By Joan Korth-Bradley
The Right Number of Elephants is a delightful children’s picture book that talks about the uses of different numbers of elephants to accomplish unique tasks. If you need to pull a train out of a tunnel and save everyone on board, the right number of elephants is 10. But, if you want a fast game of cards, the right number of elephants is three. The same discussion can be had about the number of subjects needed to adequately test a drug as it progressing through the clinical trials process. What is the right number of subjects to enroll? As readers of the book will tell you…it depends!
Recently, there have been media stories calling for clinical trial enrollment to reflect the racial and ethnic diversity of the U.S. population. Unless there are participants who look like each of the ultimate users of medications, the authors say, the clinical trials will miss important information about the appropriate dosing and safety in minority populations. While this is an understandable concern, it is practically impossible within the framework of drug development to include participants who represent all demographics that may eventually benefit from the medicine. It is important, however, to enroll patients in clinical trials who are reasonable representatives of those with the disease. For example, a study of a drug used to treat ovarian cancer must enroll women and studies of drugs used to treat sickle cell disease must enroll patients of African ancestry. But simply being a woman or having African ancestry is not enough. The patient must have the condition being investigated.
To better understand this issue, it’s important to remember that a newly approved medication is only part way along its development path. After product launch, additional translational studies along with epidemiological exploration of safety data collected through surveillance and reporting are key to personalizing treatment. This phase, soon after approval, provides an opportunity to collect and assess valuable data pertaining to drug usage among populations that may not have been significantly represented during clinical trials.
During development, in addition to clinical studies that assess safety and efficacy, other studies are performed to aid in the design and interpretation of the safety and efficacy studies. Sometimes, the question being asked in a study is simple. Do the concentrations of an antibiotic decrease when it is given with food, compared to when it is given on an empty stomach? We could answer the question, at least in a limited fashion, with a single subject and a grilled cheese sandwich. Of course, because we want a more robust answer to our question, the right number of subjects is at least 12. And because researchers want to answer the question about food, they try to enroll subjects that are as alike as possible so that differences between different subjects don’t overwhelm the difference caused by the potential food effect.
Sometimes the question being asked is more complex. Will the antibiotic cure complicated skin and skin structure infections (cSSSI), like animal bite infections or those found in decubitus ulcers, caused by different strains of bacteria? Are the pharmacokinetic parameters of the antibiotic consistent enough among all the different people with cSSSI that the same dose will work for everyone? What are the adverse events that this group of patients will have? To answer these questions, the right number of subjects is about 620 subjects, split even between two treatment arms. And to answer all of the questions that are needed to customize the treatment for all of the different people that are going to need to be treated for cSSSI, the right number of subjects will be thousands and thousands and thousands.
Drug development programs need to balance gathering the information demonstrating safety and efficacy in a reasonably representative population with an exhaustive investigation of all of the potential differences between subjects. Subjects who have conditions that could make interpretation of efficacy or safety results difficult to interpret may not be included in studies. With a clear understanding of the exposure-effect relationships, modeling and simulation techniques may be used to bridge the gaps.
Ultimately, continued monitoring of newly introduced medicines, along with continued questioning about why some patients respond and others do not, will position these new medications in the therapeutic toolbox of clinicians. What is the right number of subjects of a particular type needed in clinical studies? It depends!