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The premature marketing of investigational stem cell interventions (SCIs) is a growing market in the US. Several US states have passed legislation to permit and promote unproven and experimental SCIs for individuals with terminal or chronic diseases. These SCI medical freedom laws, which are largely based on right-to-try legislation, increase access to experimental SCIs with little to no oversight. They undermine federal regulatory authority and can compromise patient safety and informed decision-making. SCI medical freedom laws have gone largely unnoticed by scientific societies interested in the responsible translation of stem cell medicine. In this article, we analyze state SCI medical freedom laws and describe their detrimental impact on patients and society. We contend that scientific and medical societies are uniquely poised to advocate against state-based policy promoting unproven SCIs but recognize resource and other constraints to advocate for or against legislation in 50 states. We recommend societies establish coalitions and share resources to address state-based SCI medical freedom laws and other legislation surrounding unproven SCIs.
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Seguridad del Paciente , Células Madre , Humanos , Estados Unidos , LibertadRESUMEN
INTRODUCTION: Accessing compassionate access schemes to obtain novel therapeutic agents for children with hard-to-treat cancers can be fraught with challenges such as regulatory barriers and limited resources. This study aimed to explore clinician perspectives on the barriers, impacts and ethical considerations of accessing novel therapeutic agents within the context of a paediatric oncology precision medicine trial. METHODS: We gathered data from 37 semi-structured interviews with paediatric oncologists participating in the PRecISion Medicine for Children with Cancer (PRISM) study, a precision medicine clinical trial in Australia. The interviews, conducted over 2 years, focused on paediatric oncologist's experiences with the PRISM trial. Interviews were re-analysed to identify themes related to access pathways and any challenges in obtaining novel agents through thematic analysis. The resulting thematic framework was discussed and refined by a multidisciplinary team. RESULTS: Three main themes were identified: (i) barriers to access, including poor drug availability, lack of evidence and the time burden of the application process; (ii) impacts of inaccessibility, encompassing medical consequences and financial burden on families; and (iii) ethical considerations, centred around balancing realistic expectations and providing compassionate care to patients and families. Paediatric oncologists expressed frustration with the complex regulatory landscape and the lack of systematic reporting on applications and outcomes of obtaining novel agents. Lengthy wait times for decision notifications were also highlighted, raising concerns about missed therapeutic opportunities for patients. CONCLUSION: This study provides insight to the challenges faced when seeking access to novel therapies for paediatric oncology patients. There is a clear need for improved communication, streamlining processes and increased resources to facilitate access to novel agents. Further resource development is necessary to address these complexities in accessing novel therapy agents to ultimately ensure equitable and timely access.
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Accesibilidad a los Servicios de Salud , Neoplasias , Medicina de Precisión , Humanos , Neoplasias/terapia , Niño , Femenino , Masculino , Oncólogos , AustraliaRESUMEN
BACKGROUND: Hereditary transthyretin (ATTRv, v for variant) amyloidosis with polyneuropathy is a rare disease caused by mutations in the transthyretin gene. In ATTRv amyloidosis, multisystem extracellular deposits of amyloid cause tissue and organ dysfunction. Patisiran is a small interfering RNA molecule drug that reduces circulating levels of mutant and wild-type TTR proteins. Prior to its regulatory approval, patisiran was available in Italy through a compassionate use programme (CUP). The aim of this study was to analyse the long-term outcomes of patients who entered into the CUP. METHODS: This was a multicentre, observational, retrospective study of patients with ATTRv amyloidosis treated with patisiran. The analysis included change from baseline to 12, 24, 36 and 48 months in familial amyloid polyneuropathy (FAP) stage, polyneuropathy disability (PND) class, neuropathy impairment score (NIS), modified body mass index (mBMI), Compound Autonomic Dysfunction Test (CADT), Karnofsky Performance Status (KPS) scale and Norfolk Quality of Life-Diabetic Neuropathy (QoL-DN) questionnaire. Safety data were also analysed. RESULTS: Forty patients from 11 Italian centres were enrolled: 23 in FAP 1 (6 in PND 1 and 17 in PND 2) and 17 in FAP 2 (8 in PND 3a and 9 in PND 3b) stage. In this population, the mean NIS at baseline was 71.4 (± 27.8); mBMI, 917.1 (± 207) kg/m2; KPS, 67.1 (± 14.0); Norfolk QoL-DN, 62.2 (± 25.2); and CADT, 13.2 (± 3.3). Statistical analysis showed few significant differences from baseline denoting disease stability. No new safety signals emerged. CONCLUSIONS: Patisiran largely stabilised disease in patients with ATTRv amyloidosis.
