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1.
AAPS PharmSciTech ; 22(5): 172, 2021 Jun 07.
Artigo em Inglês | MEDLINE | ID: mdl-34100150

RESUMO

Vaccination development and production was an essential question for the prevention and global control of COVID-19. The strong support from governing authorities such as Operation Warp Speed and robust funding has led to the development and authorization of the tozinameran (BNT162b2) vaccine. The BNT162b2 vaccine is a lipid nanoparticle-encapsulated mRNA that encodes for SARS-CoV-2 spike protein, the main site for neutralizing antibodies. Once it binds with the host cells, the lipid nanoparticles enable the transfer of the RNA, causing S antigens' expression of the SARS-CoV-2, conferring immunity. The vaccine is administered as a 2-dose regime 21 days apart for individuals 16 years and older. Pfizer-BioNTech's BNT162b2 vaccine was the first candidate to receive FDA-Emergency Use Authorization (EUA) on December 11, 2020. During phase 2/3 clinical trials, 95% efficacy was reported among 37,706 participants over the age of 16 who received the BNT162b2 vaccination; additionally, 52% efficacy was noted 12 days following the administration of the first dose of BNT162b2, reflecting early protection of COVID-19. The BNT162b2 vaccine has exhibited 100% efficacy in clinical trials of adolescents between the ages of 12 and 15. Clinical trials in pregnant women and children under the age of 12 are expected to also exhibit promising results. This review article encompasses tozinameran (BNT162b2) vaccine journey, summarizing the BNT162b1 and BNT162b2 vaccines from preclinical studies, clinical trial phases, dosages, immune response, adverse effects, and FDA-EUA.


Assuntos
Vacinas contra COVID-19/administração & dosagem , COVID-19/prevenção & controle , Ensaios Clínicos como Assunto/métodos , Aprovação de Drogas/métodos , SARS-CoV-2/efeitos dos fármacos , Animais , Anticorpos Neutralizantes/efeitos dos fármacos , Anticorpos Neutralizantes/metabolismo , COVID-19/epidemiologia , COVID-19/metabolismo , Vacinas contra COVID-19/efeitos adversos , Vacinas contra COVID-19/metabolismo , Ensaios Clínicos como Assunto/legislação & jurisprudência , Aprovação de Drogas/legislação & jurisprudência , Avaliação Pré-Clínica de Medicamentos/métodos , Exantema/induzido quimicamente , Feminino , Humanos , Masculino , SARS-CoV-2/metabolismo , Glicoproteína da Espícula de Coronavírus/efeitos dos fármacos , Glicoproteína da Espícula de Coronavírus/metabolismo , Vacinação/legislação & jurisprudência , Vacinação/métodos
4.
Cancer Treat Rev ; 94: 102167, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33652263

RESUMO

BACKGROUND: The Fragility Indexquantifies the reliability of positive trials by estimating the number of events, which would change statistically significant results to non-significant results. METHODS: We identified randomized trials supporting drug approvals by the US FDA between 2009 and 2019 in lung, breast, prostate, and colon cancers and in melanoma. We reconstructed survival tablesand calculated the number of events, which would result in a non-significant result for the primary endpoint. The FI was then compared to the number of patients in each trial who withdrew consent or were lost to follow-up. Regression analyses were used to explore associations between RCT characteristics and FI and trials in which FI was lower or equal to number of participants who withdrew consent or were lost to follow-up. RESULTS: Among 81 RCTs, the median FI was 28. The median number of patients who withdrew consent or were lost to follow up was 27. FI was equal or lower than the number of patients who withdrew consent or were lost to follow-up in 47 trials (58%). There was a modest increase in FI over time (p = 0.02). Trials with overall survival as the primary endpoint (p = 0.006) and those in the palliative setting (p < 0.001) had lower FI. There was no association with trial sample size or duration of follow-up. FINDINGS: Statistical significance of RCTs in common solid tumours can be reversed often with a small number of additional events. Post-approval RCTs or real-world data analyses should be performed to ensure results of registration trials are robust.


