New Active Substances Research Articles

OP136 A Comparison Of Health Technology Assessment Recommendations In Australia, Canada, And England: Is There Opportunity For Further Alignment?

IntroductionOver the past decade there have been increasing interactions between health technology assessment (HTA) agencies through international networks at the policy level and European joint actions at the product level. A pilot project is underway to explore collaboration beyond Europe between HTA agencies in Australia, Canada, and the UK. This study the compared HTA recommendations of new active substances (NAS) appraised by Australia’s Pharmaceutical Benefits Advisory Committee (PBAC), Canada’s CADTH, and England’s National Institute for Health and Care Excellence (NICE).MethodsUsing publicly available data and established benchmarking methodology, we examined 45 NAS appraised by PBAC, CADTH, and NICE between 2017 and 2021. Analysis was performed to assess rollout time from regulatory to HTA recommendation, and to the first HTA recommendation.ResultsMost products were submitted to the Europe Medicine Agency first (89%). However, 71 percent of NAS in Australia and 69 percent in Canada were submitted to HTA in parallel with regulatory review, which shortened overall rollout time. The median HTA submission gap among the three agencies was 140 days in Australia, 102 days in Canada, and 8 days in England. PBAC had the highest number of negative recommendations (51%), followed by CADTH (18%), and NICE (5%). The congruence of HTA decisions was highest between CADTH and NICE (56%), compared with PBAC and CADTH (11%), and PBAC and NICE (20%)ConclusionsTo achieve a more collaborative HTA process it is necessary to understand the rollout time in these jurisdictions. This study identified submission gaps among the regulatory agencies, but there may be more synergy in the future as regulators in the three jurisdictions work collaboratively through the Access Consortium. Currently, the submission gap for the three HTA agencies was mostly within six months, making collaboration on joint assessment possible. We observed divergences in HTA recommendations due to the methodology and decision criteria applied by each agency. Therefore, collaboration on assessment should build on the clinical aspects, although HTA decisions should be grounded in the local context.

New drug submissions in Canada and a comparison with the Food and Drug Administration and the European Medicines Agency: Cross-sectional analysis.

Health Canada posts the outcomes of all New Drug Submissions. In some cases, companies have withdrawn submissions or submissions have been rejected by Health Canada for new active substances (NAS). This study explores the reasons for those decisions and compares them with decisions made by the Food and Drug Administration (FDA) and the European Medicines Agency (EMA). This is a cross-sectional analysis. Submissions for NAS between December 2015 and December 2022 were identified along with the original indications for the NAS, the information that Health Canada had available and the reasons for its decisions. Similar information was sourced from the FDA and the EMA. Their decisions were compared to those made by Health Canada. The time between decisions by Health Canada, the FDA and the EMA were calculated in months. Health Canada considered 272 NAS and approved 257. Sponsors withdrew 14 submissions for 13 NAS and Health Canada rejected submissions for 2 NAS. The FDA approved 7 of these NAS and the EMA approved 6, rejected 2 and submissions were withdrawn by 2 companies. Health Canada and the FDA considered similar information in 4 of 7 cases. Indications were the same except in one case. The FDA made decisions a mean of 15.5 months (interquartile range 11.4, 68.2) before companies withdrew their submissions from Health Canada. There were 5 cases where Health Canada and the EMA considered the same information and in 2 of those the outcome was different. Health Canada and EMA decisions were generally made within 1-2 months of each other. Indications were the same in all cases. Differences in decision making by regulators are due to more than the data which with they are presented, the timing of the presentations and the indications for the drugs. Regulatory culture may have influenced decision making.

PD63 Impact Of Parallel Submission On The Rollout Time and Health-Technology-Assessment Recommendation Of New-Active-Substances

