A comparison of the Food and Drug Administration’s and Health Canada’s regulatory decisions about failed confirmatory trials for oncology drugs: an observational study

Background Oncology drugs are frequently approved on the basis of surrogate outcomes that require further trials to confirm the benefits, but at times these trials fail and regulators need to decide whether to withdraw approval for the indication and/or to remove the drug from the market. This study compares decisions by the Food and Drug Administration and Health Canada about oncology drugs that were approved using either Accelerated Approval (FDA) or Notice of Compliance with conditions (NOC/c, Health Canada) and that failed confirmatory trials. Methods Drug/indications approved by the FDA through its Accelerated Approval Pathway and that later failed confirmatory studies were identified from a published study and additional information on these drugs was collected from Drugs@FDA. Health Canada websites were searched on September 11, 2021 for the same group of drugs to determine if they were approved in Canada under the NOC/c pathway for the same indication as in the US. Information from both the FDA and Health Canada about these products was entered into an Excel spreadsheet. Decisions about whether to withdraw the drugs or remove the failed indication for the drug and requirements for confirmatory studies were compared. In addition, the dates of decisions by the two agencies were compared. Results Ten drug/indications were available for comparison. Regulatory decisions were similar in 4 cases, different in 1 case and could not be determined in the remaining 5, in 1 case because decisions were pending in both countries and in the other 4, because the NOC/c had not been fulfilled in Canada. The requirements for the confirmatory studies were similar in both countries. Decisions were made earlier in the United States. Conclusions This study shows that decisions made by Health Canada and the FDA about whether to withdraw a drug or remove a failed indication when drug/indications fail a confirmatory trial are usually similar, although the sample size on which this conclusion is made is small. The clinical implications of these similarities and differences should be explored.

Screening and Biochemical Analysis on Blackgram Genotypes for Resistance against Storage Pest Bruchine [Callosobruchus maculatus (F.)]

Background: Blackgram [Vigna mungo (L.) Hepper] is a rich source of protein. It is one of the major crops essentially involved in daily human diets. However, storage pest bruchine [Callosobruchus maculatus (F.)] is a major production constraint for legumes. A research was formulated to assess the bruchine resistance in 20 blackgram genotypes along with the biochemical analysis to find out the active biochemical components responsible for the resistance activity.Methods: The experiment was carried out during August- October, 2019 at Entomology Laboratory, National Pulses Research Center, Vamban, India. The experimental material comprised of 20 blackgram genotypes which were screened for bruchine resistance. Further, confirmatory trial was conducted with selected resistant entries and highly susceptible entries during October- December, 2019. Both experiments were carried out in completely randomized design and replicated three times. GC-MS analysis on the resistant and susceptible entries were performed to ascertain the active biochemical components conferring resistance.Result: Among the genotypes, TU 68 had comparatively late developmental time (days), less number of adult emergence, higher mean developmental period (days), less susceptibility index, less seed damage (%) and less seed weight loss (%). Genotype TU 68 was found to be resistant in the confirmatory trial also. Less number of adult emergence and higher mean developmental period indicated the delayed developmental period which is a mechanism of bruchine resistance. GC-MS analysis on resistant (TU 68) and susceptible (MDU 1) genotypes indicated the presence of active biochemical compounds with insectifuge activity in TU 68. Hence, TU 68 could be utilized in the hybridization programmeas donor for bruchine resistance.

Safety review of hydroxyprogesterone caproate in women with a history of spontaneous preterm birth

17-alpha-hydroxyprogesterone caproate (17P) has been in use for prevention of recurrent preterm birth since 2003 when the Meis trial was published. A requirement for Food and Drug Administration approval of 17P was a confirmatory trial, called “PROLONG”, which was recently completed, but did not replicate the efficacy demonstrated in the Meis trial. This review analyzes the safety data from each trial, as well as integrated data from the two trials. The relative risks (95% CI) with 17P versus placebo in the integrated dataset were 0.66 (0.25–1.78) for miscarriage, 1.83 (0.68–4.91) for stillbirth, and 0.86 (0.53–1.41) for all fetal and neonatal death. The rate of gestational diabetes in the integrated dataset was 3.6% for 17P vs. 3.8% for placebo. Similar findings with low and comparable rates between 17P and placebo were also found for other adverse events. The integrated safety data demonstrate a favorable safety profile that was comparable to placebo.