ABSTRACT
Introducing Bioequivalence It was a rainy day, and I was looking forward to another day at the
Clinical Pharmacology Unit. We called it ‘The Unit’ for some reason. I think it was a sign of the times in the 1990s. We worked at ‘The Unit’; people from FDA worked at ‘The Center’; people in the CIA probably worked for ‘The Agency’. You get the idea. It is good that times have changed. It had been about a year and a half since I started working in statistics
in Clinical Pharmacology, and I was starting to feel like I knew what was going on when working with the teams which were making the potential drugs and designing and performing the clinical pharmacology trials. By this time, I had worked on a couple of submissions to regulatory agencies (under supervision), had been through a regulatory audit by the FDA (they come in occasionally to check all the paperwork - as long as you follow your standard operating procedures and document what you have, this is no problem and nothing to worry about), and had figured out when lunch was. I felt like I had it made until a ClinPharm physician and scientist
came into my office that morning while I was drinking my coffee. We will call them Lenny and Denny, and they both looked like they were having a bad day. They were characters. Both of them talked a lot and at great velocity most of the time, but today they were pretty quiet. They had both been at work since 6 a.m. (clinical staff usually come in early - I think it gives them more time to make mischief) and both looked like they would rather be out in the Pennsylvania thunderstorm that was now cutting loose. Over the monsoon, Denny filled me in on what the problem was. Lenny
just nodded and groaned occasionally and looked like he wanted to go home and go back to bed. I figured he brought it on himself coming to work at 6. In brief, one of our drugs was in the late stages of drug development.
The confirmatory trials were close to finishing, and the scale-up of manufacturing to make sufficient drug to supply the marketplace had been
completed about three months ago. Everything looked pretty good - the drug was safe and well tolerated in addition to being efficacious, and we expected the Regulators to approve it once we submitted it in about six to eight months. The company had spent a lot of money to buy this product (we had
bought it from whomever had invented it) and to develop it (estimates were in the range of what was discussed in Chapter 1) in addition to spending about five years in clinical development. It was a tremendous effort. The problem was that the new formulation we wanted to mass pro-
duce and prepare to market clearly did not demonstrate bioequivalence to the formulation being used in the confirmatory clinical trials in a recent study. It was close, but the study did not fully meet the regulatory standard. Lenny groaned here, but I just kept drinking my coffee. I was still too new to know how bad this was. We had a quality issue in the manufacture of the drug. This essentially meant that even if the regulators at the FDA approved
the product for safety and efficacy, the company would not be able to market it. We could not (at that time) confirm that the new formula was of a sufficiently high quality to deliver the same safety and efficacy results when used in the marketplace as achieved in the confirmatory clinical trials. When Denny explained that, suddenly my coffee did not taste as good (it was always pretty bad, actually - it was free, though). After reminding myself that I knew when lunch was supposed to be and
had gotten more sleep the night before than Lenny and Denny combined (both positive factors in my view in this situation), I got a crash course in the history of bioequivalence. We then started working through the issue of how to get the quality assessment for this drug product back on track. Biopharmaceutical statistics traditionally has focused on differentiat-
ing between products (or placebo) to provide new and enhanced treatments for the public’s benefit [384]. However, this is generally expensive and time consuming (see Chapter 1) and over time steps have been taken to reduce costs and to increase supply of pharmaceutical products while maintaining the potential for innovation. One such example pertains to bioequivalence. To call something equivalent implies a context or set of criteria for the
determination of equivalence. There are several stakeholders who have say in choosing such criteria: • Regulatory and public-health considerations: The approach used must protect public health in that the risk of a false positive (Type 1 error) market access must be controlled at a predetermined rate.
