What Is Ailing Oncology Clinical Trials? Can We Fix Them?

Evidence from phase three clinical trials helps shape clinical practice. However, a very small minority of patients with cancer participate in clinical trials and many trials are not completed on time due to slow accrual. Issues with restrictive eligibility criteria can severely limit the patients who can access trials, without any convincing evidence that these restrictions impact patient safety. Similarly, regulatory, organizational, and institutional hurdles can delay trial activation, ultimately making some studies irrelevant. Additional issues during trial conduct (e.g., mandatory in-person visits, central confirmation of standard biomarkers, and inflexible drug dosage modification) contribute to making trials non-patient-centric. These real-life observations from experienced clinical trialists can seem nonsensical to investigators and patients alike, who are trying to bring effective drugs to patients with cancer. In this review, we delve into these issues in detail, and discuss potential solutions to make clinical trials more accessible to patients.

New Anticancer Drugs: Reliably Assessing "Value" While Addressing High Prices.

Countries face challenges in paying for new drugs. High prices are driven in part by exploding drug development costs, which, in turn, are driven by essential but excessive regulation. Burdensome regulation also delays drug development, and this can translate into thousands of life-years lost. We need system-wide reform that will enable less expensive, faster drug development. The speed with which COVID-19 vaccines and AIDS therapies were developed indicates this is possible if governments prioritize it. Countries also differ in how they value drugs, and generally, those willing to pay more have better, faster access. Canada is used as an example to illustrate how "incremental cost-effectiveness ratios" (ICERs) based on measures such as gains in "quality-adjusted life-years" (QALYs) may be used to determine a drug's value but are often problematic, imprecise assessments. Generally, ICER/QALY estimates inadequately consider the impact of patient crossover or long post-progression survival, therapy benefits in distinct subpopulations, positive impacts of the therapy on other healthcare or societal costs, how much governments willingly might pay for other things, etc. Furthermore, a QALY value should be higher for a lethal or uncommon disease than for a common, nonlethal disease. Compared to international comparators, Canada is particularly ineffective in initiating public funding for essential new medications. Addressing these disparities demands urgent reform.

Timeliness of Health Technology Assessments and Price Negotiations for Oncology Drugs in Canada.

Purpose: To evaluate whether time targets for Canadian Agency for Drugs and Technologies in Health (CADTH) reimbursement reviews and pan-Canadian Pharmaceutical Alliance (pCPA) price negotiations are being achieved for oncology drugs. Materials and Methods: Recommendations, dates of submission and publication, and indications for oncology medicines issued between January 2014 and December 2023 were recorded from CADTH's reimbursement reports webpage. The date any negotiation began and the date it was completed (successfully or not), or when a decision was made not to pursue negotiation was extracted from the pCPA's webpage. The duration of each CADTH review and pCPA negotiation was calculated, together with time between CADTH's recommendation and start of the pCPA negotiation or a decision not to negotiate. Percentages of reviews completed within CADTH's target and of times taken by the pCPA to decide whether to negotiate and by its price negotiations completed within the relevant targets were calculated. Results: CADTH achieved its 270-days target in 88.2% to 100% of reviews issued between 2015 and 2019 but only in 65.9% to 73.1% of reviews issued in the last three years of the decade. CADTH's "typical timeline" of 180 days was achieved in under 40% of reviews issued in 2015 and not attained in any review in 2021, 2022 or 2023. The pCPA's target of 60 days for deciding whether to negotiate was achieved for all recommendations issued in 2014 but dropped below 40% for the last seven years of the decade; its target of 130 days for negotiations was achieved for over 85% of the recommendations in 2014 but decreased to only 14.3% in 2016 and then gradually increased to 61.5% in 2023. Conclusion: CADTH's "typical timeline" and the pCPA's targets were not met sufficiently to be meaningful. Their processes take too long for cancer drugs.

Canadian patients and providers are often frustrated and concerned about the timeliness of the country's health technology assessment (HTA) and price negotiation processes, especially for cancer drugs. HTAs are carried out to evaluate the benefit of a medicine in comparison with its cost to see whether the drug is of sufficient value to add it to the benefit lists of government drug plans. HTAs are performed by the Canadian Agency for Drugs and Technologies in Health (CADTH) for all of Canada, except the province of Quebec, and price negotiations with drug developers are carried out by the pan-Canadian Pharmaceutical Alliance (pCPA) on behalf of all government drug plans. We used data from the websites of CADTH and the pCPA on HTA reviews of cancer drugs issued between January 2014 and December 2023 and price negotiations for these drugs to assess whether CADTH and the pCPA complied with their stated target times for completing their processes. We found that CADTH's reviews and the pCPA's price negotiations failed to meet their targets for cancer drugs in the past 10 years and that the timeliness of their performance has, in most cases, deteriorated. HTA and price negotiation processes for cancer drugs take too long in Canada.

