Conditional Approval Research Articles

Pharmacokinetics (PK) and pharmacodynamics (PD) in First-MIND: A phase Ib, open-label, randomized study of tafasitamab (tafa) ± lenalidomide (LEN) in addition to R-CHOP in patients (pts) with newly diagnosed diffuse large B-cell lymphoma (DLBCL).

e19553 Background: The combination of tafa + LEN has accelerated approval in the United States (2020) and conditional approval in Canada and Europe (2021) for R/R DLBCL in ASCT-ineligible adult pts. A tolerable safety profile for R-CHOP + tafa ± LEN in pts with newly diagnosed DLBCL in the Phase Ib First-MIND study (NCT04134936) was previously reported, with numerically superior efficacy for R-CHOP + tafa + LEN (ASH 2021; #3556). We report PK, PD, and immunogenicity of R-CHOP + tafa ± LEN in this first line setting. Methods: Eligible pts ≥18 years with treatment-naïve DLBCL, IPI 2–5, and ECOG PS 0–2 were randomized 1:1 to either six 21-day (D) cycles (C) of R-CHOP (R-CHO, D1; P, D1–5) + tafa (12 mg/kg IV, D1, 8, 15) (Arm A) or R-CHOP + tafa + LEN (25 mg orally, D1–10) (Arm B). Secondary endpoints included tafa serum conc and number and percentage of pts developing anti-tafa Abs. Exploratory endpoints included natural killer (NK) cell, T-cell, and B-cell count in peripheral blood. Results: Data cut-off: 13 March 2021 for safety analysis, incl. ≥1 month follow-up after EoT visit for all pts; 15 September 2021 for efficacy. Tafa serum conc reached steady state by C3 (geometric mean trough conc: Arm A, 186.40–216.55 µg/mL; Arm B, 171.77–201.54 µg/mL) and steadily declined after treatment completion. Anti-tafa Abs were detected in 1/65 (1.5%) pts. This pt showed pre-existing tafa Abs at baseline, which decreased during treatment. Median NK cell count decreased from baseline at C1D8 but was at baseline or higher levels by EoT visit (Arm A) and C1D15 (Arm B; Table). T-cell count decreased from baseline at C1D8 in both arms but was at baseline level or higher by C1D15 (Arm A) and EoT visit (Arm B). Median B-cell count decreased from baseline to 0 cells/μL (Arm A, C1D15; Arm B, C1D8); at 6-month follow-up after EoT visit, B-cell count had recovered to measurable levels in ̃50% of pts. Conclusions: Tafa serum conc reached and maintained a therapeutic dose level in this first-line regimen and declined in line with known tafa half-life (̃16 days) after treatment completion; tafa levels were comparable between the two treatment arms. No pt developed treatment-induced or treatment-boosted anti-tafa Abs. Median NK-cell, T-cell, and B-cell counts were comparable between treatment arms in all cycles. Clinical trial information: NCT04134936. [Table: see text]

Therapeutic news in Alzheimer’s disease: soon a disease-modifying therapy?

Research on disease-modifying treatments for Alzheimer’s disease has resulted in a series of failures over the past 20 years. However, in the last 4 years, five molecules have shown significant effects in phase II or III trials on clinical endpoints (i.e., slowing of cognitive decline). Among these five molecules, three are anti-amyloid immunotherapies: aducanumab, donanemab, and lecanemab responsible for a significant clearance of cerebral amyloid deposits. These results are still awaiting confirmation in order to put an end to the controversy surrounding the Food and Drug Administration’s decision to give conditional approval to aducanumab, which is considered premature by many specialists. Confirmation is also necessary to assess the benefit (magnitude of the slowing of decline) and risk (edema and cerebral hemorrhage induced by these treatments) balance of these molecules, which appears to be so far questionable after 18 months. Masitinib, a treatment whose probable mechanism of action is neuroinflammation, has also shown positive effects that need to be confirmed. Treatments targeting the tau protein are less advanced but weak signals are emerging from immunotherapies in the moderate stages of the disease (semorinemab). There is renewed hope for patients since it may not be unreasonable that these disease-modifying therapies will be part of the French therapeutic arsenal within the next five years.

