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1.
J Biopharm Stat ; : 1-13, 2019 Nov 10.
Artigo em Inglês | MEDLINE | ID: mdl-31707908

RESUMO

In medical product development, there has been an increased interest in utilizing real-world data which have become abundant with recent advances in biomedical science, information technology, and engineering. High-quality real-world data may be analyzed to generate real-world evidence that can be utilized in the regulatory and healthcare decision-making. In this paper, we consider the case in which a single-arm clinical study, viewed as the primary data source, is supplemented with patients from a real-world data source containing both clinical outcome and covariate data at the patient-level. Propensity score methodology is used to identify real-world data patients that are similar to those in the single-arm study in terms of the baseline characteristics, and to stratify these patients into strata based on the proximity of the propensity scores. In each stratum, a composite likelihood function of a parameter of interest is constructed by down-weighting the information from the real-world data source, and an estimate of the stratum-specific parameter is obtained by maximizing the composite likelihood function. These stratum-specific estimates are then combined to obtain an overall population-level estimate of the parameter of interest. The performance of the proposed approach is evaluated via a simulation study. A hypothetical example based on our experience is provided to illustrate the implementation of the proposed approach.

2.
J Biopharm Stat ; 29(5): 749-759, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31590626

RESUMO

A question that routinely arises in medical device clinical studies is the homogeneity across demographic subgroups, geographical regions, or investigational sites of the enrolled patients in terms of treatment effects or outcome variables. The main objective of this paper is to discuss statistical concepts and methods for the assessment of such homogeneity and to provide the practitioner a statistical framework and points to consider in conducting homogeneity assessment. Demographic subgroups, geographical regions, and investigational sites are discussed separately as each has its unique issues. Specific considerations are also given to randomized controlled trials, non-randomized comparative studies, and single-arm studies. We point out that judicious use of statistical methods, in conjunction with sound clinical judgment, is essential in handling the issue of homogeneity of treatment effect in medical device clinical studies.

3.
J Biopharm Stat ; 29(5): 731-748, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31530111

RESUMO

We are now at an amazing time for medical product development in drugs, biological products and medical devices. As a result of dramatic recent advances in biomedical science, information technology and engineering, ``big data'' from health care in the real-world have become available. Although big data may not necessarily be attuned to provide the preponderance of evidence to a clinical study, high-quality real-world data can be transformed into scientific evidence for regulatory and healthcare decision-making using proven analytical methods and techniques, such as propensity score methodology and Bayesian inference. In this paper, we extend the Bayesian power prior approach for a single-arm study (the current study) to leverage external real-world data. We use propensity score methodology to pre-select a subset of real-world data containing patients that are similar to those in the current study in terms of covariates, and to stratify the selected patients together with those in the current study into more homogeneous strata. The power prior approach is then applied in each stratum to obtain stratum-specific posterior distributions, which are combined to complete the Bayesian inference for the parameters of interest. We evaluate the performance of the proposed method as compared to that of the ordinary power prior approach by simulation and illustrate its implementation using a hypothetical example, based on our regulatory review experience.

4.
J Biopharm Stat ; 29(4): 580-591, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31257999

RESUMO

Observational (non-randomized) comparative studies have been adopted in the pre-market safety/effectiveness evaluation of medical devices. There has been an increased interest in utilizing this design with the growing available real-world data. However, in such studies, biases that are introduced in every stage and aspect of study need to be addressed. Otherwise, the objectivity of study design and validity of study results will be compromised. In this paper, challenges and opportunities are discussed from the regulatory perspective. Considerations and good statistical practice to mitigate the potential bias are presented.

