Darrel Huff’s How to Lie With Statistics is an excellent overview of using mathematics and statistics mislead things that may not actually be true. At the beginning of his book, Huff starts with a quote popularized by Mark Twain and attributed to British Prime Minister Benjamin Disraeli:
There are three kinds of lies: lies, damned lies, and statistics.
The art of statistical malfeasance is regularly practiced in the realm of drug development and marketing, and today’s Tales from the Counter is a common example.
Our patient was being treated for glaucoma with latanoprost. Unfortunately, mono-therapy was not achieving the desired goal for our patient’s intraocular pressure. The ophthalmologist wrote a prescription for a second drug, timolol maleate, in hopes of better controlling the pressure in the eye. The prescription, however, was not written for generic timolol. It was written for Istalol 0.5% drops, and this is where statistics and science enter into the equation.
Istalol is a brand name version of Timolol Maleate 0.5% drops. Also available are generic Timolol Maleate 0.5% solution and Timolol Maleate 0.5% Gel-Forming Solution (GFS). In the eyes of the Food and Drug Administration, each of these drugs are scientifically and statistically different. Because of this, the pharmacist cannot substitute any of these three for another without getting a new prescription from the prescriber.
The rules of substitution enumerated in an official publication of the FDA called the Orange Book: Approved Drug Products with Therapeutic Equivalence Evaluations. This compendia of equivalent and non-equivalent dosage forms (bioequivalence) is governed by a science called pharmacokinetics. In the most basic terms, bioequivalence is achieved by statistically demonstrating similar rate and extent of absorption into the body. Bioequivalence has two opposing uses: matching rate and extent to create a substitutable generic equivalent, and purposefully modifying rate and extent to prevent equivalence, creating a non-substitutable drug entity. This last use is commonly used to create a marketing advantage.
Note that equivalence, or the lack thereof, are not inherently relevant in a clinical sense. Bioequivalence is not a measure of clinical outcome. Instead, it ensures that a given clinical outcomes should be observable using any equivalent product. Differences in rate or extent do not mean that one product is necessarily better than another.
This is the key point. Some bioequivalence differences statistically demonstrate better disease control or fewer side effects. More often, bioequivalence differences are associated with patient convenience: once-a-day dosing offering potentially better patient compliance than twice-a-day dosing. If taken properly, either will achieve the desired clinical outcomes.
It is creation of a non-substitutable drug entity that creates some of the most interesting pharmacy stories. When faced with the impending loss of patent protection, it is common for the pharmaceutical manufacturer to re-formualte their product to create a non-substitutable version of their product. This helps them extend the profitability of their product. But often these tricks offer little in terms of actual clinical advantage.
This brings us back to our timolol prescription. Istalol is non-substitutable timolol with once-a-day dosing. The Timolol Maleate solution requires twice-a-day dosing to achieve the similar therapeutic effects. Interestingly, the Timolol GFS can also be dosed once daily to achieve the desired outcome. A brief search of the literature did not reveal any obvious clinical advantages of Istalol over the other two products. Because our patient has not, as of yet, tried any timolol formulations, we have no reason to believe that they would not achieve their therapeutic goals on any of the available timolol formulations. So how do these products compare with respect to price?
- Istalol 0.5% Solution, 5 ml: $270 (Copay $135)
- Timolol Maleate 0.5% solution, 10 ml: $10 (Copay $0)
- Timolol 0.5% GFS, 5 ml: $70 (Copay $0)
Given that the Timolol GFS is dosed once-a-daily like the Istalol, and it is $135/bottle less expensive to the patient, it would be a much better first choice. Because the prescription was written for non-substitutable Istalol, the prescriber was contacted to request a new prescription. This is called making every encounter count!