[Targeted therapies and immunotherapy: Positioning in the field of innovation and challenges for the therapeutic decision-making process]. / Thérapies ciblées et immunothérapie : positionnement dans le champ de l'innovation et enjeux pour le processus de décision thérapeutique.

The better understanding of the molecular, cellular, and immunological mechanisms of cancer has led to the development of targeted therapies, then immunotherapy, which have changed the approach to cancer treatment. While these treatments differ from chemotherapy in their mechanisms of action, they also allow for increased personalization of cancer care through the development of technologies that target patients more precisely. However, they are associated with several challenges: the management of uncertainty associated with their risk-benefit balance due to the lack of long-term data and sometimes scientific evidence on their effects; the complexity of integrating molecular and immunological data into the therapeutic decision; the challenge of inequalities in access to these treatments often considered revolutionary due to the required molecular characterization and/or inclusion criteria for early-phase trials; and the challenge of their appropriation and adoption by physicians and patients. This narrative review explores each of these challenges in the context of shared decision-making, the promotion of which is a guarantee of quality and safety of care for cancer patients.

Analyzing the 7C psychological antecedents of vaccine acceptance throughout the COVID-19 pandemic among healthcare sector workers in France: A repeated cross-sectional study (CappVac-Cov).

BACKGROUND: Across various stages of the COVID-19 pandemic and related vaccine recommendations in France, we assessed the association of the 7C-psychological antecedents with vaccine uptake/intention for booster vaccination among healthcare-sector workers (HCSWs). We also assessed whether 7C-antecedent profiles changed over time. METHODOLOGY: The Research Group for the Prevention of Occupational Infections in Healthcare Workers (GERES) conducted three repeated web-surveys which were disseminated by email chain-referral among HCSWs throughout France. The questionnaires waves took place: July-November 2021, February-March 2022 and January-March 2023 (P2, P3 and P4). We also reanalysed data from a prior similar study conducted late 2020-early 2021 (Moirangthem et al. (2022)) (P1). To evaluate the association of 7C-items with vaccine uptake-intention for future vaccination, we estimated adjusted prevalence ratios (aPR) using robust variance Poisson regression. We report the 7C-item population attributable loss in vaccine intention. RESULTS: The four surveys (P1-P4) encompassed 5234, 339, 351 and 437 participants. At earlier stages of the vaccine campaign, the principal antecedents of vaccine intention were favorable perception of vaccination benefit-risk-balance (BRB) (vs. unfavorable, aPR: 2.32), reactance to employer encouragement for vaccination (motivates vs. dissuades-me, aPR:2.23), vaccine confidence (vs. not-being-confident, aPR: 1.71) and social conformism towards vaccination (favorable vs. skeptical opinion in private environment, aPR: 1.33). Under a vaccine mandate for HCSWs, only perceiving vaccination as a collective action was associated with current vaccine status (agree vs. disagree, aPR: 2.19). At later stages of the epidemic, hypothetical booster vaccine intentions were strongly associated with BRB perception (favorable vs. unfavorable, aPR: 2.07) and perceiving vaccination as a collective action (agree vs. disagree, aPR: 1.69). Fearing a severe side effect from vaccination decreased population vaccine intention by 26.2 %. CONCLUSION: Our results suggest that both 7C-antecedents and their association with vaccine behaviour can change over time, and underscore the importance of assuring confidence in vaccine safety.

Fertility preservation before cancer treatment: the dilemma of saying 'no' as the price of glory.

A great deal of work has been carried out by professionals in reproductive medicine in order to raise awareness about fertility preservation (FP) techniques, particularly for women, and to ensure that FP is included in the care of young adults treated for cancer or a pathology requiring gonadotoxic treatment. If the importance of the development of our discipline is obvious, our militancy in favour of FP and our emotional projections must not make us forget that medical thinking must be carried out not only on a case-by-case basis, weighing up the benefit-risk balance, but also without losing sight that conceiving a child with one's own gametes is not a vital issue. The cultural importance given to the genetic link with offspring may bias patients' and physicians' decisions, while other ways of achieving parenthood exist, and are often more effective. Systematic information should be provided on the existence of FP techniques, but this should not lead to their systematic implementation, nor should it obscure that early information will also allow patients to begin projecting themselves in alternative options to become parents.

Impact of a COVID-19 certificate requirement on vaccine uptake pattern and intention for future vaccination. A cross-sectional study among French adults.