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Neuropatías Amiloides Familiares , Humanos , Neuropatías Amiloides Familiares/tratamiento farmacológico , Neuropatías Amiloides Familiares/complicaciones , Italia , Masculino , Femenino , Persona de Mediana Edad , Estudios Retrospectivos , Anciano , Resultado del Tratamiento , ARN Interferente Pequeño/uso terapéutico , Calidad de VidaRESUMEN
Anxiety is one of the common psychological problems among infertile women, which affects their quality of life. The purpose of this study was to compare the effects of self-compassion intervention based on a religious and non-religious perspective regarding the anxiety and quality of life of infertile women. A randomized clinical trial design with experimental and control groups was used. A total of 78 infertile women who lived in Yazd province, Iran, were referred to Yazd reproductive sciences institute, were selected by available sampling and randomly assigned to two experimental and one control groups. The participants of the first experimental group received eight sessions of self-compassion-focused intervention based on religious instructions. The second experimental group received eight sessions of non-religious self-compassion intervention, while the control group was put on the waiting list. Data were collected using Quality of Life in Infertile Couples Questionnaire (QOLICQ) and Beck anxiety inventory (BDI) in the pretest, posttest and 2-month follow-up phases and then analyzed using repeated measures as well as one-way analysis of variance. The results showed as compared to control group at the posttest and follow-up phases, the quality of life (p < 0.001) and anxiety (p < 0.001) of infertile women increased and decreased, respectively, across both experimental groups. Comparison of experimental groups showed that although the difference between the two groups in the subscales of social relationships and sexual satisfaction was not significant, the gain scores of quality of life and anxiety were significantly greater in the first experimental group. These findings indicate that given the religious background of infertile women, religious self-compassion intervention can be relatively more effective in improving the quality of life and anxiety of infertile women than non-religious intervention.
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Cefiderocol is an option for infections caused by multidrug-resistant Pseudomonas aeruginosa, but its in vitro activity against these isolates and its clinical effectiveness for isolates with MICs of >1 µg/mL is unclear. We investigated the in vitro activity of cefiderocol against P. aeruginosa isolates collected from patients treated with cefiderocol through the compassionate use program and assessed physician-reported clinical response and 28-day all-cause mortality by cefiderocol MIC values. P. aeruginosa isolates underwent susceptibility testing to cefiderocol and comparator agents by using reference broth microdilution. U.S. Food and Drug Administration (FDA; susceptible, ≤1 µg/mL) and Clinical and Laboratory Standards Institute (CLSI; susceptible, ≤4 µg/mL) cefiderocol breakpoints were applied. Additionally, molecular characterization of ß-lactamase genes was performed. Clinical response and vital status were reported by treating physicians. Forty-six patients with P. aeruginosa infections were evaluated. Twenty-nine (63%) and 42 (91%) isolates were susceptible to cefiderocol using FDA and CLSI breakpoints, respectively. Thirty-seven (80%) and 32 (70%) isolates were not susceptible to ceftolozane-tazobactam and ceftazidime-avibactam, respectively. The clinical response rate was 69% (20/29) with a cefiderocol MIC of ≤1 µg/mL, 69% (9/13) with a cefiderocol MIC of 2 to 4 µg/mL, and 100% (4/4) with an MIC of ≥8 µg/mL, while day 28 all-cause mortality rates were 23% (6/26; MIC ≤ 1 µg/mL), 33% (4/12; MIC, 2 to 4 µg/mL), and 0% (0/4; MIC ≥8 µg/mL), respectively. Cefiderocol was active in vitro against most P. aeruginosa isolated from patients with limited or no alternative therapies. Patients with cefiderocol MICs of 2 to 4 µg/mL did not have significantly worse outcomes than those with MICs of ≤1 µg/mL.