IntroductionAustralia and Canada have parallel submission processes that allow companies to submit their dossier to the respective Health-Technology-Assessment (HTA) body before the market authorization is issued, aiming to provide timelier access to drugs. The objective of this study is to investigate the associations of parallel submissions with the rollout times and HTA recommendations of new active substances (NASs).MethodsPublic data from 208 HTA appraisals were collected from the Pharmaceutical Benefits Advisory Committee (PBAC) from Australia and the Canadian Agency for Drugs and Technology in Health (CADTH) for NASs obtaining regulatory approval between 2012 and 2020. We implemented multivariable logistic and linear regression models allowing for type of submission (parallel or sequential) and jurisdiction (Australia and Canada) to examine associations with first HTA recommendation (positive and positive with restrictions vs negative) and rollout time (regulatory submission to HTA recommendation), respectively.ResultsA total of 121 appraisals followed a parallel submission. The therapeutic products that most used a parallel submission were antineoplastic agents (Anatomical Therapeutic Chemical Code=L;47.11%). A similar proportion of chemical and biotechnological products followed parallel submissions.Multivariable linear regression showed that parallel submission presented 14-months decrease in rollout time when compared to sequential (p<0.001). Regarding jurisdictions, longer rollout times were seen for Canada when compared to Australia (β:4.0, p-value=0.024).Parallel submission showed no association with HTA recommendation. Canada had higher odds of receiving a positive recommendation (Odds Ratio:4.84, 95% confidence interval:2.63-9.18) when compared with Australia (p<0.001).ConclusionsAntineoplastic agents were the main products using parallel submissions. Appraisals following a parallel submission showed a considerably faster rollout time than those following the traditional sequential submission, illustrating the advantage of this approach for dossier submission. The submission type did not have an impact on the HTA recommendation, indicating that although quicker, the HTA decision was not affected. Canada has a more restrictive criteria regarding the timing of dossier submission compared to Australia, which may lead to disparities in their rollout time.

PD47 Associations Of Orphan Designation And Other Drug Development-Related Factors On Rollout Times And Health-Technology-Assessment Recommendations Of New-Active-Substances

IntroductionThe orphan designation has been used by the European Medicines Agency to incentivize the development of drugs treating rare diseases with high-unmet medical needs by supporting their development process and economic returns. This study evaluated the impact of the regulatory orphan designation and other drug development-related factors on the rollout times and Health-Technology-Assessment (HTA) recommendations of new active substances (NASs).MethodsA total of 656 HTA appraisals from 6 European countries were collected for NASs that received regulatory approval between 2012 and 2020. Multivariable logistic (positive and positive with restrictions vs. negative HTA recommendation as dependent variable) and linear regression (rollout time as dependent variable) models examined associations with regulatory orphan designation, expedited process, product type (biotechnological vs chemical), and jurisdiction (France, England, Germany, Poland, Scotland and Sweden). Rollout time was defined as months elapsed from regulatory submission to HTA recommendation (mean± standard deviation).ResultsMultivariable logistic regression analysis identified disparities in HTA recommendations between countries. Every month increase in rollout time conferred a 3 percent reduction in the odds of a positive recommendation (p<0.001). Review and product type did not show associations with HTA recommendation. Interestingly, orphan products showed a 99% increase in the odds of obtaining a positive HTA recommendation compared to non-orphan (p-value=0.003). We found 244 appraisals (37%) assessing an orphan product, of which 202 (83%) received a positive HTA recommendation.Multivariable linear regression analysis indicated that orphan products presented a 4.4-month rise in rollout time when compared to non-orphan products (p<0.001). The mean rollout time in months for orphan products were 25±12 in France, 30±15 in England, 21±9.1 in Germany, 37±16 in Poland, 25±12 in Scotland and 27±14 in Sweden.ConclusionsOrphan designated products showed greater odds of receiving a positive HTA recommendation compared with non-orphan. A more detailed review of orphan products could result in their longer rollout time compared with non-orphan counterparts. Considerable differences were found between HTA recommendations and rollout times between jurisdictions.

Evaluation of the Performance of the South Africa Regulatory Agency: Recommendations for Improved Patients\u2019 Access to Medicines

BackgroundTimely access to new medicines may be addressed through strengthening of registration efficiencies and timelines by establishing and refining value-added registration processes, resources, and systems. The aims of this study were to evaluate the timelines of the milestones of the South African review process and the overall approval process for new active substances (NASs) in 2015–2018 and to provide recommendations for improved patients’ access to new medicines through timely registration.MethodsData identifying the milestones and overall approval times for NASs registered by the South African Agency during 2015–2018 were collected and analyzed.ResultsThe most NASs (42) were approved in 2017 and the least (15) in 2018. The shortest median approval time (1218 calendar days) was achieved in 2015 and the longest (2124 days), in 2018. All applications were reviewed using the full review process, and 16/99 (16%) were assigned priority status and were reviewed and approved through the fast track review.ConclusionsWhile the extensive delays in NASs approvals in South Africa may be attributed to inefficient operational processes, resource constraints, and as an increased number of applications for registration, the newly established South African Heath Products Regulatory Agency has re-engineered and streamlined its regulatory review process, which has been piloted and will be enhanced prior to final implementation. Among recommendations for improvement, SAHPRA should consider measurement and monitoring of milestones, facilitated regulatory pathways, implementing a reliance strategy, and a quality management system.