2. Legislation of SAKIGAKE Designation System and Conditional Early Approval System of New Drug

2. Legislation of SAKIGAKE Designation System and Conditional Early Approval System of New Drug

Effective protection of ZF2001 against the SARS-CoV-2 Delta variant in lethal K18-hACE2 mice

To investigate the protective efficacy and mechanism of ZF2001 (a protein subunit vaccine with conditional approval in China) to SARS-CoV-2 Delta variant-induced severe pneumonia, the lethal challenge model of K18-hACE2 transgenic mice was used in this study. An inactivated-virus vaccine at the research and development stage (abbreviated as RDINA) was compared to ZF2001. We found that ZF2001 and RDINA could provide the protective effect against Delta variant-induced severe cases, as measured by the improved survival rates, the reduced virus loads, the alleviated lung histopathology and the high neutralizing antibody geomean titers, compared to aluminum adjuvant group. To prevent and control Omicron or other variant epidemics, further improvements in vaccine design and compatibilities with the novel adjuvant are required to achieve better immunogenicity.

Therapy Developments in Alzheimer's Disease

The development of new therapies to treat Alzheimer's disease is a focus of global drug discovery. Research is being conducted into more potent therapies for symptomatic treatment, particularly for behavioral disturbances, but also into drugs that intervene in the pathophysiology of the disease, with the aim of halting or at least slowing the progression of the disease. To this end, the focus of identifying people with Alzheimer's disease is shifting to stages of pre-dementia such as that of Mild Cognitive Impairment (MCI), almost synonymous with prodromal AD, or even to asymptomatic stages. Currently, passive immunization using monoclonal antibodies against Aβ42 has shown the most encouraging results. However, it has not been possible to demonstrate statistically significant differences on the primary target parameters in multiple completed pivotal trials. The anti-amyloid antibody aducanumab received conditional preliminary approval in the U.S. based on amyloid reduction; approval for its use in Europe is an ongoing process. Current pharmacological treatments of Alzheimer's disease offer limited symptomatic benefit. No drugs to delay progression of the disease is yet on the market in Germany. Therefore, it is recommended that patients, especially those in pre-dementia stages or at the onset of Alzheimer's disease, be encouraged to participate in clinical trials in order to help develop new drugs that are more effective in the treatment of this disease and that can then benefit many more patients in the future.

Are Environmental Impact Assessments effectively addressing the biodiversity issues in Brazil?

Environmental Impact Assessment (EIA) is the main legal instrument for controlling the impacts of human development projects in many countries, including Brazil. However, the way biodiversity is addressed as part of the EIA process has been discussed around the world, with concerns raised about poor-quality studies and a failure to achieve evidence-based decisions. To explore these concerns, we evaluated: 1) the quality of baseline biodiversity studies used to inform EIAs; 2) the predictions made about the impacts of the development on biodiversity and their relationship to baseline studies; and 3) the relevance of the quality of these baseline studies and the predicted impacts on the decisions made by the relevant licensing agency. To do this, we collected and analyzed EIAs associated with 78 development proposals from the State of Minas Gerais in southeastern Brazil, using medium and large-sized terrestrial mammals as indicators. We found baseline studies were basic and lacking scientific rigor, with no guiding questions or hypotheses, few ecological analyses, and that they omitted essential information about study design. The poor quality of biodiversity information in most baseline studies led to significant deficiencies in impact reports, with inadequate descriptions of the likely impacts of developments on biodiversity. Finally, we found that the shortcomings in both baseline studies and impact assessment reports had no relationship to decision-making, with poor quality EIAs still obtaining environmental licenses, which is alarming. Only in two decisions were cited some shortcoming of baseline studies as a reason for conditional approval. We conclude by providing a range of recommendations to help promote evidence-based decision-making in EIAs and improve the quality and transparency of the biodiversity data produced throughout Strategic Environmental Assessment (SEA) and EIA.

Tafasitamab Plus Lenalidomide Versus 3 Rituximab-Based Treatments for Non-Transplant Eligible Relapsed/Refractory Diffuse Large B-Cell Lymphoma: A Matching-Adjusted Indirect Comparison.