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Antibacterianos , Infecciones por Pseudomonas , Humanos , Antibacterianos/farmacología , Antibacterianos/uso terapéutico , Pseudomonas aeruginosa , Ensayos de Uso Compasivo , Infecciones por Pseudomonas/tratamiento farmacológico , Cefalosporinas/farmacología , Cefalosporinas/uso terapéutico , Ceftazidima/farmacología , Carbapenémicos/farmacología , Carbapenémicos/uso terapéutico , Pruebas de Sensibilidad Microbiana , Farmacorresistencia Bacteriana Múltiple/genética , CefiderocolRESUMEN
Patient interest in non-trial access pathways to investigational cell-and gene-based interventions, such as expanded access in the USA, is increasing, while the regulatory and business environments for non-trial access in the cell and gene therapy field are shifting. Against this background, in 2022 the International Society for Cell & Gene Therapy (ISCT) established a Working Group on Expanded Access to identify practical, ethical, and regulatory issues emerging from the use (and possible misuse) of the expanded access pathway in the cell and gene therapy field. In this Short Report, the Working Group sets the stage for its future activities by analyzing the history of expanded access and identifying three examples of questions that we anticipate arising as uses of expanded access for investigational cell and gene-based interventions increase and evolve.
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Ensayos de Uso Compasivo , Drogas en Investigación , Humanos , Terapia Genética , Ingeniería GenéticaRESUMEN
INTRODUCTION: In Europe, despite recent advances in clinical development, most of the drugs currently used to treat childhood cancers are adult medicines, prescribed outside of the authorized indication. In this context, a monocentric retrospective cohort analysis was conducted, evaluating pediatric, adolescent, and young adult patients affected by onco-hematologic disease, treated with targeted therapies used off-label or as compassionate use. METHODS: The analysis was conducted on 45 patients aged less than or equal to 30 years with cancer, having received at least one targeted therapy prescribed as off-label or compassionate use at a large Italian pediatric center between January 1, 2016 and June 30, 2021. Data collected included information on the patient and tumor, data on off-label/compassionate treatment, and data on safety and efficacy. RESULTS: Total 25 out of 45 patients treated with off-label or compassionate targeted therapies were affected by onco-hematological diseases. Overall, 22 out of the 52 agents (42%) were prescribed in patients with relapsed neoplasm and 39% (20/52) in patients with refractory diseases. Complete response was observed in more than half (27/52) of treatments. At least one adverse reaction occurred in 76% (n = 22) of agents administered to patients with onco-hematological tumor and in 43% (n = 10) of agents prescribed to patients with solid tumor. CONCLUSION: This work aims to provide a snapshot of off-label and compassionate use prescriptions in a large Italian pediatric cancer center. This study confirms that targeted agents for unauthorized indications are often prescribed in pediatric patients with cancer, especially after disease relapse and that these treatments are mostly tolerable and effective.
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Ensayos de Uso Compasivo , Uso Fuera de lo Indicado , Adolescente , Adulto Joven , Niño , Humanos , Estudios Retrospectivos , Recurrencia Local de Neoplasia , ItaliaRESUMEN
INTRODUCTION: Favipiravir, an antiviral agent with activity against SARS-CoV-2, was made available to hospitals in Japan for off-label use among COVID-19 patients between 2020 and 2021. METHODS: A nationwide observational cohort study was conducted on patients who received favipiravir as part of clinical care between February 2020 and December 2021. Information was collected on demographics, comorbidities, severity of illness, use of favipiravir and other medications targeting COVID-19, adverse events, clinical status at 7 and 14 days and clinical outcome one month after admission to the hospital. RESULTS: A total of 17,508 hospitalized patients who received favipiravir were registered from 884 hospitals. In terms of demographics, 55.9% were age ≥60 years, and 62.3% were male. At least one of the four surveyed comorbidities was present in 45.5% of the patients. The rates of clinical improvement at 7 and 14 days were 72.4ï¼ and 87.5%, 61.4% and 76.6%, and 45.4% and 59.5% for mild, moderate, and severe diseases, respectively. The case fatality rates within a month from hospitalization were 3.3%, 12.6%, and 29.1% for mild, moderate, and severe diseases, respectively. Significant correlations were observed between death and advanced age, male sex, moderate or severe disease, diabetes, cardiovascular diseases, and immunosuppression. Commonly reported adverse events included uric acid level increase or hyperuricemia (16.8%), liver function abnormalities (6.9%), and rash (1.0%). CONCLUSIONS: Favipiravir was well tolerated among COVID-19 patients. The study provides insights into the use of this agent at hospitals across Japan in the early phase of the pandemic.
