Detecting deviations from the efficacy and safety results of single-arm trials using real-world data: The case of a CAR-T cell therapy in B-cell lymphoma.

PURPOSE: Personalized therapies are leading to an increasing number of marketing authorizations based on single-arm trials, which increases the demand for better post-authorization monitoring strategies. The aim of the present study was to estimate the power over time as data accrue in population-based registries for detecting deviations from the expected efficacy/safety of chimeric antigen receptor T cell (CAR-T) therapy approved for relapsed/refractory large B-cell lymphoma (RR-LBCL). METHODS: The number of real-world RR-LBCL patients was projected over time in a general population of 5, 15, and 25 million citizens using lymphoma registry data. For each scenario, we computed the power over time for detecting significant deviations in efficacy (1-year overall survival [1yOS]) when comparing to historical controls (SCHOLAR-1 study; 1yOS, 28%) and RR-LBCL patients treated with CAR-T cell therapy in a single-arm trial (ZUMA-1; 1yOS, 59%) as well as deviations in selected adverse events (grade ≥3 aphasia) from the ZUMA-1 trial. We assumed a 10% absolute deviation in 1yOS (efficacy) and a relative increase of 50% in grade ≥3 aphasia (safety). RESULTS: Assuming a general population of 5, 15, and 25 million, the accrual time needed to achieve 80% power for detecting a significant increase over the 1yOS reported in SCHOLAR-1 was 9, 4, and 3 years, respectively, while 80% power for detecting a significant decrease in 1yOS compared to ZUMA-1 required 10.5, 4.5, and 3 years of data accrual, respectively. However, corresponding estimates for aphasia were >20, 8, and 5 years, respectively. CONCLUSIONS: Projections of the statistical power for detecting important deviations in efficacy/safety from that reported in pivotal clinical trials(s) provide critical information about the expected performance of post-authorization monitoring programs.

Potentials, challenges and future of chimeric antigen receptor T-cell therapy in non-Hodgkin lymphomas.

Background: Diffuse large B-cell lymphoma (DLBCL) is the most common lymphoma subtype. Disease progression or relapse following frontline chemoimmunotherapy, largely in the form of standard R-CHOP, occurs in 30-40% patients. Relapsed/refractory (R/R) DLBCL represents a major unmet medical need. In particular, patients with primary refractory disease or those whose lymphoma relapses after autologous stem cell transplantation have historically had poor outcomes.Material and methods: Chimeric antigen receptor T-cell (CART) therapy is a promising novel treatment with curative potential in this setting. CART is based on ex vivo genetic modification of autologous T-cells to express chimeric receptors targeting antigens highly expressed in tumors such as CD19 in DLBCL. After lymphocyte-depleting therapy, patients are infused with CARTs that expand in vivo and target CD19-positive lymphoma cells.Results: In initial phase I-II trials, investigators have demonstrated complete responses in 40-50% of patients with R/R DLBCL, resulting in durable remission approaching 3 years of follow-up in most of these patients without further treatment. The logistics of delivery are complex as cell products require timely long-distance transfer between hospitals and production facilities. The unique toxicity profile of CARTs, including the risk of fatal immunological and neurologic events, also requires specific hospital wide management approaches and education. The substantial direct and indirect costs of CART will limit access even in countries with well resourced health care systems.Conclusions: While only two products are commercially available at present, further approvals in coming years appear likely. Future directions include CARTs with reactivity to tumor antigens other than CD19 and products targeting multiple tumor antigens to overcome resistance. The availability of CART has altered the current treatment algorithm for R/R DLBCL, and indications will likely expand to earlier lines of therapy and other hematologic malignancies.

Evaluating the effectiveness of risk minimisation measures: the application of a conceptual framework to Danish real-world dabigatran data.