IntroductionTafasitamab plus lenalidomide (TAFA + LEN) received accelerated US Food and Drug Administration approval and conditional European Medicines Agency approval for treatment of adults with relapsed or refractory diffuse large B-cell lymphoma (R/R DLBCL) not eligible for autologous stem cell transplant. This study investigates the relative efficacy of TAFA + LEN versus comparator treatments.MethodsMatching-adjusted indirect comparisons (MAICs) of TAFA + LEN were performed using data from L-MIND, and comparator studies assessing rituximab-based combination therapies, including polatuzumab vedotin + bendamustine + rituximab (POLA + BR) bendamustine + rituximab (BR), and gemcitabine + oxaliplatin + rituximab (R-GEMOX) to provide relative efficacy estimates for overall survival (OS), progression-free survival (PFS), duration of response (DOR), objective response rate (ORR), and complete response rate (CRR). Patient-level data from L-MIND were weighted to match reported distributions of clinically validated prognostic factors and effect modifiers in comparator trials. MAIC results versus multiple BR studies were pooled using meta-analysis.ResultsMAICs were feasible versus POLA + BR and BR. Compared to POLA + BR, TAFA + LEN was associated with significantly longer DOR [hazard ratio (HR) 0.34 (95% CI 0.12, 0.98); p = 0.045]. Due to concerns about the proportional hazard assumption for OS and PFS, separate HRs were estimated before and after 4 months of follow-up. OS after 4 months, was significantly greater for TAFA + LEN versus POLA + BR [HR 0.41 (95% CI 0.19, 0.90); p = 0.026]. Compared with BR, TAFA + LEN was associated with significantly improved OS [GO29365 comparator trial: HR 0.39 (95% CI 0.18, 0.82); p = 0.014], PFS (pooled data: HR 0.39 (95% CI 0.29, 0.53); p < 0.001], DOR [pooled data: HR 0.35 (95% CI 0.25, 0.50); p < 0.001], and CRR [pooled data: odds ratio 2.43 (95% CI 1.33, 4.41); p = 0.004].ConclusionIn MAIC analyses, treatment with TAFA + LEN for R/R DLBCL provided better OS and PFS outcomes than standard treatment regimens. Validation from large, randomized, phase 3 clinical trials is required to confirm these results.Supplementary InformationThe online version contains supplementary material available at 10.1007/s12325-022-02094-5.

Initial and supplementary indication approval of new targeted cancer drugs by the FDA, EMA, Health Canada, and TGA

SummaryBackground. Previous research focused on the clinical evidence supporting new cancer drugs’ initial US Food and Drug Administration (FDA) approval. However, targeted drugs are increasingly approved for supplementary indications of unknown evidence and benefit. Objectives. To examine the clinical trial evidence supporting new targeted cancer drugs’ initial and supplementary indication approval in the US, EU, Canada, and Australia. Data and Methods. 25 cancer drugs across 100 indications were identified with FDA approval between 2009–2019. Data on regulatory approval and clinical trials were extracted from the FDA, European Medicines Agency (EMA), Health Canada (HC), Australian Therapeutic Goods Administration (TGA), and clinicaltrials.gov. Regional variations were compared with χ2-tests. Multivariate logistic regressions compared characteristics of initial and supplementary indication approvals, reporting adjusted odds ratios (AOR) with 95% confidence intervals (CI). Results. Out of 100 considered cancer indications, the FDA approved 96, the EMA 92, HC 86, and the TGA 83 (83%, p < 0.05). The FDA more frequently granted priority review, conditional approval, and orphan designations than other agencies. Initial approvals were more likely to receive conditional / accelerated approval (AOR: 2.69, 95%CI [1.07–6.77], p < 0.05), an orphan designation (AOR: 3.32, 95%CI [1.38–8.00], p < 0.01), be under priority review (AOR: 2.60, 95%CI [1.17–5.78], p < 0.05), and be monotherapies (AOR: 5.91, 95%CI [1.14–30.65], p < 0.05) than supplementary indications. Initial indications’ pivotal trials tended to be shorter (AOR per month: 0.96, 95%CI [0.93–0.99], p < 0.05), of lower phase design (AOR per clinical phase: 0.28, 95%CI [0.09–0.85], p < 0.05), and enroll more patients (AOR per 100 patients: 1.19, 95%CI [1.01–1.39], p < 0.05). Conclusions. Targeted cancer drugs are increasingly approved for multiple indications of varying clinical benefit. Drugs are first approved as monotherapies in rare diseases with a high unmet need. Whilst expedited regulatory review incentivizes this prioritization, indication-specific safety, efficacy, and pricing policies are necessary to reflect each indication’s differential clinical and economic value.

