Food and Drug Administration vs European Medicines Agency: Review times and clinical evidence on novel drugs at the time of approval.

The Food and Drug Administration (FDA) and European Medicines Agency (EMA) now have expedited review procedures for new drugs. We compared the review times of medicines licensed by the 2 agencies and explored differences in the evidence submitted. In 2015-2017 the FDA licensed 113 drugs, 66 of which reached Europe. The median review time was longer at the EMA than FDA and was shorter for drugs undergoing FDA-expedited programmes compared to the same drugs approved by the EMA through the standard procedure. We identified differences regarding the evidence submitted to the 2 regulators for 7 drugs. The greater use of expedited programmes by the FDA and administrative time at the European Commission mainly explain the later access of new drugs to the European market. The additional evidence submitted to the EMA is generally scant and limited to a few drugs.

Clinical evidence supporting the marketing authorization of biosimilars in Europe.

PURPOSE: To review the marketing authorization of biosimilars and provide a critical analysis of the pivotal trials supporting their approval by the European Medicines Agency (EMA). METHODS: EMA website to identify the biosimilars approved up to July 2019 and the European Public Assessment Report for information on pivotal trial design, duration, intervention and control, primary outcome, data on immunogenicity, and comparability margins. RESULTS: The EMA has approved 55 biosimilars (62% in 2017-2019) of 16 biologic products, used in several clinical indications. Some biosimilars were licensed as multiple products, with different commercial names, by the same or different companies. The comparability exercise and subsequent approval of 49/55 (89%) biosimilars were based on one or more pivotal phase III trials testing their clinical efficacy. In all, biosimilars were approved on the basis of 55 trials, mostly phase III (42/55, 76%) assessing clinical efficacy; these were mainly equivalence trials (31/55, 56%). The pivotal phase III trials assessed surrogate measures of clinical effect, and 71% reported immunogenicity data. CONCLUSION: Analysis of the approval of biosimilars in Europe depicts a complex and heterogeneous scenario. The requirement for showing similarity in terms of clinical efficacy and safety provides a robust demonstration of comparable clinical outcomes but lays a burden on biosimilar manufacturers and may delay the introduction of the drugs. The development, licensing, and monitoring of biosimilars would benefit from new strategies to accelerate access to these drugs while reducing uncertainties about their use in practice.

Benefits, benefits, once more benefits... with no risk? Stop overlooking the harms of medicines.

Consideration of drug benefits and harms is asymmetric. Approval of drugs is mainly based on efficacy, while the assessment of their safety is left to post-marketing commitments or spontaneous reporting. Benefits are overestimated as a result of pharmaceutical companies' advertisements, the paucity of independent information, and the scant understanding of the effectiveness of medicines in real life. Polypharmacy in older adults-even during the last period of their life-reflects the tendency to assign priority to efficacy and overlook harms, although nobody knows what happens when three or more drugs are given chronically. Medical journals and public research funding projects do not pay enough attention to drug toxicity. We call for a sense of purpose by all those involved in medicine to tackle this problem. European and national agencies and health authorities should promote and support independent information and experimental and clinical studies on drug toxicity. Information should rely not just on spontaneous reporting but also on active pharmacovigilance. The benefit-harm profile of drugs should be periodically reviewed in the light of toxic effects that come to light over the years. Potential interactions within polytherapies should be sought by re-assessing the pharmacokinetics and pharmacodynamics of their components.

Systemic safety of bevacizumab versus ranibizumab for neovascular age-related macular degeneration.

