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Statistics in Medicine Sep 2023Unmeasured confounding is a major obstacle to reliable causal inference based on observational studies. Instrumented difference-in-differences (iDiD), a novel idea...
Unmeasured confounding is a major obstacle to reliable causal inference based on observational studies. Instrumented difference-in-differences (iDiD), a novel idea connecting instrumental variable and standard DiD, ameliorates the above issue by explicitly leveraging exogenous randomness in an exposure trend. In this article, we utilize the above idea of iDiD, and propose a novel group sequential testing method that provides valid inference even in the presence of unmeasured confounders. At each time point, we estimate the average or conditional average treatment effect under iDiD setting using the data accumulated up to that time point, and test the significance of the treatment effect. We derive the joint distribution of the test statistics under the null using the asymptotic properties of M-estimation, and the group sequential boundaries are obtained using the -spending functions. The performance of our proposed approach is evaluated on both synthetic data and Clinformatics Data Mart Database (OptumInsight, Eden Prairie, MN) to examine the association between rofecoxib and acute myocardial infarction, and our method detects significant adverse effect of rofecoxib much earlier than the time when it was finally withdrawn from the market.
Topics: Humans; Bias; Myocardial Infarction; Safety-Based Drug Withdrawals; Statistics as Topic
PubMed: 37345519
DOI: 10.1002/sim.9836 -
AAPS PharmSciTech Apr 2019The presence of N-nitrosodimethylamine (NDMA) and N-nitrosodiethylamine (NDEA) impurities in angiotensin II receptor blocker (ARB) drugs containing tetrazole ring has...
The presence of N-nitrosodimethylamine (NDMA) and N-nitrosodiethylamine (NDEA) impurities in angiotensin II receptor blocker (ARB) drugs containing tetrazole ring has triggered worldwide product recalls. The purpose of this article is to identify the potential gap area in current pharmaceutical industry practice that might have led to the NMDA and NDEA impurities escaping the drug manufacturer's and FDA's attention. The impact of process change was not adequately assessed by the manufacturer of contaminated APIs (active pharmaceutical ingredients), and potential for generation of mutagenic or other toxic impurities was not considered. The safety and risk associated with a chemical synthetic process was also not evaluated. This is primarily due to current industry practice which focuses on controlling the impurities above reporting threshold. ICH Q3A and FDA guidance on genotoxic and carcinogenic impurities in drug substances and products need to be integrated so that the ICH Q3A decision tree (attachment 3) begins by checking whether the synthetic process has been evaluated for the potential to generate toxic impurities. The compliance with ICH Q3A limits should be carried out only after the process has been determined to be safe without the risk of generating mutagenic and carcinogenic impurities.
Topics: Angiotensin II Type 1 Receptor Blockers; Diethylnitrosamine; Dimethylnitrosamine; Drug Compounding; Drug Contamination; Drug Industry; Drug Recalls; Humans; Mutagens; Patient Safety; United States; United States Food and Drug Administration; Valsartan
PubMed: 30989447
DOI: 10.1208/s12249-019-1376-1 -
Journal of Human Hypertension Oct 2021In Germany, ~8 million patients take angiotensin receptor blockers (ARBs) and 2.25 million of them valsartan. In 2018, contamination of generic ARBs with probable...
In Germany, ~8 million patients take angiotensin receptor blockers (ARBs) and 2.25 million of them valsartan. In 2018, contamination of generic ARBs with probable carcinogenic nitrosamines resulted in more than 30 recalls. The impact of such a huge recall has never been explored in Europe. We analyzed the utilization of valsartan, all ARBs, and other alternative antihypertensive drugs in Germany. We used our database of anonymized dispensing data from >80% of community pharmacies at the expense of the statutory health insurance (SHI) funds from January 2017 to December 2019. We analyzed 290.8 million prescriptions, including all oral mono- and fixed-dose combinations of ARBs and plausible alternatives, i.e. ACE inhibitors (ACEi), beta-blockers (BB), and calcium channel blockers (CCB). Utilization was calculated by defined daily doses per 1000 SHI-insured persons per day (DID). Valsartan use decreased substantially after the recalls in July 2018 from 39.0 to 14.2 DID (-64%) in the second quarter of 2019 and to 16.9 DID (-57%) in the fourth quarter of 2019. Simultaneously, the use of alternative ARBs increased from 77.7 DID in the second quarter of 2018 to 121.9 DID (+57%) in the fourth quarter of 2019, mainly due to an increase of candesartan dispensing to 99.8 DID (+73%). There were no changes in the utilization of ACEi, BB, or CCB. The majority of recalled generic valsartan products were replaced by other ARBs, predominantly candesartan, despite documented drug shortages. In contrast to previous safety warnings/recalls, our data do not suggest an under-prescription of antihypertensives during this period.
Topics: Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Humans; Hypertension; Product Recalls and Withdrawals
PubMed: 33057175
DOI: 10.1038/s41371-020-00425-z -
The Journal of Arthroplasty Apr 2014It is often difficult for orthopedic surgeons to react to a situation where a particular implant that they have been using for many years is suddenly recalled from the...