Implications of immune cells in oncolytic herpes simplex virotherapy for glioma.

Despite current progress in treatment, glioblastoma (GBM) remains a lethal primary malignant tumor of the central nervous system. Although immunotherapy has recently achieved remarkable survival effectiveness in multiple malignancies, none of the immune checkpoint inhibitors (ICIs) for GBM have shown anti-tumor efficacy in clinical trials. GBM has a characteristic immunosuppressive tumor microenvironment (TME) that results in the failure of ICIs. Oncolytic herpes simplex virotherapy (oHSV) is the most advanced United States Food and Drug Administration-approved virotherapy for advanced metastatic melanoma patients. Recently, another oHSV, Delytact®, was granted conditional approval in Japan against GBM, highlighting it as a promising treatment. Since oncolytic virotherapy can recruit abundant immune cells and modify the immune TME, oncolytic virotherapy for immunologically cold GBM will be an attractive therapeutic option for GBM. However, as these immune cells have roles in both anti-tumor and anti-viral immunity, fine-tuning of the TME using oncolytic virotherapy will be important to maximize the therapeutic efficacy. In this review, we discuss the current knowledge of oHSV, with a focus on the role of immune cells as friend or foe in oncolytic virotherapy.

Multicancer Early Detection Technologies: A Review Informed by Past Cancer Screening Studies.

More than 75% of cancer-related deaths occur from cancers for which we do not screen. New screening liquid biopsies may help fill these clinical gaps, although evidence of benefit still needs to be assessed. Which lessons can we learn from previous efforts to guide those of the future? Screening trials for ovarian, prostate, pancreatic, and esophageal cancers are revisited to assess the evidence, which has been limited by small effect sizes, short duration of early-stage disease relative to screening frequency, study design, and confounding factors. Randomized controlled trials (RCT) to show mortality reduction have required millions of screening-years, two-decade durations, and been susceptible to external confounding. Future RCTs with late-stage incidence as a surrogate endpoint could substantially reduce these challenges, and clinical studies demonstrating safety and effectiveness of screening in high-risk populations may enable extrapolation to broader average-risk populations. Multicancer early detection tests provide an opportunity to advance these practical study designs. Conditional approvals based on RCTs with surrogate endpoints, contingent upon real world evidence generation and continuation of trials to definitive endpoints, may lower practical barriers to innovation in cancer screening and enable greater progress.

Aldafermin in non-alcoholic steatohepatitis: a cautionary tale for trial design

Non-alcoholic fatty liver disease (NAFLD) is the most prevalent liver disease worldwide with an increasing burden in terms of morbidity, mortality, and health-care costs.1 As there are still no approved pharmacological treatments, NAFLD represents an area of unmet clinical need, with the potential of conditional regulatory approval of investigational medicinal products based on improvement of surrogate endpoints. There are several drugs in phase 2 and 3 trials and the expectation is that there will be licensed treatments in the next 2–5 years.

Electronic Health Record-Triggered Research Infrastructure Combining Real-world Electronic Health Record Data and Patient-Reported Outcomes to Detect Benefits, Risks, and Impact of Medication: Development Study.