PURPOSE: For both marketing authorization holders and regulatory authorities, evaluating the effectiveness of risk minimization measures is now an integral part of pharmacovigilance in the European Union. The overall aim of activities in this area is to assess the performance of risk minimization measures implemented in order to ensure a positive benefit-risk balance in patients treated with a medicinal product. METHODS: Following a review of the relevant literature, we developed a conceptual framework consisting of four domains (data, knowledge, behaviour and outcomes) intended for the evaluation of risk minimization measures put into practice in the Danish health-care system. For the implementation of the framework, four classes of monitoring variables can be named and defined: patient descriptors, performance-related indicators of knowledge, behaviour and outcomes. RESULTS: We reviewed the features of the framework when applied to historical, real-world data following the introduction of dabigatran in Denmark for the prophylactic treatment of patients with non-valvular atrial fibrillation. CONCLUSIONS: The application of the framework provided useful graphical displays and an opportunity for a statistical evaluation (interrupted time series analysis) of a regulatory intervention. © 2017 Commonwealth of Australia. Pharmacoepidemiology & Drug Safety © 2017 John Wiley & Sons, Ltd.

Balancing benefit and risk of medicines: a systematic review and classification of available methodologies.

BACKGROUND: The need for formal and structured approaches for benefit-risk assessment of medicines is increasing, as is the complexity of the scientific questions addressed before making decisions on the benefit-risk balance of medicines. We systematically collected, appraised and classified available benefit-risk methodologies to facilitate and inform their future use. METHODS: A systematic review of publications identified benefit-risk assessment methodologies. Methodologies were appraised on their fundamental principles, features, graphical representations, assessability and accessibility. We created a taxonomy of methodologies to facilitate understanding and choice. RESULTS: We identified 49 methodologies, critically appraised and classified them into four categories: frameworks, metrics, estimation techniques and utility survey techniques. Eight frameworks describe qualitative steps in benefit-risk assessment and eight quantify benefit-risk balance. Nine metric indices include threshold indices to measure either benefit or risk; health indices measure quality-of-life over time; and trade-off indices integrate benefits and risks. Six estimation techniques support benefit-risk modelling and evidence synthesis. Four utility survey techniques elicit robust value preferences from relevant stakeholders to the benefit-risk decisions. CONCLUSIONS: Methodologies to help benefit-risk assessments of medicines are diverse and each is associated with different limitations and strengths. There is not a 'one-size-fits-all' method, and a combination of methods may be needed for each benefit-risk assessment. The taxonomy introduced herein may guide choice of adequate methodologies. Finally, we recommend 13 of 49 methodologies for further appraisal for use in the real-life benefit-risk assessment of medicines.

Use of angiotensin receptor blockers and the risk of cancer.

BACKGROUND: A recent meta-analysis of randomized trials suggested that use of angiotensin receptor blockers (ARBs) may be associated with a modestly increased risk of incident cancer, particularly lung cancer. METHODS AND RESULTS: We linked individual-level data from Danish registries on filled drug prescriptions, diagnostic information, and covariates. In a nationwide cohort of new users of ARBs and angiotensin-converting enzyme inhibitors ≥35 years of age during 1998 to 2006, we compared incidence rates of all cancer, cancer subgroups by anatomic site, and cancer mortality. Among 107 466 ARB users, 3954 cases of cancer were detected during 312 753 person-years of follow-up compared with 6214 cases during 435 207 person-years of follow-up in 209 692 angiotensin-converting enzyme inhibitor users (adjusted rate ratio, 0.99; 95% confidence interval, 0.95 to 1.03). Cancer risk did not increase with increasing duration of ARB exposure (increase in rate ratio per year, 0.99; 95% confidence interval, 0.99 to 1.00,) and was similar across individual ARBs. In subgroup analyses, there was a significant association between ARB use and cancer of male genital organs (rate ratio, 1.15; 95% confidence interval, 1.02 to 1.28), but no significantly increased risk of any of the other 15 cancer subgroups, including lung cancer (rate ratio, 0.92; 95% confidence interval, 0.82 to 1.02). For cancer mortality, the rate ratio was 0.77 (95% confidence interval, 0.72 to 0.82). CONCLUSION: In this large nationwide cohort, use of ARBs was not significantly associated with increased risk of incident cancer overall or of lung cancer.

The Randomised Controlled Trial at the Intersection of Research Ethics and Innovation.

The randomised controlled trial (RCT) has been considered for a long time as the gold standard for evidence generation to support regulatory decision making for medicines. The randomisation procedure involves an ethical dilemma since it means leaving the treatment choice to chance. Although currently contested, the ethical justification for the RCT that has gained widespread acceptance is the notion of 'clinical equipoise'. This state exists when "there is no consensus within the expert clinical community about the comparative merits of the alternatives to be tested"; it is argued that this confers the ethical grounds for the conduct of an RCT. The prominent position of the RCT is being challenged by new therapeutic modalities for which this study design may be unsuitable. Moreover, alternative approaches to evidence generation represent another area where innovation may have implications for the relevance of the RCT. Against the backdrop of the debate around the equipoise principle and some recent therapeutic and data analytical innovations, the aim of this article is to explore the current standing of the RCT from a regulatory perspective.

