Approval of Cancer Drugs With Uncertain Therapeutic Value: A Comparison of Regulatory Decisions in Europe and the United States

Policy Points

• Regulatory agencies may have limited evidence on the clinical benefits and harms of new drugs when deciding whether new therapeutic agents are allowed to enter the market and under which conditions, including whether approval is granted under special regulatory pathways and obligations to address knowledge gaps through postmarketing studies are imposed.
• In a matched comparison of marketing applications for cancer drugs of uncertain therapeutic value reviewed by both the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA), we found frequent discordance between the two agencies on regulatory outcomes and the use of special regulatory pathways. Both agencies often granted regular approval, even when the other agency judged there to be substantial uncertainty about drug benefits and risks that needed to be resolved through additional studies in the postmarketing period.
• Postmarketing studies imposed by regulators under special approval pathways to address remaining questions of efficacy and safety may not be suited to deliver timely, confirmatory evidence due to shortcomings in study design and delays, raising questions over the suitability of the FDA''s Accelerated Approval and the EMA''s Conditional Marketing Authorization as tools for allowing early market access for cancer drugs while maintaining rigorous regulatory standards.

ContextRegulatory agencies are increasingly required to make market approval decisions for new drugs on the basis of limited clinical evidence, a situation commonly encountered in cancer. We aimed to investigate how regulators manage uncertainty in the benefit‐risk profiles of new cancer drugs by comparing decisions for the world''s two largest regulatory bodies—the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA)—over a 5‐year period.MethodsWe systematically identified a set of cancer drug‐indication pairs for which data on efficacy and safety was less complete than that required for regular approval at time of market entry from 2009 to 2013, as determined by the FDA''s use of Accelerated Approval (AA) or the EMA''s use of Conditional Marketing Authorization (CMA) pathways, and matched these across the two agencies. Using publicly available information, we compared regulatory pathways and outcomes, final approved indications, and postmarketing obligations imposed by the agencies.FindingsWe identified 21 cancer drug‐indication pairs that received FDA AA, EMA CMA, or both. Although most applications relied on identical pivotal trials across the FDA and the EMA, regulatory pathways often differed; 57% of indications received either FDA AA or EMA CMA, and regular approval by the other agency. After approval, the EMA more often accepted single‐arm studies to confirm clinical benefit compared to the FDA (75% vs. 29% of indications), and the FDA more commonly requested randomized controlled trials (85% vs. 50%). Forty‐one percent of confirmatory trials after FDA AA were conducted in different populations than the approved indication, compared to 13% after EMA CMA. Both agencies relied primarily on surrogate measures of patient benefit for postmarketing obligations. After a median follow‐up of 7.25 years, 40% of FDA and 61% of EMA postmarketing obligations after AA and CMA, respectively, were delayed.ConclusionsUS and European regulators often deemed early and less complete evidence on benefit‐risk profiles of cancer drugs sufficient to grant regular approval, raising questions over regulatory standards for the approval of new medicines. Even when imposing confirmatory studies in the postmarketing period through special approval pathways, meaningful evidence may not materialize due to shortcomings in study design and delays in conducting required studies with due diligence.     

Comparison of Normal Sinus Rhythm and Pacing Rate in Children with Minute Ventilation Single Chamber Rate Adaptive Permanent Pacemakers

Rate adaptive pacemakers are used to achieve a better cardiac performance during exercise by increasing the heart rate and cardiac output. The ideal rate adaptive sensor should be able to mimic sinus node modulation under various degrees of exercise and other metabolic needs. Minute ventilation sensing has proven to be one of the most accurate sensor systems. In this study, alterations in sinus rhythm and pacing rates during daily life conditions in 11 children (median age 11 years, range 6–14 years) with minute ventilation single chamber pacemakers were investigated. Correlation of sinus rhythm with pacing rates was assessed. ECG records were obtained from 24–hour Holter monitoring. Average rates of five consecutive P waves and pace waves were determined every half hour. The average of the two values was then used to determine hourly rates. Correlation coefficients between the sinus rhythm and pacing rates were calculated. In nine patients, pacing rates correlated well to sinus rhythm (range 0.6793–0.9558. P < 0.001 and P < 0.05), whereas in two cases correlation was not sufficient (P > 0.05). Most of the patients, in whom rate response factor (RRF) measurements during peak exercise by treadmill with cnronotropic assessment exercise protocol were performed and pacemakers were programmed to these parameters, had more appropriate ventricular rates compared to spontaneous sinus rates. In these patients mean RRF value was 15.3 ± 2.7 (range 12–20, median 15). This study shows that during daily activities minute ventilation rate adaptive pacemakers can achieve pacing rates well correlated to sinus rhythm that reflects the physiological heart rate in children.     

RETICULATE ACROPIGMENTATION OF KITAMURA: TWO CASE REPORTS

Background. Reticulate acropigmentation of Kitamura (RAK) is an autosomal dominantly inherited dermatosis. Case Reports. Two patients are described with the clinical and histopathologic features of reticulate acropigmentation of Kitamura. Conclusions. We speculate that RAK and the Dowling-Degos disease (DDD) are the same diseases.     

Polyenylphosphatidylcholine pretreatment ameliorates ischemic acute renal injury in rats

AIM: Polyenylphosphatidycholine has been demonstrated to have antioxidant, cytoprotective and anti-inflammatory effects. Whether polyenylphosphatidycholine pretreatment affects ischemia/reperfusion-induced renal damage in vivo is not known and was investigated here in rats. METHODS: Forty female Sprague-Dawley rats were divided into three groups. Group 1 (n = 10) was given saline (control, sham operated). Group 2 (n = 15) were given saline, and Group 3 (n = 15) were given polyenylphosphatidycholine (100 mg/day for 10 days prior to experiment). Groups 2 and 3 were subjected to bilateral renal ischemia (60 min) followed by reperfusion (6 h). After the reperfusion period, the rats were sacrificed and kidney tissue superoxide dismutase, glutathione, total nitrite and nitrate, malondialdehyde and myeloperoxidase levels, plasma aspartate aminotransferase, blood urea nitrogen and creatinine concentrations, and nuclear factor kappa beta expression were determined. RESULTS: Serum levels of aspartate aminotransferase, blood urea nitrogen and creatinine were significantly decreased (P < 0.05) in the treatment group compared to those in the ischemic group. There were significant differences between treatment and ischemic groups regarding the tissue superoxide dismutase, glutathione, total nitrite and nitrate, malondialdehyde, and myeloperoxidase levels (P < 0.05). In addition, polyenylphosphatidycholine pretreatment reduced nuclear factor kappa beta expression in ischemic kidney tissue. Kidneys obtained from rats pretreated with polyenylphosphatidycholine demonstrated marked reduction of the histological features of renal injury compared to kidneys obtained from Group 2 rats, including a little vacuolization, pyknosis and necrosis. CONCLUSIONS: Polyenylphosphatidycholine pretreatment provided significant protection against ischemia/reperfusion injury to the kidney. This treatment could be therapeutic in kidney transplantation and other conditions associated with ischemia/reperfusion injury to the kidney.