BackgroundReal-world data from electronic health records (EHRs) represent a wealth of information for studying the benefits and risks of medical treatment. However, they are limited in scope and should be complemented by information from the patient perspective.ObjectiveThe aim of this study is to develop an innovative research infrastructure that combines information from EHRs with patient experiences reported in questionnaires to monitor the risks and benefits of medical treatment.MethodsWe focused on the treatment of overactive bladder (OAB) in general practice as a use case. To develop the Benefit, Risk, and Impact of Medication Monitor (BRIMM) infrastructure, we first performed a requirement analysis. BRIMM’s starting point is routinely recorded general practice EHR data that are sent to the Dutch Nivel Primary Care Database weekly. Patients with OAB were flagged weekly on the basis of diagnoses and prescriptions. They were invited subsequently for participation by their general practitioner (GP), via a trusted third party. Patients received a series of questionnaires on disease status, pharmacological and nonpharmacological treatments, adverse drug reactions, drug adherence, and quality of life. The questionnaires and a dedicated feedback portal were developed in collaboration with a patient association for pelvic-related diseases, Bekkenbodem4All. Participating patients and GPs received feedback. An expert meeting was organized to assess the strengths, weaknesses, opportunities, and threats of the new research infrastructure.ResultsThe BRIMM infrastructure was developed and implemented. In the Nivel Primary Care Database, 2933 patients with OAB from 27 general practices were flagged. GPs selected 1636 (55.78%) patients who were eligible for the study, of whom 295 (18.0% of eligible patients) completed the first questionnaire. A total of 288 (97.6%) patients consented to the linkage of their questionnaire data with their EHR data. According to experts, the strengths of the infrastructure were the linkage of patient-reported outcomes with EHR data, comparison of pharmacological and nonpharmacological treatments, flexibility of the infrastructure, and low registration burden for GPs. Methodological weaknesses, such as susceptibility to bias, patient selection, and low participation rates among GPs and patients, were seen as weaknesses and threats. Opportunities represent usefulness for policy makers and health professionals, conditional approval of medication, data linkage to other data sources, and feedback to patients.ConclusionsThe BRIMM research infrastructure has the potential to assess the benefits and safety of (medical) treatment in real-life situations using a unique combination of EHRs and patient-reported outcomes. As patient involvement is an important aspect of the treatment process, generating knowledge from clinical and patient perspectives is valuable for health care providers, patients, and policy makers. The developed methodology can easily be applied to other treatments and health problems.

Hurdles to the Adoption of Gene Therapy as a Curative Option for Transfusion-Dependent Thalassemia.

Beta-thalassemia is one of the most common monogenic disorders. Standard treatment of the most severe forms, i.e., transfusion-dependent thalassemia (TDT) with long-term transfusion and iron chelation, represents a considerable medical, psychological, and economic burden. Allogeneic hematopoietic stem cell transplantation from an HLA-identical donor is a curative treatment with excellent results in children. Recently, several gene therapy approaches were evaluated in academia or industry-sponsored clinical trials as alternative curative options for children and young adults without an HLA-identical donor. Gene therapy by addition of a functional beta-globin gene using self-inactivating lentiviral vectors in autologous stem cells resulted in transfusion independence for a majority of TDT patients across different age groups and genotypes, with a current follow-up of multiple years. More recently, promising results were reported in TDT patients treated with autologous hematopoietic stem cells edited with the clustered regularly interspaced short palindromic repeats-Cas9 technology targeting erythroid BCL11A expression, a key regulator of the normal switch from fetal to adult globin production. Patients achieved high levels of fetal hemoglobin allowing for discontinuation of transfusions. Despite remarkable clinical efficacy, 2 major hurdles to gene therapy access for TDT patients materialized in 2021: (1) a risk of secondary hematological malignancies that is complex and multifactorial in origin and not limited to the risk of insertional mutagenesis, (2) the cost—even in high-income countries—is leading to the arrest of commercialization in Europe of the first gene therapy medicinal product indicated for TDT despite conditional approval by the European Medicines Agency.

Aducanumab Therapy to Treat Alzheimer's Disease: A Narrative Review.

