Defining Satisfactory Methods of Treatment in Rare Diseases When Evaluating Significant Benefit–The EU Regulator's Perspective

Sheean, Maria E; Naumann‐Winter, Frauke; Capovilla, Giuseppe; Kalland, Maria Elisabeth; Malikova, Eva; Mariz, Segundo; Matusevičius, Darius; Nisticò, Robert; Schwarzer-Daum, Brigitte; Tsigkos, Stelios; Tzogani, Kyriaki; Larsson, Kristina; Magrelli, Armando; Stoyanova-Beninska, Violeta

doi:10.3389/fmed.2021.744625

Cited by 4 publications

(2 citation statements)

References 7 publications

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“…Secondly, the product must show a promise that it could be effective in treating the condition, by establishing medical plausibility (MP) that can be de ned as a demonstration of the "intention to treat", to support the rationale for the development of the product in the proposed condition and for the assumption of a clinical bene t (12). Finally, where satisfactory methods such as authorised medicines exist for the orphan condition (13), the product has to offer potential signi cant bene t (SB) to these methods. 'Signi cant bene t' is de ned in Article 3(2) of Regulation (EC) No 847/2000 as 'a clinically relevant advantage or a major contribution to patient care' (2).…”

Section: Introductionmentioning

confidence: 99%

Adoptive cell therapy for treatment of rare diseases and orphan designation.

Kalland,

Pose,

Palomo

et al. 2023

Preprint

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Adoptive cell therapies exploit the body’s immune system to target and treat oncological conditions. Many substances are developed to treat rare haematological malignancies which fulfil the criteria for being considered as orphan conditions according to the EU Orphan Regulation (1-2). Chimeric antigen receptor (CAR)-T cell products belong to this group of therapy. The Committee for Orphan Medicinal Products has reviewed 23 adoptive cell therapies which were associated with 36 different applications for orphan designation (OD) over a 10-year period, and nineteen of these were CAR-T cell products intended to treat various rare conditions. Most of these products were developed for the treatment of rare haematological malignancies. Preliminary clinical data was used in 80% (29/36) of the OD submissions to support medical plausibility (promise of efficacy) of the candidate products and an assumption of significant benefit, which is the added benefit of the new product over currently authorised medicines for the proposed orphan condition. Eighty-nine percent (32/36) cases of significant benefit were accepted based on a clinically relevant advantage. Twelve of fourteen submissions reviewed for maintenance of the OD at time of marketing authorisation or extension of indication demonstrated significant benefit of the products over existing therapies within the approved therapeutic indications, but one of these were withdrawn during the evaluation. In conclusion, adoptive cell immunotherapy is a dynamic field in the treatment of haematological malignancies. In the case of applications and ODs granted by the European Commission, autologous CAR-T cell products using a lentiviral vector represent most of the submissions, while CD19 was the most frequently targeted antigen. Clinical data was the most common type of data taken into account at the time of initial OD to support medical plausibility. A high rate of successful initial ODs for these products also seem to translate into a high success rate at the time of marketing authorisation or extension of indication.

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Section: Introductionmentioning

confidence: 99%

Adoptive cell therapy for treatment of rare diseases and orphan designation.

Kalland,

Pose,

Palomo

et al. 2023

Preprint

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“…At the time of MA, orphan designated MPs also need to confirm the orphan criteria with the Committee for Orphan Medicinal Products (COMP) (European Parliament and of the Council, 2000). Prevalence is required to be below five in 10,000 persons in the EU and "significant benefit" (SB) may need to be shown if other "satisfactory methods" already exist for the targeted therapeutic indication (Fregonese et al, 2018;Sheean et al, 2021). The less a condition is understood, the more challenging drug development may be.…”

Section: Introductionmentioning

confidence: 99%

Licensing of Orphan Medicinal Products—Use of Real-World Data and Other External Data on Efficacy Aspects in Marketing Authorization Applications Concluded at the European Medicines Agency Between 2019 and 2021

et al. 2022

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Background: Reference to so-called real-world data is more often made in marketing authorization applications for medicines intended to diagnose, prevent or treat rare diseases compared to more common diseases. We provide granularity on the type and aim of any external data on efficacy aspects from both real-world data sources and external trial data as discussed in regulatory submissions of orphan designated medicinal products in the EU. By quantifying the contribution of external data according to various regulatory characteristics, we aimed at identifying specific opportunities for external data in the field of orphan conditions.Methods: Information on external data in regulatory documents covering 72 orphan designations was extracted. Our sample comprised public assessment reports for approved, refused, or withdrawn applications concluded from 2019–2021 at the European Medicines Agency. Products with an active orphan designation at the time of submission were scrutinized regarding the role of external data on efficacy aspects in the context of marketing authorization applications, or on the criterion of “significant benefit” for the confirmation of the orphan designation at the time of licensing. The reports allowed a broad distinction between clinical development, regulatory decision making, and intended post-approval data collection. We defined three categories of external data, administrative data, structured clinical data, and external trial data (from clinical trials not sponsored by the applicant), and noted whether external data concerned the therapeutic context of the disease or the product under review.Results: While reference to external data with respect to efficacy aspects was included in 63% of the approved medicinal products in the field of rare diseases, 37% of marketing authorization applications were exclusively based on the dedicated clinical development plan for the product under review. Purely administrative data did not play any role in our sample of reports, but clinical data collected in a structured manner (from routine care or clinical research) were often used to inform on the trial design. Two additional recurrent themes for the use of external data were the contextualization of results, especially to confirm the orphan designation at the time of licensing, and reassurance of a large difference in treatment effect size or consistency of effects observed in clinical trials and practice. External data on the product under review were restricted to either active substances already belonging to the standard of care even before authorization or to compassionate use schemes. Furthermore, external data were considered pivotal for marketing authorization only exceptionally and only for active substances already in use within the specific therapeutic indication. Applications for the rarest conditions and those without authorized treatment alternatives were especially prominent with respect to the use of external data from real-world data sources both in the pre- and post-approval setting.Conclusion: Specific opportunities for external data in the setting of marketing authorizations in the field of rare diseases were identified. Ongoing initiatives of fostering systematic data collection are promising steps for a more efficient medicinal product development in the field of rare diseases.

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