Assessment Of New Medicines Research Articles

АВТОМАТИЗИРОВАННЫЙ МЕТОД РАСЧЁТА ПАРАМЕТРОВ ОСТРОЙ ТОКСИЧНОСТИ ХИМИЧЕСКИХ И БИОЛОГИЧЕСКИХ СОЕДИНЕНИЙ

The article presents a method for calculating the parameters of acute toxicity of chemical and biological compounds using digital technologies. The software is designed to calculate the minimum tolerated dose, LD16, LD50, LD84, LD100 и SLD50 of chemical and biological compounds. Determination of acute toxicity parameters is one of the important stages in the creation of new biological and chemical compounds for the treatment and prevention of animal and human diseases. There are various GOST standards and methodological guidelines for determining the parameters of acute toxicity of biological and chemical compounds (GOST 32379–2020, interstate standard or GOST 32644–2014, test methods for the effects of chemical products on the human body). The automated method presented in the article for determining the parameters of acute toxicity makes it possible to standardize and automate the toxicological assessment of new medicines and is based on the "Methodological guidance, on toxicological assessment, of new drugs for the treatment and prevention of non-infectious animal diseases" dated January 29, 1987. The software can be used in research institutions engaged in the development of medicines for veterinary and medical use, feed additives and biologically active substances. The software can be used at enterprises engaged in the supervision of the production of veterinary and medical medicines. Program functionality: calculation of the minimum tolerated dose, LD16, LD50, LD84, LD100 и SLD50 chemical and biological compounds. Probit regression construction with visualization of the following data: LD0, LD16, LD50, LD84, LD100 .

PP74 Taking A Lifecycle Approach To Scottish Medicines Consortium Budget Impact Analysis

IntroductionThe Scottish Medicines Consortium (SMC) conducts early health technology assessment of new medicines in Scotland. While budget impact is not a factor in decisions on reimbursement, budget impact information is provided initially through horizon scanning reports for high impact medicines (estimated net budget impact >GBP 500,000 [EUR 585,710] per annum) to aid financial planning and implementation of advice at the local level, and later through budget impact templates from the submitting company issued alongside SMC advice. This research aimed to understand how the information is used and to evaluate the benefits of a lifecycle approach to budget impact analysis.MethodsHealth Board users of the budget impact templates were surveyed to explore the degree of utilization and identify areas for improvement, including the need to cross-validate the horizon scanning estimates with those of the submitting company. Responses were analyzed quantitatively and qualitatively, with comments coded in Nvivo (QSR International) and themes established through thematic analysis.ResultsThe initial responses received (n=17) provided representation from 57 percent of Health Boards (i.e., payers) covering 79 percent of the population. Preliminary results showed that while the budget impact templates were valued, 69 percent of respondents found them ‘somewhat useful’, suggesting scope for improvement. Almost half (48%) of the respondents used the templates for high impact medicines, with only 30 percent using them for all medicines. The majority (76%) of those surveyed thought there would be value in linking budget impact information throughout the SMC process. An emerging theme was that some users found the templates complex and inflexible, and that a simpler, more adaptable tool to aid the planning process would be welcomed. Priorities identified for improving template included adapting them to the local population and adjusting medicine prices to reflect confidential discounts.ConclusionsThis research suggests that budget impact information is valued by Health Boards and that there is strong support for linking budget impact estimates and engaging stakeholders throughout a medicine’s lifecycle. Simplifying the templates, increasing their adaptability, and providing guidance and training in their use will be key steps in improving this important part of SMC process.

Patient Global Impression of Benefit-Risk (PGI-BR): Incorporating Patients' Views of Clinical Benefit-Risk into Assessment of New Medicines.