Background Aducanumab, a new monoclonal antibody that targets β-amyloid aggregates, has been granted conditional approval by the U.S. FDA for treatment of mild Alzheimer's disease (AD). The approval of this drug without a confirmed significant clinical impact has resulted in several debates. Objective In this narrative review, aducanumab approval-related controversy, the drug's pharmacokinetics and pharmacodynamic characteristics, evidence from the efficacy and safety trials of aducanumab, implications of the drug approval, and the future directions in the management of patients with AD are summarized. Methods Using relevant keywords, Google Scholar, Web of Science, and MEDLINE databases and manufacturer's website were searched. Results Infusion of aducanumab at a higher dose resulted in a modest slowing of cognitive decline among patients with mild cognitive impairment or early-onset AD dementia. The drug however can cause amyloid-related imaging abnormalities. Due to modest impact on cognition, the use of this drug by patients with AD will most likely be limited. The manufacturer is required to run an extended phase IIIb trial to verify the benefit of this drug. Access to therapy requires a careful selection of patients and periodic monitoring to ensure the optimal use of the drug. Conclusion Despite the limitations, aducanumab is the first disease-modifying therapy approved for the treatment of AD. Aducanumab addresses a part of the pathogenesis of AD; therefore, drugs that can act on multiple targets are needed. In addition, the search for preventive strategies, validated plasma-based assays, and newer drugs for AD, which are effective, safe, convenient, and affordable, is vital.

Policy Updates on Access to and Affordability of Innovative Medicines in China

IntroductionIn China, efforts to qualify innovative medical products for reimbursement used to be subject to substantial delays after regulatory approval due to fiscal and bureaucratic barriers. In this review, we surveyed the Chinese government’s most recent initiatives to improve access to innovative medicines from both the regulatory and the reimbursement aspects, which not only accelerated the launching of drugs in the Chinese market but also expanded the reimbursement coverage of such products. We also provided a discussion of the current challenges. Areas CoveredWe provided a comprehensive review of the updates in China’s national reimbursement listing policies of medicines. Expert OpinionAs the most recognized regulatory shortcuts, priority and conditional approvals have expedited the authorization of many innovative medicines. In addition, the national negotiation process was institutionalized to enable timely access to innovative medicines through the National Reimbursement Drug List, leading examples of which were new anticancer drugs. Other impactful reimbursement policies in recent years included dynamic updates of the National Reimbursement Drug List, manufacturer-initiated reimbursement coverage applications, and parallel fund robustness tests and pharmacoeconomic analyses for price estimation. Recent administrative efforts have substantially improved the access to and affordability of innovative medicines in China. Nevertheless, standardized and transparent evidence appraisal processes need to be established for informed decision making in the future.

Bile acid metabolism and FXR-mediated effects in human cholestatic liver disorders.

Intrahepatic cholestasis is the main feature of a group of liver diseases that are characterized by hepatic and systemic accumulation of bile acids due to impaired excretion of bile, based on inflammation of intrahepatic and extrahepatic bile ducts or dysfunction of hepatobiliary transport proteins. The nuclear bile acid sensor farnesoid X receptor (FXR) is central for the regulation of bile acid turnover, including synthesis, hepatic excretion and intestinal and hepatic uptake. Several drugs targeting FXR have been developed for the treatment of cholestatic liver diseases, and so far one of them has been granted conditional approval. In this review, we will discuss the current knowledge and the clinical and experimental data available on agents affecting FXR and bile acid turnover.

Feasibility of a "Salvage Regimen" Using Home-based Intravenous Meropenem Therapy With a Delamanid/Bedaquilline Containing Regimen in the Management of MDR/XDR Pediatric Tuberculosis.

