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Clinical Trial Evidence Supporting FDA Approval of Novel Therapeutic Agents
Many patients and physicians assume that the safety and effectiveness of newly approved therapeutic agents is well understood; however, the strength of the clinical trial evidence supporting approval decisions by the US Food and Drug Administration (FDA) has not been evaluated.
To characterize pivotal efficacy trials (clinical trials that serve as the basis of FDA approval) for newly approved novel therapeutic agents.
Design and Setting:
Cross-sectional analysis using publicly available FDA documents for all novel therapeutic agents approved between 2005 and 2012.
Main Outcomes and Measures:
Pivotal efficacy trials were classified according to the following design features: randomization, blinding, comparator, and trial end point. Surrogate outcomes were defined as any end point using a biomarker expected to predict clinical benefit. The number of patients, trial duration, and trial completion rates were also determined.
Between 2005 and 2012, the FDA approved 188 novel therapeutic agents for 206 indications on the basis of 448 pivotal efficacy trials. The median number of pivotal trials per indication was 2 (interquartile range, 1-2.5), although 74 indications (36.8%) were approved on the basis of a single pivotal trial. Nearly all trials were randomized (89.3% [95% CI, 86.4%-92.2%]), double-blinded (79.5% [95% CI, 75.7%-83.2%]), and used either an active or placebo comparator (87.1% [95% CI, 83.9%-90.2%]). The median number of patients enrolled per indication among all pivotal trials was 760 (interquartile range, 270-1550). At least 1 pivotal trial with a duration of 6 months or greater supported the approval of 68 indications (33.8% [95% CI, 27.2%-40.4%]). Pivotal trials using surrogate end points as their primary outcome formed the exclusive basis of approval for 91 indications (45.3% [95% CI, 38.3%-52.2%]), clinical outcomes for 67 (33.3% [95% CI, 26.8%-39.9%]), and clinical scales for 36 (17.9% [95% CI, 12.6%-23.3%]). Trial features differed by therapeutic and indication characteristics, such as therapeutic area, expected length of treatment, orphan status, and accelerated approval.
Conclusions and Relevance:
The quality of clinical trial evidence used by the FDA as the basis for recent approvals of novel therapeutic agents varied widely across indications. This variation has important implications for patients and physicians as they make decisions about the use of newly approved therapeutic agents.
The approval of a drug by the US Food and Drug Administration (FDA) conveys that the product is safe and effective. An Internet-based survey of a national probability sample of 4316 US adults (2944 respondents [68% response rate]) found that 39% report believing that the FDA approves only “extremely effective” drugs and 25% only drugs without serious adverse effects. Some physicians make similar assumptions about effectiveness and safety, expecting that patients are likely to benefit from newly approved therapies.
FDA review of new drug applications is guided by the Federal Food, Drug, and Cosmetic Act, which requires “adequate and well controlled investigations” to determine efficacy. FDA guidance suggests that drug manufacturers submit at least 2 trials, each providing independent evidence of efficacy—such studies are known as “pivotal” efficacy trials—but also implies flexibility, describing circumstances in which a single efficacy trial might be sufficient to support approval. Moreover, for certain applications, the FDA provides written guidance on the design of pivotal efficacy trials, including features of trial design, such as sample selection and choice of comparator, and may provide further guidance in meetings with individual sponsors. As an example, for therapeutic agents evaluated through the accelerated approval pathway, which aims to speed approval of therapeutic agents that treat life-threatening diseases, the FDA permits pivotal efficacy trials to use surrogate end points that are “reasonably likely” to predict clinical benefit.
The clinical research findings available at the time of a drug’s approval have important implications: if made public, these findings represent the only source of information available to patients and their physicians as they decide whether to use a newly approved drug. However, flexible approval standards may lead to some therapeutic agents being approved by the FDA on the basis of numerous rigorously designed clinical trials and others on the basis of fewer or less robust studies, leading to differing levels of certainty about the risks and benefits of newly approved drugs. Accordingly, we sought to systematically examine this issue, evaluating the strength of the clinical trial evidence supporting FDA approval decisions for novel therapeutic agents—pharmacologics and biologics—between 2005 and 2012 by characterizing key features of pivotal efficacy trials, such as trial size, design, duration, and end points.