BACKGROUND: In August 2021, France enacted a COVID-19 certificate requirement (vaccination/recovery/test) to access specific services, with mandates for professional groups. We evaluated the impact of this incentive-coercive policy in terms of vaccine uptake equality, future vaccine intention and confidence in authorities' crisis management. METHODS: In late August 2021, a representative sample of adults (18-75 years) completed an internet-based questionnaire. We classified vaccinated participants by stated reasons for vaccination and estimated adjusted prevalence ratios (aPR) using multivariable Poisson regression. Counterfactual vaccine status assumed non-vaccination of those vaccinated for the certificate. We analysed the association of free-text testimonial themes with level of confidence in authorities. RESULTS: Among 972 participants, 85.7% were vaccinated or intended vaccination: 3.6% only for certificate/mandate, 17.7% mainly for certificate/mandate plus other reasons, and 64.4% mainly for other reasons. In the counterfactual situation, vaccine uptake would have been significantly more likely among older vs. younger participants (aPR = 1.35) and among those with moderate-high vs. low levels of confidence in authorities for COVID-19 crisis management (aPR = 2.04). In the observed situation, confidence was the only significant determinant of vaccine status (moderate-high vs. low, aPR = 1.39). Among those without genuine motivation for vaccination, professionally active persons were more likely to have ceded to the certificate requirement (aPR = 3.76). Those vaccinated only for the certificate were more likely to express future COVID-19 vaccine intention than unvaccinated persons (aPR = 6.41). Themes significantly associated with lower confidence were criticism of morality (aPR = 1.76) and poor communication by the authorities (aPR = 1.66). CONCLUSION: The incentive-coercive policy has reduced the negative association of vaccine status with younger age and low confidence in authorities, but may have reinforced isolation of professionally inactive persons. The requirement did not negatively impact future COVID-19 vaccine intention. Future vaccine-incentive policies should pay special attention to populations with low levels of confidence in authorities.

Do Patients With Low-Risk Pulmonary Arterial Hypertension Really Benefit From Upfront Combination Therapy?: Insight From the AMBITION Trial.

BACKGROUND: Based on results of the Ambrisentan and Tadalafil in Patients with Pulmonary Arterial Hypertension (AMBITION) trial, upfront combination therapy is recommended for treatment-naive patients with low-risk pulmonary arterial hypertension (PAH). However, conflicting data exist whether adopting this treatment strategy in this risk group is beneficial or well tolerated. RESEARCH QUESTION: Do patients with low-risk PAH really benefit from upfront combination therapy? STUDY DESIGN AND METHODS: Using the data from the original AMBITION trial, patients with PAH were classified as low, intermediate, or high risk using the Registry to Evaluate Early and Long-term PAH Disease Management 2.0 (REVEAL 2.0) score and the Pulmonary Hypertension Outcomes and Risk Assessment (PHORA) tool. The primary end point was time to clinical worsening (including death, hospitalization for PAH worsening, and disease progression) censored at 1- and 3-year post-enrollment. Side effects that led to withdrawal of treatment were also considered. RESULTS: Patients with low-risk PAH categorized by REVEAL 2.0 and PHORA did not see a statistically significant benefit of upfront combination therapy vs monotherapy for time to clinical worsening at 1 and 3 years' post-enrollment using Cox proportional analysis (3-year hazard ratio of 0.40 [95% CI, 0.15-1.06; P = .07] and 0.55 [95% CI, 0.26-1.18; P = .12] for REVEAL 2.0 and PHORA, respectively) or considering time to clinical worsening or side effects (3-year hazard ratio of 0.75 [95% CI, 0.39-1.47; P = .4] and 0.87 [95% CI, 0.49-1.54; P = .63] for REVEAL 2.0 and PHORA). Patients with low-risk PAH on upfront combination therapy experienced a higher but not significant incidence of side effects using REVEAL 2.0 and PHORA. In contrast, patients at intermediate or high risk saw a statistically significant benefit of upfront combination therapy considering each of the end points regardless of side effects. INTERPRETATION: This analysis suggests that perhaps some patients with low-risk PAH should be further stratified using other modalities prior to committing to upfront combination therapy, especially when the occurrence of side effects is considered. Further prospective data are needed to validate this hypothesis prior to changes in current guideline directed therapy are contemplated.

Safety Surveillance During Drug Development: Comparative Evaluation of Existing Regulations.

