Real-world data cannot replace post-approval confirmatory trials

Biosimilars/Research | Posted 21/01/2022 post-comment0 Post your comment

A study published in JAMA Network Open [1] finds that real-world data are not sufficient to confirm the benefits of drugs approved by the US Food and Drug Administration’s (FDA) accelerated approval programme, and therefore cannot replace post-approval confirmatory trials.

16 AA010705

Under FDA’s accelerated approval pathway, therapeutic agents for serious or life-threatening diseases can be approved using surrogate markers that predict clinical benefit, conditional on post-approval confirmatory trials.

However, there is interest in using real-world data to emulate post-approval trials, as these trials often face challenges in recruitment and can be delayed for years following approval.

A recently published cross-sectional study [1] therefore investigated whether real-world data (such as billing claims and electronic health record (EHR) data) could replace post-approval confirmatory trials.

The study investigated whether real-world data could provide sufficient clinical evidence to fulfil the post-approval study requirements, such as data on interventions, indications, trial inclusion and exclusion criteria, and primary endpoints.

The authors used the Drugs@FDA database to identify post-approval confirmatory trials for all new small molecule and biological drugs that were granted accelerated approval by FDA between 2009 and 2018.

The authors reviewed the study descriptions, information and abstracts to determine the proportion of trials for which the clinical indication, (at least 80% of) clinical inclusion and exclusion criteria, the comparator, and the primary endpoint(s) could be routinely determined using real-world data.

They identified 41 new therapeutic agents approved under the accelerated approval pathway between 2009 and 2018, requiring a total of 50 post-approval confirmatory trials.

Of these trials, less than a quarter (24%) had a clinical indication that could be routinely determined using real-world data. The vast majority (76%) required non-routinely ascertainable disease severity or treatment-related qualifiers.

Of the trials for which clinical inclusion and exclusion criteria were available, only 4% had at least 80% of criteria that could be routinely ascertained using real-world data. Of those with a comparator arm, 54% used active comparators, all of which could be ascertained using real-world data. Of those for which primary endpoint information was available, 40% had at least 1 endpoint that could be routinely ascertained using real-world data. However, none of the trials met all of the criteria. The authors cited problems including difficulty in extracting data from EHRs and in identifying inclusion and exclusion criteria.

As a result, the authors conclude that none of the trials could have been emulated using currently available real-world data. They say that while real-world data can be useful to determine clinical outcomes, it is unlikely to replace post-approval confirmatory trials.

A related study, also published in JAMA Network Open [2] and by the same lead author, investigated the duration of post-approval trials. The duration of these trials has come under criticism recently, particularly following the accelerated approval of aducanumab for Alzheimer disease, which included a 9-year deadline for completion of the confirmatory trial.

Whether post-approval trials justify the timelines set by FDA is important, as drugs can remain on the market for an extended period of time without confirmatory evidence.

To investigate this, the authors compared the duration of pivotal trials for the same set of drugs and biologicals granted accelerated approval between 2009 and 2018, a total of 31 agents for 32 indications.

They found that post-approval trials had a median duration of 17 months, while pivotal trials had a median duration of 10 months. However, the median time between accelerated approval to FDA’s post-approval trial results reporting deadlines was 50 months – a median of 30 months longer than post-approval trial durations.

As a result, the authors question the use of post-approval confirmatory trials under the accelerated approval programme, ‘especially if post-approval confirmatory trials neither consistently evaluate clinical outcomes nor are much longer than pivotal trials using surrogate endpoints’, they conclude.

GaBI Journal Citation Impact
1.9 – CiteScore 2020 (calculated on 5 May 2021)
2.2 – CiteScoreTracker 2021 (Last updated on 5 January 2022)

Submit a manuscript to GaBI Journal

Related articles
FDA issues new guidance on biosimilar development and the BPCI Act

FDA reaches 100 generic approvals

Clinical data requirements for biosimilars in the EU


The new section of the ‘Latin American Forum’ on GaBI has been launched. The objective of this new section is to provide you with all the latest news and updates on developments of generic and biosimilar medicines in Latin America in Spanish.

View last week’s headline article: Diferencias en estudios clínicos y farmacovigilancia de medicamentos biológicos en América Latina

Browse the news in the Latin American Forum!

Register to receive the GaBI Latin American Forum newsletter. Inform colleagues and friends of this new initiative.


Se ha lanzado la nueva sección del ‘Foro Latinoamericano’ sobre GaBI. El objetivo de esta nueva sección es brindarle las últimas noticias y actualizaciones sobre desarrollos de medicamentos genéricos y biosimilares en América Latina en español.

Vea el artículo principal de la semana pasada: Diferencias en estudios clínicos y farmacovigilancia de medicamentos biológicos en América Latina

Explore las noticias en el Foro Latinoamericano!

Regístrese para recibir el boletín informativo GaBI Foro Latinoamericano. Informe a colegas y amigos sobre esta nueva iniciativa. 


1. Wallach JD, Zhang AD, Skydel JJ, et al. Feasibility of using real-world data to emulate postapproval confirmatory clinical trials of therapeutic agents granted US Food and Drug Administration accelerated approval. JAMA Network Open. 2021;4(11).e2133667.
2. Wallach JD, Ramachandran R, Bruckner T. Comparison of duration of postapproval vs pivotal trials for therapeutic agents granted US Food and Drug Administration accelerated approval. 2009-2018. JAMA Network Open. 2021;4(11):e2133601.

Permission granted to reproduce for personal and non-commercial use only. All other reproduction, copy or reprinting of all or part of any ‘Content’ found on this website is strictly prohibited without the prior consent of the publisher. Contact the publisher to obtain permission before redistributing.

Copyright – Unless otherwise stated all contents of this website are © 2022 Pro Pharma Communications International. All Rights Reserved.

comment icon Comments (0)
Post your comment
Most viewed articles
About GaBI
Home/About GaBI Posted 05/08/2009
EU guidelines for biosimilars
EMA logo 1 V13C15
Home/Guidelines Posted 08/10/2010