Shortcomings in the clinical evaluation of new drugs: acute myeloid leukemia as paradigm

Abstract

Drugs introduced over the past 25 years have benefitted many patients with acute myeloid leukemia (AML) and provided cure for some. Still, AML remains difficult to treat, and most patients will eventually die from their disease. Therefore, novel drugs and drug combinations are under intense investigation, and promising results eagerly awaited and embraced. However, drug development is lengthy and costs are staggering. While the phase 1-phase 2-phase 3 sequence of clinical drug testing has remained inviolate for decades, it appears intrinsically inefficient, and scientific flaws have been noted by many authors. Of major concern is the high frequency of false-positive results obtained in phase 2 studies. Here, we review features of phase 2 trials in AML that may contribute to this problem, particularly lack of control groups, patient heterogeneity, selection bias, and choice of end points. Recognizing these problems and challenges should provide us with opportunities to make drug development more efficient and less costly. We also suggest strategies for trial design improvement. Although our focus is on the treatment of AML, the principles that we highlight should be broadly applicable to the evaluation of new treatments for a variety of

Diagnosis and management of AML in adults: 2017 ELN recommendations from an international expert panel

“…The frequent failure of therapies found "promising" in single-arm phase 2 trials to translate into truly successful treatments because of various biases in phase 2 is well known. 266 Because these biases can only be addressed by randomization, there has been increasing interest in randomized phase 2 designs, also known as "selection" or "pick-a-winner" designs. 267,268 Here, randomization between a standard and a new treatment begins sooner than currently.…”

How to manage high-risk acute myeloid leukemia

“…Also contributing to the difficulty is the observation that initially promising results typically do not ultimately translate into meaningful improvements in survival and are often even difficult to reproduce. 2 Under these circumstances, I tend to use the patient's probability of TRM to help decide which new investigational therapy might be preferred, as indicated in Table 2. It is important to recall that age is just one of several factors contributing to TRM (and resistance) and that it may to some extent be a surrogate for other factors.…”

“…This preference reflects the possibility that investigational therapy will be worse than standard; absent this possibility randomized trials comparing standard and investigational treatments would be ethically problematic. Furthermore, for reasons detailed in reference, 2 reports of 'promising' new therapies often do not stand the test of time. Because of the resultant uncertainty regarding the results with any given investigational therapy, the decision to opt for investigational therapy must rest on dissatisfaction with the (well-known) results of standard therapy.…”

Acute myeloid leukemia therapy and the chosen people

“…Ten years ago one of us (EE) reported about 70% of 91 abstracts describing 39 new therapies for AML presented at the American Society of Hematology (ASH) annual meetings 1993-2001 described promising or encouraging data. 3,4 Only 15% of studies were declared negative; the other 15% were inconclusive. About 45 of the 63 positive abstracts eventuated in peer-reviewed publications, 38 of which reported favorable outcomes.…”