Assuntos
Antineoplásicos/uso terapêutico , Neoplasias/tratamento farmacológico , Ensaios Clínicos Controlados Aleatórios como Assunto/estatística & dados numéricos , Antineoplásicos/normas , Ensaios Clínicos Fase II como Assunto/normas , Ensaios Clínicos Fase II como Assunto/estatística & dados numéricos , Ensaios Clínicos Fase III como Assunto/normas , Ensaios Clínicos Fase III como Assunto/estatística & dados numéricos , Intervalo Livre de Doença , Aprovação de Drogas/métodos , Aprovação de Drogas/estatística & dados numéricos , Humanos , Ensaios Clínicos Controlados Aleatórios como Assunto/normas , Reprodutibilidade dos Testes
8.
Biochem Pharmacol ; 189: 114424, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33482149

RESUMO

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a global pandemic. Three viral proteins, the spike protein (S) for attachment of virus to host cells, 3-chymotrypsin-like cysteine protease (Mpro) for digestion of viral polyproteins to functional proteins, and RNA-dependent-RNA-polymerase (RdRp) for RNA synthesis are the most critical proteins for virus infection and replication, rendering them the most important drug targets for both antibody and chemical drugs. Due to its low-fidelity polymerase, the virus is subject to frequent mutations. To date, the sequence data from tens of thousands of virus isolates have revealed hundreds of mutations. Although most mutations have a minimum consequence, a small number of non-synonymous mutations may alter the virulence and antigenicity of the mutants. To evaluate the effects of viral mutations on drug safety and efficacy, we reviewed the biochemical features of the three main proteins and their potentials as drug targets, and analyzed the mutation profiles and their impacts on RNA therapeutics. We believe that monitoring and predicting mutation-introduced protein conformational changes in the three key viral proteins and evaluating their binding affinities and enzymatic activities with the U.S. Food and Drug Administration (FDA) regulated drugs by using computational modeling and machine learning processes can provide valuable information for the consideration of drug efficacy and drug safety for drug developers and drug reviewers. Finally, we propose an interactive database for drug developers and reviewers to use in evaluating the safety and efficacy of U.S. FDA regulated drugs with regard to viral mutations.


Assuntos
COVID-19/tratamento farmacológico , COVID-19/genética , Mutação/genética , RNA/genética , SARS-CoV-2/genética , Glicoproteína da Espícula de Coronavírus/genética , Animais , Antivirais/metabolismo , Antivirais/uso terapêutico , COVID-19/metabolismo , Aprovação de Drogas/métodos , Desenvolvimento de Medicamentos/métodos , Desenvolvimento de Medicamentos/tendências , Humanos , RNA/metabolismo , RNA/uso terapêutico , SARS-CoV-2/efeitos dos fármacos , SARS-CoV-2/metabolismo , Glicoproteína da Espícula de Coronavírus/metabolismo
10.
BMJ ; 371: m3434, 2020 10 07.
Artigo em Inglês | MEDLINE | ID: mdl-33028575

RESUMO

OBJECTIVE: To characterize the therapeutic value of new drugs approved by the US Food and Drug Administration (FDA) and European Medicines Agency (EMA) and the association between these ratings and regulatory approval through expedited programs. DESIGN: Retrospective cohort study. SETTING: New drugs approved by the FDA and EMA between 2007 and 2017, with follow-up through 1 April 2020. DATA SOURCES: Therapeutic value was measured using ratings of new drugs by five independent organizations (Prescrire and health authorities of Canada, France, Germany, and Italy). MAIN OUTCOME MEASURES: Proportion of new drugs rated as having high therapeutic value; association between high therapeutic value rating and expedited status. RESULTS: From 2007 through 2017, the FDA and EMA approved 320 and 268 new drugs, respectively, of which 181 (57%) and 39 (15%) qualified for least one expedited program. Among 267 new drugs with a therapeutic value rating, 84 (31%) were rated as having high therapeutic value by at least one organization. Compared with non-expedited drugs, a greater proportion of expedited drugs were rated as having high therapeutic value among both FDA approvals (45% (69/153) v 13% (15/114); P<0.001) and EMA approvals (67% (18/27) v 27% (65/240); P<0.001). The sensitivity and specificity of expedited program for a drug being independently rated as having high therapeutic value were 82% (95% confidence interval 72% to 90%) and 54% (47% to 62%), respectively, for the FDA, compared with 25.3% (16.4% to 36.0%) and 90.2% (85.0% to 94.1%) for the EMA. CONCLUSIONS: Less than a third of new drugs approved by the FDA and EMA over the past decade were rated as having high therapeutic value by at least one of five independent organizations. Although expedited drugs were more likely than non-expedited drugs to be highly rated, most expedited drugs approved by the FDA but not the EMA were rated as having low therapeutic value.


