Eligibility Criteria Are Not Associated with Expected or Observed Adverse Events in Randomized Controlled Trials (RCTs) of Hematologic Malignancies
Authors: Statler Abby , Radivoyevitch Tomas , Siebenaller Caitlin , Gerds Aaron T. , Kalaycio Matt , Kodish Eric , Mukherjee Sudipto , Cheng Connie , Sekeres Mikkael A. 
Published: October 2019

Abstract
Background: RCTs play a key role in advancing treatment for hematologic malignancies and are often a requisite for regulatory approval. To maximize this potential for registration, eligibility criteria for RCTs may be overly restrictive so as to avoid toxicities that may be attributed to the study drug. We hypothesized that RCTs in hematologic malignancies exclude patients (pts) irrespective of adverse events (AEs) that would be expected based on drug class, or that are ultimately observed.
Methods: We searchedjournals with an impact factor ≥5 for therapeutic phase II and III hematologic malignancy RCTs in adults published from 01/10 to 01/15. Trial eligibility criteria were extracted from clinicaltrials.gov, the International Standard Randomized Controlled Trial Number (ISRCTN) registry, or the protocol, when available. AEs were collected from package inserts or published manuscripts for the following drug classes: alkylators, antimetabolites, anthracyclines, topoisomerase inhibitors, microtubule inhibitors, proteasome inhibitors, and monoclonal antibodies. Toxicities of these drug classes were compared to corresponding trial exclusion criteria using the exact binomial test. We examined reported AEs occurring in ≥10% of subjects within trials, the threshold applied in medication labels. Poisson distributions, with means = 10% of sample sizes of studies (with exclusion criteria), were assumed in calculating the binomial probability for each AE; we considered AEs relevant to the most commonly used organ function exclusion criteria: hepatic, kidney, cardiac, and neurological.
Results: Of 252 full publications identified, 91 (36%) were not RCTs; 27 (11%) were pediatric; 23 (9%) did not meet other inclusion criteria, and 13 (5%) were "kin" publications of the same trial, leaving 98 trials in the final analysis. Of these, 32 (33%) were leukemia trials, 27 (28%) were lymphoma, 34 (35%) were multiple myeloma, and 5 (5%) were myelodysplastic syndromes or myelofibrosis. The majority of studies were phase III (n=77, 79%), multi-center (n=92, 94%), and/or multi-national (n=63, 64%). Of the 98 trials, 12 (12%) contributed pivotal registration data leading to a label change or new approval for 8 drugs.
Key trial exclusion criteria were medical comorbidities (e.g. active or prior cancer, previous cardiac conditions, HIV infection, hepatitis, or psychiatric disease, in 97% of studies); inadequate organ function (in 89%), and poor performance status (in 67%). Exclusion criteria relevant to baseline organ function did not reflect established safety profiles, as the proportion of studies excluding pts with specific organ dysfunction was significantly greater than the proportion of drug classes with known hepatic (85/98 [87%] vs. 75%; P=.007), cardiac (73/98 [74.5%] vs. 62.5%; P=.02), and renal (72/98 [73.5%] vs. 50%; P<.0001) toxicities. Conversely, the proportion of studies excluding patients with neurological deficits was lower than the proportion of drug classes with known neurological toxicities (22/98 [22%] vs. 50%; P<.0001).
Similarly, the number of studies that reported ≥10% patients with a ≥grade 1 toxicity was considerably lower than the number of studies expected, assuming study treatments lead to an AE in 10% of pts (Figure): 19 (22%) vs. 41 (48%) of 85 studies for hepatic AEs (P<.0001); 23 (32%) vs. 35 (48%) of 73 studies for cardiac AEs (P=.003), and 4 (6%) vs. 35 (49%) of 72 studies for renal AEs (P <.0001). Of the 22 studies that excluded pts with peripheral neuropathy, 14 (64%) reported ≥10% of pts with this toxicity, vs. the 11 (50%) expected (P=.95).
Conclusions: The proportion ofRCTs in hematologic malignancies published in high impact medical journals excluding pts with comorbidities and/or organ function abnormalities does not reflect the expected or observed AEs in these patients. This suggests that landmark RCTs, with an eye to registration, may be overly conservative in using restrictive exclusion criteria. The widespread use of these criteria, many of which may not be appropriate given the toxicity profile of the investigational product, may lead to the systematic exclusion of specific patient populations, limiting trial result generalizability.

Disclosures
Kodish: Biogen Idec: Consultancy. Sekeres:Celgene Corporation: Membership on an entity's Board of Directors or advisory committees; TetraLogic: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees.