The use of external controls: To what extent can it currently be recommended?

With more and better clinical data being captured outside of clinical studies and greater data sharing of clinical studies, external controls may become a more attractive alternative to randomized clinical trials. Both industry and regulators recognize that in situations where a randomized study cannot be performed, external controls can provide the needed contextualization to allow a better interpretation of studies without a randomized control. It is also agreed that external controls will not fully replace randomized clinical trials as the gold standard for formal proof of efficacy in drug development and the yardstick of clinical research. However, it remains unclear in which situations conclusions about efficacy and a positive benefit/risk can reliably be based on the use of an external control. This paper will provide an overview on types of external control, their applications and the different sources of bias their use may incur, and discuss potential mitigation steps. It will also give recommendations on how the use of external controls can be justified

Perspectives on a Way Forward to Implementation of Precision Medicine in Patients With Diabetic Kidney Disease; Results of a Stakeholder Consensus-Building Meeting

Aim: This study aimed to identify from different stakeholders the benefits and obstacles of implementing precision medicine in diabetic kidney disease (DKD) and to build consensus about a way forward in order to treat, prevent, or even reverse this disease. Methods: As part of an ongoing effort of moving implementation of precision medicine in DKD forward, a two-day consensus-building meeting was organized with different stakeholders involved in drug development and patient care in DKD, including patients, patient representatives, pharmaceutical industry, regulatory agencies representatives, health technology assessors, healthcare professionals, basic scientists, and clinical academic researchers. The meeting consisted of plenary presentations and discussions, and small group break-out sessions. Discussion topics were based on a symposium, focus groups and literature search. Benefits, obstacles and potential solutions toward implementing precision medicine were discussed. Results from the break-out sessions were presented in plenary and formed the basis of a broad consensus discussion to reach final conclusions. Throughout the meeting, participants answered several statement and open-ended questions on their mobile device, using a real-time online survey tool. Answers to the statement questions were analyzed descriptively. Results of the open-ended survey questions, the break-out sessions and the consensus discussion were analyzed qualitatively. Results and conclusion: Seventy-one participants from 26 countries attended the consensus-building meeting in Amsterdam, April 2019. During the opening plenary on the first day, the participants agreed with the statement that precision medicine is the way forward in DKD (n = 57, median 90, IQR [75–100]). Lack of efficient tools for implementation in practice and generating robust data were identified as significant obstacles. The identified benefits, e.g., improvement of the benefit-risk ratio of treatment, offer substantive incentives to find solutions for the identified obstacles. Earlier and increased multi-stakeholder collaboration and specific training may provide solutions to alter clinical and regulatory guidelines that lie at the basis of both obstacles and solutions. At the end of the second day, the opinion of the participants toward precision medicine in DKD was somewhat more nuanced (n = 45, median 83, IQR [70–92]) and they concluded that precision medicine is an important way forward in improving the treatment of patients with DKD

The role of stakeholder involvement in the evolving EU HTA process:Insights generated through the European Access Academy’s multi-stakeholder pre-convention questionnaire

Involvement of all relevant stakeholders will be of utmost importance for the success of the developing EU HTA harmonization process. A multi-step procedure was applied to develop a survey across stakeholders/collaborators within the EU HTA framework to assess their current level of involvement, determine their suggested future role, identify challenges to contribution, and highlight efficient ways to fulfilling their role. The ‘key’ stakeholder groups identified and covered by this research included: patients‘, clinicians‘, regulatory, and Health Technology Developer representatives. The survey was circulated to a wide expert audience including all relevant stakeholder groups in order to determine self-perception by the ‘key’ stakeholders regarding involvement in the HTA process (self-rating), and in a second, slightly modified version of the questionnaire, to determine the perception of ‘key’ stakeholder involvement by HTA bodies, payers, and policymakers (external rating). Predefined analyses were conducted on the submitted responses. Fifty-four responses were received (patients 9; clinicians: 8; regulators: 4; HTDs 14; HTA bodies: 7; Payers: 5; policymakers 3; others 4). The mean self-perceived involvement score was consistently lower for each of the ‘key’ stakeholder groups than the respective external ratings. Based on the qualitative insights generated in the survey, a RACI Chart (Responsible/Accountable/Consulted/Informed) was developed for each of the stakeholder groups to determine their roles and involvement in the current EU HTA process. Our findings suggest extensive effort and a distinct research agenda are required to ensure adequate involvement of the key stakeholder groups in the evolving EU HTA process.</p

Evaluation der Experimentierklausel nach § 6c SGB II - Vergleichende Evaluation des arbeitsmarktpolitischen Erfolgs der Modelle der Aufgabenwahrnehmung "Optierende Kommune" und "Arbeitsgemeinschaft"; Untersuchungsfeld 2: Implementations- und Governanceanalyse; Zwischenbericht Mai 2007 an das BMAS

Zwischenbericht 2007 der FH Frankfurt, Institut für Stadt- und Regionalentwicklung, und des Instituts für angewandte Sozialwissenschaft (infas) zur Implementations- und Governanceanalyse im Rahmen der Evalouation der Experimentierklausel nach § 6c SGB II. Die Implementations- und Governanceanalyse untersucht die Umsetzung der durch das SGB II definierten Leistungsprozesse anhand einer Stichprobe von 154 regionalen Einheiten aus allen Arbeitsgemeinschaften (ARGEn), zugelassenen kommunalen Trägern und Fällen getrennter Aufgabenwahrnehmung. Der Bericht analysiert im ersten Teil überregionale Governance-Strukturen (z. B. rechtliche und finanzielle Vorgaben, Zielvereinbarungen), die Auswirkungen auf die Leistungserbringung der SGB II-Einheiten haben. Im zweiten Teil werden die lokalen Steuerungs- und Organisationsstrukturen in den Formen der Aufgabenwahrnehmung untersucht und wird eine Typologie der Organisation des Leistungsprozesses entwickelt. Der dritte Teil beschäftigt sich mit der Ausgestaltung der Schnittstellen zwischen SGB II, SGB III und SGB VIII, insbesondere im Hinblick auf Eingliederungsleistungen für Jugendliche und junge Erwachsene sowie die Organisation der Arbeitsvermittlung

The Partitur Format at BAS

Most spoken language resources are produced and disseminated together with symbolic information relating to the speech signal. These are for instance orthographic transcript labeling and segmentation on the phonologic phoneti prosodic phrasal level. Most of the known formats for these symbolic data are defined in a ‘closed form’ that is not fexible enough to allow simple and platform independent processing and easy extensions. At the Bavarian Archive for Speech Signals (BAS) a new format has been developed and used over the last few years that shows some significant advantages over other existing formats. This paper describes the basic principles behind this format discusses briefly the advantages and gives detailed definitions of the description levels used so far

The Partitur Format at BAS

Most spoken language resources are produced and disseminated together with symbolic information relating to the speech signal. These are for instance orthographic transcripts, labelling and segmentation on the phonologic, phonetic, prosodic, phrasal level. Most of the known formats for these symbolic data are defined in a &apos;closed form&apos; that is not flexible enough to allow simple and platformindependent processing and easy extensions. At the Bavarian Archive for Speech Signals (BAS) a new format has been developed and used over the last few years that shows some significant advantages over other existing formats. This paper describes the basic principles behind this format, discusses briefly the advantages and gives detailed definitions of the description levels used so far. Furthermore, we will give some examples for easy processing of the format and distributed work on the same data. In the future all corpora produced and disseminated by BAS will be distributed with the new BAS Partit..

Single‐arm clinical trials as pivotal evidence for cancer drug approval:a retrospective cohort study of centralized European marketing authorizations between 2010 and 2019

Abstract The traditional drug development paradigm, consisting of sequential phases and randomized studies, has been challenged in oncology and hemato‐oncology. In the regulatory context, a number of new products have been authorized based on nonrandomized efficacy and safety data. We retrospectively analyzed the European public assessment reports for anticancer treatments authorized between 2010 and 2019 to describe the data behind such approvals. Twenty‐two initial marketing authorizations, mainly conditional, were identified. Fifty percent of the products had an orphan indication, and 77% had received previous scientific advice. Conclusions of clinical benefit were based on tumor responses, ranging between 15.8 and 88%. Our data shows that single‐arm clinical studies leading to positive regulatory outcomes share common methodological approaches and end points, mostly comparing the overall response rate with a fixed success threshold as the primary analysis. The clinical indications in these approvals are clustered in late‐line settings, hematological malignancies, and lung cancer. Our findings underline the need to reflect on the current practice, the methodological aspects, and end points in single‐arm studies, and develop specific regulatory guidance on nonrandomized and novel study designs

990916.march

ABSTRACT. Objective. To investigate the presence of continuing endothelial cell activation in patients with systemic lupus erythematosus (SLE) and its relationship with lupus nephritis. Methods. We measured plasma concentrations of soluble thrombomodulin (sTM), vascular cellular adhesion molecule-1 (sVCAM-1), von Willebrand factor (vWf), sP-selectin, and ED1-fibronectin in 75 SLE patients with a median SLE disease activity index (SLEDAI) of 4. Forty patients with a history of lupus nephritis, confirmed by renal biopsy in 33, were compared with 35 patients without lupus nephritis and 25 controls. For subgroup analysis in patients with clinically stable remission we excluded patients with a SLEDAI &gt; 6 or with evidence of renal disease activity. Results. In the total SLE patient group sTM, sVCAM-1, vWf, and sP-selectin were significantly elevated compared with controls. In patients with a history of lupus nephritis plasma levels of sTM and vWf were significantly increased compared with SLE patients without nephritis. After adjustment for significantly associated variables, especially creatinine clearance and age, in a multivariate linear regression analysis, sTM remained significantly elevated in patients with a history of lupus nephritis (difference 28.9 ng/ml, 95% CI 11.5-46.4). In the subgroup analysis of 57 patients, the results remained unchanged. Conclusion. The increase of sVCAM-1, sP-selectin, sTM, and vWf reflects a state of persistent endothelial cell activation. Multivariate regression analysis shows that the elevated sTM levels are strongly associated with a history of lupus nephritis, independent of creatinine clearance or disease activity, suggesting endothelial cell activation specifically localized in the kidneys. (J Rheumatol 2001;28:514-9

Generating the Right Evidence at the Right Time: Principles of a New Class of Flexible Augmented Clinical Trial Designs.

To support informed decision making, clear descriptions of the beneficial and harmful effects of a treatment are needed by various stakeholders. The current paradigm is to generate evidence sequentially through different experiments. However, data generated later, perhaps through observational studies, can be difficult to compare with earlier randomized trial data, resulting in confusion in understanding and interpretation of treatment effects. Moreover, the scientific questions these later experiments can serve to answer often remain vague. We propose Flexible Augmented Clinical Trial for Improved eVidence gEneration (FACTIVE), a new class of study designs enabling flexible augmentation of confirmatory randomized controlled trials with concurrent and close-to-real-world elements. Our starting point is to use clearly defined objectives for evidence generation, which are formulated through early discussion with health technology assessment (HTA) bodies and are additional to regulatory requirements for authorization of a new treatment. These enabling designs facilitate estimation of certain well-defined treatment effects in the confirmatory part and other complementary treatment effects in a concurrent real-world part. Each stakeholder should use the evidence that is relevant within their own decision-making framework. High quality data are generated under one single protocol and the use of randomization ensures rigorous statistical inference and interpretation within and between the different parts of the experiment. Evidence for the decision making of HTA bodies could be available earlier than is currently the case