BACKGROUND: Neovascular age-related macular degeneration (AMD) is the leading cause of legal blindness in elderly populations of industrialised countries. Bevacizumab (Avastin®) and ranibizumab (Lucentis®) are targeted biological drugs (a monoclonal antibody) that inhibit vascular endothelial growth factor, an angiogenic cytokine that promotes vascular leakage and growth, thereby preventing its pathological angiogenesis. Ranibizumab is approved for intravitreal use to treat neovascular AMD, while bevacizumab is approved for intravenous use as a cancer therapy. However, due to the biological similarity of the two drugs, bevacizumab is widely used off-label to treat neovascular AMD. OBJECTIVES: To assess the systemic safety of intravitreal bevacizumab (brand name Avastin®; Genentech/Roche) compared with intravitreal ranibizumab (brand name Lucentis®; Novartis/Genentech) in people with neovascular AMD. Primary outcomes were death and All serious systemic adverse events (All SSAEs), the latter as a composite outcome in accordance with the International Conference on Harmonisation Good Clinical Practice. Secondary outcomes examined specific SSAEs: fatal and non-fatal myocardial infarctions, strokes, arteriothrombotic events, serious infections, and events grouped in some Medical Dictionary for Regulatory Activities System Organ Classes (MedDRA SOC). We assessed the safety at the longest available follow-up to a maximum of two years. SEARCH METHODS: We searched CENTRAL, MEDLINE, EMBASE and other online databases up to 27 March 2014. We also searched abstracts and clinical study presentations at meetings, trial registries, and contacted authors of included studies when we had questions. SELECTION CRITERIA: Randomised controlled trials (RCTs) directly comparing intravitreal bevacizumab (1.25 mg) and ranibizumab (0.5 mg) in people with neovascular AMD, regardless of publication status, drug dose, treatment regimen, or follow-up length, and whether the SSAEs of interest were reported in the trial report. DATA COLLECTION AND ANALYSIS: Two authors independently selected studies and assessed the risk of bias for each study. Three authors independently extracted data.We conducted random-effects meta-analyses for the primary and secondary outcomes. We planned a pre-specified analysis to explore deaths and All SSAEs at the one-year follow-up. MAIN RESULTS: We included data from nine studies (3665 participants), including six published (2745 participants) and three unpublished (920 participants) RCTs, none supported by industry. Three studies excluded participants at high cardiovascular risk, increasing clinical heterogeneity among studies. The studies were well designed, and we did not downgrade the quality of the evidence for any of the outcomes due to risk of bias. Although the estimated effects of bevacizumab and ranibizumab on our outcomes were similar, we downgraded the quality of the evidence due to imprecision.At the maximum follow-up (one or two years), the estimated risk ratio (RR) of death with bevacizumab compared with ranibizumab was 1.10 (95% confidence interval (CI) 0.78 to 1.57, P value = 0.59; eight studies, 3338 participants; moderate quality evidence). Based on the event rates in the studies, this gives a risk of death with ranibizumab of 3.4% and with bevacizumab of 3.7% (95% CI 2.7% to 5.3%).For All SSAEs, the estimated RR was 1.08 (95% CI 0.90 to 1.31, P value = 0.41; nine studies, 3665 participants; low quality evidence). Based on the event rates in the studies, this gives a risk of SSAEs of 22.2% with ranibizumab and with bevacizumab of 24% (95% CI 20% to 29.1%).For the secondary outcomes, we could not detect any difference between bevacizumab and ranibizumab, with the exception of gastrointestinal disorders MedDRA SOC where there was a higher risk with bevacizumab (RR 1.82; 95% CI 1.04 to 3.19, P value = 0.04; six studies, 3190 participants).Pre-specified analyses of deaths and All SSAEs at one-year follow-up did not substantially alter the findings of our review.Fixed-effect analysis for deaths did not substantially alter the findings of our review, but fixed-effect analysis of All SSAEs showed an increased risk for bevacizumab (RR 1.12; 95% CI 1.00 to 1.26, P value = 0.04; nine studies, 3665 participants): the meta-analysis was dominated by a single study (weight = 46.9%).The available evidence was sensitive to the exclusion of CATT or unpublished results. For All SSAEs, the exclusion of CATT moved the overall estimate towards no difference (RR 1.01; 95% CI 0.82 to 1.25, P value = 0.92), while the exclusion of LUCAS yielded a larger RR, with more SSAEs in the bevacizumab group, largely driven by CATT (RR 1.19; 95% CI 1.06 to 1.34, P value = 0.004). The exclusion of all unpublished studies produced a RR of 1.12 for death (95% CI 0.78 to 1.62, P value = 0.53) and a RR of 1.21 for SSAEs (95% CI 1.06 to 1.37, P value = 0.004), indicating a higher risk of SSAEs in those assigned to bevacizumab than ranibizumab. AUTHORS' CONCLUSIONS: This systematic review of non-industry sponsored RCTs could not determine a difference between intravitreal bevacizumab and ranibizumab for deaths, All SSAEs, or specific subsets of SSAEs in the first two years of treatment, with the exception of gastrointestinal disorders. The current evidence is imprecise and might vary across levels of patient risks, but overall suggests that if a difference exists, it is likely to be small. Health policies for the utilisation of ranibizumab instead of bevacizumab as a routine intervention for neovascular AMD for reasons of systemic safety are not sustained by evidence. The main results and quality of evidence should be verified once all trials are fully published.

Placebo? no thanks, it might be bad for me!