Direct-acting oral anticoagulants (DOACs) in pregnancy: new insight from VigiBase®.

We aimed to perform an analysis of individual case safety reports retrieved after the Standardized MedDRA Query "Pregnancy and neonatal topics" for which Direct-Acting Oral Anticoagulants (DOACs) were claimed as suspected/interacting drugs. Additionally, to investigate if exists a disproportion of cases reporting "Pregnancy and neonatal topics" adverse events rather than other adverse events for DOACs in comparison with all other drugs registered in VigiBase or warfarin. VigiBase, the World Health Organization (WHO)'s global database of individual case safety reports was used as data source. Forty-two cases of abortion were detected of which 18 (42.8%) had alternative causes for its occurrence. Fourteen cases reported congenital anomaly (8 cases) or low birth weight baby/fetal growth restriction (6 cases) of which 62.5% and 33.3% had at least one confounder, respectively. In the disproportionality analyses, a potential safety signal for spontaneous abortion emerged for rivaroxaban (Reporting Odds Ratio, ROR 2.70; 95% CI 1.79-4.07) and apixaban (ROR 6.76; 95% CI 2.99-15.25). However, when the same analyses were performed using only cases without alternative causes, no statistically significant associations for rivaroxaban when compared to all other drugs (ROR 1.05; 95% CI 0.54-2.02) or warfarin (ROR 0.79; 95% CI 0.47-1.32) were found. For apixaban, we found a statistically significant ROR for induced abortion when compared to all other drugs or warfarin. For the majority of cases claiming DOACs-induced teratogenic effects, spontaneous or induced abortion there was at least one alternative cause explaining the occurrence of the adverse events. For rivaroxaban, when cases without confounders were considered, no safety signals emerged. However, for apixaban, we found a potential safety signal suggesting an increased probability of reporting spontaneous/induced abortion rather than other events when compared to all other drugs or warfarin.

Monitoring CAR-T-Cell Therapies Using the Nordic Healthcare Databases.

Following intense research efforts, modulation of the immune system has finally proved to be a viable approach for treating malignant disease. Recently, chimeric antigen receptor redirected T cells have achieved promising outcomes in patients with B-cell malignancies and they are currently also being investigated in other haematological malignancies, solid tumours and viral infections. Compared with traditional biopharmaceuticals, the properties of genetically modified chimeric antigen receptor redirected T-cell therapies differ in many aspects, thereby posing challenges in terms of post-authorisation data collection and data analysis. We believe that the network of population-based Nordic healthcare databases has some characteristics that can help provide important data on these new types of advanced products. In particular, the possibility of very long follow-up periods with a limited loss to follow-up is an important strength. Given the limited source population and slow access to data, a Nordic chimeric antigen receptor redirected T-cell monitoring project should be seen as complementary to other surveillance initiatives.

The effectiveness of direct to healthcare professional communication - A systematic review of communication factor studies.

BACKGROUND: Direct to healthcare professional communication (DHPC) is the prevalent regulatory measure to inform about and potentially mitigate newly identified drug risks in EU and USA. According to multiple studies and reviews, however, the effectiveness of DHPC to reduce risk is less than optimal. Prior systematic reviews have indicated that contextual, qualitative knowledge of communication factors related to the clinical setting is needed to further explain and supplement findings in quantitative effectiveness studies. OBJECTIVES: This article systematically reviews studies of DHPC and, on that basis, describes the communication factors that influence the effectiveness of DHPC in order to discuss future research trajectories. METHODS: PubMed, Scopus (including Embase) and Web of Science databases were searched for studies on communication about emergent drug risk to healthcare professionals, excluding studies limited to the quantifiable effect of communication. The search results were deductively categorized using the Communication Sequence Model. Then, prevalent themes within categories were identified and described using thematic analysis. RESULTS: A total of 16 studies published between 1993 and 2017 were included; 12 based on surveys, 2 on document analysis, and 2 primarily on interviews. The prevalent themes included "Health Care Professionals (HCPs) have less trust in communication from industry than authorities and medical associations", "HCPs have diverse preferences for how to receive drug risk information" and "Clinical usability of the presented information is less than optimal." CONCLUSION: Communication factors in DHPCs are multiple, multi-facetted and are examined primarily by surveys. Future research would benefit from identifying nationally dependent factors and employing methods that better provide knowledge on the qualitative reception and handling of drug risk communication.

