Must everything be a randomized, placebo-controlled trial?

By Michael Murphy, M.D., Ph.D., Chief Medical and Scientific Officer,


This question seems particularly appropriate in the midst of the coronavirus pandemic, given Dr. Anthony Fauci’s expressed support for a more rigorous investigational approach in response to a question about the published results of an open‐label non‐randomized clinical trial involving the use of hydroxychloroquine and azithromycin in treating patients with COVID-19. While neither anecdotal evidence nor observational research alone can justify the unquestioned endorsement of a novel interventional agent (based upon preliminary evidence of efficacy), the situation we face today does prompt us to ask the question that we at Worldwide often ask: Might a nontraditional but nevertheless methodologically rigorous approach to study design offer advantages compared to a conventionally structured clinical program, particularly for patients with significant unmet medical need?


This isn’t a new question. A decade ago, Charles L. Sawyers, Chairman of the Human Oncology and Pathogenesis Program at Memorial Sloan Kettering Cancer Center, put the question this way in The New York Times in response to an emerging innovative class of therapeutic agents called BRAF inhibitors targeting melanoma:

“With chemotherapy, you’re subjecting patients to a toxic treatment, and the response rates are much lower, so it’s important to answer ‘Are you really helping the patient?’ But with these drugs that have minimal side effects and dramatic response rates, where we understand the biology, I wonder, why do we have to be so rigorous?”

The answer then, as now, is that innovative trial designs exist that are no less rigorous. We don’t always need to default to trial designs that represent only a limited subset within a broader portfolio of evidence-based trial designs upon which critical decision-making can be based. These hierarchically arranged criteria include USPSTF grades of evidence, as well as those associated with revised Oxford levels of evidence and the Centre for Evidence-Based Medicine. Alternative strategies acknowledging a sophisticated tiered system for evaluating novel therapeutics exist, and they are indeed both informed and quite rigorous. Moreover, under appropriate medical oversight, such strategies can offer high-risk patients a more rapid method of product introduction.

For companies striving to bring therapeutic products to consumers, consideration of experimental design options – that span a range of possibilities, including the use of nontraditional methods of data collection, such as the use of mobile applications — may deliver insights of equal value compared to a standard approach while improving program efficiency and reducing time to approval.

Worldwide has experience with a variety of alternative trial methodologies, including the following:

  • Normal volunteers, patients, hybrids for first-in-human (FIH) studies
  • Parallel groups (flexible, fixed, flexible-fixed-dosage escalation)
  • Crossover, Latin square designs to reduce sample sizes
  • Enrichment designs (based either on compliance, safety, efficacy, or a combination)
  • Delayed start designs/randomized withdrawals
  • Group sequential designs
  • Single arm, external controlled studies
  • Adaptive hypotheses (superiority to non-inferiority)
  • Sample size re-estimation procedures (Frequentist and Bayesian concepts)
  • Operationally or inferentially seamless adaptive phase 2/3 trials
  • Antecedent, concurrent, or piggyback observational studies to inform assessments and analyses

Moreover, Worldwide has played a key role in the design and implementation of nontraditional technologies — including wearable devices and smartphone technologies — for patient-based assessments:

  • Examination of recidivism in patients with substance use disorder using a phone application for real-time assessment of changes in mood state and a geolocation component that facilitates an estimation of the influence that environmental stressors have on a patient’s propensity to use substances with high abuse liability.
  • Affective disease using a phone application that permits delivery of cognitive behavioral therapy for the purposes of reducing response to placebo prior to patient randomization.
  • Estimation of CNS pharmacodynamic effects in normal volunteers in a first-in-human trial through use of both voice and facial analytics technologies yoked to investigational product administration.
  • Assessment of potentially beneficial effects in a lysosomal storage disorder through the use of structured voice acquisition via smartphone. This real-time technology assesses changes in motor, cognitive, or affective domains influencing speech metrics. It also has served as a functional biomarker for the dose ranging in sample size re-estimation purposes during an unblinded interim analysis in a neurodegenerative disorder.
  • Assessment of movement-related disorders and sleep parameters using actigraphy in indications as diverse as neurobehavioral orphan disease, idiopathic pulmonary fibrosis-pulmonary arterial hypertension, intractable cancer pain, Parkinson’s disease, and Duchenne’s muscular dystrophy.

To be sure, the benefits of a traditional, randomized, placebo-controlled trial are well-known and well-documented, and there is a huge legacy of data that fully informs the method of analysis and interpretation. But novel circumstances — whether that be new technologies, new global health threats, the rarity of novel disease patients, or simply the anticipation of a known outcome in the presence of a placebo adjunctively with standards of care (which can be deduced from historical trial data) — raise important questions about whether “the way it has always been done” is the best way to move forward. Experience with a portfolio of experimental design options, coupled with an adherence to the highest standards of ethical study conduct and methodology, enables Worldwide to offer new designs, new technologies, and new approaches to the care of populations with substantial, potentially life-threatening, unmet clinical needs. We offer integrated solutions for a wide range of clinical programs and have a strong track record for representing the rationales and the methods associated with diverse approaches during regulatory interactions, for both proof-of-concept as well as potentially pivotal trials.