An estimate of rate of deviation from NCCN guideline recommendations for central nervous system imaging in trials forming basis for drug approval in first line advanced non-small cell lung cancer (NSCLC)

Importance It is unknown whether and to what degree trials submitted to the US FDA to support drug approval adhere to NCCN guideline-recommended care in their baseline and surveillance CNS imaging protocols. Objective We sought to characterize the frequency with which the trials cited in US FDA drug approvals for first line advanced NSCLC between 2015 and 2020 deviated from NCCN guideline-recommended care for baseline and surveillance CNS imaging. Design, setting, and participants Retrospective observational analysis using publicly available data of (1) list of trials cited by the FDA in drug approvals for first line advanced NSCLC from 2015 to 2020 (2) individual trial protocols (3) published trial data and supplementary appendices (4) archived versions of the NCCN guidelines for NSCLC from 2009 to 2018 (the years during which the trials were enrolling). Main outcomes and measures Estimated percentage of trials for first line advanced NSCLC leading to FDA approval which deviated from NCCN guideline-recommended care with regards to CNS baseline and surveillance imaging. Results A total of 14 studies that had been cited in FDA drug approvals for first line advanced NSCLC met our inclusion criteria between January 1, 2015 and September 30, 2020. Of these trials, 8 (57.1%) deviated from NCCN guidelines in their baseline CNS imaging requirement. The frequency of re-assessment of CNS disease was variable amongst trials as well, with 9 (64.3%) deviating from NCCN recommendations. Conclusions and relevance The trials supporting US FDA drug approvals in first line advanced NSCLC often have CNS imaging requirements that do not adhere to NCCN guidelines. Many trials permit alternative, substandard methods and the proportion of patients undergoing each modality is uniformly not reported. Nonstandard CNS surveillance protocols are common. To best serve patients with advanced NSCLC in the US, drug approvals by the FDA must be based on trials that mirror clinical practice and have imaging requirements consistent with current US standard of care.

Resilient Clinical Trial Infrastructure in Response to the COVID-19 Pandemic: Lessons Learned from the TOGETHER Randomized Platform Clinical Trial

In response to the COVID-19 pandemic, clinical research groups across the world developed trial protocols to evaluate the safety and efficacy of treatments for COVID-19. Despite this initial enthusiasm, only a small portion of these protocols were implemented. Of those implemented, a fraction successfully recruited their target sample size to analyze and disseminate findings. More than a year and a half into the COVID-19 pandemic, only a few clinical trials evaluating treatments for COVID-19 have generated new evidence. Productive randomized platform clinical trials evaluating COVID-19 treatments may attribute their success to intentional investments in developing resilient clinical trial infrastructures. Health system resiliency discourse provides a conceptual framework for characterizing attributes for withstanding shocks. This framework may also be useful for contextualizing the attributes of productive clinical trials evaluating COVID-19 therapies. We characterize the successful attributes and lessons learned in developing the TOGETHER Trial infrastructure using a health system resiliency framework. This framework may be considered by clinical trialists aiming to build resilient trial infrastructures capable of responding rapidly and efficiently to global health threats.

Compliance of Clinical Trial Protocols for Foods with Function Claims (FFC) in Japan: Consistency between Clinical Trial Registrations and Published Reports

Background: A new type of foods with a health claims notification system, the Foods with Function Claims (FFC), was introduced in Japan in April 2015. This cross-sectional study sought to clarify compliance of clinical trial protocols reported as the scientific basis of efficacy in the FFC system. Methods: All articles based on clinical trials published on the Consumer Affairs Agency website from 1 July 2018 to 30 June 2021 were reviewed. Items assessed included first author characteristics (for-profit or academia), journal name, year published, journal impact factor in 2020, article language, name of clinical trial registration (CTR), and seven compliance items (Title: T, Participant: P, Intervention: I, Comparison: C, Outcome: O, Study design: S, and Institutional Review Board, IRB). Among studies that conducted CTR, consistency with these seven compliance items was evaluated. Results: Out of 136 studies that met all inclusion criteria, 103 (76%) performed CTR, and CTR was either not performed or not specified for 33 (24%). Compliance between the protocol and the text was high (≥96%) for items P and S, but considerably lower for items T, I, C, O, and IRB (52%, 15%, 13%, 69%, and 27%, respectively). Furthermore, 43% of protocols did not include functional ingredients or food names in items T or I. The total score was 3.7 ± 1.1 pts (out of 7). Conclusions: Some CTs had no protocol registration, and even registered protocols were suboptimal in transparency. In addition to selective reporting, a new problem identified was that the content of the intervention (test food) was intentionally concealed.