Assuntos
Aprovação de Drogas , Avaliação de Medicamentos , Serviços de Informação sobre Medicamentos , Disseminação de Informação , Vigilância de Produtos Comercializados , Aprovação de Drogas/métodos , Aprovação de Drogas/estatística & dados numéricos , Avaliação de Medicamentos/métodos , Avaliação de Medicamentos/estatística & dados numéricos , Serviços de Informação sobre Medicamentos/organização & administração , Serviços de Informação sobre Medicamentos/normas , Serviços de Informação sobre Medicamentos/estatística & dados numéricos , Europa (Continente) , Humanos , Vigilância de Produtos Comercializados/métodos , Vigilância de Produtos Comercializados/estatística & dados numéricos , Desenvolvimento de Programas , Melhoria de Qualidade , Estudos Retrospectivos , Estados Unidos
11.
Anesthesiology ; 133(4): 740-749, 2020 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-32773684

RESUMO

The United States Food and Drug Administration is tasked with ensuring the efficacy and safety of medications marketed in the United States. One of their primary responsibilities is to approve the entry of new drugs into the marketplace, based on the drug's perceived benefit-risk relationship. The Anesthetic and Analgesic Drug Product Advisory Committee is composed of experts in anesthesiology, pain management, and biostatistics, as well as consumer and industry representatives, who meet several times annually to review new anesthetic-related drugs, those seeking new indications, and nearly every opioid-related application for approval. The following report describes noteworthy activities of this committee since 2017, as it has grappled, along with the Food and Drug Administration, to balance the benefit-risk relationships for individual patients along with the overarching public health implications of bringing additional opioids to market. All anesthesia advisory committee meetings since 2017 will be described, and six will be highlighted, each with representative considerations for potential new opioid formulations or local anesthetics.


Assuntos
Comitês Consultivos/normas , Analgésicos Opioides/química , Analgésicos/química , Anestésicos/química , Aprovação de Drogas/métodos , Transtornos Relacionados ao Uso de Opioides/prevenção & controle , Analgésicos/efeitos adversos , Analgésicos Opioides/efeitos adversos , Anestésicos/efeitos adversos , Congressos como Assunto/normas , Tomada de Decisões , Preparações de Ação Retardada/efeitos adversos , Preparações de Ação Retardada/química , Humanos , Oximorfona/efeitos adversos , Oximorfona/química , Compostos de Espiro/efeitos adversos , Compostos de Espiro/química , Tiofenos/efeitos adversos , Tiofenos/química , Estados Unidos
13.
PLoS One ; 15(7): e0236345, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32706800

RESUMO

Regulatory agencies around the world have been using flexible requirements for approval of new drugs, especially for cancer drugs. The US Food and Drug Administration (FDA) is mostly the first agency to approve new drugs worldwide, mainly due to the faster terms of the accelerated pathway and breakthrough therapy designation. Surrogate endpoints and preliminary data (e.g. single-arm and phase 2 studies) are used for these new approvals, however larger effect sizes are expected. We aim to compare FDA Accelerated vs Regular Pathway approvals and Breakthrough therapy designations (BTD) for lung cancer treatments between 2006 and 2018 regarding study design, sample size, outcome measures and effect size. We assessed the FDA database to collect data from studies that formed the basis of approvals of new drugs or indications for lung cancer spanning from 2006 to 2018. We found that accelerated pathway approvals are based on significantly more single-arm studies with small sample sizes and surrogate primary endpoints. However, effect size was not different between the pathways. A large proportion of studies used to support regular pathway approvals also showed these characteristics that are related to low quality and uncertain evidence. Compared to other approvals, BTD were more frequently based on single-arm studies. There was no significant difference in use of surrogate endpoints or sample size. 44% of BTD were based on studies demonstrating large effect sizes, proportionally more than approvals not receiving this designation. In conclusion, based on the indicators of evidence quality we extracted, criteria's for granting accelerated approval and breakthrough therapy designation seen not clear. Faster approvals are in the majority full of uncertainties which should be viewed with caution and the patient have to be communicated to allow shared decision making. Post-marketing validation is essential.


