Hwang, Thomas J

Tibau, Ariadna

Trinh, Quoc Dien

Vokinger, Kerstin N

English

ZORA

Zurich Open Repository andArchiveUniversity of ZurichUniversity LibraryStrickhofstrasse 39CH-8057 Zurichwww.zora.uzh.chYear: 2022Reforms to accelerated approval of new medicines: long overdueHwang, Thomas J ; Trinh, Quoc Dien ; Tibau, Ariadna ; Vokinger, Kerstin NDOI: https://doi.org/10.1016/s0140-6736(22)01276-4Posted at the Zurich Open Repository and Archive, University of ZurichZORA URL: https://doi.org/10.5167/uzh-222980Journal ArticleOriginally published at:Hwang, Thomas J; Trinh, Quoc Dien; Tibau, Ariadna; Vokinger, Kerstin N (2022). Reforms to acceleratedapproval of new medicines: long overdue. The Lancet, 400(10349):357-358.DOI: https://doi.org/10.1016/s0140-6736(22)01276-4Correspondencewww.thelancet.com   Vol 400   July 30, 2022 357intervention irrespective of the result. We therefore restrict use of plaque haemorrhage MRI to borderline cases where the result is most likely to inform the clinical decision on whether to offer intervention, although we would much prefer to offer this more widely. Accordingly, the current recom-mendations in our unit are as follows. Plaque haemorrhage MRI is recommended for: patients with a recent stroke or transient ischaemic attack and less than 70% stenosis in the ipsilateral carotid artery; patients with comorbidities or adverse vascular anatomy who are at increased risk for intervention; and patients with asymptomatic severe stenosis (rare in our unit, but we believe that intervention should not be considered in patients with PH–ve carotid disease, whereas on rare occasions it can be considered in patients with PH+ve carotid disease).Contraindications for imaging include: known indication for carotid endarterectomy or carotid stenting (carotid stenosis >70% with recent ipsilateral symptoms of ischaemic stroke or transient ischaemic attack); patients not being fit enough to have the intervention; and contra-indications for MRI (eg, non-MRI cardiac pacemaker, aneurysmal clips in the brain, and other standard contraindications for MRI).We strongly believe that updated recommendations are overdue and urge NICE to consider this.We declare no competing interests.*Shane MacSweeney, Ganesh Subramanian, Anna Podlasek, Dorothee Auer shane.macsweeney@nuh.nhs.ukDepartment of Vascular Surgery (SM) and Department of Stroke Medicine (GS), Nottingham University Hospital, Nottingham, NG5 1PB, UK; Division of Radiological and Imaging Sciences, University of Nottingham, Nottingham, UK (AP, DA)1 Schindler A, Schinner R, Altaf N, et al. Prediction of stroke risk by detection of haemorrhage in carotid plaques: meta-analysis of individual patient data. JACC Cardiovasc Imaging 2020; 13: 395–406.Urgent need to update NICE guidelines on imaging for transient ischaemic attackResults of a recent meta-analysis showed that MRI of carotid plaque haemorrhage was the best indicator of risk of future strokes.1 The risk of stroke is up to 20 times higher in patients with plaque haemorrhage positive (PH+ve) carotid disease than in patients with plaque haemorrhage negative (PH–ve) carotid disease. For example, annual risk of stroke in patients with more than 70% symptomatic stenosis is 29·3% for PH+ve carotid disease versus 1·5% for PH–ve carotid disease1 (an example of plaque haemorrhage imaging is shown in the appendix). This information is extremely helpful in identifying patients for carotid intervention, both those at highest risk and therefore most likely to benefit from intervention, and to avoid the risk and expense of intervention in those at lower risk of stroke.Recommendations released by the National Institute for Health and Care Excellence (NICE) on imaging for people who have had a suspected transient ischaemic attack or acute non-disabling stroke make no reference to this technique,2 instead focusing on using imaging to quantify the degree of stenosis and to exclude alternative causes of symptoms. It is high time that these recommendations were updated, particularly since there are severe pressures on MRI facilities (partly as a result of the backlog caused by the pandemic). Updated recommendations would assist in prioritising the need for scanning.In the absence of updated NICE recommendations, and in view of the pressure on MRI facilities, we avoid plaque haemorrhage MRI in patients currently judged at highest risk of stroke who would probably be offered Published Online  July 12, 2022 https://doi.org/10.1016/S0140-6736(22)01281-8See Online for appendixPublished Online July 11, 2022 https://doi.org/10.1016/S0140-6736(22)01276-4Reforms to accelerated approval of new medicines: long overdueIn June, 2022, the US House of Representatives passed the first legislative reforms to the accelerated approval pathway since its creation by the US Food and Drug Administration (FDA) in 1992 during the HIV/AIDS epidemic.1 Although the FDA has increasingly used accelerated approval (with 278 accelerated approvals from 1992 to 2021), this pathway has been controversial, particularly because of these drugs’ high cost, uncertain efficacy, and absence of completed confirmatory studies. For example, aducanumab received accelerated approval for Alzheimer’s disease despite a negative pivotal trial and the advisory committee voting against approval. This accelerated approval resulted in a 14% initial