Drug safety monitoring is essential for developing efficient and safe treatments. It starts with preclinical toxicology studies and continues with the observation and analysis of potentially harmful effects in humans throughout the whole drug life cycle. Safety surveillance during the clinical phase is of paramount importance for protecting the health of clinical trial (CT) participants at a period when relatively little is known about the drug safety profile, and for reassuring that detected risks are minimized when the product obtains marketing approval. This review aimed to investigate current safety surveillance methods during drug development worldwide, in order to identify potential gaps and opportunities for amelioration. To this end, international guidelines, standards, and local legislations about CTs were reviewed and compared. Our review revealed common strategies, mainly in alignment with international guidelines, especially concerning the systematic collection, assessment, and expedition of adverse events by investigators and sponsors and the preparation of periodic aggregate safety reports by sponsors, as a means to inform health authorities (HAs) about the evolving benefit-risk balance of the investigational product. Inconsistencies in safety surveillance mainly concerned local expedited reporting requirements. Significant gaps were identified in the methodologies for aggregate analyses and the responsibilities of HAs. Addressing the regulatory discrepancies and harmonizing the safety surveillance processes at a global level would increase the usability of safety data accumulated by clinical studies worldwide, thus enabling and hopefully accelerating the development of safe and efficient drug therapies.

Management of postmenopausal women: Collège National des Gynécologues et Obstétriciens Français (CNGOF) and Groupe d'Etude sur la Ménopause et le Vieillissement (GEMVi) Clinical Practice Guidelines.

AIM: The aim of these recommendations is to set forth an individualized approach to the management of early postmenopausal women (i.e., within the first 10 years after natural menopause) covering all aspects of lifestyle and therapeutic management, with or without menopause hormone therapy (MHT). MATERIALS AND METHODS: Literature review and consensus of French expert opinion. Recommendations were graded according to the HAS methodology and levels of evidence derived from the international literature, except when there was no good-quality evidence. SUMMARY RECOMMENDATIONS: The beginning of menopause is an ideal time for each woman to evaluate her health status by assessing her bone, cardiovascular, and cancer-related risk factors that may be amplified by postmenopausal estrogen deficiency and by reviewing her lifestyle habits. Improving lifestyle, including nutrition and physical activity, and avoiding risk factors (notably smoking), should be recommended to all women. MHT remains the most effective treatment for vasomotor symptoms but it could be also recommended as first-line treatment for the prevention of osteoporosis in early postmenopausal women at low to moderate risk for fracture. The risks of MHT differ depending on its type, dose, duration of use, route of administration, timing of initiation, and whether a progestogen is used. There is reasonable evidence that using transdermal estradiol in association with micronized progesterone or dydrogesterone may limit both the venous thromboembolic risk associated with oral estrogens and the risk of breast cancer associated with synthetic progestins. Treatment should be individualized to each woman, by using the best available evidence to maximize benefits and minimize risks, with periodic reevaluation of its benefit-risk balance. For bothersome genitourinary syndrome of menopause (GSM) symptoms, vaginal treatment with lubricants and moisturizers is recommended as first-line treatment together with low-dose vaginal estrogen therapy, depending on the clinical course. No recommendation of an optimal duration of MHT can be made, but it must take into consideration the initial indication for MHT as well as each woman's benefit-risk balance. Management of gynecological side-effects of MHT is also examined. These recommendations are endorsed by the Groupe d'Etude sur la Ménopause et le Vieillissement hormonal (GEMVI) and the Collège National des Gynécologues-Obstétriciens Français (CNGOF).

Safety profile of hydroxychloroquine used off-label for the treatment of patients with COVID-19: A descriptive study based on EudraVigilance data.

At the beginning of the COVID-19 pandemic, worldwide attempts were made to identify potential drugs effective against the COVID-19. Hydroxychloroquine was among the first receiving attention. However, following its use in therapy, it has been shown that hydroxychloroquine was not only ineffective but probably, due to its known side effects, even responsible of increased mortality of patients. The objective of this study was to review the safety profile of hydroxychloroquine used off-label for the treatment of COVID-19. We analyze the reports of suspected adverse drug reactions (ADRs) collected in EudraVigilance, the European database of ADR reports. We collected 2266 reports for 2019 and 6525 for 2020. The most reported ADRs during 2020 were those relating to cardiac, hepatic, renal toxicity such as QT prolongation with 400 cases in 2020 (of which, 345 cases-9.97%-with COVID-19 as a therapeutic indication) versus 1 case only in 2019 (0.01%), long QT syndrome: 38 cases in 2020 (36 as COVID-19 treatment) versus 0 in 2019, hepatitis: 13 cases in 2019 (0.11%) and 132 in 2020, and 32 cases (24, 0.69%) of acute kidney injury in 2020 and only 3 cases in 2019. Moreover, some important vision-related ADRs also increased significantly during 2020, such as retinal toxicity with 92 cases in 2020 versus 7 in 2019. Even though with its intrinsic limitations, our results may be added to the most recent scientific evidence to confirm the unfavorable risk profile of hydroxychloroquine in its off-label use in the treatment of COVID-19 disease.