Easily find safe and trusted apps to help you manage your health
” The Health Apps Library makes it simple for you to you to easily find safe and trusted apps to help you manage your health. These have been reviewed by the NHS to ensure they are clinically safe and relevant to people living in England. They then get rated by you and the health care community.
All apps submitted to the Health Apps Library are checked to make sure that they are relevant to people living in England, comply with data protection laws and comply with trusted sources of information, such as NHS Choices.
Once an app has met these minimum requirements, we then check to see whether the app could potentially cause harm to a person’s health or condition. For example, is the app limited to providing information from a trusted source – or might it go on to provide personalised medical recommendations or treatment options? If so then potentially there could be harm caused by improper use of the app, and so it’s these apps that we want to check out to make sure that they are safe.
Our clinical assurance team – which is made up of doctors, nurses and safety specialists, work with the developer to make sure the app adheres to our safety standards. During this process any potential safety concerns are identified and either designed out or dealt with so that any remaining risk is at an acceptable level.
As this is new territory, we are learning as we go along – and it’s likely that the review process will be updated and improved over time. But we will always ensure that there is a clear explanation about the current process and the work that we are doing as regards safety in health technology.
If you have thoughts about how it could be improved, please do fill in the feedback Form. ”
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Effects of physiologic testosterone therapy on quality of life, self-esteem, and mood in women with primary ovarian insufficiency
With plummeting hormone levels, natural menopause before age 40 can put a damper on women’s mental well being and quality of life. But bringing testosterone back up to normal may not bring them the boost some hoped for, found a new study published online today in Menopause, the journal of The North American Menopause Society (NAMS).
“… Our findings suggest that augmentation of standard estrogen/progestin therapy with physiologic testosterone therapy in young women with POI neither aggravates nor improves baseline reports of quality of life or self-esteem and had minimal effects on mood… ”
Women with primary ovarian insufficiency (POI) display low androgen levels, which could contribute to mood and behavioral symptoms observed in this condition. We examined the effects of physiologic testosterone therapy added to standard estrogen/progestin therapy on quality of life, self-esteem, and mood in women with POI.
One hundred twenty-eight women with 46,XX spontaneous POI participated in a 12-month randomized, placebo-controlled, parallel-design investigation of the efficacy of testosterone augmentation of estrogen/progestin therapy. Quality of life, self-esteem, and mood symptoms were evaluated with standardized rating scales and a structured clinical interview. Differences in outcome measures between the testosterone and placebo treatments were analyzed by Wilcoxon rank sum tests.
No differences in baseline characteristics, including serum hormone levels (P > 0.05), were found. Baseline mean (SD) Center for Epidemiologic Studies Depression Scale scores were 10.7 (8.6) and 9.2 (7.8) for testosterone and placebo, respectively (P = 0.35). After 12 months of treatment, measures of quality of life, self-esteem, and mood symptoms did not differ between treatment groups. Serum testosterone levels achieved physiologic levels in the testosterone group and were significantly higher compared with placebo (P < 0.001). Baseline testosterone levels were not associated with either adverse or beneficial clinical effects.
A 150-μg testosterone patch achieves physiologic hormone levels in women with POI. Our findings suggest that augmentation of standard estrogen/progestin therapy with physiologic testosterone therapy in young women with POI neither aggravates nor improves baseline reports of quality of life or self-esteem and had minimal effects on mood. Other mechanisms might play a role in the altered mood accompanying this disorder.
We Are Giving Ourselves Cancer
Despite great strides in prevention and treatment, cancer rates remain stubbornly high and may soon surpass heart disease as the leading cause of death in the United States. Increasingly, we and many other experts believe that an important culprit may be our own medical practices: We are silently irradiating ourselves to death.
The use of medical imaging with high-dose radiation — CT scans in particular — has soared in the last 20 years…
Continue reading We Are Giving Ourselves Cancer, The NewYork Times, 30 Jan 2014. An Opinion Page by Rita F. Redberg, cardiologist, and Rebecca Smith-Bindman, radiologist, from the UCFS Medical Center.