Assuntos
Antineoplásicos/uso terapêutico , Bases de Dados de Produtos Farmacêuticos/estatística & dados numéricos , Aprovação de Drogas/métodos , Neoplasias Pulmonares/tratamento farmacológico , United States Food and Drug Administration/estatística & dados numéricos , Humanos , Marketing , Avaliação de Resultados em Cuidados de Saúde/estatística & dados numéricos , Projetos de Pesquisa/estatística & dados numéricos , Tamanho da Amostra , Incerteza , Estados Unidos
14.
Nat Rev Drug Discov ; 19(9): 589-608, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32728208

RESUMO

Radiopharmaceutical therapy (RPT) is emerging as a safe and effective targeted approach to treating many types of cancer. In RPT, radiation is systemically or locally delivered using pharmaceuticals that either bind preferentially to cancer cells or accumulate by physiological mechanisms. Almost all radionuclides used in RPT emit photons that can be imaged, enabling non-invasive visualization of the biodistribution of the therapeutic agent. Compared with almost all other systemic cancer treatment options, RPT has shown efficacy with minimal toxicity. With the recent FDA approval of several RPT agents, the remarkable potential of this treatment is now being recognized. This Review covers the fundamental properties, clinical development and associated challenges of RPT.


Assuntos
Neoplasias/tratamento farmacológico , Compostos Radiofarmacêuticos/farmacologia , Compostos Radiofarmacêuticos/uso terapêutico , Animais , Aprovação de Drogas/métodos , Humanos , Distribuição Tecidual/fisiologia , Estados Unidos , United States Food and Drug Administration
16.
Obstet Gynecol ; 135(5): 1207-1213, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32282587

RESUMO

Before 2011, 17α-hydroxyprogesterone caproate (17P) was used to prevent recurrent preterm birth in women with singleton pregnancies and was compounded at a low cost (∼$15 per injection). In 2011, the U.S. Food and Drug Administration (FDA) approved a commercial version of 17P (trade name "Makena") through their Accelerated Approval Program, and the price of 17P subsequently increased by nearly 100-fold. This approval was largely based on a methodologically limited, placebo-controlled trial, which found that although 17P significantly reduced preterm births, the placebo group had significantly more participants with a history of preterm birth, potentially confounding the results. The FDA required a confirmatory trial for continued approval that demonstrated clinical benefit. Eight years after accelerated approval, the confirmatory trial, PROLONG (Progestin's Role in Optimizing Neonatal Gestation), found no evidence of an effect of Makena for reducing recurrent preterm birth or perinatal mortality. Trial completion triggered an automatic review of Makena by an advisory committee, which voted 9-7 to recommend revoking approval of Makena for preterm birth. Although the FDA created the Accelerated Approval Program to introduce therapies for serious conditions that lacked treatment options, Makena is an example of the limitations of this program. We encourage the FDA to re-evaluate their program and consider improvements, such as shorter timeframes to complete confirmatory trials, potentially revoking approval if the studies are not completed within a predefined timeframe, and to hold manufacturers responsible, in part, for the costs of therapy if they cannot prove a clinical benefit.


Assuntos
Caproato de 17 alfa-Hidroxiprogesterona/uso terapêutico , Ensaios Clínicos como Assunto/legislação & jurisprudência , Aprovação de Drogas/métodos , Nascimento Prematuro/prevenção & controle , United States Food and Drug Administration , Ensaios Clínicos como Assunto/métodos , Feminino , Humanos , Recém-Nascido , Mortalidade Perinatal , Gravidez , Resultado do Tratamento , Estados Unidos
17.
Lancet ; 395(10228): 986-997, 2020 03 21.
Artigo em Inglês | MEDLINE | ID: mdl-32199486

