Approvals of drugs with uncertain benefit–risk profiles in Europe

doi:10.1016/j.ejim.2015.08.008

European Journal of Internal Medicine

Volume 26, Issue 8, October 2015, Pages 572-584

https://doi.org/10.1016/j.ejim.2015.08.008 Get rights and content

Highlights

•
There is a pressure for early access to new drugs for unmet medical needs.
•
Conditional approvals aim to achieve this goal.
•
Conditional approvals are granted to drugs with unsettled benefit–risk profiles.
•
Fulfilment of obligations imposed to cover the information gap is suboptimal.
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Early approval may put ineffective and/or unsafe drugs onto the market for long periods.

Abstract

Purpose

This paper examines conditional approvals that allow the marketing of medicines with unsettled benefit–risk profiles in the European Union.

Methods

We identified medicines that had received conditional approval from the European Medicines Agency in the period January 2006–June 2015. We searched the reasons and bases for approvals, the median time to address the specific obligations imposed in order to cover the information gap and allow regular authorisations, and their extent of fulfilment.

Results

Of the 26 products conditionally authorised two were withdrawn for commercial reasons, ten were switched to regular approval, and 14 are still under conditional approval. Conditional approval was granted mainly to medicinal products intended for seriously debilitating disease or life-threatening disease. The median time to address the specific obligations was four years (range 0.2 to 7.7). There were delays or discrepancies in the fulfilment of these obligations in more than one third of the authorisation procedures.

Conclusions

In most cases there was limited evidence supporting the positive benefit–risk balance at the time of approval. Delays or discrepancies in the fulfilment of obligations allow medicinal products with unsettled benefit–risk profiles onto the market for several years. This should be taken into account when further early or step-wise licensing strategies are considered.

Introduction

Early access to new medicinal products is a controversial matter [1], [2]. Regulatory agencies are often criticised by pharmaceutical companies and patients' advocacy groups for delaying access to promising therapies [3], [4]. However, shrinking the premarketing development procedures may increase the risks of approving drugs that are ineffective, unsafe, or both [5], [6]. The European Medicines Agency (EMA), which is responsible for centralised approvals in Europe (Box 1), has implemented two different procedures to grant marketing authorisations on the basis of incomplete data, with a view to meeting “unmet medical needs of patients and in the interests of public health” [7]. Unlike approvals passed under exceptional circumstances, conditional approvals are granted when the risk–benefit balance is based on preliminary, not yet full, evidence (Box 2) [7], [8]. The marketing authorisation holder is given obligations, such as a requirement for further studies, which in principle should fill the information gaps so as to permit a marketing authorisation that is no longer subject to specific obligations. Depending on the fulfilment of these requirements over time, conditional approval may benefit patients by making innovative treatments available sooner but, on the other hand, medicines may be authorised with incomplete information, which may jeopardise rather than benefit public health.

This cross-sectional study examined the conditional approval procedure after its establishment in 2006 [8], and tracking the follow-up of the specific obligations, including the switch to regular approval.

Section snippets

Methods

We searched the EMA website to identify products that had received conditional marketing authorisation in the period January 2006–June 2015. From the European Public Assessment Report (EPAR) on the relevant drugs, we retrieved data on the pivotal studies supporting the marketing authorisation, the reasons for granting conditional approval, and the specific obligations imposed by the EMA. To track the specific obligations and the status of the marketing authorisation (still conditional or

Results

Out of 490 medicinal products authorised by the EMA between 2006 and June 2015 (excluding generics and biosimilars), 26 were granted conditional approval (5.3%). We excluded two vaccines approved during the H1N1 pandemic influenza outbreak that the authorisation holder subsequently withdrew from the market for commercial reasons. Of the remaining 24, none was subsequently withdrawn by the Agency, ten were switched to regular approval and 14 are still under conditional approval (Fig. 1). Table 1

Discussion

EMA conditional approval is a regulatory tool developed for granting European marketing authorisations to medicinal products on the basis of incomplete data with a view to allowing early access to new treatments [8]. Conditional approval is usually granted to drugs intended to address unmet medical needs, i.e. “any seriously debilitating or life-threatening condition for which there exists no satisfactory […] treatment authorised” [8]. The benefit to public health of immediate availability of

Conclusions

Our analysis of conditional approvals granted by the EMA highlights inconsistencies with regard to the fulfilment of the criteria for this kind of authorisation and the specific obligations imposed at the time of approval. The benefit–risk profile of medicines conditionally allowed onto the market is rarely reassuring and strong enough to make the expected public health advantage outweigh the risks of limited clinical information.

The regulatory tools adopted to grant marketing authorisation on

Learning points

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Though advocated by pharmaceutical companies and patient groups, early access to new medicinal products may increase the risks of approving drugs that are ineffective, unsafe, or both.
•
Regulatory authorities have adopted tools that favour early access to the market of medicines with still unsettled benefit–risk profiles, while hoping to fill the gaps promptly.
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Since 2006 the “conditional approvals” have been intended to serve this purpose in Europe.
•
Analysis of the EMA conditional approvals

Authors' contributions

SG proposed a systematic assessment of the EMA procedure to grant early marketing access to medicines in Europe. RB and VB planned the analysis and RB, CG, VB extracted the data and verified their accuracy. RB drafted the initial manuscript and all the authors commented the drafts, contributed to the final text and approved it. All authors had full access to all the data. SG served as a member and VB as an expert on the Committee for Proprietary Medicinal Products at the EMEA (now Committee for

Funding

This study was supported by internal funds of the Mario Negri Institute.

Conflict of interests

None of the authors have financial or non-financial personal competing interests to be declared.

Acknowledgements

We thank Judith Baggott for editing and Teresa Leonardo Alves for comments on an early draft of the manuscript.

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Original ArticleApprovals of drugs with uncertain benefit–risk profiles in Europe

Highlights

Abstract

Purpose

Methods

Results

Conclusions

Introduction

Section snippets

Methods

Results

Discussion

Conclusions

Learning points

Authors' contributions

Funding

Conflict of interests

Acknowledgements

Epilepsy Res

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Nat Rev Drug Discov

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Original Article
Approvals of drugs with uncertain benefit–risk profiles in Europe