OBJECTIVE: To assess the potential damage to patients from the inappropriate use of placebo. METHODS: Pivotal clinical trials of new drugs were evaluated for the treatment of multiple sclerosis following effective treatment with beta interferons and glatiramer acetate. The differences in the relapse rate between the experimental arms of the trials with interferons and glatiramer and the placebo groups were calculated. RESULTS: In ten pivotal trials, 2,752 patients were given placebo instead of the best proven treatments. The annualized relapse rate was reported for 2,405 of these patients. Patients receiving placebo suffered 630 more relapses than those treated with interferons or glatiramer. CONCLUSIONS: The inappropriate use of placebo in clinical trials unduly harms patients. The use of standard active comparators would preserve patients' rights and better define the respective clinical value of new medicines.

Orphan drugs, orphan diseases. The first decade of orphan drug legislation in the EU.

PURPOSE: To assess the methodological quality of Orphan Medicinal Product (OMP) dossiers and discuss possible reasons for the small number of products licensed. METHODS: Information about orphan drug designation, approval, refusal or withdrawal was obtained from the website of the European Medicines Agency and from the European Public Assessment Reports. RESULTS: From 2000 up to 2010, 80.9 % of the 845 candidate orphan drug designations received a positive opinion from the European Medicines Agency (EMA)'s Committee on Orphan Medicinal Products. Of the 108 OMP marketing authorizations applied for, 63 were granted. Randomised clinical trials were done for 38 OMPs and placebo was used as comparator for nearly half the licensed drugs. One third of the OMPs were tested in trials involving fewer than 100 patients and more than half in trials with 100-200 cases. The clinical trials lasted less than one year for 42.9 % of the approved OMPs. CONCLUSION: Although there may have been some small improvements over time in the methods for developing OMPs, in our opinion, the number of patients studied, the use of placebo as control, the type of outcome measure and the follow-up have often been inadequate. The present system should be changed to find better ways of fostering the development of effective and sustainable treatments for patients with orphan diseases. Public funds supporting independent clinical research on OMPs could bridge the gap between designation and approval. More stringent criteria to assess OMPs' efficacy and cost/effectiveness would improve the clinical value and the affordability of products allowed onto the market.

Ethics in clinical research.

R&D of new drugs is driven by pharmaceutical companies that invest considerable amounts of money for this purpose. This may introduce bias, to emphasize the clinical value of drugs to be allowed onto the market. Bias is caused by methodological flaws including the population under study, the choice of inadequate comparators or of their dosage, the adoption of surrogate or composite endpoints, the decision to publish mainly positive findings or to overlook some safety concerns, etc. All this happens in a legal context that requires no added value for new drugs to be approved for the market. This encourages the use of placebo even when active comparators are available, or the search for non-inferiority of new products in comparison with active comparators. Superiority over placebo and non-inferiority to active comparators may allow drugs onto the market that are in fact less active (or safe, tolerable, convenient, etc.) than those already available, usually with consolidated properties and lower costs. In addition, they do not meet patients' or physicians' needs of defining the place in therapy and respective roles of new and available treatments. The current legislative and regulatory setting seems designed to meet commercial interests rather than public health needs.

Limits of add-on trials: antirheumatic drugs.

PURPOSE: This paper assesses the design of clinical studies used in the process of regulatory approval, focusing on how add-on studies affect regulatory decisions. METHODS: The sample case taken is that of the new agents for rheumatoid arthritis (RA) authorised by the European Medicine Agency (EMEA). The European Public Assessment Reports (EPARs) accompanying the marketing authorisations were the source of information on the studies presented in the registration dossiers. RESULTS: The recently approved anti-RA agents are all indicated in combination with methotrexate (MTX) for treating adults with active RA who have responded inadequately to disease-modifier drugs (DMARDs). The add-on design was frequently used in registration studies. For infliximab, etanercept, adalimumab and rituximab, add-on trials contributed, together with parallel-group trials, to gaining the approval as combination therapy. Anakinra and abatacept were authorised on the basis of add-on trial results only. CONCLUSIONS: Add-on trials do not allow assessment of the intrinsic efficacy and safety of new agents and their value as alternatives to available treatments. The indications granted for the new anti-RA agents do not specify whether newer drugs can replace standard treatments in nonresponders, can do better in the overall patient population or can be used as first-line treatment.

New Direct-Acting Antivirals for the Treatment of Patients With Hepatitis C Virus Infection: A Systematic Review of Randomized Controlled Trials.