RESUMO

Fewer than half of new drugs have data on their comparative benefits and harms against existing treatment options at the time of regulatory approval in Europe and the USA. Even when active-comparator trials exist, they might not produce meaningful data to inform decisions in clinical practice and health policy. The uncertainty associated with the paucity of well designed active-comparator trials has been compounded by legal and regulatory changes in Europe and the USA that have created a complex mix of expedited programmes aimed at facilitating faster access to new drugs. Comparative evidence generation is even sparser for medical devices. Some have argued that the current process for regulatory approval needs to generate more evidence that is useful for patients, clinicians, and payers in health-care systems. We propose a set of five key principles relevant to the European Medicines Agency, European medical device regulatory agencies, US Food and Drug Administration, as well as payers, that we believe will provide the necessary incentives for pharmaceutical and device companies to generate comparative data on drugs and devices and assure timely availability of evidence that is useful for decision making. First, labelling should routinely inform patients and clinicians whether comparative data exist on new products. Second, regulators should be more selective in their use of programmes that facilitate drug and device approvals on the basis of incomplete benefit and harm data. Third, regulators should encourage the conduct of randomised trials with active comparators. Fourth, regulators should use prospectively designed network meta-analyses based on existing and future randomised trials. Last, payers should use their policy levers and negotiating power to incentivise the generation of comparative evidence on new and existing drugs and devices, for example, by explicitly considering proven added benefit in pricing and payment decisions.


Assuntos
Aprovação de Equipamentos/normas , Aprovação de Drogas/métodos , Segurança de Equipamentos , Segurança , Biomarcadores Farmacológicos/análise , Tolerância a Medicamentos , Medicina Baseada em Evidências , Humanos , Estados Unidos , United States Food and Drug Administration
18.
Lancet ; 395(10228): 998-1010, 2020 03 21.
Artigo em Inglês | MEDLINE | ID: mdl-32199487

RESUMO

Certain limitations of evidence available on drugs and devices at the time of market approval often persist in the post-marketing period. Often, post-marketing research landscape is fragmented. When regulatory agencies require pharmaceutical and device manufacturers to conduct studies in the post-marketing period, these studies might remain incomplete many years after approval. Even when completed, many post-marketing studies lack meaningful active comparators, have observational designs, and might not collect patient-relevant outcomes. Regulators, in collaboration with the industry and patients, ought to ensure that the key questions unanswered at the time of drug and device approval are resolved in a timely fashion during the post-marketing phase. We propose a set of seven key guiding principles that we believe will provide the necessary incentives for pharmaceutical and device manufacturers to generate comparative data in the post-marketing period. First, regulators (for drugs and devices), notified bodies (for devices in Europe), health technology assessment organisations, and payers should develop customised evidence generation plans, ensuring that future post-approval studies address any limitations of the data available at the time of market entry impacting the benefit-risk profiles of drugs and devices. Second, post-marketing studies should be designed hierarchically: priority should be given to efforts aimed at evaluating a product's net clinical benefit in randomised trials compared with current known effective therapy, whenever possible, to address common decisional dilemmas. Third, post-marketing studies should incorporate active comparators as appropriate. Fourth, use of non-randomised studies for the evaluation of clinical benefit in the post-marketing period should be limited to instances when the magnitude of effect is deemed to be large or when it is possible to reasonably infer the comparative benefits or risks in settings, in which doing a randomised trial is not feasible. Fifth, efficiency of randomised trials should be improved by streamlining patient recruitment and data collection through innovative design elements. Sixth, governments should directly support and facilitate the production of comparative post-marketing data by investing in the development of collaborative research networks and data systems that reduce the complexity, cost, and waste of rigorous post-marketing research efforts. Last, financial incentives and penalties should be developed or more actively reinforced.


Assuntos
Aprovação de Equipamentos , Aprovação de Drogas/métodos , Segurança de Equipamentos , Vigilância de Produtos Comercializados/métodos , Tolerância a Medicamentos , Medicina Baseada em Evidências , Humanos , Estados Unidos , United States Food and Drug Administration
19.
Expert Opin Biol Ther ; 20(2): 151-161, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31815548

RESUMO

Introduction: Therapeutic goals in inflammatory bowel diseases (IBD) have evolved, over the last decades, from clinical response to complete remission (clinical and endoscopic remission).Areas covered: Development of biologics and small molecules has been associated with the development of new endpoints in IBD trials that could not have been achieved in the pre-biologics era. Herein, we focus on evolving endpoints for approved biologics and small molecules. We searched for relevant publications using Medline/PubMed, Embase and the Cochrane Library from their inception to 1 July 2019.Expert opinion: Endpoints differ between induction (clinical and endoscopic response) and maintenance trials (clinical and endoscopic remission) because the goal is to evaluate the anti-inflammatory effect of a given drug during induction, whereas full disease control is the ultimate goal during the maintenance phase in order to change patients' life and disease course. Histological healing has recently emerged as a new co-primary endpoint in ulcerative colitis, and is now part of the definition of mucosal healing in these trials. Whether new endpoints such as transmural and radiologic healing could become an endpoint and replace endoscopy in Crohn's disease trials in the near future requires further investigation.