increase in Medicare Part B insurance premiums this year.2In exchange for earlier market access, sponsors are expected to conduct postapproval studies to confirm clinical benefit. However, most postapproval studies have been delayed or not completed, and, until recently, accelerated approval was not often withdrawn when confirmatory studies failed.3 In a recent initiative, sponsors of several cancer medicines have voluntarily withdrawn accelerated approvals with negative postapproval studies.4 Without such cooperation from the sponsor, withdrawal of accelerated approval by the FDA has been protracted and exceedingly rare—bevacizumab for metastatic breast cancer is the only non-voluntary withdrawal to date.52 National Institute for Health and Care Excellence. Stroke and transient ischaemic attack in over 16s: diagnosis and initial management. 1.2 Imaging for people who have had a suspected TIA or acute non-disabling stroke. April 13, 2022. https://www.nice.org.uk/guidance/ng128 (accessed July 11, 2022).Correspondence358 www.thelancet.com   Vol 400   July 30, 2022School, Boston 02115, MA, USA; Cancer Innovation and Regulation Initiative, Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute and Brigham and Women’s Hospital, Boston, MA, USA (TJH, KNV); Department of Oncology (AT) and Department of Medicine (AT), Hospital de la Santa Creu i Sant Pau, Autonomous University of Barcelona, Barcelona, Spain; Institute of Law, University of Zurich, Zurich, Switzerland (KNV)1 Congress.gov. Food and drug amendments of 2022. June 8, 2022. https://www.congress.gov/bill/117th-congress/house-bill/7667 (accessed June 25, 2022).2 Centers for Medicare and Medicaid Services. Medicare program: Medicare part B monthly actuarial rates, premium rates, and annual deductible beginning January 1, 2022. Nov 17, 2021. https://www.federalregister.gov/documents/2021/11/17/2021-25050/medicare-program-medicare-part-b-monthly-actuarial-rates-premium-rates-and-annual-deductible (accessed June 25, 2022).3 Naci H, Smalley KR, Kesselheim AS. Characteristics of preapproval and postapproval studies for drugs granted accelerated approval by the US Food and Drug Administration. JAMA 2017; 318: 626–36.4 Beaver JA, Pazdur R. “Dangling” accelerated approvals in oncology. N Engl J Med 2021; 384: e68.5 Carpenter D, Kesselheim AS, Joffe S. Reputation and precedent in the bevacizumab decision. N Engl J Med 2011; 365: e3.The Food and Drug Amendments of 2022 grant the FDA explicit legal authority to require initiation of confirmatory studies prior to accelerated approval, setting of enrolment targets, and biannual (twice yearly) reporting of study progress. The legislation also codifies an expedited withdrawal procedure that can be triggered if the sponsor fails to conduct the required postapproval study, the confirmatory study does not confirm benefit, other evidence shows the product is not safe and effective, or the sponsor disseminates false or misleading promotional materials.These provisions are important reforms to the accelerated approval programme, which we believe could be further modernised. In addition to study progress reporting, the FDA could require an annual review of the overall benefit–risk balance of accelerated approvals (as is done by the European Medicines Agency for conditional marketing authorisation). In addition, as underscored by the aducanumab approval (for which <1% of study participants were Black), the FDA could make accelerated approval conditional on adequately inclusive clinical trials, and, if such studies are not completed before approval, the FDA should require that successful completion of postapproval requirements is defined as enrolment of participants representative of the national disease population. Ultimately, these reforms would advance timely evidence generation, the safety of medications available on the market, and equity in clinical trials for medicines receiving accelerated approval.Q-DT reports personal fees from Astellas, Bayer, and Janssen, and a grant from Pfizer, unrelated to this Correspondence. All other authors declare no competing interests.*Thomas J Hwang, Quoc-Dien Trinh, Ariadna Tibau, Kerstin N Vokingerthomas_hwang@dfci.harvard.eduDivision of Urological Surgery (TJH, Q-DT) and Center for Surgery and Public Health (Q-DT), Brigham and Women’s Hospital, Harvard Medical Department of ErrorBurton R, Sheron N. Complex relationship between health and moderate alcohol use. Lancet 2022; 400: 141–43—In this Comment, the email has been corrected. This correction has been made to the online version as of July 18, 2022.Samarasekera U. Leandro Mena: advancing sexual health in the USA. Lancet 2022; 400: 89—In this Profile, the abbreviation for the state Mississippi in the fourth paragraph has been corrected. This correction has been made to the online version as of July 18, 2022.GBD 2020 Alcohol Collaborators. Population-level risks of alcohol consumption by amount, geography, age, sex, and year: a systematic analysis for the Global Burden of Disease Study 2020. Lancet 2022; 400: 185–235—Appendices 1 and 2 of this Article have been corrected as of July 19, 2022.

Reforms to accelerated approval of new medicines: long overdue

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Reforms to accelerated approval of new medicines: long overdue

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