Conditional Marketing Authorization Research Articles

Regulatory histories of recently withdrawn ovarian cancer treatment indications of 3 PARP inhibitors in the US and Europe: lessons for the accelerated approval pathway.

Withdrawals of drug indications may reveal potential inadequacies in the regulatory approval processes of new drugs. Understanding potential weaknesses of the regulatory approval process is paramount given the increasing use of expedited pathways. In this paper, we focus on three poly-ADP-ribose polymerase inhibitors (olaparib, rucaparib and niraparib) for the treatment of women with heavily pretreated, recurrent ovarian cancer, which were eventually withdrawn. We use a comparative case study approach to evaluate the regulatory histories of these drug indications in the US and Europe. Two drug indications benefited from the FDA's accelerated approval pathway, which explicitly lowers the bar for evidence of efficacy at the time of approval. Following accelerated approval, manufacturers are mandated to conduct post-marketing studies to confirm clinical benefit. The FDA granted accelerated approval to olaparib and rucaparib based on data on surrogate endpoints and converted the approval to regular approval after the submission of additional data on surrogate endpoints from one of two required confirmatory trials, that is, without data on clinical benefit. Niraparib directly received regular approval based only on data on a surrogate endpoint. By contrast, the EMA granted conditional marketing authorisation to rucaparib and was quicker to restrict usage than the FDA. The regulatory histories of these drug indications highlight the need to reform the accelerated approval pathway by ensuring that post-marketing requirements are followed, and that regular approval is only based on evidence of clinical benefit.

Unlocking hope: talquetamab in multiple myeloma treatment: a bispecific breakthrough targeting CD3 and GPRC5D

Multiple myeloma (MM) presents a significant global health burden, with disparities in incidence and outcomes reflecting challenges in recognition and treatment. Talquetamab, a bispecific CD3 T-cell engager targeting G-protein coupled receptor family C group 5 member D (GPRC5D), has emerged as a promising immunotherapy for relapsed/refractory MM (RRMM). In August 2023, talquetamab received accelerated approval from the US FDA for RRMM treatment, followed by conditional marketing authorization from the EMA. Clinical trials demonstrated talquetamab's efficacy, with overall response rates (ORR) of 69% and 76% in heavily pretreated RRMM patients. The phase I monumenTAL-1 trial showcased talquetamab's effectiveness, particularly in high-risk MM and extramedullary disease, with ORRs around 71-74%. Subsequent phase 2 results reaffirmed its efficacy, even in patients with prior T-cell redirection therapies. Combination therapy with daratumumab further enhanced talquetamab's efficacy, addressing concerns of T cell exhaustion. Pharmacokinetic studies revealed sustained responses and manageable adverse events with subcutaneous administration, facilitating convenient dosing regimens. However, talquetamab carries risks of cytokine release syndrome (CRS) and neurologic toxicity, necessitating close monitoring and prompt management. Common adverse events included fever, CRS, musculoskeletal pain, and infections, although severe events were infrequent. Vigilant management strategies, including prophylactic measures and supportive care, mitigate these risks. In conclusion, talquetamab represents a significant advancement in RRMM treatment, offering a promising avenue for T-cell redirection therapy. Ongoing research aims to optimize treatment sequencing and combination strategies, fostering improved outcomes for MM patients. Continued investigation will refine the strategic integration of talquetamab and other immunotherapies, paving the way for enhanced treatment efficacy and patient care in RRMM.

Cost-Effectiveness Analysis of Etranacogene Dezaparvovec Versus Extended Half-Life Prophylaxis for Moderate-to-Severe Haemophilia B in Germany.

