Figure. Kaplan-Meier estimate of new active substance survival without a safety warning and/or withdrawal. Sixty-eight products had serious safety warnings only; 9 products had serious safety warnings and were then withdrawn; and 7 products were withdrawn without prior serious safety warnings.The red lines represent the 95% confidence intervals.
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Lexchin J. New Drugs and SafetyWhat Happened to New Active Substances Approved in Canada Between 1995 and 2010?. Arch Intern Med. 2012;172(21):1680–1681. doi:10.1001/archinternmed.2012.4444
Monitoring the safety of drugs is increasingly recognized as a major issue in light of recent experience with products such as rofecoxib and rosiglitazone. Previous work found that the probability of new drugs either acquiring a black box safety warning or being withdrawn for safety reasons was 20% over a 25-year period1 and that oncology drugs that were granted a priority review were more likely to be subject to labeling changes than were drugs with a standard review.2
This study was undertaken to answer 2 questions. What is the percentage of drugs approved in Canada that subsequently either acquire serious safety warnings or have to be withdrawn from the market for safety reasons (hereafter referred to collectively as serious safety issues)? Is there a difference between priority and standard review drugs according to this measure, and if so, what is the main reason for this difference: the length of the review time, the inherent characteristics of the drug, or the disease for which the drug is approved?
A list of new active substances (NASs) (the equivalent of new molecular entity) approved between January 1, 1995, and December 31, 2010, was compiled from the annual reports of the Therapeutic Products Directorate and the Biologic and Genetic Therapies Directorate (available from email@example.com). All serious safety warnings (those using boldface black print or boxed warnings) and drug withdrawals for the period January 1, 1995, to October 31, 2011, were identified from the MedEffect Canada website (http://www.hc-sc.gc.ca/dhp-mps/medeff/advisories-avis/prof/index-eng.php). Kaplan-Meier survival curves were calculated to estimate the probability that any NAS would have a serious safety issue during the study period and separately for an NAS with a priority and a standard review.
The characteristics of drugs with a priority approval might account for differences in the percentage with safety issues compared with drugs with standard reviews. Drugs that received a priority approval but were not considered to be major therapeutic advances were compared with drugs that received a standard review.
Drugs are usually assigned a priority review for important clinical problems and may be licensed with a lower benefit to harm threshold, leading to a higher rate of safety warnings. Drugs with priority reviews for 5 serious diseases—cancer, human immunodeficiency virus/AIDS, in-born errors of metabolism, multiple sclerosis, and the prevention of transplant rejection—were compared with drugs with standard reviews for the same diseases. Kaplan-Meier survival curves were calculated using XLSTAT add-in for Excel (Addinsoft).
A total of 434 NASs were approved from January 1, 1995, to December 31, 2010; 84 (19.4%) had a serious safety issue. The probability of an NAS acquiring a serious safety issue was 23.7% (95% CI, 19.1-28.3) (Figure).
Three hundred twenty-one NASs (74.4%) had a standard review, and 112 (25.6%) had a priority review. (The approval status of 1 product could not be determined.) For products with a standard review, there was a 19.8% (95% CI, 14.8-24.8) estimate of acquiring a serious safety issue compared with a 34.2% (95% CI, 24.3-44.2) estimate for an NAS with a priority review (P = .005, log-rank test). Eighty-one NASs with a priority review that were not major therapeutic advances were compared with the 321 NASs with a standard review. The estimate of this group of priority review NASs having a serious safety issue was 36.0% (95% CI, 24.3-47.7) compared with 19.8% (95% CI, 14.8-24.8) for standard review NASs (P = .004, log-rank test).
Priority reviews and standard reviews were assigned to 42 and 45 NASs, respectively, for 5 serious diseases. The estimate of the first group having a serious safety issue was 31.1% (95% CI, 14.3-46.0) vs 34.9% (95% CI, 16.8-52.9) for the second group (P = .96, log-rank test).
Just fewer than one-fourth (23.7%) of all NASs introduced between 1995 and 2010 had serious safety issues. This result is similar to that reported by Lasser et al.1 The difference between drugs with a standard approval and those with a priority approval in terms of their safety record may be attributable to the shorter period that the latter spends in the approval process and may reflect deficiencies in Health Canada's priority review process.
Alternative explanations for the difference between standard and review NASs are less likely. Priority review drugs that were not major therapeutic advances were still more likely to acquire serious safety issues than standard review NASs. If priority review drugs for serious diseases were approved with a lower benefit to harm ratio, they should be more likely to develop serious safety issues than standard review drugs for the same diseases. However, there was no difference between the 2 groups. New products that offer major therapeutic advantages should be embraced even with the significant lacunae that exist about their safety, but because most NASs do not fall into this category,3,4 clinicians and patients should use these drugs very cautiously.
Correspondence: Dr Lexchin, School of Health Policy and Management, York University, 4700 Keele St, Toronto, ON M3J 1P3, Canada (firstname.lastname@example.org).
Published Online: October 8, 2012. doi:10.1001/archinternmed.2012.4444
Financial Disclosure: None reported.