IntroductionThere is a need to understand how patients assess perceived benefits and risks of treatments.ObjectivesThe study aimed to (i) elucidate how patients evaluate treatment experiences and (ii) develop a brief patient-reported outcome (PRO) instrument for use across disease areas for perceived benefit–risk evaluation of a new medicine in a clinical trial setting.MethodsConcepts relating to patient-perceived benefit–risk were identified from literature reviews and qualitative concept elicitation interviews with patients across a variety of primary medical conditions. Draft instrument items were developed from identified concepts and evaluated for clarity, relevance and appropriateness of response options in cognitive interviews. Items were iteratively revised to address patient feedback.ResultsQualitative interviews were conducted with 47 patients (primary condition: 20 oncological, 12 respiratory, 10 metabolic, 5 cardiovascular), of whom 32 contributed to concept elicitation and 42 to cognitive debriefing. Elicited concepts could be grouped into four medication-related categories: effectiveness of treatment, burden of side effects, convenience of use and overall acceptance/satisfaction. Cost, trial experience and altruism were additional concept categories unrelated to medication. The final instrument contained one item each on the medication’s effectiveness, side effects and convenience, and an overall item capturing patient benefit–risk assessment. An upfront question was included to separate out non-medication aspects of patients’ experiences.ConclusionWe developed a brief PRO instrument, the Patient Global Impression of Benefit–Risk (PGI-BR), which can be applied across disease areas to assess patient views of benefit–risk of a new medicine in the clinical trial setting.

Can Standardisation of the Public Assessment Report Improve Benefit-Risk Communication?

BackgroundNational regulatory authorities (NRAs) make the decision to register a medicine based on an assessment of its benefits and risks and publicly available assessment reports are used as a tool to communicate the basis for the decision. The Universal Methodology for Benefit-Risk Assessment (UMBRA) has also been used to effectively communicate the basis of regulatory decisions. Many NRAs in emerging markets place reliance on the public assessment reports (PARs) of reference agencies to inform about their own regulatory decisions. However, PAR users often criticise the redacted nature of PARs and may be challenged in identifying key benefits and risks, value judgements, and benefit-risk (BR) trade-offs.MethodsPARs for ertugliflozin l-pyroglutamic acid, erenumab, and durvalumab published by regulatory bodies in Australia, Europe, Canada, and the United States were compared with the validated UMBRA Benefit-Risk Template to evaluate the BR decision documentation. Published validation of UMBRA included report of a consortium of four regulatory authorities in Australia, Canada, Switzerland, and Singapore indicating that their clinical assessment templates were modified to align with the UMBRA approach. A focus group discussed the use of PARs as potential knowledge management tools for stakeholder understanding of regulatory decision making. The South African Health Product Regulatory Authority (SAHPRA) approach to document and communicate the BR decisions was evaluated.ResultsResults indicate key elements to include in the PARs including regulatory history, an effects table and a record of the strengths and uncertainties for each benefit and risk. Focus group participants agreed that a harmonised PAR template would support improved regulatory decision-making transparency. SAHPRA communication of BR decisions could be improved through the use of the UMBRA BR Template as a guidance for BR assessment and the basis of the South Africa public assessment report format.ConclusionSAHPRA's use of a structured template that supports transparent and quality decision making could have a major impact in ensuring consistency in the BR assessment of new medicines. The implementation of this effective approach for communicating BR decisions will advance agency goals of being a trusted, responsive, accountable regulatory body in which all healthcare stakeholders may rely on with confidence.

Commentary: “Healthcare Professionals’ Preferred Efficacy Endpoints and Minimal Clinically Important Differences in the Assessment of New Medicines for Chronic Obstructive Pulmonary Disease” by Dankers M et al. in Frontiers in Pharmacology 2020; 10: 1519

Commentary: “Healthcare Professionals’ Preferred Efficacy Endpoints and Minimal Clinically Important Differences in the Assessment of New Medicines for Chronic Obstructive Pulmonary Disease” by Dankers M et al. in Frontiers in Pharmacology 2020; 10: 1519

Development and Validation of an Hplc Quantitative Determination Procedure for Paeoniflorin in Dry Garden Peony Extract

Quality control of herbal medicines requires standardization of the contents of biologically active compounds. Therefore, development and validation of analytical procedures used for quality assessment of new medicines is relevant. Roots of garden peony (Paeonia lactiflora), which is a ancestor of European peony varieties, were standardized for paeoniflorin. The possibility of using HPLC for quantitative determination of paeoniflorin in dry garden peony extract was an important aspect of designing garden peony products. A chromatographic procedure was developed and validated for quantitative determination of paeoniflorin and inclusion in quality control regulations for dry garden peony extract.