Haemophilia B is a rare genetic disease that is caused by a deficiency of coagulation factor IX (FIX) in the blood and leads to internal and external bleeding. Under the current standard of care, haemophilia is treated either prophylactically or on-demand via intravenous infusions of FIX. These treatment strategies impose a high burden on patients and health care systems as haemophilia B requires lifelong treatment, and FIX is costly. Etranacogene dezaparvovec (ED) is a gene therapy for haemophilia B that has been recently approved by the United States Food and Drug Administration and has received a recommendation for conditional marketing authorization by the European Medicines Agency. We aimed to examine the cost-effectiveness of ED versus extended half-life FIX (EHL-FIX) prophylaxis for moderate-to-severe haemophilia B from a German health care payer perspective. A microsimulation model was implemented in R. The model used data from the ED phase 3 clinical trial publication and further secondary data sources to simulate and compare patients receiving ED or EHL-FIX prophylaxis over a lifetime horizon, with the potential for ED patients to switch treatment to EHL-FIX prophylaxis when the effectiveness of ED waned. Primary outcomes of this analysis included discounted total costs, discounted quality-adjusted life years (QALYs), incremental cost-effectiveness, and the incremental net monetary benefit. The annual discount rate for costs and effects was 3%. Uncertainty was examined via probabilistic analysis and additional univariate sensitivity analyses. Probabilistic analysis indicated that patients treated with ED instead of EHL-FIX prophylaxis gained 0.50 QALYs and experienced cost savings of EUR 1,179,829 at a price of EUR 1,500,000 per ED treatment. ED was the dominant treatment strategy. At a willingness to pay of EUR 50,000/QALY, the incremental net monetary benefit amounted to EUR 1,204,840. Depending on the price, ED can save costs and improve health outcomes of haemophilia patients compared with EHL-FIX prophylaxis, making it a potentially cost-effective alternative. These results are uncertain due to a lack of evidence regarding the long-term effectiveness of ED.

Primary biliary cholangitis drug evaluation and regulatory approval: Where do we go from here?

Primary biliary cholangitis (PBC) is a chronic cholestatic liver disease. The management landscape was transformed 20 years ago with the advent of Ursodeoxycholic Acid (UDCA). Up to 40% of patients do not, however, respond adequately to UDCA and therefore still remain at risk of disease progression to cirrhosis. The introduction of Obeticholic acid (OCA) as second-line therapy for patients failing UDCA has improved outcomes for PBC patients. There remains, however, a need for better treatments for higher risk patients. The greatest threat facing our efforts to improve treatment in PBC is, paradoxically, the regulatory approval model providing conditional marketing authorisation for new drugs based on biochemical markers on the condition that long-term, randomized placebo-controlled outcomes trials are performed to confirm efficacy. As demonstrated by the COBALT confirmatory study with OCA, it is difficult to retain patients in the required follow-on confirmatory placebo-controlled PBC outcomes trials when a licensed drug is commercially available. New PBC therapies in development such as the PPAR agonists, face even greater challenges in demonstrating outcomes benefit through randomized placebo-controlled studies once following conditional marketing authorisation, as there will be even more treatment options available. A recently published EMA Reflection Paper provides some guidance on the regulatory pathway to full approval but fails to recognise the importance of Real-World Data in providing evidence of outcomes benefit in rare diseases. Here we explore the impact of the EMA reflection paper on PBC therapy and offer pragmatic solutions for generating evidence of long-term outcomes through Real World data collection.

Added benefit and revenues of oncology drugs approved by the European Medicines Agency between 1995 and 2020: retrospective cohort study

ObjectivesTo evaluate the added benefit and revenues of oncology drugs, explore their association, and investigate potential discrepancies between added benefit and revenues across different approval pathways of the European Medicines...