On pharmaceutical risk minimization.

Current regulatory guidelines related to pharmaceutical risk minimization put most emphasis on risk communication and control of the use of drugs. Little, if any, consideration is given to those aspects of an adverse drug reaction that ultimately determine whether the risk can be minimized. However, this limited scope is unfortunate and could prevent risk minimization activities from improving drug use safety. This article attempts to present an overview of possible elements of pharmaceutical risk minimization and to place these in a framework. The promotion of drug safety through risk communication and control of use should be advanced, with more attention to actionable and evidence-based guidance relating to the 'pretreatment evaluation', and in particular the 'on-treatment management' of the patient.

Use of the dose, time, susceptibility (DoTS) classification scheme for adverse drug reactions in pharmacovigilance planning.

In the process of conceiving a pharmacovigilance plan, as proposed in the International Conference on Harmonisation E2E guideline, the challenge will be how to address possible safety issues with a set of appropriate pharmacovigilance methods. For successful planning, the various and sometimes complex dimensions of the adverse drug reaction in question have to be appropriately described. In order to accommodate these better, a 3-dimensional approach, based on dose, time and patient susceptibility, has recently been proposed (the DoTS model). This approach offers a way of presenting the various dimensions of the problem graphically. The aim of this article is to propose how an extended DoTS model, applied to three different scenarios, could give a better understanding of adverse drug reactions and assist in preparing a pharmacovigilance plan.

From protocol to published report: a study of consistency in the reporting of academic drug trials.

BACKGROUND: Unacknowledged inconsistencies in the reporting of clinical trials undermine the validity of the results of the trials. Little is known about inconsistency in the reporting of academic clinical drug trials. Therefore, we investigated the prevalence of consistency between protocols and published reports of academic clinical drug trials. METHODS: A comparison was made between study protocols and their corresponding published reports. We assessed the overall consistency, which was defined as the absence of discrepancy regarding study type (categorized as either exploratory or confirmatory), primary objective, primary endpoint, and--for confirmatory trials only--hypothesis and sample size calculation. We used logistic regression, χ(2), and Fisher's exact test. RESULTS: A total of 282 applications of academic clinical drug trials were submitted to the Danish Health and Medicines Authority in 1999, 2001, and 2003, 95 of which fulfilled the eligibility criteria and had at least one corresponding published report reporting data on trial subjects. Overall consistency was observed in 39% of the trials (95% CI: 29 to 49%). Randomized controlled trials (RCTs) constituted 72% (95% CI: 63 to 81%) of the sample, and 87% (95% CI: 80 to 94%) of the trials were hospital based. CONCLUSIONS: Overall consistency between protocols and their corresponding published reports was low. Motivators for the inconsistencies are unknown but do not seem restricted to economic incentives.

The precautionary principle and pharmaceutical risk management.

Although it is often vigorously contested and has several different formulations, the precautionary principle has in recent decades guided environmental policy making in the face of scientific uncertainty. Originating from a criticism of traditional risk assessment, the key element of the precautionary principle is the justification for acting in the face of uncertain knowledge about risks. In the light of its growing invocation in various areas that are related to public health and recently in relation to drug safety issues, this article presents an introductory review of the main elements of the precautionary principle and some arguments conveyed by its advocates and opponents. A comparison of the characteristics of pharmaceutical risk management and environmental policy making (i.e. the setting within which the precautionary principle evolved), indicates that several important differences exist. If believed to be of relevance, in order to avoid arbitrary and unpredictable decision making, both the interpretation and possible application of the precautionary principle need to be adapted to the conditions of pharmaceutical risk management.

The influence of lithium on the antidiuretic effect of desmopressin.