Healthcare Professionals' Preferred Efficacy Endpoints and Minimal Clinically Important Differences in the Assessment of New Medicines for Chronic Obstructive Pulmonary Disease.

BackgroundRegistration authorities evaluate effects of new medicines for chronic obstructive pulmonary disease (COPD) on airway obstruction, dyspnea, health status and exacerbations. To establish clinical relevance, minimal clinically important differences (MCIDs) are used. The aim of this study was to investigate which efficacy endpoints and MCIDs healthcare professionals consider clinically relevant for new COPD medicines.Materials and Methods7,731 Healthcare professionals received an electronic questionnaire. Participants were asked for: 1) preferred efficacy endpoints for new COPD medicines and 2) cut-off values defining clinical relevance for forced expiratory volume in 1 sec (FEV1), Transition Dyspnea Index (TDI) and St. George’s Respiratory Questionnaire (SGRQ). Those cut-off values were compared to the MCIDs used by registration authorities, namely 100 ml for FEV1, 1 unit for TDI and 4 units for SGRQ.Results227 Healthcare professionals responded to the questionnaire. Most preferred efficacy endpoints were exacerbations (51.0%), airway obstruction (46.9%) and health status (44.9%). Mean cut-off values for TDI and SGRQ were significantly higher than the corresponding MCIDs, mean differences 1.5 (95%CI = 1.3–1.8, p < 0.001) and 7.0 (95%CI = 5.1–8.8, p < 0.001), respectively. The mean cut-off value for FEV1 was comparable to the MCID (mean difference 2.2, 95%CI = -19.9–24.3, p = 0.84).ConclusionsHealthcare professionals largely agree with efficacy endpoints used for the evaluation of new COPD medicines. However, they seem to prefer higher cut-off values for clinical relevance for TDI and SGRQ than the registration authorities. Effects of new medicines on TDI and SGRQ that are considered clinically relevant by registration authorities do, therefore, not necessarily reflect healthcare professionals’ perspectives on clinical relevance.

OP172 Do Expedited Regulatory Pathways Affect Time To Health Technology Assessment Decision?

Introduction:In an effort to speed the assessment of new medicines while maintaining the quality of the regulatory review, facilitated regulatory pathways (FRPs) have been introduced in many countries. In this study, the effects of FRPs (expedited and conditional reviews) were investigated in terms of their influence on HTA outcomes and timing.Methods:HTA recommendations issued between 2014 and 2016 were collected from CADTH (Canada), HAS (France), IQWIG (Germany), SMC (Scotland) and TLV (Sweden) for 90 internationalized medicines (new active substances approved between 2012 and 2016 by all regulatory agencies in the five jurisdictions). The HTA decisions were then classified into the following categories: positive, positive with restrictions, negative and multiple.Results:Of this cohort of internationalized medicines that received an HTA recommendation, 31 percent in Canada and 28 percent in Europe were approved via a FRP. With the exception of Scotland, expedited medicines were more likely to be appraised within a year from regulatory approval and had a shorter median time between regulatory approval to HTA recommendation than standard medicines. The largest difference was seen in Sweden, where medicines were 66.5 days faster than standard pathways when it underwent the expedited pathways. Compared to standard pathways, there were generally a higher proportion of positive and positive with restrictions recommendations when expedited pathways were used. Germany reported the largest proportional difference (31 percent) between the two pathways.Conclusions:Medicines being designated for an expedited review pathway show a reduced time from regulatory approval to HTA decision. This finding suggests there is an alignment between regulators and HTA agencies on which medicines require expedited HTA pathways; however, from this data it cannot be assessed whether the reduced time from approval to HTA decision is attributed to the company strategy, HTA review time or both. Further investigation is required.