Tafasitamab in Combination with a CD20xCD3 Bispecific T-Cell Engager Significantly Prolongs Survival in Preclinical Lymphoma Models

R-CHOP remains the standard of care for newly diagnosed DLBCL patients. However, 30-40% of patients are refractory or relapse after initial response to the immunochemotherapy, indicating a high-unmet medical need for these patients. Tafasitamab is a CD19-targeting, Fc-modified humanized monoclonal antibody mediating antibody-dependent cellular cytotoxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP) and direct cytotoxicity. Tafasitamab was granted accelerated approval by the FDA in 2020 and conditional marketing authorization by the EMA in 2021 for the treatment of transplant-ineligible adult patients with relapsed or refractory (R/R) DLBCL in combination with the immunomodulatory drug lenalidomide. CD20xCD3 T-cell engagers are currently under clinical investigation or recently received FDA approval in 2L+ DLBCL (Thieblemont 2023; Dickinson 2022). CD19- and CD20-targeting antibodies might complement each other, as I) CD19 could compensate for CD20-low/ -negative settings and vice versa and II) monoclonal antibodies and T-cell engagers combine powerful and distinct immune pathways holding great potential to increase responses in patients who may need additional therapeutic options. The aim of this study was to investigate the combination of tafasitamab and MOR212, a proprietary proof-of-concept CD20xCD3 T-cell engaging antibody, in preclinical models of lymphoma. First, MOR212 was characterized in vitro and in vivo to ensure comparability with other CD20xCD3 bispecific antibodies (comp1-3) currently under clinical investigation. In in vitro cytotoxicity assays, MOR212 demonstrated similar (comp1-2), or improved (comp3) cytotoxicity (MOR212 vs comp1 and 2 p>0.05 vs comp3 p=0.03; exemplary data for EC50 in SU-DHL-4 cells; n=6), cytokine secretion (MOR212 vs comp1-3 p>0.05; exemplary data for EC50 TNFα; n=4) and T-cell activation (MOR212 vs comp1 p=0.05; vs comp2 p>0.05 vs comp3 p=0.003; exemplary data for % CD69 on CD8 T-cells; n=6) in cell lines expressing different levels of CD20. In a lymphoma in vivo model co-engrafted with human T-cells, MOR212 prolonged progression-free survival of mice to a similar extent as two comparator molecules that were tested head-to-head (MOR212 vs comp1 and 3 p>0.05;) at a dose of 0.1 mg/kg. Next, we investigated the combination of tafasitamab and MOR212 in vitro. Due to the differential killing kinetics of a monoclonal antibody and a T-cell engager, we made use of a real time live-cell imaging assay. Lymphoma cells were co-cultured with healthy donor peripheral blood mononuclear cells (PBMCs) and tafasitamab and MOR212 were added in different concentration combinations. Tumor cell killing was monitored every 3 hours for 72 hours and revealed improved target cell killing by the combination of both compounds (signal/background caspase 3/7 staining at 48h: MOR212 24.2 vs tafasitamab 28.2 vs MOR212+tafasitamab 111.5; n=1). To confirm these findings in vivo, we used human CD34+ engrafted NCG mice with a huIL15 boost allowing for the development of human T-cells as well as NK-cells, as essential effector cells for the combination of both compounds. Raji lymphoma cells were engrafted and treatment with the single or combination therapy was started once tumors reached a pulpable size. Combination of tafasitamab and MOR212 significantly improved progression-free survival in animals compared to monotherapy treatment (tafasitamab+MOR212 vs tafasitamab only p=0.0002 and MOR212 only p=0.0098). In addition, the combined treatment regimen appeared to be safe in mice as no side effects on both body weight loss and clinical score were recorded throughout the entire observation period. Our findings prove that the combination of tafasitamab and a CD20xCD3 T-cell engaging antibody significantly increases tumor cell eradication both in vitro and in vivo and lay the ground to potentially translate the results into improved outcome for patients with aggressive lymphoma in future clinical trials.