Equity in Vaccine Trials for Higher Weight People? A Rapid Review of Weight-Related Inclusion and Exclusion Criteria for COVID-19 Clinical Trials

Higher weight status, defined as body mass index (BMI) ≥ 30 kg/m2, is frequently described as a risk factor for severity and susceptibility to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) disease (known as COVID-19). Therefore, study groups in COVID-19 vaccine trials should be representative of the weight spectrum across the global population. Appropriate subgroup analysis should be conducted to ensure equitable vaccine outcomes for higher weight people. In this study, inclusion and exclusion criteria of registered clinical trial protocols were reviewed to determine the proportion of trials including higher weight people, and the proportion of trials conducting subgroup analyses of efficacy by BMI. Eligibility criteria of 249 trial protocols (phase I, II, III and IV) were analysed; 51 protocols (20.5%) specified inclusion of BMI > 30, 73 (29.3%) specified exclusion of BMI > 30, and 125 (50.2%) did not specify whether BMI was an inclusion or exclusion criterion, or if BMI was included in any ‘health’ screenings or physical examinations during recruitment. Of the 58 protocols for trials in phase III and IV, only 2 (3.4%) indicated an intention to report subgroup analysis of vaccine efficacy by weight status. Higher weight people appear to be significantly under-represented in the majority of vaccine trials. This may result in reduced efficacy and acceptance of COVID-19 vaccines for higher weight people and exacerbation of health inequities within this population group. Explicit inclusion of higher weight people in COVID-19 vaccine trials is required to reduce health inequities.

How Much Is the Lack of Retention Evidence Costing Trial Teams in Ireland and the United Kingdom?

BackgroundEvidence to support the use of many retention strategies in clinical trials is lacking. Despite this, trial teams still need to have some form of retention strategy in their trials to try and avoid high attrition rates. This study aimed to estimate how much this lack of retention evidence might be costing trials in Ireland and the United Kingdom.Methods We selected the top ten most routinely used retention strategies by Clinical Trial Units in the United Kingdom and made assumptions as to how each of these strategies was most likely to be conducted and the costs involved. We applied our costing model to a hypothetical trial scenario in both Ireland and the United Kingdom as well as to three published trial protocols. We developed the costing model and calculated the costs in Microsoft Excel.Results Retention strategies can be extremely expensive, some of the costliest interventions included “a timeline of participant visits for sites” (with integrated participant reminders) (€1,418.44 - €108,471.99), “routine site visits by CTU staff” (€777.67 - €14,753.48), and “data collection scheduled with routine care” (€900 - €32,503.25). Others such as “telephone reminders for questionnaire response” (€34.58 - €568.62), “inclusion of pre-paid envelopes” (€93.44 - €942.50), and “targeted recruitment of sites/GPs” (€30 - €1,620) were less costly compared to the other interventions. DiscussionThe resources invested in the use of some retention interventions may outweigh known or imagined benefits on retention. Where benefits are imagined, evaluation should be a priority. Conclusion More evaluation of the effectiveness and cost of trial retention strategies is needed to avoid widespread use of strategies that are both expensive and ineffective.

Infusing Representativeness and Cultivating Harmonization in Alzheimer’s Trials: World Wide FINGERS

World Wide Fingers is a network involving over 30 countries organized to conduct randomized controlled clinical trials to slow the progression of cognitive decline and reduce dementia risks. Trials are designed to parallel the successful Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER) trial of a multidomain lifestyle intervention featuring increased physical activity, improved diet, cognitive training, and metabolic risk factor monitoring. While FINGER found that its intervention significantly benefited cognitive function, it is not clear whether this approach might be successfully tailored to other cultures and environments to yield similar results. This is the goal of World Wide FINGERS. It infuses representativeness by enrolling cohorts that reflect the communities in which it is conducted. For findings across the many trials to be integrated, it is necessary for protocols to be harmonized as much as possible. The COVID-19 pandemic presents special challenges towards harmonization as its disruptions of trial protocols and conduct vary among countries and over time. This symposium is organized to provide the scientific background and framework for the World Wide FINGERS. Novel grassroots efforts towards enrolling representative cohorts in the US will be described. Plans for harmonization and federated data analyses spanning international boundaries and regulations will be outlined. Integrated approaches to challenges of COVID-19 pandemic across trials will be presented. The conclusion of this session will be a discussion of how World Wide FINGERS may serve as a model for collaborative approaches to identify effective, translatable approaches to reduce risks for Alzheimer’s disease.