Detecting drug-induced changes in ECG parameters using jacketed telemetry: Effect of different data reduction techniques

IntroductionContinuous cardiovascular data is routinely collected during preclinical safety assessment of new medicines. This generates large datasets, which must be summarised to analyse and interpret drug effects. We assessed four methods of data reduction of continuous electrocardiogram (ECG) data and examined the impact on the statistical power of the assay. MethodsContinuous ECG data were collected from a validation study in 6 cynomolgus monkeys using jacketed telemetry. Animals received either vehicle or vehicle followed by ascending doses of moxifloxacin each on a different dosing day. Recordings made for 25h on each dosing day were reduced to discrete time-points using: 1-min average snapshots, 15-min average snapshots, large duration averages (0.5–4h) or super-intervals (3.5–9h averages). ResultsThere was no difference in the ability to detect moxifloxacin-induced QTc prolongation between the 1- and 15-min snapshots and the large duration averages data reduction methods (minimum detectable change in QTca of 20, 17 and 18ms, respectively at 80% power). The super-intervals method detected slightly smaller changes in QTc (15ms), but did not detect a statistically significant increase in QTc after the lowest dose of moxifloxacin, in contrast to the other methods. There were fewer statistically significant differences between dosing days in animals given vehicle when the large duration averages and super-interval reduction techniques were used. DiscussionThere is no marked difference in the power of detection of drug-induced ECG changes in cynomolgus monkeys when using either small duration average or large duration average data reduction techniques. Use of larger duration averages or super-intervals may facilitate data interpretation by reducing the incidence of spurious significant differences that occur by chance between dosing days.

3.2 - Rapid Health Technology Assessment Of New Medicines: Lessons From 15 Years Experience In Scotland

3.2 - Rapid Health Technology Assessment Of New Medicines: Lessons From 15 Years Experience In Scotland

How Excluding Some Benefits from Value Assessment of New Medicines Impacts Innovation

Payers often assess the benefits of new drugs relative to costs for reimbursement purposes, but they frequently exclude some drugs’ option-related benefits, reducing their reimbursement chances, and making them less attractive R&D investments. We develop and test a real options model of R&D investment that shows that excluding option-related benefits heightens drug developers’ incentives to avoid high-risk (volatile) R&D investments, and instead encourages them to focus on “safer” (positively skewed) investments. Our model and empirical results could partly explain the decline in the number of risky new molecular entities (NMEs).

NICE proposals on value-based assessment of new medicines criticised

NICE proposals on value-based assessment of new medicines criticised

Standardizing the Benefit-Risk Assessment of New Medicines

Pharmaceutical scientists and healthcare professionals participating in the development of new medicines bring important practical perspectives to the evaluation of benefits and risks. Within pharmaceutical companies, these specialists can serve to inform the benefit-risk (BR) assessment process, particularly in the latter stages of drug development. However, pharmaceutical scientists may not be aware of the current state of activity in the ongoing efforts to standardize the BR assessment process. In this article, we discuss the role of BR assessment frameworks, activities that are underpinning the standardization of these approaches, and suggest considerations for pharmaceutical scientists to incorporate these into medicine development programmes, regulatory dossiers and clinician communications. Over the past decade there has been an increasing awareness of the potential benefits that can derive from the use of a standardized methodology to assess and communicate a product’s BR profile. Frameworks (in this context defined as the tools and guidelines for their use to facilitate communication of benefits and risks) being developed by the European Medicines Agency, the Pharmaceutical Research and Manufacturers of America Benefit-Risk Action Team (PhRMA BRAT) initiative and the Centre for Innovation in Regulatory Sciences (CIRS), share a common basis in multi-criteria decision analysis and are introduced in this article. To date, quantitative approaches to BRhave been used cautiously because they have lacked the appropriate sophistication, flexibility, ease of use and ability to communicate BR findings. As a result, while a number of quantitative methods have been developed, none have yet achieved widespread endorsement or adoption. Nevertheless, weighting and valuing the underlying criteria can drive a more visual-based presentation of the results, such as through the use of forest plots. BR criteria can be applied to all stage-gate decisions in the lifecycle of a new medicine. Companies should consider developing a skeletal BR model (one based on a consistently applied BR framework) early in a product’s development cycle by assessing whether the product is likely to meet the minimally acceptable thresholds for benefits and risks based on preclinical data and mechanism of action. This process can be used to identify important areas from which to collect information to narrow gaps in knowledge about the BR profile of the product. BR criteria can also inform phase III go/no go decisions. These criteria are then described within the regulatory application to present data using comparable scales. By using a standardized assessment approach that can easily accommodate the parameters associated with the medicine under development, methods can be designed to help communicate the BR profile to a variety of decision stakeholders.