Realmind: A Prospective and Retrospective Study to Characterize Real-World Use of Tafasitamab Plus Lenalidomide in US Patients with Relapsed/Refractory Diffuse Large B-Cell Lymphoma, with a Focus on Patients from Minority Groups

Background The combination of the anti-CD19 monoclonal antibody tafasitamab and the immune modulatory drug lenalidomide (LEN) has been commercially available in the US for adult patients with relapsed/refractory diffuse large B-cell lymphoma (R/R DLBCL) not otherwise specified, including DLBCL arising from low-grade lymphoma, and who are ineligible for autologous stem cell transplant (ASCT) since August 05, 2020. It was granted accelerated FDA approval and EU conditional marketing authorization after the primary analysis of Phase II L-MIND study (NCT02399085) demonstrated safety and efficacy in this setting. To complement clinical data, it is important to assess real-world safety and effectiveness given the heterogeneity of routine clinical care. Furthermore, focusing on patients from racial and ethnic minorities, who may face challenges in receiving optimal access to care, may help to identify and address inequities. realMIND is an observational study of the real-world safety and effectiveness of tafasitamab + LEN for the treatment of R/R DLBCL among patients in the US by race and ethnicity. Using prospective and, where necessary, retrospective data collection, this non-interventional study will also provide a deeper understanding of treatment patterns of US patients with R/R DLBCL treated with tafasitamab, and its use in a real-world setting in terms of treatment duration, dose modifications, and post-tafasitamab + LEN combination partners and monotherapy use. Methods realMIND (NCT04981795) is a multicenter, observational, prospective and retrospective Phase IV trial-in-progress study targeting ≥100 US patients with R/R DLBCL treated with tafasitamab + LEN. To ensure diversity, Group 1 will enroll patients from racial and ethnic minorities (n≥50), while Group 2 will comprise non-Hispanic White (NHW) patients (n≥50) (Figure 1). Eligible patients are ≥18 years old with histologically confirmed R/R DLBCL, ≥1 prior line of treatment, and have initiated or will be initiating tafasitamab treatment (except in the context of an interventional study). Prospective data collection began at study sites in September 2021, and retrospective data (from study sites or vendor databases) may include patients with a tafasitamab start date (index date) from August 05, 2020, onwards. The primary endpoints include safety and effectiveness outcomes (Table 1). Serious adverse events (SAEs) and treatment-emergent adverse events (TEAEs) will be reported. Effectiveness will be assessed in terms of tumor response rates and time-to-event endpoints, while secondary endpoints include treatment line and dose information (Table 1). Patient data for this observational study will be collected by prospective follow-up of patients included at study sites, or by retrospective collection of data from patient records, at study sites or from vendor databases. Prospective and retrospective data will be analyzed separately, as well as pooled. No formal sample size calculation was performed due to the descriptive nature of the study and no hypothesis testing is planned. Study status The in-progress non-interventional realMIND study is expected to end by approximately December 2025, or earlier, when: ≥50 patients treated with tafasitamab + LEN have been recruited into each of Group 1 and Group 2 with either prospective or retrospective data collection; and all prospectively-followed patients have ≥6 months follow-up after starting tafasitamab treatment, or have discontinued from the study for any reason, whichever occurs earlier. The results are anticipated to describe the real-world safety and effectiveness of tafasitamab for R/R DLBCL in US patients, with a focus on underrepresented racial and ethnic minorities, to help optimize outcomes of treatment and identify opportunities for further studies.

The characteristics and regulations of adaptive designs from 2008 to 2020: An overview of European Medicines Agency approvals.