The objective of this study was to investigate the graded influence from lithium on the antidiuretic effects of desmopressin. Eight healthy male subjects participated in this open, randomised cross-over study with two periods comprising 6 days each. For each subject, one of the study days (6th day) was preceded by a period of lithium treatment. On the study days the subjects were orally water loaded to achieve a state of overhydration with a high urine flow rate. When a steady-state diuresis was achieved after approximately 2 h, 0.396 microg of desmopressin was administered intravenously as a bolus injection. An indirect-response model, where desmopressin was assumed to inhibit the elimination of response, was fitted to the urine osmolarity data. The effects of the independent variables, Uflow(baseline) (baseline urine flow rate), R0 (baseline osmolarity) and serum lithium concentration, on IC50 (concentration producing 50% of the maximum inhibition) could be expressed by multiple linear regression. In conclusion, we found that an indirect-response model can be a useful tool in investigating and describing the pharmacodynamic interaction between drugs, in this particular case, between lithium and desmopressin.

A pharmacokinetic and pharmacodynamic study of desmopressin: evaluating sex differences and the effect of pre-treatment with piroxicam, and further validation of an indirect response model.

Desmopressin is a synthetic vasopressin analogue mainly used in treatment of diabetes insipidus and nocturia. Studies in rats have revealed a sex difference in the response to a vasopressin infusion, which was diminished after treatment with an NSAID. This study was performed in man to investigate the influence of sex and concomitant treatment of piroxicam on the pharmacokinetics and dynamics of desmopressin, and to validate a previously described indirect response model. Eight healthy males and eight healthy females participated in the trial, which was conducted in a pharmacokinetic (PK) part followed by a pharmacodynamic (PD) part. Desmopressin was administered intravenously as a single dose (PK = dose 2 microg, PD = dose 0.2 microg). Piroxicam was administered to achieve steady state. The pharmacokinetic parameters of desmopressin were estimated and calculated by means of two-compartmental analysis. In the dynamic part a study design based on an oral hydration model was used. Parameters for urine flow and urine osmolality were estimated. Individual estimates of the pharmacokinetic parameters served as input to the indirect response model that subsequently was fitted to urine osmolality data. The pharmacokinetics of desmopressin after a fixed bolus injection was neither influenced by piroxicam nor sex of the subject. The pharmacodynamics of desmopressin showed a sex difference where females exhibited a more pronounced antidiuretic effect than males, which was statistically significant when the effects were submaximal (>4.5 h after dose). The sex differences were diminished after pre-treatment with piroxicam, indicating a prostaglandin PGE(2)-mediated mechanism. The indirect response model was confirmed, although the modelling could not distinguish a sex difference, indicating a limitation of this model compared with traditional descriptive statistics.

Efficacy and safety of dabigatran etexilate and warfarin in "real-world" patients with atrial fibrillation: a prospective nationwide cohort study.

OBJECTIVES: The aim of this study was to assess the efficacy and safety in an "everyday clinical practice" population of anticoagulant-naïve patients with atrial fibrillation (AF) treated with dabigatran etexilate after its post-approval availability in Denmark, compared with warfarin. BACKGROUND: Concerns have been raised about an excess of bleeding events or myocardial infarction (MI) among patients treated with the new oral direct thrombin inhibitor, dabigatran etexilate. METHODS: From the Danish Registry of Medicinal Product Statistics, we identified a dabigatran-treated group and a 1:2 propensity-matched warfarin-treated group of 4,978 and 8,936, respectively. Comparisons on efficacy and safety outcomes were made on the basis of Cox-proportional hazards models stratified on propensity-matched groups. RESULTS: Stroke and systemic embolism were not significantly different between warfarin- and dabigatran-treated patients. Adjusted mortality was significantly lower with both dabigatran doses (110 mg b.i.d., propensity-match group stratified hazard ratio [aHR]: 0.79, 95% confidence interval [CI]: 0.65 to 0.95; 150 mg b.i.d., aHR: 0.57, 95% CI: 0.40 to 0.80), when compared with warfarin. Pulmonary embolism was lower compared with warfarin for both doses of dabigatran. Less intracranial bleeding was seen with both dabigatran doses (110 mg b.i.d., aHR: 0.24, 95% CI: 0.08 to 0.56; 150 mg b.i.d., aHR: 0.08, 95% CI: 0.01 to 0.40). The incidence of MI was lower with both dabigatran doses (110 mg b.i.d., aHR: 0.30, 95% CI: 0.18 to 0.49; 150 mg b.i.d., aHR: 0.40, 95% CI: 0.21 to 0.70). Gastrointestinal bleeding was lower with dabigatran 110 mg b.i.d. (aHR: 0.60, 95% CI: 0.37 to 0.93) compared with warfarin but not dabigatran 150 mg b.i.d. The main findings were broadly consistent in a subgroup analysis of dabigatran users with ≥1-year follow-up (median follow-up 13.9 months [interquartile range: 12.6 to 15.3 months]). CONCLUSIONS: In this "everyday clinical practice" post-approval nationwide clinical cohort, there were similar stroke/systemic embolism and major bleeding rates with dabigatran (both doses) compared with warfarin. Mortality, intracranial bleeding, pulmonary embolism, and MI were lower with dabigatran, compared with warfarin. We found no evidence of an excess of bleeding events or MI among dabigatran-treated patients in this propensity-matched comparison against warfarin, even in the subgroup with ≥1-year follow-up.