The prevalence of multidrug resistant (MDR) tuberculosis (TB) with additional resistance to fluoroquinolones or second-line injectables (MDRFQ/SLI)/extensively drug-resistant TB (XDR-TB) in children is high in Mumbai. There are limited therapeutic options available in management of such children. Carbapenems, although approved for this indication, requires 2 to 3 daily injections, which are cumbersome. Bedaquilline (Bdq) and Delamanid (Dlm), the new antitubercular drugs still remain inaccessible to this subset of patients caused by conditional approvals. Hence, newer strategies to combat MDRFQ/SLI/XDR-TB needs to be explored. To study feasibility and interim outcomes of a "salvage regimen" using home-based carbapenem therapy through peripherally inserted central catheter as part of a longer (18-20 months) optimized background regimen including Dlm or Bdq or both in pediatric MDRFQ/SLI/XDR-TB patients who failed a standard MDR-TB regimen under the National Tuberculosis Elimination Programme in Mumbai, India. Retrospective descriptive analysis study. National Tuberculosis Elimination Programme medical records of all MDRFQ/SLI/XDR-TB patients enrolled at the pediatric TB clinic at BJ Wadia Hospital for Children, Mumbai who were initiated on such "salvage regimen" during the period between April 2018 and December 2020 were retrospectively studied. Treatment outcomes and adverse events were described. Of the 15 patients enrolled, mean age of the patient population was 12.53 ± 2.47 years and the female:male ratio was 13:2. Seven patients had XDR-TB while 8 patients had MDRFQ/SLI. Most common adverse event noted was dyselectrolytemia (3 patients). Catheter-related complications were reported in 5 patients and included catheter blockage, leak, and thrombosis. Sputum culture conversion was reported in all of the patients. One child mortality was reported and 2 patients were lost to follow up during study period. Home-based meropenem therapy using peripherally inserted central catheter is feasible with few adverse effects. This can be a promising strategy in the management of MDRFQ/SLI/XDR-TB when an effective oral regimen cannot be otherwise constituted and needs to be explored further.

Conditional Drug Approval as a Path to Market for Oncology Drugs in Canada: Challenges and Recommendations for Assessing Eligibility and Regulatory Responsiveness.

International drug regulators use conditional drug approval mechanisms to facilitate faster patient access to drugs based on a lower evidentiary standard typically required of drug approvals. Faster and earlier access is justified by limiting eligibility to drugs intended for serious and life-threatening diseases and by requiring post-market evidence collection to confirm clinical benefit. One such mechanism in Canada, the Notice of Compliance with Conditions (NOC/c) policy, was introduced in 1998. Today, most of the drugs approved under the NOC/c policy are for oncology indications. We analyze oncology drugs approvals under the NOC/c policy to inform discussions of two tradeoffs applied to conditional drug approvals, eligibility criteria and post-market evidence. Our analysis informs recommendations for Canada's proposed regulatory reforms approach to conditional approvals pathways. Our analysis demonstrates that under the current policy, eligibility criteria are insufficiently defined, resulting in their inconsistent application by Health Canada. Regulatory responsiveness to post-market evidence from post-market clinical trial and foreign jurisdiction regulatory decisions is slow and insufficient. In the absence of sufficient regulatory responsiveness, physicians and patients must make clinical decisions without the benefit of the best available evidence. Together, our analysis of the two core tradeoffs in Canada's conditional drug approval provides insight to inform the further development of Canada's proposed agile regulatory approach to drugs and devices that will expand the use of terms and conditions.

Accelerated Approval Is Not Conditional Approval

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FDA Accelerated Approval for Malignant Hematology and Oncology Indications in the Canadian Environment.

Accelerated approval (AA) by the FDA enables earlier access to promising new therapies. Health Canada has a similar process. Canada implemented a national health technology assessment (HTA) for reimbursement decisions in 2011. This study evaluated regulatory and funding timelines and decisions for FDA AA cancer therapies in Canada. The FDA’s AA of malignant hematology and oncology from January 2000–December 2019 was reviewed. Dates from Health Canada, HTA decisions and provincial listings were collected. There were 94 FDA AAs, two of which were subsequently withdrawn. Of the 92 AAs, 70 received full (46)/conditional (24) Health Canada approval, and 22 were not filed. Since the introduction of HTA, 31 out of 45 of Health Canada’s approved indications underwent HTA review: 18 received a positive recommendation conditional on cost-effectiveness, 8 were not recommended and 5 were withdrawn/suspended. The median time from the AA to any Health Canada approval is 9.4 months, from any Health Canada approval to HTA decision is 5.8 months and from HTA decision to the first formulary listing is 12.0 months. The access and timeline for the first formulary listing differences were observed between the USA and Canada due to the decision of pharmaceutical companies to submit (or not) to regulatory/HTA bodies, national procedural delays with different healthcare delivery models and submission timelines. This study demonstrates that there is delayed access to promising new therapies in Canada.