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Rare Diseases Drug Development
Published in Wei Zhang, Fangrong Yan, Feng Chen, Shein-Chung Chow, Advanced Statistics in Regulatory Critical Clinical Initiatives, 2022
Shein-Chung Chow, Shutian Zhang, Wei Zhang
For many rare diseases, well-established efficacy endpoints for the disease may not be available. Thus, FDA suggested that a sponsor should define a trial endpoint by selecting a patient assessment to be used as an outcome measure and define when in the trial the patient would be assessed (FDA, 2019a). As indicated in the draft guidance, endpoint selection in a clinical trial involves the knowledge and understanding of the following: (i) the range and course of clinical manifestations associated with the disease, (ii) the clinical characteristics of the specific target population, which may be a subset of the total population with a disease, (iii) the aspects of the disease that are meaningful to the patient and that could be assessed to evaluate the drug's effectiveness, (iv) the possibility of using the accelerated approval pathway. Despite continuing efforts to develop novel surrogate endpoints, FDA emphasized that only the usual clinical endpoints for the adequate and well-controlled trials can provide the substantial evidence of effectiveness supporting marketing approval of the drug (FDA, 2019a). Thus, it is suggested that sponsors should select endpoints considering the objectives of each trial in the context of the overall clinical development program.
Selected Statistical Topics of Regulatory Importance
Published in Demissie Alemayehu, Birol Emir, Michael Gaffney, Interface between Regulation and Statistics in Drug Development, 2020
Demissie Alemayehu, Birol Emir, Michael Gaffney
The US FDA relies on the accelerated-approval regulatory process to enhance the accessibility of medicines to patients with unmet needs, especially for conditions leading to death or serious illness. The process involves granting approvals to market interventions that demonstrate strong effects with respect to reasonably likely surrogate endpoints, i.e., reasonably likely to predict a clinical benefit. This implies that the evidentiary strength of the effect of treatment on the surrogate must be strong. The approval is granted with a requirement that the sponsors also conduct postapproval clinical trials to show that these markers can be relied upon to predict, or correlate with, clinical benefit. However, as argued in Fleming (2005), the use of such surrogate markers in accelerated approvals requires addressing important operational challenges, including timely completion of the postapproval commitment trials, to protect the best interest of public health.
Introduction
Published in Nusrat Rabbee, Biomarker Analysis in Clinical Trials with R, 2020
The area of validating biomarkers as surrogate endpoints is an active area of research in the FDA. Consequently, more and more biomarkers are being qualified with the advancement of our understanding of their role in the disease and the therapeutic intervention process on the disease. Between 2010 and 2012, the FDA approved 45% of new drugs based on surrogate endpoint. When the surrogate endpoint has been validated, the approval type is regular for a trial using that surrogate endpoint in that disease area. When the biomarker is shown as a surrogate endpoint, which is ‘reasonably likely to predict the clinical benefit’, the approval type is accelerated with full approval conditional on data being available from the true clinical endpoint. The accelerated approval allows a more expedient access to the new treatment to patients. When the biomarker is a novel candidate for a clinical endpoint, a type C meeting is recommended between the sponsor and the FDA in the preliminary stages of clinical development for appropriate strategy.
Antibodies to watch in 2023
Published in mAbs, 2023
Hélène Kaplon, Silvia Crescioli, Alicia Chenoweth, Jyothsna Visweswaraiah, Janice M. Reichert
For the past several years, however, BLAs for some antibody therapeutics have required second cycles of review, which delays, but does not necessarily derail, their approval. Each BLA is unique, and the reasons for second cycles vary, but FDA has recently started placing increased emphasis on confirmatory clinical studies for drugs in development by companies that aim for an accelerated approval, with a particular focus on cancer drugs. The accelerated approval pathway allows FDA to approve products intended for serious or life-threatening disease based on the drug’s effect on a surrogate endpoint that is reasonably likely to predict a clinical benefit to patients, but a required post-approval trial is needed to verify that the drug provides the expected clinical benefit. If no benefit is confirmed, then the product may be removed from the market either voluntarily by the sponsoring company or by FDA.
Antibodies to watch in 2022
Published in mAbs, 2022
Hélène Kaplon, Alicia Chenoweth, Silvia Crescioli, Janice M. Reichert
As of November 15, a total of 11 antibody therapeutics had been granted first approvals in either the US or EU in 2021, which is within the range of 6–13 product approvals that have occurred each year since 2014 (Figure 4). Details for 9 of the 11 products, evinacumab, dostarlimab loncastuximab tesirine, amivantamab, aducanumab, tralokinumab, anifrolumab, bimekizumab, and tisotumab vedotin, are summarized below; regdanvimab and the combination of casirivimab and imdevimab were discussed in the section on ‘COVID-19 interventions.’ Of the 11 products (Table 2), 7 were approved in the US; BLAs for two mAbs, tralokinumab and bimekizumab, have been submitted but seem unlikely to be approved for reasons explained in the summaries for the respective molecules below. The FDA granted accelerated approval to five of the seven products, dostarlimab (dostarlimab-gxly), loncastuximab tesirine (loncastuximab tesirine-lpyl), amivantamab (amivantamab-vmjw), aducanumab (aducanumab-avwa), and tisotumab vedotin (tisotumab vedotin-tftv). The accelerated approval pathway enables FDA to approve products based on the drug’s effect on a surrogate endpoint that is reasonably likely to predict a clinical benefit to patients, but a required post-approval trial is needed to verify that the drug provides the expected clinical benefit.
Antibodies to watch in 2021
Published in mAbs, 2021
Hélène Kaplon, Janice M. Reichert
The accelerated approval program allows FDA to approve drugs for serious conditions to fill an unmet medical need based on a surrogate endpoint, i.e., a result that is reasonably likely to predict a clinical benefit to patients, but additional clinical trials are required to confirm the clinical benefit. In July 2020, Immunomedics announced that the confirmatory Phase 3 ASCENT study (NCT02574455) of TrodelvyTM met its primary endpoint of PFS and key secondary endpoints in brain metastasis-negative patients with metastatic TNBC who have previously received at least two prior therapies for metastatic disease.35 While Immunomedics has indicated that they plan to submit a supplemental BLA to support full approval of TrodelvyTM in the US in the fourth quarter of 2020 and that they are on track to file for regulatory approval in the EU in the first half of 2021, in September 2020 Gilead Sciences, Inc. and Immunomedics announced that they entered into a definitive agreement pursuant to which Gilead will acquire Immunomedics.