It is often difficult for orthopedic surgeons to react to a situation where a particular implant that they have been using for many years is suddenly recalled from the market by either the manufacturer or the United States Food and Drug Administration. This report briefly summarizes some of the issues that may arise when such a circumstance occurs. We briefly outline what an implant recall is, what measures the orthopedic surgeon should take when an implant is permanently recalled, what litigation issues may arise, and describe the resources available to the orthopedic surgeon for the evaluation of these patients. It is important to understand that the manufacturer and the insurance companies often bear the burden of the financial loss, although the anguish, time loss for patients, and the effect on clinical practice are issues which are largely inevitable. Nevertheless, it is essential for the orthopedic community to be aware and be prepared for these unlikely situations should they occur, so that we will remain the patient's best advocate at all times.
Topics: Biocompatible Materials; Hip Prosthesis; Humans; Medical Device Recalls; Metals
PubMed: 24655611
DOI: 10.1016/j.arth.2014.02.004 -
The Veterinary Clinics of North... Nov 2018Commercial pet foods are usually safe, but incidents of contamination can have a devastating impact on companion animals and their owners. There are numerous possible... (Review)
Review
Commercial pet foods are usually safe, but incidents of contamination can have a devastating impact on companion animals and their owners. There are numerous possible contaminants ranging from natural contaminants to nutrient imbalances to chemical adulteration, making it impossible to predict what will cause the next pet food recall. Veterinarians involvement with pet food recalls includes examining and treating affected animals, documentation and sample collection, and communicating with pet food manufacturers and regulatory agencies.
Topics: Animal Feed; Animals; Autopsy; Cat Diseases; Cats; Dog Diseases; Dogs; Food Contamination; Pets; Product Recalls and Withdrawals; Professional Role; Social Control, Formal; United States; United States Food and Drug Administration; Veterinarians
PubMed: 30173926
DOI: 10.1016/j.cvsm.2018.07.005 -
Cancer Discovery Jun 2021The FDA's Accelerated Approval program is under scrutiny after four drug companies announced plans in recent months to withdraw indications for checkpoint inhibitors...
The FDA's Accelerated Approval program is under scrutiny after four drug companies announced plans in recent months to withdraw indications for checkpoint inhibitors that, despite showing early promise, failed to demonstrate a survival benefit in confirmatory trials. The agency's Oncologic Drugs Advisory Committee will meet in late April to discuss whether six more indications for some of these same immunotherapies should be nullified as well.
Topics: Drug Approval; Humans; Immune Checkpoint Inhibitors; Safety-Based Drug Withdrawals; United States; United States Food and Drug Administration
PubMed: 33863711
DOI: 10.1158/2159-8290.CD-ND2021-0106 -
Biomedical Instrumentation & Technology 2015
Topics: Humans; Medical Device Recalls; United States; United States Food and Drug Administration
PubMed: 25621636
DOI: 10.2345/0899-8205-49.1.3 -
Perfusion Jan 2013Heparin is one of the oldest drugs still in widespread clinical use. Its discovery in 1916 predates the establishment of the Food and Drug Administration. Since 1935,...
Heparin is one of the oldest drugs still in widespread clinical use. Its discovery in 1916 predates the establishment of the Food and Drug Administration. Since 1935, over 15,000 research papers have been published on the effects of heparin. Because the exact chemical formula of heparin is unknown, synthetic manufacturing has proven difficult. In 2008, a worldwide recall of heparin occurred. Scientists determined that a contaminant known as oversulfated chondroitin sulfate was responsible for the numerous deaths and adverse events. This contaminant was first traced to a chemical plant in Changzou, China. This article will review the discovery of heparin and the adulteration process that jeopardized the world's heparin supply.
Topics: China; Chondroitin Sulfates; Drug Contamination; Drug Recalls; Heparin; Humans
PubMed: 23042900
DOI: 10.1177/0267659112462274 -
Nature Reviews. Drug Discovery Feb 2015
Topics: Drug Approval; Drug Industry; Safety-Based Drug Withdrawals; United States; United States Food and Drug Administration
PubMed: 25633781
DOI: 10.1038/nrd4545 -
Clinical Infectious Diseases : An... Feb 2011This article reviews events that led to the withdrawal of the only vaccine to prevent Lyme disease licensed in the United States. The primary issues that led to the... (Review)
Review
This article reviews events that led to the withdrawal of the only vaccine to prevent Lyme disease licensed in the United States. The primary issues that led to the vaccine's withdrawal appear to be a combination of vaccine safety concerns, sparked by a molecular mimicry hypothesis that suggested that the vaccine antigen, outer surface protein A, serves as an autoantigen and hence was arthritogenic; concerns raised by anti-vaccine groups regarding vaccine safety; vaccine cost; a difficult vaccination schedule and the potential need for boosters; class action lawsuits; uncertainty regarding risk of disease; and low public demand. This article reviews lessons learned from these events and proposes that future candidate Lyme disease vaccines are unlikely to be developed, tested, and used within the United States in the near future, thus leaving at-risk populations unprotected.
Topics: Attitude to Health; Borrelia burgdorferi; Clinical Trials as Topic; Drug Approval; Health Priorities; Humans; Immunization Schedule; Lyme Disease; Lyme Disease Vaccines; Molecular Mimicry; Product Recalls and Withdrawals; United States; United States Food and Drug Administration
PubMed: 21217172
DOI: 10.1093/cid/ciq116