The aim of this study was to identify and characterize all European Medicines Agency (EMA) approvals derived from adaptive designs in clinical trials and to provide an update of the current status of these drugs. Relevant files were identified in the EMA database for annual reports for the period between 2008 and 2020 using a list of suitable keywords related to adaptive designs. We recorded trial characteristics from drug approvals and used Fisher exact test to compare the characteristics. A total of 1,054 EMA approvals were identified, and the percentage of EMA approvals planned with adaptive trial designs increased from 1.85% in the period 2008-2012 to 6.19% in between 2017-2020. A total of 41 approvals were identified among 91 original EMA files that contained adaptive designs. The types of adaptive designs used in clinical trials increased after 2017 where the most common type used was the most common (17/41). Most approvals (32/41) comprised pivotal trials, and most assessments had not been accelerated (38/41). Of 32 confirmatory trials planned with adaptive designs, the proportion of those with additional monitoring (AM) increased significantly (p<0.0001) from 0% in the 2008-2012 period to 90.48% in the 2017-2020 period. The percentage of approved antitumor drugs in approved drugs in ongoing clinical trials was 82.35%, compared to 20.83% in trials that were completed (p=0.0001). The proportion of drug approved but where clinical trials were still ongoing in companies requiring post-authorization safety studies (PASSs) or post-authorization efficacy studies (PAESs) or who were granted conditional marketing authorization (CMA) significantly differed from the group of drugs approved where clinical trials were completed (p=0.0230). A trend showing an increased number of EMA approvals related to adaptive designs was observed for the period from 2008 to 2020. Different types of adaptive trial designs could be encouraged for the designation of clinical trials, especially for antitumor drugs; meanwhile, more stringent monitoring regulations seemed to be conducted for ongoing trials of antitumor drugs with adaptive design.

Talquetamab: First Approval.

Talquetamab (talquetamab-tgvs; TALVEY®), a humanized, bispecific G-protein coupled receptor family C group 5 member D (GPRC5D)-directed CD3 T-cell engager, is being developed by Janssen for the treatment of multiple myeloma (MM). In early August 2023, talquetamab was granted accelerated approval in the USA for the treatment of adults with relapsed or refractory MM (RRMM) and in late August 2023, talquetamab was granted conditional marketing authorisation in the EU for the treatment of adult patients with RRMM. This article summarizes the milestones in the development of talquetamab leading to this first approval for RRMM.

Neurological side effects and drug interactions of antiviral compounds against SARS-CoV-2.

The COVID-19 pandemic, caused by severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2), rapidly spread across the globe. Tremendous efforts have been mobilized to create effective antiviral treatment options to reduce the burden of the disease. This article summarizes the available knowledge about the antiviral drugs against SARS-CoV-2 from a neurologist's perspective. We summarize neurological aspects of antiviral compounds against SARS-CoV-2 with full, conditional, or previous marketing authorization by the European Medicines Agency (EMA). Nirmatrelvir/ritonavir targets the SARS-CoV-2 3c-like protease using combinatorial chemistry. Nirmatrelvir/ritonavir levels are affected by medications metabolized by or inducing CYP3A4, including those used in neurological diseases. Dysgeusia with a bitter or metallic taste is a common side effect of nirmatrelvir/ritonavir. Molnupiravir is a nucleotide analog developed to inhibit the replication of viruses. No clinically significant interactions with other drugs have been identified, and no specific considerations for people with neurological comorbidity are required. In the meantime, inconsistent results from clinical trials regarding efficacy have led to the withdrawal of marketing authorization by the EMA. Remdesivir is a viral RNA polymerase inhibitor and interferes with the production of viral RNA. The most common side effect in patients with COVID-19 is nausea. Remdesivir is a substrate for CYP3A4. Neurological side effects and drug interactions must be considered for antiviral compounds against SARS-CoV-2. Further studies are required to better evaluate their efficacy and adverse events in patients with concomitant neurological diseases. Moreover, evidence from real-world studies will complement the current knowledge.

Marketing authorisations for unmet medical needs: A critical appraisal of regulatory pathways in the European Union

For unmet medical needs, the European Union has established fast-track regulatory pathways for ensuring patients’ access to essential treatments. It is the case of the Conditional Marketing Authorisation (CMA) and the Authorisation under “Exceptional Circumstances” (EXC), which can be granted even if the clinical part of a medicinal product’s dossier is not yet complete. The article aims to discuss the peculiarity of such regulatory pathways and assess the impact of their application on products’ market access and penetration. A review of the regulatory history of medicines authorised with EXC or CMA has been performed on European Institutional databases (e.g., EMA portal, Union Register). Excluding vaccines, 71 CMAs and 51 EXCs were granted in the EU from 2002 and 2006, respectively, to 2022. Most CMAs have been released for the treatment of different types of tumours, while most of EXCs for alimentary tract and metabolism diseases, especially in the paediatric population, addressing unmet medical needs. Therefore, both regulatory pathways are effective for placing on the market essential medicines, preserving the initial positive benefit-risk balance. However, on average, CMAs are converted into “normal” authorisations only after a time which is significantly longer than the provided one-year renewal period, suggesting that such a regulatory pathway is still far from optimized.

