Approval of modified-release products by FDA without clinical efficacy/safety studies: A retrospective survey from 2008 to 2017

Wang, Yilin; Chang, Yi-Ting; Yang, Shih-ying; Chang, Ya‐Wen; Kuan, Mei-Hsien; Tu, Chien‐Lung; Hong, Hui-Chun; Lai, I-Rue; Gau, Churn-Shiouh; Hsu, Li-Feng

doi:10.1016/j.yrtph.2019.01.037

Cited by 3 publications

(4 citation statements)

References 7 publications

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“…[1, p.3] Occasionally, efficacy can also be established based on "data from one adequate, wellcontrolled clinical investigation" [1, p.3] or existing efficacy studies of closely-related drugs, for example for modified-release (MR) variants of previously approved drugs. [1][2][3] In some cases, the current statistical evaluation process may lead to suboptimal decisions. The assumption that at least two independent RCTs, or even fewer, provide substantial evidence of drug efficacy has been questioned.…”

Section: Introductionmentioning

confidence: 99%

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Comparing the Evidential Strength for Psychotropic Drugs: A Bayesian Meta-Analysis

Pittelkow

Vries

Monden

et al. 2021

Preprint

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Objective: Approval and prescription of drugs should be informed by the strength of evidence for efficacy. While there is no formal policy towards different standards for drug approval, the typical strength of evidence might differ for different psychotropic drug groups. Using a Bayesian framework, we examine (1) whether psychotropic drugs are supported by substantial evidence (at the time of Food and Drug Administration [FDA] approval), and (2) whether there are systematic differences across drug groups. Methods: Data from short-term, placebo-controlled phase II/III clinical trials for 15 antipsychotics, 16 antidepressants for depression, nine antidepressants for anxiety, and 20 drugs for ADHD were extracted from FDA reviews evaluating efficacy prior to marketing approval. Bayesian model-averaged meta-analysis was performed and strength of evidence was quantified with the Bayes factor (BFBMA). Results: We observed substantial variation in strength of evidence and trialling between approved psychotropic drugs: Median evidential strength was extremely strong for ADHD medication (BFBMA = 1820.4), but considerably lower and more frequently classified as weak or moderate for antidepressants for both depression (BFBMA = 94.2) and anxiety (BFBMA = 49.8). Differences might be accounted for by varying median effect sizes (schizophrenia: ESBMA = 0.45, depression: ESBMA = 0.30, anxiety: ESBMA = 0.37, ADHD: ESBMA = 0.72), sample sizes (schizophrenia: N = 324, depression: N = 218, anxiety: N = 254, ADHD: N = 189.5), and numbers of trials (schizophrenia: Nr = 3, depression: Nr = 5.5, anxiety: Nr = 3, ADHD: Nr = 2). Limitations: The analysis only included pre-marketing studies. Conclusion: Evidential strength varied across drug groups: Although most psychotropic drugs were supported by strong evidence at the time of approval, some drugs only had moderate or even ambiguous evidence. These results show the need for more systematic quantification and classification of statistical evidence for psychotropic drugs, and for transparent and clear communication of evidential strength toward clinical decision makers.

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Section: Introductionmentioning

confidence: 99%

“…[1, p.3] Occasionally, efficacy can also be established based on “data from one adequate, well-controlled clinical investigation”[1, p.3] or existing efficacy studies of closely-related drugs, for example for modified-release (MR) variants of previously approved drugs. [1–3]…”

Section: Introductionmentioning

confidence: 99%

Comparing the Evidential Strength for Psychotropic Drugs: A Bayesian Meta-Analysis

Pittelkow

Vries

Monden

et al. 2021

Preprint

View full text Add to dashboard Cite

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“…The FDA states that substantial evidence for efficacy is provided by 'at least two adequate and wellcontrolled studies, each convincing on their own' (U.S. Food and Drug Administration, 1998, p. 3). Occasionally, efficacy can also be established based on 'data from one adequate, wellcontrolled clinical investigation' (U.S. Food and Drug Administration, 1998, p. 3) or existing efficacy studies of closely related drugs, for example for modified-release variants of previously approved drugs (U.S. Food and Drug Administration, 1997Administration, , 1998Wang et al, 2019).…”

Section: Introductionmentioning

confidence: 99%

Comparing the evidential strength for psychotropic drugs: a Bayesian meta-analysis

et al. 2021

View full text Add to dashboard Cite

Approval and prescription of psychotropic drugs should be informed by the strength of evidence for efficacy. Using a Bayesian framework, we examined (1) whether psychotropic drugs are supported by substantial evidence (at the time of approval by the Food and Drug Administration), and (2) whether there are systematic differences across drug groups. Data from short-term, placebo-controlled phase II/III clinical trials for 15 antipsychotics, 16 antidepressants for depression, nine antidepressants for anxiety, and 20 drugs for attention deficit hyperactivity disorder (ADHD) were extracted from FDA reviews. Bayesian model-averaged meta-analysis was performed and strength of evidence was quantified (i.e. BFBMA). Strength of evidence and trialling varied between drugs. Median evidential strength was extreme for ADHD medication (BFBMA = 1820.4), moderate for antipsychotics (BFBMA = 365.4), and considerably lower and more frequently classified as weak or moderate for antidepressants for depression (BFBMA = 94.2) and anxiety (BFBMA = 49.8). Varying median effect sizes (ESschizophrenia = 0.45, ESdepression = 0.30, ESanxiety = 0.37, ESADHD = 0.72), sample sizes (Nschizophrenia = 324, Ndepression = 218, Nanxiety = 254, NADHD = 189.5), and numbers of trials (kschizophrenia = 3, kdepression = 5.5, kanxiety = 3, kADHD = 2) might account for differences. Although most drugs were supported by strong evidence at the time of approval, some only had moderate or ambiguous evidence. These results show the need for more systematic quantification and classification of statistical evidence for psychotropic drugs. Evidential strength should be communicated transparently and clearly towards clinical decision makers.

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“…According to these guidelines, "substantial" statistical evidence for efficacy is provided by "at least two adequate and well-controlled studies, each convincing on their own" (p.3, U.S. Food and Drug Administration, 1998). Occasionally, efficacy can also be established based on "data from one adequate, well-controlled clinical investigation" (p.3, U.S. Food and Drug Administration, 1998) or existing efficacy studies of closely-related drugs, for example for modified-release (MR) variants of previously approved drugs (U.S. Food and Drug Administration, 1997Administration, , 1998Wang et al, 2019).…”

Section: Introductionmentioning

confidence: 99%

Assessing evidence and uncertainty

Pittelkow

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Approval of modified-release products by FDA without clinical efficacy/safety studies: A retrospective survey from 2008 to 2017

Cited by 3 publications

References 7 publications

Comparing the Evidential Strength for Psychotropic Drugs: A Bayesian Meta-Analysis

Comparing the Evidential Strength for Psychotropic Drugs: A Bayesian Meta-Analysis

Comparing the evidential strength for psychotropic drugs: a Bayesian meta-analysis

Assessing evidence and uncertainty

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