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Phase I in the Age of Precision Medicine and Patient Diversity

As clinical research evolves and becomes more refined, the industry is coming to acknowledge a simple truth: that everyone is different. A drug that works wonders for one individual may have little to no effect on, or even be detrimental to, another. Alternatively, the discovery that a treatment is ineffective or dangerous in a small group of clinical trial patients may cause the discontinuation of that drug’s development, allowing its potential to help the general population to go undiscovered. The trends toward precision medicine and patient diversity show that the clinical research industry is making stronger efforts to acknowledge the genetic, ethnic, and biological differences among patients that lead to these disparities. Spurring these trends are some startling statistics: some of the highest-grossing medications in the United States work as intended for only 4% of the patients who take them.1

But precision medicine is about more than efficacy. Physiological differences between individuals and groups don’t just impact who a drug works for; they affect the appropriate dosage for those people as well. Will new levels of dosage specificity pursued through precision medicine lead to fundamental changes in the ways dosage and tolerability are determined in Phase I clinical trials?


Patient diversity and new Phase I intricacies

There are various ways Phase I clinical trials could evolve as a result of these growing trends. One thing that may change is the size of Phase I patient populations. In order to gain reliably predictive safety and dosage data, every patient demographic incorporated into a trial would need to be represented by numerous subjects. Currently, patient totals for smaller Phase I trials start at about 20. But is this enough to accommodate a truly diverse patient population, with each demographic sufficiently represented? Some medical professionals are calling for future study protocols, informed by this new focus on comprehensiveness, to have higher patient totals than the current norm.

Alternatively, some investigators have taken a more focused approach to patient diversity, with potentially different effects on patient population size. In San Antonio, Texas, for example, a lack of data on how breast cancer affects Hispanic women has led to breast cancer trials that recruit solely from that demographic.2 In cases like these, in which acknowledging the ethnicity-based differences in responses to treatment and disease means recruiting from just one demographic group instead of as many as possible, could investigators in fact afford to recruit fewer patients? Will it be necessary to recruit up to 100, as some Phase I trials do? More focused trials with fewer patients could mean fewer variables and less complexity.

We may see even more customization, with dosage determination zeroing in not just on demographics, but on individuals. Recent reports have appeared of researchers modifying the dosage of a drug to new levels of specificity for certain Phase I patients based on physiological differences among those patients. In one such study, researchers developed an algorithm to optimize dosage on a patient-to-patient basis,3 requiring the collection of specific biomarker data from each patient so researchers can, theoretically, incorporate 90 different doses of a drug in a trial with as many patients.


Precision medicine and N-of-1 clinical trials

All of these potential changes presume that group-based trials remain the norm in clinical research. But many in the industry see precision medicine leading to a shift away from the group in favor of one-person, or N-of-1, clinical trials. These trials allow researchers to develop treatment plans based on specific genetic, environmental, and lifestyle data for one individual, and project success for those plans for individuals in the general population with similar profiles.

While N-of-1 trials are, of course, much smaller than traditional ones, they will still require comprehensive physiological patient profiles, as well as precise dosage levels specifically tailored to each patient.1 Fortunately, the trend toward precision medicine is developing in tandem with technological advancements that could make this easier. The recent FDA approval of the use of 3D printers to produce pills, for example, allows for more precise dose customization than was previously pragmatic.

It has been nearly two years since the announcement of the president’s Precision Medicine Initiative. In that time, precision medicine has blossomed into a major medical philosophy driving innovation in clinical research and in healthcare at large. It may only be a matter of time before we see that philosophy reflected in fundamental upgrades to the conduct of clinical trials.


1 Schork, Nicholas J., Personalized Medicine: Time for one-person trials; Nature; 29 April 2015
2 Rambaldi, Camilla; Hispanic women needed in clinical trials for breast cancer research; News 4 San Antonio; 7 October 2016
3 Guo, Beibei & Yuan, Ying; Bayesian Phase I/II Biomarker-based Dose Finding for Precision Medicine with Molecularly Targeted Agents; Journal of the American Statistical Association; 9 September 2016



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