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COVID-19 , Humanos , Masculino , Persona de Mediana Edad , Femenino , SARS-CoV-2 , Amidas/efectos adversos , Antivirales/efectos adversos , Estudios de Cohortes , Resultado del TratamientoRESUMEN
This review is an outlook on CAR-T development up to the beginning of 2023, with a special focus on the European landscape and its regulatory field, highlighting the main features and limitations affecting this innovative therapy in cancer treatment. We analysed the current state of the art in the EU and set out a showcase of the field's potential advancements in the coming years. For this analysis, the data used came from the available scientific literature as well as from the European Medicines Agency and from clinical trial databases. The latter were investigated to query the studies on CAR-Ts that are active and/or relevant to the review process. As of this writing, CAR-Ts have started to move past the "ceiling" of third-line treatment with positive results in comparison trials with the Standard of Care (SoC). One such example is the trial Zuma-7 (NCT03391466), which resulted in approval of CAR-T products (Yescarta™) for second-line treatment, a crucial achievement for the field which can increase the use of this type of therapy. Despite exciting results in clinical trials, limitations are still many: they regard access, production, duration of response, resistance, safety, overall efficacy, and cost mitigation strategies. Nonetheless, CAR-T constructs are becoming more diverse, and the technology is starting to produce some remarkable results in treating diseases other than cancer.
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Neoplasias , Receptores Quiméricos de Antígenos , Humanos , Inmunoterapia Adoptiva/métodos , Neoplasias/tratamiento farmacológico , Receptores Quiméricos de Antígenos/uso terapéutico , Tecnología , Ensayos Clínicos como AsuntoRESUMEN
BACKGROUND: Patients with immunodeficiency-associated antibody disorders are at a higher risk of prolonged/persistent COVID-19 infection, having no viable treatment options. METHODS: A retrospective analysis of patients with primary and/or secondary immunodeficiency-associated antibody disorders who received casirivimab and imdevimab (REGEN-COV®) under emergency compassionate use. Objective were to describe safety and response to REGEN-COV, focusing on the subset of patients who had COVID-19 duration ≥21 days before treatment. RESULTS: Quantitative (change in oxygenation status and/or viral load) and/or qualitative (physician-reported clinical status) outcomes data are reported from 64 patients. Improvement in ≥1 outcome was observed in 90.6% of the overall patient group. Thirty-seven of these had COVID-19 duration ≥21 days before treatment; median time from diagnosis to REGEN-COV treatment was 60.5 days. Of the 29 patients with COVID-19 duration ≥21 days before treatment and available outcome data, 96.6% showed improvement in ≥1 outcome. In the 14 patients with post-treatment reverse transcription-polymerase chain reaction (RT-PCR) results available, 11 (78.6%) reported a negative RT-PCR following treatment, with 5 (45.5%) and 8 (72.7%) patients reporting a negative RT-PCR within 5 days and 21 days of treatment, respectively. Ten of 85 patients (11.8%) experienced serious adverse events; only one was an infusion-related reaction, possibly related to REGEN-COV. Two deaths were reported; neither were attributed to REGEN-COV. CONCLUSIONS: In this retrospective analysis of immunodeficient patients granted REGEN-COV under emergency compassionate use, REGEN-COV treatment was associated with rapid viral clearance and clinical improvement in patients with longstanding COVID-19. Adverse events were consistent with COVID-19 and its associated complications, and due to patients' concurrent medical conditions.