Innovation in Times of Uncertainty: Clinical Trials in Nursing Homes During SARs-CoV-2

In March 2020 the Centers for Medicare & Medicaid Services (CMS) announced restrictions on visitors and nonessential personnel in nursing homes to protect residents and facilities from SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) outbreaks. At the time, these measures were “temporary” but they continued well into 2021 resulting in a prolonged pause on in-person study activities in a palliative care clinical trial in 12 nursing homes. This session will address the impact of this pause and decisions made to overcome the potential failure of the trial. Of utmost importance was respecting nursing homes rapidly changing context, continued communication with the site leadership, transitioning to phone and video-conference study activities, and designing a retrospective study using existing data to answer a different but similar research question. As clinical researchers move forward implementing trials and complex interventions in nursing homes, we must use the lessons learned to design flexible trial protocols.

Systematic Omission of Pregnant and Lactating Women from Malignant Haematology Trials Perpetuates a Cycle of Exclusion, Data Shortage and Disadvantage

Background: Pregnant or breastfeeding women are routinely excluded from clinical trials due to fear of teratogenicity and toxicity of therapeutic agents, despite a paucity of evidence to support this practice. In response to the diethylstilbesterol (DES) and thalidomide-induced embryopathy in the mid-20 th century, the US Food and Drug Administration (FDA) released new regulations excluding Women of Child-Bearing Potential (WoCBP) from phase I and II trial participation, followed by an introduction of a new pregnancy category labelling system in 1979. The legacy of these measures is a reliance on accidental exposure pregnancy data rather than rigorous clinical trial efficacy and safety data for medication use in pregnancy and lactation. WoCBP when enrolled in clinical trials are often subjected to prescriptive contraceptive requirements to mitigate the risk of accidental pregnancy, without informed consent for the contraceptive side effects. These barriers to trial participation for WoCBP, particularly in the setting of life-threatening haematological diseases, prevent timely access to therapies only accessible via clinical trial participation. Lymphoma and leukaemia in pregnancy occur with an approximate incidence of 1 in 6000 and 1 in 75,000-100,000 pregnancies respectively. We examined the rates and rationale for exclusion of these patients from clinical trials, as well as contraceptive requirements for WoCBP. Methods: We conducted a cross-sectional observational study of clinical trial protocols recruiting patients with potentially life-threatening haematological malignancies. We searched the clinicaltrials.gov clinical trials database for trial protocols enrolling acute myeloid leukaemia (AML), acute lymphoblastic leukaemia (ALL), Hodgkin lymphoma (HL) and/or Diffuse Large B Cell lymphoma (DLBCL) between January 2016 and January 2021. Studies were included if they included WoCBP (15-55 years of age). Studies without complete electronic protocol access were excluded. The following data was collected: target disease, study phase, study location, age of patients, whether pregnant or lactating women were excluded (rationale if provided including evidence of teratogenicity), type of contraception and duration mandated and presence or absence of informed consent for contraception. Results: We identified 68 trials for AML, ALL, DLBCL and HL (40%, 26%, 21% and 13% respectively) (Table 1). Most were phase I-II studies (91%) of novel agents (90%) and of note, the majority were of non-chemotherapy agents (83%). The majority (97%) excluded pregnant women and (69%) without providing rationale. Only 2% cited evidence for embryopathy in either human or animal studies. Most studies (84%) explicitly excluded lactating women, of which 85% did not provide justification. Contraception was mandatory in 90% of the protocols, with 47% of these requiring at least two different forms of contraception for the entire study period. These included hormone-based contraception, barrier methods and abstinence. None of the protocols provided informed consent for the potential side effects of the mandated contraceptive methods in the context of the study. Conclusion: The theoretical harm from anti-cancer therapy to the foetus is typically given greater moral precedence than is a pregnant woman's autonomy. Pregnant and lactating women were almost universally excluded from the trials in this study with limited rationale provided. Study protocols frequently mandated contraception without informed consent of its associated risks in the context of the study. This perpetuates the lack of efficacy and safety data in this patient population, and drives a cycle of systematic exclusion, data shortage, and inequity. Pregnant and lactating women with life threatening haematological malignancies with no alternative treatment options should be eligible for clinical trials where this offers potentially life-saving therapy, with appropriate informed consent around the indefinable and potentially harmful effects on their foetus. We propose obligatory rationale for exclusion of pregnant and breastfeeding women in all clinical trials, using safety data from either human or animal studies and contraception informed consent. Figure 1 Figure 1. Disclosures Hamad: Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.