A pipe dream or nearly a reality? How close are we to a medicine that is precisely matched to your unique genetic makeup, environment, and lifestyle? Such a highly personalized medicine would not only give you the best possible clinical outcomes but would likely also cause less side effects. The reality is that such medicines are not yet standard but they will “sooner than later” replace the “large population” drugs that have dominated drug development for the past 40 years. Those blockbuster drugs represented breakthroughs in treating so many common conditions, including cancer, cardiovascular disease, neuromuscular conditions, inflammatory diseases, and immune disorders. But because they were developed for use in patients highly diverse in other characteristics, the benefits and adverse effects often varied significantly from one patient to another. In contrast, the new generation of personalized, precision, or targeted medicines designed to treat specific subsets of patients not only produce superior desired outcomes but also less unwanted effects. A future where highly specialized therapies will be the “new norm”, even for the most common conditions, is definitely within sight and indeed gaining momentum thanks to initiatives such as the Precision Medicine Initiative launched by US President Barack Obama¹, the Canadian Institute for Health Research Personalized Medicine Initiative², and European Commissions on personalized medicine pilot projects.³

Given the seemingly haphazard results from many of the current blockbuster drugs – some have been shown to only improve the condition in as few as 1 in 20 persons⁴ – the impetus toward personalized therapies is not only desirable but highly overdue. According to the US National Institutes of Health, precision medicine is ‘an emerging approach for disease prevention and treatment that takes into account people’s individual variations in genes, environment and lifestyle’.⁵ BUT … in order to develop and approve drugs that are tailored to specific people, the entire clinical trial process needs to follow a personalized approach.

Clinical trials should focus on individual, not average, responses to therapy.

Classical clinical trials are based on findings from hundreds or even thousands of participants, collecting a limited number of parameters, often not taking into account many additional factors – like genetic makeup or lifestyle – that shape a person’s response to a certain treatment. The large number of participants is necessary in order to increase the chance of achieving statistically significant results. However, these large trials are not very good at predicting which individuals will respond positively and also which develop adverse effects. Post-trial analyses are required to determine which factors were responsible for the different outcomes in different people. Moreover, because extraneous information may not have been collected or sufficiently documented in the course of the trial, additional studies are often required to identify meaningful differentiations among potential users.

In contrast, targeted drug development is based on alternative trial designs that attempt to accommodate relevant variability among patients from the outset. Basket trials, often used for cancer research, test drugs based on their mode of action rather than a specific cancer site. Participants included in a single basket trial may have different types of cancer, for example breast cancer or colon cancer, but all have a common causative or facilitating factor, such as tumour expression of an abnormal protein, which is the target of the investigated drug.⁶

Umbrella trials follow an opposite strategy. In an umbrella trial, participants have the same clinical diagnosis but they vary in terms of specific genetic markers or other factors. Patients are assigned to a test therapy according to their individual profile, so several different drugs may be tested for the same disease in one trial.⁶

Finally, in cases where there may be considerable uncertainty as to the probable impact of an investigative therapy, researchers and regulators are collectively designing and approving adaptive trial protocols that allow modifications in interventions for a subset of or individual participants while the study is ongoing, based on participant responses.⁶

These alternative trial designs are a step in the right direction, but some experts claim that these studies are still not sufficiently personalized. Consider a hypothetical basket trial for KRAS-mutated tumours. Mutations in the KRAS gene may be evident in many different kinds of cancers⁷, and a single investigative drug against various types of cancer cells with this mutation is tested using a basket trial design. However, even if the patients’ tumours were tested positively for the presence of KRAS-mutated cells, we cannot guarantee success for all affected patients since many other factors are involved in the treatment response. Another problem is that diseases like cancer might ‘evolve’ in the course of the therapy and become resistant to a previously effective treatment.⁸

N-of-1 trials can give patients a sense of empowerment and more control and understanding of their condition

According to Nicholas J. Schork, director of human biology at the J. Craig Venter Institute in La Jolla, California, a better solution is ‘clinical trials that focus on individual, not average, responses to therapy’. In other words, we need to utilize N-of-1 trials.⁴

N-of-1 or single subject trials are not a new concept. In fact, physicians have been doing this for a long time as part of their clinical practice. In certain areas of medicine such as rare diseases, N-of-1 trials have been utilized based on necessity. However, the results from these trials, when conducted in an ad hoc fashion, are not easily extrapolated to other patients.⁴ A more formalized approach may be necessary to provide guidance to other clinicians and/or to lead to an expanded approved indication for the therapy.

In well-designed N-of-1 trials, different treatments – either active treatments or placebo – are evaluated in just one patient over a period of time. Despite the simplicity of this approach, N-of-1 trials require elaborate study design, including sound statistical methodology and strategies, such as patient and clinician blinding. Although the participant is the main beneficiary of these kinds of trials, combined results of many equally designed N-of-1 trials can provide medical information for subsets of the population or even the general population.⁹

In addition to the medical benefit, research has shown that N-of-1 trials can give patients a sense of empowerment and more control and understanding of their condition.¹⁰ By collaborating with their health care professionals and playing an active role in their treatment, patients have the chance to be study contributors rather than study subjects.