How does the vaccine approval procedure affect COVID-19 vaccination intentions?

People's willingness to vaccinate is critical to combating the COVID-19 pandemic. We devise a representative experiment to study how the design of the vaccine approval procedure affects trust in newly developed vaccines and consequently public attitudes towards vaccination. Compared to an Emergency Use Authorization, choosing the more thorough Conditional Marketing Authorization approval procedure increases vaccination intentions by 13 percentage points. The effects of the increased duration of the approval procedure are positive and significant only for Emergency Use Authorization. Treatment effects do not differ between relevant subgroups, such as respondents who had (did not have) COVID-19, or between vaccinated and unvaccinated respondents. Increased trust in the vaccine is the key mediator of treatment effects on vaccination intentions.

Glofitamab: First Approval.

Glofitamab (Columvi®) is a CD20 × CD3 T-cell-engaging bispecific monoclonal antibody being developed by Roche for the treatment of B-cell non-Hodgkin lymphomas, including diffuse large B-cell lymphoma (DLBCL). Glofitamab received its first approval (with conditions) on 25 March 2023, in Canada, for the treatment of adult patients with relapsed or refractory DLBCL not otherwise specified, DLBCL arising from follicular lymphoma, or primary mediastinal B-cell lymphoma, who have received two or more lines of systemic therapy and are ineligible to receive or cannot receive CAR T-cell therapy or have previously received CAR T-cell therapy. Glofitamab is also under regulatory review for relapsed or refractory DLBCL in the EU and USA and in April 2023 received a positive opinion recommending the granting of a conditional marketing authorization in the EU. Clinical development of glofitamab, as a monotherapy and in combination with other agents for the treatment of non-Hodgkin lymphomas, is continuing worldwide. This article summarizes the milestones in the development of glofitamab leading to this first approval for relapsed or refractory DLBCL.

Comparison of novel oncology drugs that received dual approval from the US accelerated approval and EU conditional marketing authorisation pathways, 2006–2021: a cross-sectional study

ObjectiveWe aimed to provide insight into differences in drug review decisions made by the US Food and Drug Administration’s (FDA) accelerated approval (AA) pathway and the European Medicines Agency’s (EMA)...

Conditional early approval for new drug applications in Japan: Current and emerging issues.

Conditional early approval for new drug applications in Japan: Current and emerging issues.

European Conditional Marketing Authorization in a Rapidly Evolving Treatment Landscape: A Comprehensive Study of Anticancer Medicinal Products in 2006-2020.

Since 2006, the European conditional marketing authorization (CMA) aims to facilitate timely patient access to medicinal products for which there is an unmet medical need by accepting less comprehensive data than normally required. The granting of CMA requires a positive benefit-risk balance, unmet medical needs to be fulfilled, likely submission of comprehensive data postauthorization, and the benefit of immediate availability to outweigh the risks of data noncomprehensiveness. Since its first use, more than half of all CMAs represent (hemato-)oncology indications. Therefore, we aimed to investigate the conditions in which CMA has been applied for anticancer medicinal products and whether they have changed over time. We retrospectively assessed the European public assessment reports of the 30 anticancer medicinal products granted CMA in 2006-2020 (51% of all 59 CMAs). Comparison of 2006-2013 to 2014-2020 highlighted increased proportions of proactively requested CMAs (+40%), medicinal products that addressed unmet medical needs by providing a major therapeutic advantage over authorized treatments (+38%), and orphan designated indications (+32%). In contrast, it showed decreased proportions of medicinal products for which a scientific advisory group was consulted (-55%) and phase III randomized controlled trial data were available (-38%). This suggests that applicants and the European Medicines Agency have learned how to use the CMA as a regulatory tool, among others, through better planning and proactive interaction. However, the increasing number of granted CMAs complicates the establishment of unmet medical need and the benefit-risk balance, especially in crowded indications and when only phase II uncontrolled trials are available.