Spontaneous reporting of adverse events following immunisation against pandemic influenza in Denmark November 2009-March 2010.

Our study reviews the spontaneous reports of adverse events following immunisation submitted to the Danish Medicines Agency during the 2009-2010 influenza A/H1N1v season. During the study period (4 November 2009-31 March 2010), 607 reports comprising 1885 adverse events were reported among 339,507 influenza A/H1N1v vaccinated individuals (reporting rate, 179 per 100,000 vaccinated). The majority of individual case safety reports (85%) were submitted by physicians and other health care professionals and concerned known and non-serious reactions occurring within 1 day of vaccination (82%). Events of special interest as defined by EMA prior to vaccination campaign start, comprised 1% of all events. In conclusion, we did not observe any strong signals of any unknown or serious adverse events associated with influenza A/H1N1v vaccination in Denmark. Our experience also demonstrates the well-known limitations of spontaneous reports with respect to evaluation of a casual relationship and highlights the importance for a timely availability of background events rates and the need for new approaches to study late adverse effects following immunisation.

Temporal data mining for adverse events following immunization in nationwide Danish healthcare databases.

BACKGROUND: A rarely used opportunity in pharmacovigilance is data mining for adverse drug reactions (ADRs) in population-based healthcare databases. OBJECTIVE: To evaluate the potential of data mining for ADRs in the nationwide Danish healthcare databases. We specifically considered hospital contacts following measles, mumps and rubella (MMR) immunization. METHODS: We constructed a cohort consisting of all children born in Denmark from 1995 to 2007 (n = 918,831) with individual-level linked data on childhood vaccinations and hospital contacts from the nationwide Danish healthcare databases. We applied a cohort-based data mining methodology to compare the observed versus the expected incidence of adverse event in different time periods relative to immunization. With this approach we evaluated temporal associations between MMR immunization and 5915 different diagnoses occurring in the cohort. In order to evaluate the ability of our approach to detect signals, we singled out a set of four adverse events previously recognized as being associated with the MMR vaccine. RESULTS: We were able to link a total of 3,162,251 hospital contacts and 5915 different diagnoses to the children in the cohort. Previously recognized temporal associations between adverse events (febrile convulsions, idiopathic thrombocytopenic purpura, lymphadenopathy and rash) and MMR immunization were identified in the Danish databases by our method. CONCLUSIONS: Data mining in the Danish population-based healthcare databases provides adequate ability to detect adverse events. Pharmacovigilance using electronic healthcare databases holds potential as an important supplement to traditional pharmacovigilance.

Human papillomavirus immunisation of adolescent girls and anticipated reporting of immune-mediated adverse events.

Determining incidence rates of potential adverse events before and after an immunisation programme is initiated, provides a useful framework for the evaluation of vaccine safety concerns. Human papillomavirus vaccination (HPV) of adolescent girls has recently been introduced in Denmark. Using a nationwide hospitalisation registry we estimated incidence rates of immune-mediated disorders before HPV vaccination in a cohort of 418,289 Danish girls aged 12-15 years. We further estimated the expected number of cases of immune-mediated disorders occurring in temporal relationship to a hypothetical HPV vaccination schedule purely by chance. Our results and analytical approach provides a framework for the evaluation of adverse event reports following immunisation of adolescent girls.