Impact of physicians’ participation in non-interventional post-marketing studies on their prescription habits: A retrospective 2-armed cohort study in Germany

Koch, Cora; Schleeff, Jörn; Techen, Franka; Wollschläger, Daniel; Schott, Gisela; Kölbel, Ralf; Lieb, Klaus

doi:10.1371/journal.pmed.1003151

Cited by 5 publications

(5 citation statements)

References 27 publications

(41 reference statements)

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“…This rate is comparable to that observed for postmarket clinical studies overall, which are primarily sponsored by industry, 32 frequently evaluate new therapeutic uses, 33,34 and may play a role in promoting medication use after approval. 35 This has also been observed for therapeutics receiving accelerated approval designation, which are integrated into clinical practice, including new applications, without confirmation of clinical benefit for original indications. 36 New prospective clinical studies investigating therapeutic uses not included in their original approved indications may reflect interest in generating evidence for anticipated off-label uses.…”

Section: Discussionmentioning

confidence: 95%

US Food and Drug Administration utilization of postmarketing requirements and postmarketing commitments, 2009–2018

et al. 2021

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Background/Aims The US Food and Drug Administration outlines clinical studies as postmarketing requirements and commitments to be fulfilled following approval of new drugs and biologics (“therapeutics”). Regulators have increasingly emphasized lifecycle evaluation of approved therapeutics, and postmarketing studies are intended to advance our understanding of therapeutic safety and efficacy. However, little is known about the indications that clinical studies outlined in postmarketing requirements and commitments investigate, including whether they are intended to generate evidence for approved or other clinical indications. Therefore, we characterized US Food and Drug Administration postmarketing requirements and commitments for new therapeutics approved from 2009 to 2018. Methods We conducted a cross-sectional study of all novel therapeutics, including small-molecule drugs and biologics, receiving original US Food and Drug Administration approval from 2009 to 2018, using approval letters accessed through the Drug@FDA database. Outcomes included the number and characteristics of US Food and Drug Administration postmarketing requirements and commitments for new therapeutics at original approval, including the types of studies outlined, the indications to be investigated, and the clinical evidence to be generated. Results From 2009 to 2018, the US Food and Drug Administration approved 343 new therapeutics with 1978 postmarketing requirements and commitments. Overall, 750 (37.9%) postmarketing requirements and commitments outlined clinical studies. For 71 of 343 (20.7%) therapeutics, no postmarketing requirements or commitments for clinical studies were outlined, while at least 1 was outlined for 272 (79.3%; median 2 (interquartile range: 1–4)). Among these 272 therapeutics, the number of postmarketing requirements and commitments for clinical studies per therapeutic did not change from 2009 (median: 2 (interquartile range: 1–4)) to 2018 (median: 2 (interquartile range: 1–3)). Among the 750 postmarketing requirements and commitments for clinical studies, 448 (59.7%) outlined new prospective cohort studies, registries, or clinical trials, while the remainder outlined retrospective studies, secondary analyses, or completion of ongoing studies. Although 455 (60.7%) clinical studies investigated only original approved therapeutic indications, 123 (16.4%) enrolled from an expansion of the approved disease population and 61 (8.1%) investigated diseases unrelated to approved indications. Conclusions The US Food and Drug Administration approves most new therapeutics with at least 1 postmarketing requirement or commitment for a clinical study, and outlines investigations of safety or efficacy for both approved and unapproved indications. The median number of 2 clinical studies outlined has remained relatively constant over the last decade. Given increasing emphasis by the US Food and Drug Administration on faster approval and lifecycle evaluation of therapeutics, these findings suggest that more postmarketing requirements and commitments may be necessary to address gaps in the clinical evidence available for therapeutics at approval.

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Section: Discussionmentioning

confidence: 95%

US Food and Drug Administration utilization of postmarketing requirements and postmarketing commitments, 2009–2018

et al. 2021

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“…This trial was conducted between March 2006 and February 2007, and had an identical design and outcome, and planned the same ratio patient/investigator, but included fewer participants and was still unpublished. Non-interventional postmarketing studies seem suspicious especially since it has been shown that participating physicians prescribe more of the investigated drug 17. It is worth noting that the PAXIL (paroxetine) study 329 is a well-described example of mismatches between marketing claims made in the study and the data shown in an independent reanalysis 18.…”

Section: Discussionmentioning

confidence: 99%

“…Non-interventional postmarketing studies seem suspicious especially since it has been shown that participating physicians prescribe more of the investigated drug. 17 It is worth noting that the PAXIL (paroxetine) study 329 is a well-described example of mismatches between marketing claims made in the study and the data shown in an independent reanalysis. 18 There were also Open access major documented breaches in scientific integrity for paroxetine, including a ghost management programme ironically called CASSPER (Case Study for Peer Review).…”