Access to Oncology Medicines in Canada: Consensus Forum for Recommendations for Improvement.

Patient access to new oncology drugs in Canada is only possible after navigating multiple sequential systemic checkpoints for national regulatory approval, health technology assessment (HTA) and collective government price negotiation. These steps delay access and prevent health care providers from being able to prescribe optimal therapy. Eighteen Canadian oncology clinicians from the medicine, nursing and pharmacy professions met to develop consensus recommendations for defining reasonable government performance standards around process and timeliness to improve Canadian cancer patients' access to best care. A modified Delphi methodology was used to identify consensus on 30 questions involving five themes: accountability, disparities, endpoints, timeliness, and cost-effectiveness. It was agreed that greater transparency is required across regulatory and HTA processes. Health professionals in oncology are frustrated for their patients because they are unable to deliver the modern guideline-supported therapies they want to provide due to delays in approval or funding. Canadian health care providers request improvements in timely access to life-saving therapeutics in line with other comparator countries. Clinicians expect urgent improvements in Canadian health systems to give our patients their best chance of survival.

Risk factors predicting the need for intensive care unit admission within forty-eight hours of emergency department presentation: A case-control study.

BACKGROUND: Patients admitted from the emergency department to the wards, who progress to a critically unwell state, may require expeditious admission to the intensive care unit. It can be argued that earlier recognition of such patients, to facilitate prompt transfer to intensive care, could be linked to more favourable clinical outcomes. Nevertheless, this can be clinically challenging, and there are currently no established evidence-based methods for predicting the need for intensive care in the future. OBJECTIVES: We aimed to analyse the emergency department data to describe the characteristics of patients who required an intensive care admission within 48 h of presentation. Secondly, we planned to test the feasibility of using this data to identify the associated risk factors for developing a predictive model. METHODS: We designed a retrospective case-control study. Cases were patients admitted to intensive care within 48 h of their emergency department presentation. Controls were patients who did not need an intensive care admission. Groups were matched based on age, gender, admission calendar month, and diagnosis. To identify the associated variables, we used a conditional logistic regression model. RESULTS: Compared to controls, cases were more likely to be obese, and smokers and had a higher prevalence of cardiovascular (39 [35.1%] vs 20 [18%], p = 0.004) and respiratory diagnoses (45 [40.5%] vs 25 [22.5%], p = 0.004). They received more medical emergency team reviews (53 [47.8%] vs 24 [21.6%], p < 0.001), and more patients had an acute resuscitation plan (31 [27.9%] vs 15 [13.5%], p = 0.008). The predictive model showed that having acute resuscitation plans, cardiovascular and respiratory diagnoses, and receiving medical emergency team reviews were strongly associated with having an intensive care admission within 48 h of presentation. CONCLUSIONS: Our study used emergency department data to provide a detailed description of patients who had an intensive care unit admission within 48 h of their presentation. It demonstrated the feasibility of using such data to identify the associated risk factors to develop a predictive model.

Population Survival Kinetics Derived from Clinical Trials of Potentially Curable Lung Cancers.

Using digitized data from progression-free survival (PFS) and overall survival Kaplan-Meier curves, one can assess population survival kinetics through exponential decay nonlinear regression analyses. To demonstrate their utility, we analyzed PFS curves from published curative-intent trials of non-small cell lung cancer (NSCLC) adjuvant chemotherapy, adjuvant osimertinib in resected EGFR-mutant NSCLC (ADAURA trial), chemoradiotherapy for inoperable NSCLC, and limited small cell lung cancer (SCLC). These analyses permit assessment of log-linear curve shape and estimation of the proportion of patients cured, PFS half-lives for subpopulations destined to eventually relapse, and probability of eventual relapse in patients remaining progression-free at different time points. The proportion of patients potentially cured was 41% for adjuvant controls, 58% with adjuvant chemotherapy, 17% for ADAURA controls, not assessable with adjuvant osimertinib, 15% with chemoradiotherapy, and 12% for SCLC. Median PFS half-life for relapsing subpopulations was 11.9 months for adjuvant controls, 17.4 months with adjuvant chemotherapy, 24.4 months for ADAURA controls, not assessable with osimertinib, 9.3 months with chemoradiotherapy, and 10.7 months for SCLC. For those remaining relapse-free at 2 and 5 years, the cure probability was 74%/96% for adjuvant controls, 77%/93% with adjuvant chemotherapy, 51%/94% with chemoradiation, and 39%/87% with limited SCLC. Relatively easy population kinetic analyses add useful information.