Clinical Pharmacology Safety Studies

Introduction One day, out of seemingly nowhere, I received a very strange request

from a clinical scientist. We will call her Betty, and she asked if I could round off a confidence interval? My immediate response was, ‘No. Why would anyone want to do that?’ In essence, we had derived an upper bound in a drug interaction trial

of 1.2538 for AUC. Evaluation of this value relative to the acceptance level of 1.25 showed that it was higher than 1.25. We could not conclude the two treatments were equivalent. Pretty elementary. Betty wanted to round it off, so she could claim equivalence had been demonstrated. I told her no, and left it at that. Such would misrepresent the data, and

the statistics underlying the upper bound could not support ‘rounding it off’. Clearly as the value was higher than 1.25, the null hypothesis had not been rejected, and it was out of the realm of possibility. To my mind it was also a matter of professional integrity, and I was a bit surprised that anyone would ask such a thing. The less I said, the better off we would both be. However, I was still new on the job, and did not know that some people

will not take no for an answer, even if it is a matter of professional integrity. So began one of my most important ‘learning experiences’ on the job. ‘Learning experiences’ are a business euphemism for an experience no one in their right mind wants any part of, but you are stuck with it because you work there. Rounding off turned out to be really, very important to Betty and the

physician for whom she worked, and a major disagreement at the company developed. Peoples’ egos became involved, and everyone who had even only a nebulous stake in this (or a potentially related) issue felt compelled to comment. Academic experts were paid and consulted. Opinions were sought from the FDA on the topic. Many internal meetings on the topic were held, and (despite their best efforts to avoid it) several senior vice presidents had to be consulted and in the end backed us up, ‘No rounding’. Years later FDA guidance [135] was issued saying the same thing, but

as is often the case, such business precedes regulatory guidance by many years. Guess who was at the center of this argument? It was a rough expe-

rience (for what I still feel was a ridiculous request), but I learned a lot from interacting with such people on such a thing and from watching how they and many other people behaved. If had it to do over again, I would have followed a different approach to dealing with such people. I call it the ‘Nurse’ approach in honor of the people whom I saw do it. We had a drug intended for the treatment of hypertension (high blood

pressure) which caused migraines if given at high doses. We discovered this in the first study in man (which is designed for this purpose, see Section 7.1), and carefully worked out at which dose the problem started. These were bad migraines - the throwing-up kind. The study team wanted to stop the study, but a chief medic said to continue. The rationale was that they wanted to explore more doses before going to the next study. There was no point in continuing. The study had defined the maximum

tolerated dose, completing its objective. We were at an impasse with the medic involved. We discussed the ethical issue of continuing (i.e., not), but were told headache and emesis were not a serious enough side effect to warrant not exploring further. Egos began to become involved. Senior vice presidents were again getting phone calls. This came to an abrupt stop, and the nurses put a stop to it. I am

told that they told chief medic that if he wanted to continue, he’d have to come down and clean up the vomit himself. The study ended the next day. That was not the official reason logged in the study file, and it is hearsay, but I think it is probably true. The moral of the story is that when you are asked to do something

you consider inappropriate, put the person who is asking in your shoes. When they will actually have to get their own hands (or shoes) dirty to do such a thing and take personal accountability for it, you will be surprised at how the pressure to do so suddenly lets up. If not, then try ‘No’. When exploring safety, it is important that we get it right for the

sake of each and every patient who will take the product. Everyone has a stake in this assessment. Even the people who develop and sell drugs may themselves have to take them one day! All drugs have side-effects and should be presumed to be unsafe if used incorrectly. Some side-effects can be very serious and life-threatening. The role of clinical pharmacology safety studies is to define how the

body handles the drug such that side-effects can be predicted in a rational, scientific manner. This assessment determines how the drug should be used correctly to treat the condition under study. Every decimal point matters. Do not cut any corners which would compromise patients’ safety,

and ensure your findings represent the data accurately, so that the people using the drug can make a fully informed decision.