BACKGROUND: New direct-acting antiviral agents (DAAs) approved for the treatment of patients infected by Hepatitis C virus (HCV) are well tolerated and increase sustained virological response (SVR) rate. We summarize current evidence on the efficacy and safety from comparative randomized controlled trials (RCTs) of DAAs. METHODS: We systematically searched MEDLINE, Embase, Scopus, CENTRAL, and Lilacs as well as a list of reference literature. We included RCTs comparing DAAs with placebo or active control and reporting response rates and adverse events according to antiviral regimens. Risk ratios (RRs) were pooled as appropriate. We assessed the risk of bias of included studies and graded the quality of evidence according to the GRADE method. RESULTS: We included 28 RCTs, enrolling more than 7000 patients. The quality of evidence was generally low. Twelve-week treatment with DAAs in naïve patients significantly increased SVR12 and SVR24 compared with placebo (RR 1.4, 95% CI 1.3-1.6; RR 1.5, 95% CI 1.4-1.6, respectively). This means that for every 1000 patients, 240 or 260 more patients experienced SVR12 or SVR24 if treated with any DAAs. We could not find RCTs assessing progression of liver disease or development of hepatocellular carcinoma. DAAs were not associated with higher incidence of serious adverse events or discontinuation due to adverse events. CONCLUSIONS: This systematic review confirms that new DAAs are more effective in inducing SVR than placebo. Outside clinical trials, in real word, HCV cure with DAA regimens occurs in less than 90% of patients, so further comparative evaluations are needed to establish their long-term effects.

Thrombolysis or nothing for acute myocardial infarction? It's all the same!

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT: The methodological and ethical value of equivalence and non-inferiority trials is questioned. These studies are still increasingly used in drug evaluation and accepted by the scientific community and the regulatory authorities. WHAT THIS STUDY ADDS: By applying the hypothesis of an equivalence trial of saruplase and streptokinase (SK) we proved that the no-thrombolysis approach in the GISSI trial was equivalent to thrombolysis with SK, i.e. death rates in patients given SK or not were similar enough to consider the no-thrombolysis regimen equivalent to thrombolytic treatment. These data illustrate the unreliability of equivalence trials, which can even disprove consolidated clinical evidence such as the efficacy of thrombolysis in acute myocardial infarction. Equivalence trials should not be considered an option by the scientific community and should not be accepted as a basis for marketing authorization by the regulatory authorities. AIMS To assess the reliability of equivalence trials we tested whether the no-thrombolysis approach was equivalent to thrombolysis with streptokinase (SK) in acute myocardial infarction. METHODS: We applied the hypothesis of an equivalence trial of a recombinant plasminogen activator and SK to the GISSI-1 control group. RESULTS: In at least one of three subsets randomly extracted from the GISSI database the equivalence criterion was satisfied, i.e. death rates in patients given SK or not were similar enough to consider the no-thrombolysis regimen equivalent to thrombolytic treatment. Two-thirds of 100 replications of the sampling gave this result. CONCLUSIONS: These findings suggest the unreliability of equivalence trials, which should neither be adopted by the scientific community nor accepted by the regulatory authorities.

Recent national and regional drug reforms in Sweden: implications for pharmaceutical companies in Europe.

With an aging population and increased prevalence of chronic diseases, such as obesity and diabetes mellitus, drug reforms are needed across Europe to ensure the continued provision of comprehensive healthcare. It is also a challenge, with the limited resources available, to fund new innovative drugs that significantly improve patient health. Recent national and regional reforms in Sweden have moderated the rate of increase in drug expenditure, despite increased volumes of drug use and the launch of new, expensive drugs. National reforms include the adoption of economic principles when assessing the value and subsequent reimbursement of new and existing drugs, as well as reforms to obtain low prices for generic drugs. Regional reforms aim to encourage the rational use of medicines through the establishment of drug and therapeutic committees, development of guidelines, academic detailing, continuous benchmarking of prescribing patterns, and financial incentives. Some of these reforms provide examples to other European countries, whilst others duplicate existing measures. As such, we believe other European countries can benefit from an analysis of the Swedish reforms. We believe the pharmaceutical industry can also benefit from this analysis by working with key regional payers involved with developing and implementing the reforms as they moderate and refine their future activities, including finding acceptable ways of introducing new expensive drugs.

Peripheral arterial disease: Changes in clinical outcomes and therapeutic strategies in two cohorts, from 2002 to 2008 and from 2008 to 2014. A population-based study.