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Tratamiento Farmacológico de COVID-19 , Anticuerpos Monoclonales Humanizados , Anticuerpos Neutralizantes , Ensayos de Uso Compasivo , Combinación de Medicamentos , Humanos , Estudios Retrospectivos , SARS-CoV-2RESUMEN
AIM: This paper describes the emergency, compassionate use of the COVID-19 vaccination for high-risk adolescents aged 12-15 years prior to approval by the American Food and Drugs Administration in May 2021. The target audience had underlying health conditions associated with severe disease and multisystem inflammatory syndrome in children (MIS-C) or severely immunosuppressed household members. METHODS: An orderly approval system was established in Israel for adolescents aged 12-15 years, based on a professional position paper and compassionate treatment regulations. From 12 February 2021, eligible adolescents were referred to the Israeli Ministry of Health for permission to vaccinate, via four health maintenance organisations. Data were collected about adverse events after vaccinations and the incidence of any cases of COVID-19. RESULTS: By 15 March 2021, the vaccine had been approved for 607 adolescents: 333 had received one dose, and 92 had received two doses. The median age was 14.6 years, and the major indication was obesity. Only one child tested positive for the virus, 4 days after vaccination, and no adverse effects were recorded. CONCLUSION: The emergency use of COVID-19 vaccination for 333 adolescents aged 12-15, 92 of them with 2 doses, based on a position paper and compassionate treatment regulations, did not result in any adverse effects. Since 27 July 2021, the same process was further applied in Israel among younger children, aged 5-11, preceding formal release of the clinical trial.
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Vacunas contra la COVID-19 , COVID-19 , Adolescente , COVID-19/complicaciones , COVID-19/prevención & control , Vacunas contra la COVID-19/efectos adversos , Niño , Preescolar , Ensayos de Uso Compasivo , Humanos , Israel , SARS-CoV-2 , Síndrome de Respuesta Inflamatoria Sistémica , Estados Unidos , VacunaciónRESUMEN
AIM: Safe, effective SARS-CoV-2 treatment has not yet been determined, though some drugs have favourable mortality and morbidity benefits in specific situations. No treatments have been explicitly tested in children, who are, therefore, once again therapeutic orphans. METHOD: We echo calls to enrol patients, including children, into trials but those children recruited to date have largely been additions to adult studies. Few were recruited during the initial pandemic despite the emergence of PIMS-TS/MIS-C, which surely demands paediatric-specific research. RESULT: Must children be proscribed treatments effective in adults until child-specific data emerges, even in a pandemic? Will appropriately powered dedicated trials ever determine specific child-COVID-19 treatment pathways? Is the protracted time frame to assemble such data acceptable to children with severe COVID-19 today? Such factors are relevant in considering whether children should have access to compassionate, innovative, pandemic-disease treatment. CONCLUSION: We argue that children should be permitted, indeed have a right, to access innovative treatments early in any future pandemic, following an individual best interests consideration. This will remain the case until formal studies powered to determine children's optimal treatment commence, when the moral duty switches to ensuring children are enrolled, with any preceding innovative-use data made available to researchers.
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Tratamiento Farmacológico de COVID-19 , COVID-19 , Adulto , COVID-19/complicaciones , Empatía , Humanos , SARS-CoV-2 , Síndrome de Respuesta Inflamatoria SistémicaRESUMEN
When seriously ill patients reach the end of the standard treatment trajectory for their condition, they may qualify for the use of unapproved, investigational drugs regulated via expanded access programs. In medical-ethical discourse, it is often argued that expanded access to investigational drugs raises 'false hope' among patients and is therefore undesirable. We set out to investigate what is meant by the false hope argument in this discourse. In this paper, we identify and analyze five versions of the false hope argument which we call: (1) the limited chance at benefit argument, (2) the side effects outweighing benefits argument, (3) the opportunity costs argument, (4) the impossibility of making informed decisions argument, and (5) the difficulty of gaining access argument. We argue that the majority of these five versions do not provide normative ground for disqualifying patients' hopes as false. Only when hope is rooted in a mistaken belief, for example, about the likelihood of benefits or chances on medical risks, or when hope is directed at something that cannot possibly be obtained, should it be considered false. If patients are adequately informed about their odds of obtaining medical benefit, however small, and about the risks associated with an investigational treatment, it is unjustified to consider patients' hopes to be false, and hence, to deny them access to investigational drug based on that argument.