To what degree are review outcomes aligned for new active substances (NASs) between the European Medicines Agency and the US Food and Drug Administration? A comparison based on publicly available information for NASs initially approved in the time period 2014 to 2016

ObjectiveTo compare review outcome alignment between European Medicines Agency (EMA) and US Food and Drug Administration (FDA) for medicines approved by both agencies in the time period 2014–2016.DesignUsing publicly available...

PP30 Do Conditional Regulatory Pathways Affect Health Technology Assessment Recommendations?

IntroductionIn an effort to expedite the approval of drugs treating serious illnesses or addressing unmet medical need, conditional approvals have been used by the European Medicines Agency. In this study, the effects of conditional approvals were investigated in terms of health technology assessment (HTA) recommendations and timing in Europe.MethodsFirst HTA recommendations of new active substances (NASs) issued between 2015 and 2017 were collected from the National Institute for Health and Care Excellence (England), Haute Autorité de Santé (France), Institute for Quality and Efficiency in Health Care (Germany), Scottish Medicine Consortium (Scotland) and Tandvårds-Läkemedelförmånsverket (Sweden). The HTA recommendations were then classified into the following categories: positive, positive with restrictions, negative and multiple and if the regulatory approval pathway had been standard or conditional.ResultsOf this cohort of NASs that received an HTA recommendation, eight of 56 in England, 12 of 83 in France, 11 of 77 in Germany, nine of 58 in Scotland and four of 49 in Sweden were approved via a conditional review. Generally, except in England, there were a higher proportion of positive first recommendations for conditional approvals when compared to standard approvals, with Germany showing the largest proportional difference (43 percent) between the two pathways and also a faster time to recommendation. This may relate to the proportion of conditional assessments that were orphan medicines. With the exception of Germany, the time taken from regulatory approval to first HTA recommendation for products with conditional approvals is higher than those for standard approvals, with the largest difference seen in Sweden (241 days longer).ConclusionsConditionally approved NASs showed a variable HTA outcome; although there was generally a higher proportion of positive recommendations thus enabling more likely access in conditional approvals, the timing from regulatory approval to HTA recommendation was longer compared with standard approvals. This warrants a better understanding of the factors and uncertainties underlying these recommendations, supporting timely access of NASs with conditional approval.

A Comparison of Reimbursement Recommendations by European HTA Agencies: Is There Opportunity for Further Alignment?

Introduction: In Europe and beyond, the rising costs of healthcare and limited healthcare resources have resulted in the implementation of health technology assessment (HTA) to inform health policy and reimbursement decision-making. European legislation has provided a harmonized route for the regulatory process with the European Medicines Agency, but reimbursement decision-making still remains the responsibility of each country. There is a recognized need to move toward a more objective and collaborative reimbursement environment for new medicines in Europe. Therefore, the aim of this study was to objectively assess and compare the national reimbursement recommendations of 9 European jurisdictions following European Medicines Agency (EMA) recommendation for centralized marketing authorization.Methods: Using publicly available data and newly developed classification tools, this study appraised 9 European reimbursement systems by assessing HTA processes and the relationship between the regulatory, HTA and decision-making organizations. Each national HTA agency was classified according to two novel taxonomies. The System taxonomy, focuses on the position of the HTA agency within the national reimbursement system according to the relationship between the regulator, the HTA-performing agency, and the reimbursement decision-making coverage body. The HTA Process taxonomy distinguishes between the individual HTA agency's approach to economic and therapeutic evaluation and the inclusion of an independent appraisal step. The taxonomic groups were subsequently compared with national HTA recommendations.Results: This study identified European national reimbursement recommendations for 102 new active substances (NASs) approved by the EMA from 2008 to 2012. These reimbursement recommendations were compared using a novel classification tool and identified alignment between the organizational structure of reimbursement systems (System taxonomy) and HTA recommendations. However, there was less alignment between the HTA processes and recommendations.Conclusions: In order to move forward to a more harmonized HTA environment within Europe, it is first necessary to understand the variation in HTA practices within Europe. This study has identified alignment between HTA recommendations and the System taxonomy and one of the major implications of this study is that such alignment could support a more collaborative HTA environment in Europe.