Background The aim of our study was to evaluate whether treatments for peripheral artery disease changed in two different cohorts identified in 2002 and 2008, and whether this had an impact on mortality and major clinical outcomes after six years of follow-up. Methods Using administrative health databases of the largest region in Northern Italy, we identified patients admitted to hospital for peripheral artery disease in 2002 and 2008. Both cohorts were followed for six years. All cause death, acute coronary syndrome, stroke and major amputations, cardiovascular prevention drugs and revascularization procedures were collected. Incidence of events was plotted using adjusted cumulative incidence function estimates. The risk, for each outcome, was compared between 2002-2008 and 2008-2014 using a multivariable Fine and Gray's semiparametric proportional subdistribution hazards model. Results In 2002 and 2008, 2885 and 2848 patients were identified. Adjusting for age, sex, Charlson comorbidity index and severity of peripheral artery disease we observed a significant reduction (in 2008 vs. 2002) in the risk of acute coronary syndrome (28%), stroke (27%) and major amputation (17%). No change was observed in the risk of death. The percentages of patients with peripheral artery revascularizations, during the hospital stay, increased: 43.8% in 2002 vs. 49.0% in 2008, p < 0.001. From 2002 to 2008 there was a significant absolute increase in the prescription of lipid-lowering drugs (+18%), antiplatelets (+7.2%) and angiotensin-converting enzyme inhibitors/angiotensin receptor blockers (+11.8%), p < 0.001. Conclusions In six years of follow-up we observed a reduction in risk of major cardiovascular events in 2008-2014 in comparison with the 2002-2008 cohort. Increasing use of revascularization interventions and cardiovascular prevention drugs could have contributed to the better prognosis.

A disease looking for innovative drugs: The case of pulmonary arterial hypertension.

BACKGROUND: Pulmonary arterial hypertension (PAH) is a life-threatening rare disease. Between 2001 and 2016 the European Medicines Agency (EMA) approved nine drugs to treat PAH. Considering the poor prognosis of patients with PAH it would be useful to understand whether the approved therapies can change the natural history of the disease. We assessed the therapeutic value and the quality of the evidence on medicines that have been authorized by the EMA in the 2000s. METHODS: Information about drug approval was obtained from the EMA website and the European Public Assessment Reports. MedLine, Embase, and Cochrane databases were systematically searched for published randomized clinical trials and meta-analyses of the selected drugs and their combinations. RESULTS: At the time of approval no medicine had been proved to reduce mortality or slow the progression of the disease or to improve patients' quality of life. Recent meta-analyses concluded that, compared to placebo, active treatments reduced mortality but there was no conclusion on any preferred therapeutic option. Approvals of monotherapies in the absence of best evidence of their efficacy, have prompted the search for better efficacy of their combinations. Three meta-analyses found no advantage in survival from combinations as opposed to monotherapies. CONCLUSIONS: This model case confirms previous analyses that marketing authorizations granted in spite of low evidence of therapeutic efficacy not only expose patients to treatments with unknown benefit-risk profiles but also hamper post-marketing research aimed at filling the information gap.

Preapproval and postapproval evidence on drugs for multiple sclerosis.

OBJECTIVE: To review the evidence supporting the European Union marketing authorization of drugs for multiple sclerosis (MS) and assess how far postmarketing research addresses information gaps at the time of approval. METHODS: Through its database, we identified drugs approved by the European Medicines Agency and gathered data on pivotal trials from the European Public Assessment Reports and corresponding publications. We searched Medline, Embase, Cochrane Library, and trial registries for postmarketing randomized controlled trials testing the drugs identified in any form of the disease. RESULTS: Since approval of interferon and glatiramer up to 2017, the Agency has examined 10 drugs for the treatment of MS, and 8 were included in this study: alemtuzumab, daclizumab, dimethyl fumarate, fampridine, fingolimod, peginterferon-ß-1a, natalizumab, and teriflunomide. We analyzed 16 pivotal trials enrolling almost 16,000 participants. Eleven compared new drugs to placebo, 5 to interferon-ß-1a. Annualized relapse rate was the primary outcome in two-thirds and coprimary with disability progression in the 2 studies of alemtuzumab. Of the 52 postmarketing trials, 24 reported final results and 28 were ongoing, terminated, or completed but no results were available. None directly compared the approved drugs, thus leaving their respective therapeutic values unknown. Data on the prevention of disease progression were scarce: none of the disease-modifying drugs showed any effect on disability progression. CONCLUSION: The lack of comparative evidence and data on clinical effectiveness hamper the assessment of therapeutic value and place in therapy of drugs approved for MS.