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Ensayos de Uso Compasivo , Drogas en Investigación , Humanos , Drogas en Investigación/efectos adversos , Disentimientos y Disputas , InvestigaciónRESUMEN
Definition of the problem: Compassionate use is the use of unapproved drugs in groups of patients suffering from a disease that, in the absence of an alternative treatment option, is life-threatening or leads to severe disability. Physicians are not in charge because access to the drug is only granted by pharmaceutical companies, which comes along with many ethical issues. Launched in 2020, the program of Onasemnogenum abeparvovecum against spinal muscular atrophy in children reached a new dimension. The intent of this drug is to stop the progression of the disease with just a single dose, but the company limited the doses in the program to only 100. The global allocation was by lottery, which was considered a novelty in compassionate use history and therefore widely criticized. This paper investigates alternative allocation principles. Arguments: Each possible principle is accompanied by many aspects that need to be considered with regard to urgency and global distribution. This makes some principles like first-come-first-served seem negligible. Remaining principles are ordered hierarchically to derive an algorithm that can represent an alternative to a lottery. A combination of willingness to participate in research, urgency, and likelihood of success (relative to the availability of supportive treatment options) may be considered in similar cases in future global compassionate use programs with children. Conclusion: Since universal algorithms are difficult to define, allocation criteria should always be discussed by an independent panel of experts. Both the constitution of such a panel and its mandatory consultation are necessary in order to decrease the burden for all those involved and to prevent arbitrariness.
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Expanded access is a treatment use of investigational drugs, biologicals or medical devices outside of clinical trials. The purpose of our study was to assess self-reported conflicts of interest (COIs) in oncology expanded access studies. One hundred fifty-eight oncology expanded access studies published from 2013 through 2020 were included. The pharmaceutical industry funded either completely or in part 94 studies (59.49%). The authors disclosed mostly financial COIs, while the number of the reported nonfinancial conflicts was relatively small (3528 and 57 COIs, respectively). The number of articles in which at least one author had a financial COI was 118 (74.68%). The most common financial COI types included advisory board membership/consulting (1471 COIs; 41.7%), followed by honoraria (570 COIs; 16.16%) and research funding (441 COIs; 12.5%). Logistic regression was performed to identify predictors of disclosing financial COIs and positive study's conclusions. On univariate analysis, financial COIs were more likely to occur in studies with at least one center located in the United States (odds ratio [OR], 5.62; 95% confidence interval [CI], 1.57-35.98; P = .02). We also found that positive conclusions about the studied treatments were less likely in studies without industry funding (OR, 0.26; CI, 0.08-0.77; P = .01). Most of the research on COIs in oncology performed to date focused on other types of studies, especially clinical trials. To our knowledge, our study is the first to evaluate COIs in oncology expanded access studies.