Formulary status of drugs in Ontario after Health Canada has issued a serious safety warning: a cohort study.

Drugs are approved for formulary listing based on limited knowledge of their safety. Serious safety issues are often identified after a drug is marketed. To determine whether the listing status of drugs on the Ontario Drug Benefit (ODB) Formulary changes following the identification of safety concerns by Health Canada and whether the results of reviews by people responsible for the ODB Formulary are made public. All new active substances (NAS) approved by Health Canada from January 1, 2002 to March 31, 2012 that subsequently had a warning issued about a serious safety concern were identified. Editions of the ODB Formulary were searched to find which of these drugs were listed on the Formulary before the safety warning was issued. A total of 263 NAS were approved of which 42 subsequently acquired one or more serious safety warnings and 15 of these were listed on the ODB Formulary before the safety warning was issued. The listing status of 14 of the 15 drugs was unchanged after the release of the safety warning. No information is available about whether the listing status of these 14 drugs was reassessed. The ODB Formulary should develop a set of criteria to determine whether the listing status of drugs should be reviewed after Health Canada issues a serious safety warning. The results of any reconsiderations should made public so that prescribers and patients alike know that the ODB Formulary officials still regard the drugs as having a positive benefit to harm ratio.

Evaluation of the Gulf Cooperation Council Centralized Procedure: The Way Forward.

The aim of the study was to evaluate the Gulf Cooperation Council (GCC) centralized regulatory review process. Regulatory review times-including submission and application dates for new active substances (NASs) and existing active substances (EASs) using a standardized template for the period of 2006 to 2010-were collected directly from the GCC office located in Riyadh, Saudi Arabia. A total of 413 products (96 NASs and 317 EASs) were approved during the period, with an overall significant increase in the EASs ( P < .001). The median approval times increased from 107 calendar days in 2006 to 265 in 2010 ( P < .001). The lowest approval time was for EASs submitted by the Gulf companies (134 days) and the longest for NASs submitted by international companies (346 days) ( P < .001). These data were also analyzed according to therapeutic classes and dosage forms. The results also showed that the lowest number (n = 16) approved during the period was in 2010, and this was due to a major regulatory change implementing the International Conference on Harmonisation product stability guideline for the region. The findings indicate that the delay and the wide range in approval times could be reduced by utilizing a standard assessment template for product review and the implementation of a clock stop system for company responses to questions from the GCC central registration committee. Furthermore, using information technology tools would speed up the registration process rather than the manual exchange of product registration files between the executive office and the member states.

The Costs and Effects of Post-Authorisation Safety Studies For New Active Substances.

At market entry, there usually is uncertainty regarding a new medicine’s benefit-risk profile. Therefore, regulatory authorities may request additional pharmacovigilance (PhV) activities. Regulatory Authorities can request a Post-Authorisation Safety Study (PASS) such as a registry, database study, survey, or clinical trial to reduce the uncertainty regarding certain safety risks. We aimed to assess the costs and effects of PASS for centrally approved new active substances (NAS) in Europe in 2007. We compared two scenarios for all NAS (n=47): (1) Full regulation: routine PhV activities (spontaneous adverse drug reaction (ADR) reporting) with additional PASSs for some NAS; (2) Limited regulation: only routine PhV activities. For a follow-up period of six years after marketing we assessed the safety-related labeling changes for NAS and identified the source of these changes (PASS, spontaneous ADR reporting or other). Data on labeling changes was extracted from the European Medicines Agency's website. A survey among pharmaceutical companies was used to estimate the costs of all requested PASSs. For 23 of the 47 NAS, at least one PASS (33 PASS in total) was requested in 2007. After six years, on average 8.1 safety-related labeling changes were identified per NAS. Requested PASS were the source of ~4% of all cases of new safety information identified. The total estimated costs of the 33 requested PASS were between €50 and €150 million. For the 2007 cohort of NAS approved in Europe, the total costs of all requested PASS were substantial and yet these PASS contributed to the identification of only 4% of all new safety information identified post-marketing for NAS. However, PASS primarily aim to reduce uncertainty regarding safety risks and the (societal) value of this uncertainty reduction might not fully be captured by assessing health effects alone.

Postmarket safety in Canada: are significant therapeutic advances and biologics less safe than other drugs? A cohort study

ObjectivesExamine the probability of new active substances (NASs) approved in Canada between 1 January 1997 and 31 March 2012 acquiring a serious postmarket safety warning.DesignCohort study.Data sourcesAnnual reports of the...