Analysis of participant-reported adverse events following the first dose of inactivated SARS-Cov-2 vaccine (TURKOVAC™) through telephone survey in Türkiye

Background/Objective(s)/Introduction TURKOVAC™ is a whole-virion inactivated COVID-19 vaccine, which was developed and recently granted emergency use authorization (conditional marketing authorization) in Türkiye. The objective of this study is to assess the spectrum and the distribution of adverse events reported following the administration of the first 150,000 doses as primary and booster vaccine doses in 22 state hospitals of 17 provinces in Türkiye. Patients/Materials and methods In this cohort study, a verbal survey was conducted via telephone calls between 10 January and 17 January 2022, utilizing a structured questionnaire algorithm on a sample group of 20,000 persons on the third- and seventh-days following vaccination. The algorithm consisted of two parts focusing on both systemic and local adverse effects. Other adverse events reported by the participants were also recorded. 6023 people and 5345 people agreed to participate in the telephone survey on the 3rd- and 7th- days of having received the first dose of the vaccine, respectively. Results Thirty-six-point-six percent of the participants on the 3rd day and 22.5% of the participants on the 7th day reported any adverse event following the first dose of the vaccine. On both follow-up days, the most commonly reported (29.7% for Day 3 and 13.1% for Day 7) adverse events were on the injection site. Among the local adverse events, the most frequently reported one was the pain on the injection site (27.9% for Day 3 and 12.4% for Day 7), induration (4.8% for Day 3 and 2.7% for Day 7) and swelling (3.5% for Day 3 and 2.0% for Day 7). Fatigue/weakness (9.6% for Day 3 and 8.3% for Day 7) and headache (7.9% for Day 3 and 8.0% for Day 7) were the most frequent systemic adverse events. Younger age, vaccine dose, and female sex were associated with having any adverse event and pain (on the injection site). Female sex was associated with more swelling (on the injection site), induration (on the injection site), fever, and a higher impact on daily living. Conclusion(s) In this study, we conducted a rapid assessment of adverse events following the first dose of the TURKOVAC vaccine. The vaccine appears to have a good safety profile in the first 7 days following vaccination. Younger age, vaccine dose, and female sex are associated with any adverse event and pain (on the injection site). These results present valuable information for the community and may contribute to increasing vaccine confidence. KEY MESSAGES As a whole-virion inactivated SARS-CoV-2 vaccine, the TURKOVAC™ vaccine, which has a favorable safety profile, can be an alternative to other COVID-19 vaccines including mRNA and viral vector vaccines.

Self-Reported Allergic Adverse Events Following Inactivated SARS-CoV-2 Vaccine (TURKOVAC™) among General and High-Risk Population.