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Ensayos de Uso Compasivo/economía , Conflicto de Intereses/economía , Revelación/estadística & datos numéricos , Oncología Médica/economía , Neoplasias/economía , Derivación y Consulta/economía , Ensayos de Uso Compasivo/métodos , Humanos , Modelos Logísticos , Oncología Médica/métodos , Análisis Multivariante , Neoplasias/terapia , AutoinformeRESUMEN
BACKGROUND: The arrival of immunotherapies and targeted therapies challenged the authorities to make them available as soon as possible. France has effective tools, such as clinical trials (CTs) and a national early access program (temporary authorizations for use [ATUs] and temporary recommendations for use [RTUs]), allowing the use of innovative drugs, whether or not they have been authorized or used off-label, for cases that have reached a therapeutic impasse. METHODS: The methodology involved real-time data collection from ATUs, RTUs (between September 1, 2009 and September 1, 2019), and CT authorizations (from December 1, 2017 to September 1, 2019) that were filed and reviewed by the French National Agency for Medicines for metastatic melanoma (MM). RESULTS: In total, 45 CTs were authorized for MM (51% early phase trials and 44% phase 2 and 3 trials), mainly for the metastatic line (86%) and with an industrial sponsor (73%). Immunotherapies and targeted therapies (63% and 24%, respectively) mostly were used in combination. Three RTUs were authorized for the adjuvant treatment of MM, whereas 13 drugs were available through nominal ATUs (nATUs), of which 5 were awarded a cohort ATU (cATU). This enabled the treatment of 6538 patients (28% through nATUs and 72% through cATUs). All of these drugs were granted marketing authorization and were included in the reimbursement list. CONCLUSIONS: Thanks to CTs and the national early access program, patients in France have been able to benefit from innovative MM treatments. LAY SUMMARY: Several tools allow the use of innovative drugs in France, even if they are not yet authorized or used off-label. From December 1, 2017 to September 1, 2019, 45 clinical trials have been authorized for metastatic melanoma, mostly using immunotherapy (63%) and targeted therapy (24%) at an early phase (51%). Since 2010, the national early access program has treated 6538 patients, including 28% under nominative temporary authorizations for use and 72% under cohort temporary authorizations for use. Fourteen drugs are available through nominative temporary authorizations for use, and 5 are available through cohort temporary authorizations for use, and all of these drugs were granted marketing authorization.
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Melanoma , Neoplasias Cutáneas , Francia , Humanos , Inmunoterapia , Melanoma/tratamiento farmacológico , Neoplasias Cutáneas/terapiaRESUMEN
AIMS: Expanded access is the use of investigational treatments outside of clinical trials. Results of expanded access studies provide insights into how investigational treatments work in real-world settings. The objective of this study was to evaluate public availability of results of expanded access studies. METHODS: Eligible expanded access studies were identified in ClinicalTrials.gov (CT.gov). Publications matching records of individual studies were searched for in Medline and Embase. In addition, we assessed whether results of the included studies were publicly available from other sources including CT.gov, sponsor web sites and conference proceedings. RESULTS: After median time of 49.5 (interquartile range, 36.7-64.7) months from study completion, the results of 69 out of the 152 included studies (45.39%) were publicly available, either as a journal publication (53 studies; 34.87%) or from other source (16 studies; 10.52%). The percentage of studies whose results were available as a journal publication after 12, 24, 36 and 48 months from study completion was 13.2, 21.1, 33.1 and 35.7%, respectively. The percentage of studies whose results were publicly available from any source (including journal publications) at 12, 24, 36 and 48 months were 19.1, 29.6, 43.2 and 47.5%, respectively. CONCLUSION: Results of a considerable proportion of expanded access studies are not publicly available. In view of the growing importance of real-world data, sponsors and principal investigators of those studies should always consider making their findings public.
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Ensayos de Uso Compasivo , Investigación , Humanos , Sistema de RegistrosRESUMEN
BACKGROUND: Compassionate use programs (CUP) for medicines respond to the ethical imperative of providing access to medicines before marketing approval to patients not recruited in trials. The economic impact of clinical trials has previously been investigated. No evidence on the net economic benefit of CUP exists. This research aims to address this information gap by estimating the economic consequences of 11 CUP in Italy conducted between March 2015 and December 2020 from the perspective of public health care system in Italy (National Health Service). Eight programs concern cancer treatments, two refer to spinal muscular atrophy, and one is indicated for multiple sclerosis. METHODS: Since CUP medicines are covered by the industry, the net economic benefit includes: (i) avoided costs of the Standard of Care (SoC) the patients would have received had they not joined the CUP, (ii) costs not covered by the pharmaceutical industry sponsor, but instead sustained by payers, such as those associated with adverse events (only severe side effects resulting in hospitalisation and attributable to CUP medicines), and (iii) costs for combination therapies and diagnostic procedures not used with the SoC. The SoC costing relied on publicly available data. Information on adverse events and diagnostic procedures was retrieved from the CUP and monetized using the relevant fee for episode or service. One CUP was excluded since a SoC was not identified. RESULTS: 2,713 patients were treated in the 11 CUP where a SoC was identified. The SoC mean cost per patient ranged from 11,415 to 20,299. The total cost of the SoC ranged between 31.0 and 55.1 million. The mean cost per patient covered by hospitals hosting CUP was equal to 1,646, with a total cost of 4.5 million. The net economic benefit ranged 26.5 million - 50.6 million. CONCLUSIONS: Despite research limitations, this paper illustrates for the first time the net economic impact of CUP from a public payer perspective. It is important to integrate these estimates with the prospective effects of CUP implementation, i.e., the economic value of the comparative benefit profile of medicines used in CUP versus the SoC, including effects from a societal perspective.