Emerging Markets and Emerging Agencies: A Comparative Study of How Key Regulatory Agencies in Asia, Latin America, the Middle East, and Africa are Developing Regulatory Processes and Review Models for New Medicinal Products

An ongoing study has been set up by the CMR International Institute for Regulatory Science to record and analyze the regulatory procedures for the authorization of new medicines in 13 key countries, outside the ICH regions, where the pharmaceutical market is expanding or the regulatory agency plays an important role in regional development. These countries are Argentina, Brazil, Mexico, Egypt, Saudi Arabia, South Africa, China, India, Indonesia, Malaysia, Singapore, South Korea, and Chinese Taipei. In the study, data were collected from senior personnel in the national agencies and from multinational pharmaceutical companies on the review and assessment processes for new active substances (NASs) and major line extensions (MLEs). The quality measures being applied by the agencies to monitor those procedures were also recorded. The design of the study collected information for a status report at one time point, as summarized here, but also provides the basis for recording and benchmarking the progress and changes made by the agencies over time. A cross-comparison of information from the authorities indicated that regulatory aspirations, barriers, and priorities are essentially similar across agencies. The review steps are also similar although there are major differences in the assessment process. Most agencies are using risk stratification methods for their review of new medicines, based on the level of regulatory scrutiny the product has already undergone by agencies elsewhere. There is an awareness of the importance of building quality into agencies’ regulatory processes and practices and this is a changing and evolving area.

Clinical Development of Therapeutic Medicines: A Biopharmaceutical Versus Pharmaceutical Product Comparison

The clinical development of therapeutic medicines is a time-consuming and resource intensive process. The published literature documents the length of clinical phases, but there are few published reports on the number of clinical studies and the number of human subjects involved in the development of therapeutic medicines. In this Tufts Center for the Study of Drug Development investigation, clinical study data for 12 new biopharmaceutical products approved in 1994 through 2000 were analyzed and compared to the results of published clinical studji data for new molecular entities (NMEs) and new active substances (NASs) approved during the same time period. We found that, on average, development of the biopharniaceuticals involved significantly fewer studies per application compared with the studies of NASs (11.8 studies vs. 37 studies) and also fewer subjects per application compared with the studies of either NMEs or NASs (1014 subjects vs. 5697 subjects for NMEs approved in 1998, 4980 subjects for NMEs approved in 1999, or 4478 subjects for NASs). A possible reason for this finding is that many of the biopharniaceuticals included in the analysis were treatments for diseases that affect a potentially small number of subjects. that is, rare, serious, or life-threatening diseases.

Methods of collecting and evaluating non-clinical cardiac electrophysiology data in the pharmaceutical industry: results of an international survey.

To assess current practice in the pharmaceutical industry for assessing the potential for QT interval prolongation by non-cardiovascular medicinal products. The survey was based on responses from the Toxicology and (Safety) Pharmacology laboratories (a total of 74 laboratories) of 54 companies based in Europe, Japan/Asia and the USA, received between January and March 1999. All 54 companies conducted preclinical in vivo electrocardiography (EGG) evaluation of new active substances (NASs). Thirty of these companies also conducted in vitro cardiac electrophysiology studies on their compounds. The majority of in vivo work was done in conscious beagle dogs. There was no consistency within the industry in defining the magnitude of change in QT interval that is considered biologically important. Most companies considered a change greater than 10% to be important, although the design of the studies suggested that group sizes used may not give sufficient statistical power to detect this size of change. Bazett's formula was used by 41% of laboratories to correct QT for changes in heart rate, despite the fact that this formula is generally deemed to be unsuitable for use in dogs. For studies in anaesthetised dogs, the majority of laboratories used barbiturate anaesthesia, but researchers should be aware of the effects of this and some other anaesthetic agents on QT interval. As for in vitro cardiac electrophysiology, there was wide diversity in the testing methodologies, particularly with regard to the test species and tissue type. As with QT prolongation, there was no consensus on the degree of action potential prolongation to cause concern. For both in vitro and in vivo testing, the majority of companies tested a minimum of three dose (or concentration) levels in order to ascertain any dose-response relationship. The survey provides a snapshot of the practice in the industry prior to any internationally-agreed consensus on the most effective and efficient approaches to minimising the risk of QT prolongation by new drugs in man. It must be stated that for any given methodology, the 'majority view' in the industry is not necessarily best practice.