Section: Statement Of Principal Findingsmentioning

confidence: 97%

Are large prospective trials on antidepressants in mental disorders seeding trials? A descriptive study of trials registered on ClinicalTrials.gov

et al. 2023

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ObjectivesThis descriptive study of registered trials aimed to identify large clinical trials on antidepressants for mental disorders: (1) to assess what proportion could be labelled as ‘seeding trials’ (trials for marketing purposes) and (2) to describe their methodological characteristics and outcomes.DesignA search was conducted across all trials registered on ClinicalTrials.gov by drug name in March 2017.SettingAll trials registered in the database of ClinicalTrials.gov were screened. Large registered studies were received and studies focusing prospectively on the effects of antidepressants in mental health disorders. Specific data items were extracted automatically, and subsequently inspected, corrected and completed by hand.ParticipantsProspective studies were selected focusing on the effects of antidepressants in any mental health disorder with 800 participants or more planned for inclusion.Main outcome measuresThree members from the study team independently assessed the following ‘seeding trial’ characteristics in each registered study: a high level of involvement of the product manufacturer in the study design, in the data analysis and reporting of the study, an abnormally low ratio of patient numbers to study site, spin and/or omissions of clinically relevant findings in the abstracts, and conclusions that focused on secondary endpoints and surrogate markers. Secondary outcomes were the exploration of a functional outcome and suicidality.Results31 trials were identified from clinical trials database. 18/31 were published (58%). 8 of these 18 (44%) studies were identified as possible seeding trials. 13/31 (42%) large trials planned to explore functioning and 5/31 (16%) suicidality.ConclusionsLarge trials are rare in the field of antidepressant research. Some could be ‘seeding trials’. Few explored suicidality. Identifying seeding trials from incomplete data entries in registries, especially when almost half of the studies were still unpublished, posed considerable challenges. The delay between our research and publication limits the strength of our conclusions.PROSPERO registration numberCRD42017065591.

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“…Previous studies have noted that postmarket clinical studies by industry sponsors frequently evaluate new therapeutic uses, 14 while others have suggested they play a role in promoting medication use after approval. 30 This has been observed for therapeutics receiving accelerated approval designation, which are integrated into clinical practice, including new applications, without confirmation of clinical benefit for original indications. 31 We also identified PMRs and PMCs describing new prospective clinical studies potentially investigating modified or new indications.…”

Section: Discussionmentioning

confidence: 99%

U.S. Food and Drug Administration utilization of postmarketing requirements and postmarketing commitments, 2009-2018

Skydel

Zhang

Dhruva

et al. 2020

Preprint

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Background/Aims: The U.S. Food and Drug Administration (FDA) outlines clinical studies as postmarketing requirements and commitments to be fulfilled following FDA approval of new drugs and biologics ("therapeutics"). As regulators have increasingly emphasized lifecycle evaluation of approved therapeutics, postmarketing studies are intended to advance our understanding of therapeutic safety and efficacy, yet little is known about how often clinical studies are outlined or the indications they investigate. To assess FDA's use of postmarket clinical studies to generate evidence of therapeutic safety and efficacy, we characterized FDA postmarketing requirements and commitments for new therapeutics approved from 2009-2018. Methods: We conducted a cross-sectional study of all novel therapeutics, including small molecule drugs and biologics, receiving original FDA approval from 2009-2018, using approval letters accessed through the Drug@FDA database. Outcomes included the number and characteristics of FDA postmarketing requirements and commitments for new therapeutics at original approval, including types of studies outlined, indications to be investigated, and clinical evidence to be generated. Results: From 2009-2018, FDA approved 343 new therapeutics with 1978 postmarketing requirements and commitments. Overall, 750 (37.9%) postmarketing requirements and commitments outlined clinical studies. For 71 of 343 (20.7%) therapeutics, no postmarketing requirements nor commitments for clinical studies were outlined, while at least 1 was outlined for 272 (79.3%; median = 2 (IQR, 1-4)). Among these 272 therapeutics, the number of postmarketing requirements and commitments for clinical studies per therapeutic did not significantly change from 2009 (median 2 (IQR, 1-4)) to 2018 (median 2 (IQR, 1-3); P = .54). Among the 750 postmarketing requirements and commitments for clinical studies, 448 (59.7%) outlined new prospective cohort studies, registries, or clinical trials, while the remainder outlined retrospective studies, secondary analyses, or completion of ongoing studies. Although 455 (60.7%) clinical studies investigated only original approved therapeutic indications, 123 (16.4%) enrolled from an expansion of the approved disease population and 61 (8.1%) investigated diseases unrelated to approved indications. Conclusions: Most therapeutics are approved by FDA with at least 1 postmarketing requirement or commitment for a clinical study, which outline investigations of safety or efficacy for both approved and unapproved indications. However, the median number of 2 clinical studies outlined has remained relatively constant over the last decade, despite increasing emphasis on lifecycle evaluation of approved therapeutics.

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Impact of physicians’ participation in non-interventional post-marketing studies on their prescription habits: A retrospective 2-armed cohort study in Germany

Cited by 5 publications

References 27 publications

US Food and Drug Administration utilization of postmarketing requirements and postmarketing commitments, 2009–2018

US Food and Drug Administration utilization of postmarketing requirements and postmarketing commitments, 2009–2018

Are large prospective trials on antidepressants in mental disorders seeding trials? A descriptive study of trials registered on ClinicalTrials.gov

U.S. Food and Drug Administration utilization of postmarketing requirements and postmarketing commitments, 2009-2018

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