Benefits and risks associated with different uses of the COVID-19 vaccine Vaxzevria: a modelling study, France, May to September 2021.

Thrombosis with thrombocytopenia (TTS) has been identified as a rare adverse event following COVID-19 vaccination with Vaxzevria. We modelled the benefits and risks of Vaxzevria distribution from May to September 2021 in metropolitan France where other vaccines are available, considering French hospitalisation data and European data on TTS. Across different scenarios, benefits of Vaxzevria distribution in people 55 years and older exceeded the risk of death from COVID-19. In young adults, risks were at least of similar magnitude as benefits.

Uncertainties that threaten the benefit/risk balance in early treatment lines for advanced or metastatic soft tissue sarcoma.

Sarcoma oncologists face many uncertainties which can threaten the benefit/risk balance during early management of patients with advanced or metastatic soft tissue sarcoma. This point is illustrated by a clinical case involving an elderly patient with comorbidities and a diagnosis of metastatic leiomyosarcoma. The patient was not a candidate for doxorubicin-based chemotherapy because of his cardiac history and was hesitant about systemic chemotherapy, ultimately expressing a preference for a well-tolerated regimen. After evaluating the treatment alternatives, trabectedin was chosen based on its indication for use in persons unsuited to receive anthracyclines and evidence supporting its efficacy and safety in elderly patients. The patient received 17 cycles of trabectedin for a best response of stable disease with good quality of life.

The benefit-risk balance for biological agents in juvenile idiopathic arthritis: a meta-analysis of randomized clinical trials.

OBJECTIVE: To assess the net benefit of biological agents (BA) used in JIA. METHODS: We systematically searched databases up to March 2019 for randomized controlled trials (RCT) performed in JIA disease. Separate random-effects meta-analyses were conducted for efficacy (ACR paediatric score 30%, ACRpedi30) and serious adverse events for safety. In order to standardize the baseline risk, we performed a meta-analysis of baseline risk in the control group (for both efficacy and safety meta-analysis). The net benefit was determined as the risk difference of efficacy subtracted by the risk difference of safety. RESULTS: We included 19 trials: 11 parallel RCTs (754 patients) and 8 withdrawal RCTs (704 patients). The net benefit ranged from 2.4% (adalimumab) to 17.6% (etanercept), and from 2.4% (etanercept) to 36.7%, (abatacept) in parallel and withdrawal trials assessing non-systemic JIA, respectively. In the systemic JIA category, the net benefit ranged from 22.8% (rilonacept) to 70.3% (canakinumab), and from 32.3% (canakinumab) to 58.2% (tocilizumab) in parallel and withdrawal trials, respectively. CONCLUSION: The results suggest that a greater number of patients experienced therapeutic success without serious adverse events in the systemic onset JIA category compared with the BAs for non-systemic JIA categories. Baseline risk, design of trial and JIA categories impact the measure of net benefit of BAs in JIA patients.

Real-world outcomes of rivaroxaban treatment in elderly Japanese patients with nonvalvular atrial fibrillation.