TURKOVAC™ is a whole-virion inactivated COVID-19 vaccine which was developed and granted emergency use and conditional marketing authorization in December 2021 in Türkiye. The objective of this study is to assess the distribution and the severity of allergic adverse events following the administration of the vaccine as the primary or the booster dose in 15 provinces in Türkiye. In this cohort study, between February and May 2022, in the selected 15 provinces having an adequate number of health care personnel in the community health centers to conduct the study, 32,300 people having the first, the second, or the booster dose of the vaccine were invited to the survey. A total of 29,584 people voluntarily agreed to participate to the survey and were given a structured questionnaire after a minimum of 10 days following the vaccination. In our study, only 0.5% of the participants (142 persons) reported to experience any allergic reaction, and 12 of them (8.5%) reported to be given medical treatment in a health center. Male predominance (55.6%) was observed among participants reported to experience any allergic reaction. No hospitalization was recorded. Of the participants, 4.4% (1315 people) reported to have a history of allergy. The most reported allergens were drugs. Among the participants without a known history of allergy (n = 28,269), 0.4% of them (110 people) reported to experience an allergic reaction following the vaccination, and 5.4% of the allergic reactions (six people) were reported to be treated in a health center. The percentage of the participants given any medical treatment among the participants without a known history of allergy is 0.02%. No immediate or anaphylactic reaction was reported. Among the participants with a known history of allergy (n = 1315), 32 people (2.4% of them) reported to experience an allergic reaction following the vaccination, and 18.7% of the allergic reactions (six people) were reported to be prescribed a medical treatment. The percentage of the participants given any medical treatment among the participants with a known history of allergy is 0.4%. A known history of allergy increased the risk of having an allergic experience by approximately six times following vaccination. As a whole-virion inactivated SARS-CoV-2 vaccine, the TURKOVAC™ vaccine, with a low allergic reaction-related adverse event profile, can be an alternative to other COVID-19 vaccines.

Launch sequencing of pharmaceuticals with multiple therapeutic indications: evidence from seven countries

BackgroundNew medicines are increasingly being identified as efficacious across multiple indications. The impact of current pricing and reimbursement policies on launch decisions across these indications remains unclear.ObjectiveThis paper, first, maps marketing authorisation and HTA coverage recommendation sequences of multi-indication medicines across Germany, France, England, Scotland, Canada, Australia, and the USA, and, second, evaluates the clinical characteristics, clinical development time and coverage recommendation time of multi-indication medicines, drawing comparisons between the first and subsequent indications of an approved molecule.MethodsMedicine approvals by the Food and Drug Administration between 2009–2019 were screened to identify multi-indication products with approved oncology indications. Data on clinical trial characteristics, clinical performance and HTA outcomes were extracted from publicly available regulatory approval and HTA reports.ResultsRelative to subsequent indications, first indications were more likely to receive conditional marketing authorisation, have an orphan designation, have a single arm phase II pivotal trial and lower MCBS score. Subsequent indications had faster HTA coverage recommendation times in England and Canada. While the majority of first indications received HTA coverage recommendations across all settings, the proportion of subsequent indications with HTA coverage recommendations was lower and uptake varied considerably across settings.ConclusionsDiscordance in the value of first versus subsequent indications can pose major challenges in systems that define price based on the initial indication. Current pricing and reimbursement systems generate significant fragmentation in the approval and availability of multi-indication products across settings.

Clinical Treatment Guidelines for Tafasitamab Plus Lenalidomide in Patients with Relapsed or Refractory Diffuse Large B-Cell Lymphoma.

Diffuse large B-cell lymphoma (DLBCL) accounts for approximately 24% of new cases of B-cell non-Hodgkin lymphoma in the US each year. Up to 50% of patients relapse or are refractory (R/R) to the standard first-line treatment option, R-CHOP. The anti-CD19 monoclonal antibody tafasitamab, in combination with lenalidomide (LEN), is an NCCN preferred regimen for transplant-ineligible patients with R/R DLBCL and received accelerated approval in the US (July 2020) and conditional marketing authorization in Europe (August 2021) and other countries, based on data from the L-MIND study. The recommended dose of tafasitamab is 12 mg/kg by intravenous infusion, administered in combination with LEN 25 mg for 12 cycles, followed by tafasitamab monotherapy until disease progression or unacceptable toxicity. Tafasitamab + LEN is associated with durable responses in patients with R/R DLBCL. The majority of clinically significant treatment-associated adverse events are attributable to LEN and can be managed with dose modification and supportive therapy. We provide guidelines for the management of patients with R/R DLBCL treated with tafasitamab and LEN in routine clinical practice, including elderly patients and those with renal and hepatic impairment, and advice regarding patient education as part of a comprehensive patient engagement plan. Our recommendations include LEN administration at a reduced dose if required in patients unable to tolerate the recommended dose. No dose modification is required for tafasitamab in special patient populations.