Posters

A poster presentation on the Scottish medicines consortium. SMC advises NHS Scotland about the status of newly licensed medicines, new formulations of existing medicines and new indications for established products. An investigation was undertaken to identify how SMC has impacted on NHS board Area Drug and Therapeutics Committees (ADTCs) in their assessment of new medicines, and the views of key stakeholders (ADTCs, public partners and pharmaceutical industry).

Antinociceptive effect from Davilla elliptica hydroalcoholic extract

Davilla elliptica St Hill (Dilleniaceae) is widely used for multiple purposes in Brazil. The aim of this study was to verify the pharmacological support of this folk use and evaluate its use as antinociceptive. The hydroalcoholic extract of the stems (100–1000 mg/kg, p.o.) induced reduction of response in the formalin test inflammatory phase in mice. This antinociceptive effect does not involve the opioidergic pathway since it was not reverted by pre-treatment with naloxone nor due to myorelaxant activity since it did not affect rota-rod and tail-flick performance. Our results indicate a participation of the nitrergic pathway and may be of particular potential importance in clinical medicine, in view of the current interest in the assessment of new medicines originated from plants.

Availability of comparative trials for the assessment of new medicines in the European Union at the moment of market authorization

To investigate the availability of information about premarketing randomized active-control trials (RaCTs) involving medicines with a new active substance at the moment of market authorization in the European Union. Information was obtained from the EMEA European Public Assessment Reports and the MEDLINE and EMBASE databases. Between 1999 and 2005, 48% of recently approved medicines (n = 122) had been studied in comparison with existing medicines at the moment of market authorization. About one-third of these trials were published and publicly available at that moment. For most new medicines evidence-based assessment of the (added) therapeutic value is not really possible at the moment of market authorization.

Influence of the National Hospital Pharmaceutical Strategy on the Assessment of New Medicines in New Zealand Public Hospitals

ABSTRACTBackgroundIn 2002, New Zealand's Pharmaceutical Management Agency (PHARMAC) began implementing the National Hospital Pharmaceutical Strategy (NHPS) with the assessment of new medicines as a key area of focus.AimTo determine the influence of the NHPS on processes for assessing new medicines in New Zealand public hospitals.MethodIn July 2002, and in July 2004, a questionnaire‐based, cross‐sectional survey was undertaken of the processes used for assessing new medicines in all New Zealand public hospitals that employed one or more pharmacists.ResultsFor both surveys a 97% response rate was achieved, 75% of hospitals used formal assessment processes, 93% had multidisciplinary Medicine and Therapeutics Committees, and over 75% of new medicine applications were approved by these committees and budget holders. 16 hospitals used application forms in 2002 and 18 in 2004. In both surveys over 75% of forms required efficacy, safety and cost data. By 2004, questions on cost effectiveness and prescribing restrictions significantly increased (p ≤ 0.05), more supplementary questions were asked (p ≤ 0.001), and 11 hospitals introduced questions from a PHARMAC template. By 2004, pharmacy/pharmacology departments and clinicians provided more pharmacoeconomic data for assessments than in 2002.ConclusionThe NHPS appears to have influenced the assessment of new medicines in New Zealand public hospitals. In both surveys, hospitals used formal assessment processes and key considerations were efficacy, safety and acquisition cost. By 2004, cost‐effectiveness became an important consideration, more hospitals used application forms, forms were more complex and use of pharmacoeconomic data increased.