Direct oral anticoagulants (DOACs), such as rivaroxaban, reduce the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation (NVAF). However, it is still unclear whether the stroke reduction benefit outweighs the bleeding risk in elderly Japanese patients with NVAF. The Xarelto Post-Authorization Safety and Effectiveness Study in Japanese Patients with Atrial Fibrillation (XAPASS) was a real-world, prospective observational, post-marketing surveillance study on the safety and effectiveness of rivaroxaban in Japanese clinical practice. This sub-analysis evaluated the clinical outcomes of elderly patients aged ≥ 75 years. At the 1-year follow-up, there were 4,685 (48.91%) and 4,893 (51.09%) patients aged ≥ 75 and < 75 years, respectively. Safety and effectiveness outcomes were compared between patients aged ≥ 75 years and those aged < 75 years, and among 3 elderly sub-populations (age ranges: 75-79, 80-84, and ≥ 85 years). Patients aged ≥ 75 years had higher rates of major bleeding [2.22 vs. 1.35 events per 100 patient-years, hazard ratio (HR) 1.63, 95% confidence interval (CI) 1.17-2.28] and composite of stroke (ischemic or hemorrhagic)/non-central nervous system (non-CNS) systemic embolism (SE)/myocardial infarction (MI) (2.41 vs. 1.21 events per 100 patient-years, HR 1.97, 95% CI 1.40-2.77) compared to patients aged < 75 years. Intracranial hemorrhage rates were < 1 event per 100 patient-years in both groups (0.85 vs. 0.59 events per 100 patient-years, HR 1.43, 95% CI 0.85-2.40). Kaplan-Meier curves of major bleeding and stroke/non-CNS SE/MI showed that no significant differences of cumulative event rates were identified among the 3 elderly sub-populations. Stepwise Cox regression analyses revealed that creatinine clearance (CrCl) (<50 mL/min), hepatic impairment, and hypertension were specific predictors for major bleeding and no specific predictors were found for stroke/non-CNS SE/MI in patients aged ≥ 75 years. In conclusion, safety and effectiveness event rates were higher in patients aged ≥ 75 years compared with those aged < 75 years, yet, no distinct differences were observed among the 3 elderly sub-populations.

Ivabradine drug utilization study in five European countries: A multinational, retrospective, observational study to assess effectiveness of risk-minimization measures.

PURPOSE: This drug utilization study of ivabradine evaluated prescriber compliance with the new risk minimization measures (RMMs), communicated starting 2014 following preliminary results from the SIGNIFY study. METHODS: This was a multinational (five European countries) chart review study with two study periods: pre-RMM and post-RMM. Patients initiating ivabradine for chronic stable angina pectoris in routine clinical practice were identified across general practitioners and specialists. The primary outcome analysis evaluated the compliance with the new RMMs, ie, use in patients with a heart rate greater than or equal to 70 bpm at initiation, no doses higher than those recommended in the summary of product characteristics (SmPC) at initiation and during 6 months of follow-up, and no concomitant use of verapamil or diltiazem. RESULTS: Overall, 711 and 506 eligible patients were included in the pre-RMM and post-RMM periods, respectively. The percentage of patients prescribed ivabradine according to the new RMMs increased significantly in the post-RMM period (70.6% and 78.4% in the pre- and post-RMM periods respectively; P value = .0035). The compliance to RMMs increased for all the criteria assessed independently: the proportions of patients with (a) heart rate ≥ 70 bpm at initiation (79.4% and 85.2%, respectively; P value = .0141), (b) no dose higher than the SmPC doses at initiation and during follow-up (92.8% and 94.1%, respectively; P value = .3957), and (c) no concomitance with verapamil or diltiazem (96.1% and 99.2%, respectively; P value = .0007). CONCLUSIONS: The RMMs for ivabradine were well implemented across the five participating European countries confirming a favorable benefit-risk balance of ivabradine in chronic stable angina pectoris.

Regulatory and Evidence Requirements and the Changing Landscape in Regulation for Marketing Authorisation.

In this chapter, we describe the changing landscape of the EU pharmaceutical legislation concerning regulation and evidence requirements for marketing authorisation. First, we describe the legal requirements for marketing authorisation and the development of EU pharmaceutical legislation and the concept of risk-benefit balance. Second, we describe special types of authorisation, such as conditional approval and approval under exceptional circumstances, and special provisions such as incentives for orphan medicinal products and paediatric investigational plans. Lastly, we describe the available methodological guidelines focussing on choice of endpoints.

Ivabradine: Do the Benefits Outweigh the Risks?