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Ensayos de Uso Compasivo , Esclerosis Múltiple , Análisis Costo-Beneficio , Humanos , Italia , Medicina EstatalRESUMEN
BACKGROUND: ClinicalTrials.gov (CT.gov) is the most comprehensive internet-based register of different types of clinical studies. Expanded access is the use of unapproved drugs, biologics, or medical devices outside of clinical trials. One of the key problems in expanded access is the availability to both health care providers and patients of information about unapproved treatments. OBJECTIVE: We aimed to evaluate CT.gov as a potential source of information about expanded access programs. METHODS: We assessed the completeness of information in the records of 228 expanded access programs registered with CT.gov from February 2017 through May 2020. Moreover, we examined what percentage of published expanded access studies has been registered with CT.gov. Logistic regression (univariate and multivariate) and mediation analyses were used to identify the predictors of the absence of some information and a study's nonregistration. RESULTS: We found that some important data were missing from the records of many programs. Information that was missing most often included a detailed study description, facility information, central contact person, and eligibility criteria (55.3%, 54.0%, 41.7%, and 17.5% of the programs, respectively). Multivariate analysis showed that information about central contact person was more likely to be missing from records of studies registered in 2017 (adjusted OR 21.93; 95% CI 4.42-172.29; P<.001). This finding was confirmed by mediation analysis (P=.02). Furthermore, 14% of the programs were registered retrospectively. We also showed that only 33 of 77 (42.9%) expanded access studies performed in the United States and published from 2014 through 2019 were registered with CT.gov. However, multivariate logistic regression analysis showed no significant association between any of the variables related to the studies and the odds of study nonregistration (P>.01). CONCLUSIONS: Currently, CT.gov is a quite fragmentary source of data on expanded access programs. This problem is important because CT.gov is the only publicly available primary source of information about specific programs. We suggest the actions that should be taken by different stakeholders to fully exploit this register as a source of information about expanded access.
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Publicaciones , Investigación , Estudios de Cohortes , Humanos , Estudios Retrospectivos , Estados UnidosRESUMEN
BACKGROUND: In recent years, an increasing spectrum of systemic therapies has become available in the field of dermatology. Some of these drugs are used off-label, which for example can lead to problems with reimbursement. This article is therefore intended to provide an overview of the currently approved systemic therapies in dermatology and to point out further alternatives such as Compassionate Use and Early Access Programs. MATERIALS AND METHODS: The search for approved drugs in Germany was conducted online in the database for drugs of the Federal Institute for Drugs and Medical Devices. In addition, a comparison was made with the information provided from the Rote Liste. RESULTS: For a total of 50 dermatologically relevant diseases, the respective approved system therapies are presented in tabular form. CONCLUSIONS: It can be stated that the enormous developments over the last few years and the increasingly good evidence offer in many cases very promising systemic treatment concepts despite the frequent lack of clinical studies in the field of dermatology. However, the often necessary off-label use can cause difficulties in everyday clinical practice. The attending physician should therefore always be informed if a planned therapy involves off-label use. Previously approved alternatives should be considered and patients should be adequately informed.