Assuntos
Produtos Biológicos/uso terapêutico , Aprovação de Drogas , Determinação de Ponto Final/tendências , Doenças Inflamatórias Intestinais/tratamento farmacológico , Ensaios Clínicos Controlados Aleatórios como Assunto , Biomarcadores/análise , Colite Ulcerativa/tratamento farmacológico , Colite Ulcerativa/história , Doença de Crohn/tratamento farmacológico , Doença de Crohn/história , Aprovação de Drogas/história , Aprovação de Drogas/métodos , Determinação de Ponto Final/história , Determinação de Ponto Final/métodos , História do Século XX , História do Século XXI , Humanos , Doenças Inflamatórias Intestinais/história , Bibliotecas/história , Bibliotecas/tendências , Ensaios Clínicos Controlados Aleatórios como Assunto/história , Ensaios Clínicos Controlados Aleatórios como Assunto/métodos , Bibliotecas de Moléculas Pequenas/química , Bibliotecas de Moléculas Pequenas/uso terapêutico , Cicatrização/efeitos dos fármacos
20.
J Natl Cancer Inst ; 112(4): 335-342, 2020 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-31651981

RESUMO

BACKGROUND: The US Food and Drug Administration's accelerated approval and later withdrawal of bevacizumab in patients with metastatic breast cancer (mBC) is a seminal case for ongoing debates about the validity of using progression-free survival (PFS) as a surrogate measure for overall survival (OS) in cancer drug approvals. We systematically reviewed and meta-analyzed the evidence around bevacizumab's regulatory approval and withdrawal in mBC. METHODS: We searched for all published phase II or III clinical trials testing bevacizumab as a first-line therapy for patients with mBC. Data were extracted on trial demographics, interventions, and outcomes. Descriptive analysis was stratified by whether the trial was initiated before, during, or after the accelerated approval. We used a cumulative random-effects meta-analysis to assess the evolution of evidence of the effect of bevacizumab on PFS and OS. We estimated the association between the trial-level PFS and OS effect using a nonlinear mixed-regression model. RESULTS: Fifty-two studies were included. Trial activity dramatically dropped after the accelerated approval was withdrawn. Eight clinical trials reported hazard ratios (hazard ratios) and were meta-analyzed. The cumulative hazard ratio for PFS was 0.72 (95% CI = 0.65 to 0.79), and the cumulative hazard ratio for OS was 0.90 (95% CI = 0.80 to 1.01). The regression model showed a statistically nonsignificant association between PFS benefit and OS benefit (ß = 0.43, SE = 0.81). CONCLUSION: The US Food and Drug Administration's decision-making in this case was consistent with the evolving state of evidence. However, the fact that seven clinical trials are insufficient to conclude validity (or lack thereof) for a trial-level surrogate suggests that it would be more efficient to conduct trials using the more clinically meaningful endpoints.


Assuntos
Bevacizumab/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Aprovação de Drogas/métodos , Antineoplásicos Imunológicos/uso terapêutico , Neoplasias da Mama/patologia , Ensaios Clínicos Fase II como Assunto/métodos , Ensaios Clínicos Fase II como Assunto/estatística & dados numéricos , Ensaios Clínicos Fase III como Assunto/métodos , Ensaios Clínicos Fase III como Assunto/estatística & dados numéricos , Tomada de Decisões , Determinação de Ponto Final , Feminino , Humanos , Legislação de Medicamentos , Metástase Neoplásica , Dinâmica não Linear , Intervalo Livre de Progressão , Ensaios Clínicos Controlados Aleatórios como Assunto/métodos , Ensaios Clínicos Controlados Aleatórios como Assunto/estatística & dados numéricos , Análise de Regressão , Taxa de Sobrevida , Estados Unidos , United States Food and Drug Administration
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