Ivabradine is a selective I f current inhibitor that is used to lower the heart rate (HR) of patients with angina and/or heart failure. It is approved for use in several countries, including the United Kingdom, Australia, Saudi Arabia, and the United States. The drug was studied in several clinical trials, and it exhibited beneficial effects on the approved indicators. However, there are some concerns with the safety profile of this drug, especially its effect in reducing HR and causing severe bradycardia. Therefore, the current review assessed the benefit-risk balance of ivabradine. A literature review of the major published studies that assessed the efficacy and safety of ivabradine was performed. The online VigiBase adverse drug reaction (ADR) reporting system was also accessed to investigate reports associated with this drug. A full benefit-risk assessment was performed using the collected data from the above-mentioned resources. Most of the reviewed studies concluded that ivabradine exerted beneficial effects with a tolerable safety profile. Specifically, a favorable benefit-risk profile was found when ivabradine was used for patients with an HR ≥70 beats per minute. Reports revealed that the most common ADR was bradycardia, which was expected. Other safety risks or ADRs were comparable to other prescribed drugs. This review presents an up-to-date analysis of ivabradine from the latest literature and reports. These studies suggest that ivabradine exhibits an acceptable and favorable benefit-risk profile, and this drug should be considered as a viable option in patients with angina pectoris and chronic heart failure.

The new EU regulation on in vitro diagnostics: potential issues at the interface of medicines and companion diagnostics.

The new European regulation for in vitro diagnostics (IVD) divides the certification of IVD including companion diagnostics (CDx) by notified bodies (NB) from the market authorization of medicines. With the new regulation, CDx will require conformity assessment which is expected to include clinical evidence by NB. This is a significant change from the current situation: until now most IVD have been certified based on their manufacturers' assessment. For one medicine assessed by the EMA, certification of several different CDx by different NB is possible. As the benefit-risk balance of the medicine may depend on the performance (e.g., sensitivity and specificity) of its CDx, a close cooperation of EMA and NB will be necessary. The availability of detailed information on CDx used in the pivotal clinical trials for the medicine's authorization will become crucial for the assessment of alternative or competing CDx.

Statin prescribing according to gender, age and indication: what about the benefit-risk balance?

RATIONALES, AIMS AND OBJECTIVES: The increasing dispensing of statins has raised concern about the appropriateness of prescribing to various population groups. We aimed to (1) investigate incident and prevalent statin prescribing according to indication, gender and age and (2) relate prescribing patterns to evidence on beneficial and adverse effects. METHODS: A cohort of Danish inhabitants (n = 4 424 818) was followed in nationwide registries for dispensed statin prescriptions and hospital discharge information. We calculated incidence rates (2005-2009), prevalence trends (2000-2010) and absolute numbers of statin users according to register proxies for indication, gender and age. RESULTS: In 2010, the prevalence became highest for ages 75-84 and was higher in men than women (37% and 33%, respectively). Indication-specific incidences and prevalences peaked at ages around 65-70, but in myocardial infarction, the prevalence was about 80% at ages 45-80. Particularly, incidences tended to be lower in women until ages of about 60 where after gender differences were negligible. In asymptomatic individuals (hypercholesterolaemia, presumably only indication) aged 50+, dispensing was highest in women. The fraction of statin dispensing for primary prevention decreased with age: higher for incident than prevalent prescribing. Independent of age, this fraction was highest among women, e.g. 60% versus 45% at ages 55-64. The fraction for potential atherosclerotic condition (PAC, e.g. heart failure) increased with age. CONCLUSION: Prevalence of statin utilization was highest for ages 75-84, although indication-specific measures were relatively low. Despite inconclusive evidence for a favourable risk-benefit balance, statin prescribing was high among people aged 80+, asymptomatic women and PAC patients.

The burden of adverse drug events.

Drug safety should be considered as part of the balance between benefit and risk, and represents a burden to the patient, the healthcare professional, the regulator and industry. Each of these has a different view on adverse drug reactions and these are discussed in this article.

Assessment of benefits and risks in development of targeted therapies for cancer--The view of regulatory authorities.

Drug licensing and approval decisions involve the balancing of benefits against the risks (harms) in the presence of uncertainty. Typically, the benefits are estimated from primary efficacy endpoints from confirmatory (phase III) clinical trials although exceptions where promising early data from single-arm studies have led to accelerated approvals are not uncommon, particularly for cancer drugs. The challenge for regulators is to balance early evidence of efficacy that might support approval versus the need to establish clinical benefit based on conclusive evidence. Targeted agents offer the promise that knowledge about the mechanism of the disease will help identify patients with tumors likely to respond, resulting in higher efficacy and less toxicity, and earlier regulatory decisions based on convincing evidence of clinical benefit. In this paper, we describe methods and examples of benefit-risk assessment of targeted drugs, recent initiatives from EMA and FDA on improving communication about benefits and risks, and discuss future steps.