations providing genetic screening tests. The essence of the article was that individuals should not be trusted with information about their own health. That should be left up to the FDA and such individuals’ physicians, because, presumably, they know better. So I decided to go to the FDA website and see what it is that they do and whether they had my best interests in mind. I began by looking at a page listing drugs that have been recently approved and I picked Vivitrol because it sounded nice. It turns out that Vivitrol was approved a few years back, but has just received a modified and expanded indication approval. Vivitrol or naltrexone is used for treating alcohol dependence and more recently for opioid use.
For the original FDA approval process, Vivitrol’s manufacturer tried to make the case to the FDA that Vivitrol has a positive impact for alcoholics by reducing both the frequency and amount of alcohol used by patients. An “event rate of heavy drinking” measure was used as an index to reflect both the incidence and severity of drinking. The FDA felt that, whereas the index was novel, it was too complex to understand and did not match what treating physicians might consider a desirable outcome. Instead, the FDA proposed that the target measure should be a reduction to zero days of heavy drinking. So far so good. The FDA seems to be on track and diligent about its process. But here is where things get weird. Heavy drinking is defined by the FDA has having five or more drinks a day for men and four or more for women. So if you are an male alcoholic, and you reduce your intake to four drinks a day, that is considered a success! This seems to me more like treading water than success and intuitively, the four-drinks-a-day patient is likely to fall off the wagon in the near future. Thus even before we do a lick of testing, the question of the appropriateness of the target for a successful outcome is surely open to debate.
The FDA then analyzed the results of Vivitrol on patients who were abstaining from drinking when they started the test program and patients who were still drinking at the start of the program. The overwhelming majority of patients fall in the latter category. The FDA, in its approval, concluded that Vivitrol had no positive impact on the latter group, but that it does positively effect the former group. The FDA states:
…the proportion of patients meeting the definition of treatment success greatly increased, and a difference between Vivitrol and placebo groups was suggested for patients abstinent at baseline. The efficacy results are summarized in the table below:
Actual number of heavy drinking days per month N (%) Placebo 190 mg 380 mg All patients (abstinent and non-abstinent at baseline)
Patients abstinent at baseline
The table refers to the drug study test used by the FDA to assess the drug. So what does this table mean? “N” is the number of positive outcomes, the percentages represent the ratio of N to the number total patients with positive and negative outcomes, “190 mg” is the first dose option for Vivitrol and “380 mg” is the second dose option for Vivitrol. Some more digging showed that of those that took Vivitrol in the test at the 380 mg dose, only 17 fell into the category “Patients at abstinent baseline” (i.e. not drinking alcohol at the start of the test period) and who were prescribed the 380 mg dose. Of these 6 or 35% were deemed successful outcomes and did not drink “heavily” during the trial period. This compares to the Placebo group from which 2 or 11% did not drink “heavily”. Since the FDA only approved the drug for people in this “abstinent at baseline” category, it is apparent that the approval process for the 380 mg dose is solely based on a single trial of 17 patients “abstinent at baseline”. Four more patients in this group abstained from “heavy” drinking compared to the Placebo group, and voila, the drug is approved. Four patients. Four. One, two, three, four. 4. IV. That’s all it took to get this drug approved with a stamp of approval from the FDA that Vivitrol “greatly” increases success.
Even with this scant evidence, let’s test whether the FDA’s conclusions are reasonable. We need to look no further than the FDA’s own statistician who reviewed the drug test study. The statistician wrote a dense 38 page paper of which only a single paragraph discusses the “special / subgroup” of patients that were “abstinent at baseline”. The paragraph states, “Since the number of patients abstinent at baseline was very small, I explored the possible effect of treatment on the subgroup …. without any attempt to draw a formal statistical inference.” The statistician then produces a lengthier version of the table shown above.
The FDA’s approval states the drug “greatly” increased success. But the FDA’s own statistician states the sample is too small and no “formal statistical inference” is even attempted. With a bit of magic, the FDA turned its own statistician’s analysis upside down to rationalize the approval of this drug.
Now we start entering into Stephen King territory. For the next thing that I did was go to the Vivitrol’s website and read the “Highlights of Prescribing Information”. The document warns of potential side effects of the drug, including:
- Injection site reaction
- Eosinophilic pneumonia
- Hypersensitivity including anaphylaxis
- Depression and suicidality
The document also tells you that “Any attempt by a patient to overcome the blockade produced by VIVITROL by taking opioids is very dangerous and may lead to fatal overdose.” Is this the equivalent of “Fall off the wagon and die”? I believe it was after reading this that Quitter’s Inc. uncomfortably bubbled up from my subconscious. Vivitrol’s website is also kind enough to tell you how often one might expect a side effect. Here are some of them:
- Nausea – 33% of patients in the trial
- Injection site conditions – 69%
- Headache – 25%
What can be done about this sorry situation? Most importantly, the drug efficacy study should be done in conjunction with analyzing the potential dangers and side effects of the drug, rather than as two separate studies. I have discussed a conceptual model of ranking good vs. bad outcomes here. Secondly, particularly when dealing with behavioral issues such as abstaining from drinking, I propose a new approach: the anti-placebo. Whereas a placebo is designed to do nothing, an anti-placebo is designed to do something. In particular, it should mimic the side effects of the drug under investigation and cause a bit of pain and anguish. For example, how about creating a control group and giving each person in the group something like a shot of dishwashing liquid, or a sucker punch in the gut? Yes, this does have severe side effects, but would you really want to go boozing it it up with your buddies at the local hot spot, if your stomach were in pain? This is a barbaric test, yet how much more barbaric is it than subjecting a patient to hepatoxicity, pneumonia, and suicidality, not to mention the potential risk of a “fatal overdose” if the patient falls off the opioid wagon? A painful belly does not seem too bad when compared to death or suicide. Simply put, perhaps Vivitrol’s limited positive impact has more to do with making its users sick and unmotivated to drink than any biomechanical mechanism which causes a reduction in alcohol intake? This issue was not pursued by the FDA, but should have been.
All this brings me back to my original quest of getting a better understanding of the FDA and whether it has my best interests in mind. I will let the above analysis speak for itself.
The FDA is not run by the mob. It is run by the government. Given the statistical evidence of the efficacy of this drug, the line in Vivitrol’s Highlights of Prescribing Information, “Any attempt by a patient to overcome the blockade produced by VIVITROL by taking opioids is very dangerous and may lead to fatal overdose,” could have been written by Stephen King. I shudder now and reach for my mental safety line, but all I grab is “It’s reality not fiction, reality not fiction…”