5.
Ther Innov Regul Sci ; : 2168479019830385, 2019 Feb 27.
Artigo em Inglês | MEDLINE | ID: mdl-30813775

RESUMO

There is an increasing demand for utilization of external data, such as historical study data and patient registry data, to augment the control group in a randomized controlled trial. While such a study design could reduce the time and cost, how to maintain the study validity and integrity is one major statistical challenge that needs to be carefully addressed. We discuss a study design quality process to enhance the study validity and integrity when using this approach. The discussed quality process is tailored to the confirmatory study using a 2-stage design with an emphasis on the interaction process among stakeholders. In an example, the quality process covers a 2-step assessment of the similarity in patient characteristics between the current study and the external data source, and between the treatment and augmented control groups.

6.
J Biopharm Stat ; 29(1): 143-150, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-29985744

RESUMO

Noninferiority trials are commonly utilized to evaluate the safety and effectiveness of medical devices. It could happen that the noninferiority hypothesis is rejected while the performance of the active control is clinically not satisfactory. This may pose a great challenge when making a regulatory decision. To avoid such a difficult situation, we propose to conduct a companion test to assess the performance of the active control when testing the main noninferiority hypothesis and to incorporate such a test into the study design. Under our proposal, the noninferiority of the investigational device to the active control can only be claimed when both hypotheses are rejected. The operating characteristics of the proposed study design based on these two tests can be fully evaluated at the design stage. This proposed approach is aimed to facilitate regulatory decision making in a more transparent manner.

7.
J Speech Lang Hear Res ; 60(5): 1223-1235, 2017 05 24.
Artigo em Inglês | MEDLINE | ID: mdl-28388709

RESUMO

Purpose: The objective was to investigate acoustic cue processing in lexical-tone recognition by pediatric cochlear-implant (CI) recipients who are native Mandarin speakers. Method: Lexical-tone recognition was assessed in pediatric CI recipients and listeners with normal hearing (NH) in 2 tasks. In Task 1, participants identified naturally uttered words that were contrastive in lexical tones. For Task 2, a disyllabic word (yanjing) was manipulated orthogonally, varying in fundamental-frequency (F0) contours and duration patterns. Participants identified each token with the second syllable jing pronounced with Tone 1 (a high level tone) as eyes or with Tone 4 (a high falling tone) as eyeglasses. Results: CI participants' recognition accuracy was significantly lower than NH listeners' in Task 1. In Task 2, CI participants' reliance on F0 contours was significantly less than that of NH listeners; their reliance on duration patterns, however, was significantly higher than that of NH listeners. Both CI and NH listeners' performance in Task 1 was significantly correlated with their reliance on F0 contours in Task 2. Conclusion: For pediatric CI recipients, lexical-tone recognition using naturally uttered words is primarily related to their reliance on F0 contours, although duration patterns may be used as an additional cue.


Assuntos
Implante Coclear , Surdez/reabilitação , Reconhecimento Fisiológico de Modelo , Percepção da Fala , Estimulação Acústica/métodos , Adolescente , Criança , Feminino , Humanos , Masculino , Espectrografia do Som , Adulto Jovem
8.
J Biopharm Stat ; 26(6): 1136-1145, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27540636

RESUMO

Regulatory decisions are made based on the assessment of risk and benefit of medical devices at the time of pre-market approval and subsequently, when post-market risk-benefit balance needs reevaluation. Such assessments depend on scientific evidence obtained from pre-market studies, post-approval studies, post-market surveillance studies, patient perspective information, as well as other real world data such as national and international registries. Such registries provide real world evidence and are playing a more and more important role in enhancing the safety and effectiveness evaluation of medical devices. While these registries provide large quantities of data reflecting real world practice and can potentially reduce the cost of clinical trials, challenges arise concerning (1) data quality adequate for regulatory decision-making, (2) bias introduced at every stage and aspect of study, (3) scientific validity of study designs, and (4) reliability and interpretability of study results. This article will discuss related statistical and regulatory challenges and opportunities with examples encountered in medical device regulatory reviews.


Assuntos
Aprovação de Equipamentos , Regulamentação Governamental , Sistema de Registros , Viés , Confiabilidade dos Dados , Tomada de Decisões , Humanos , Reprodutibilidade dos Testes , Projetos de Pesquisa , Medição de Risco
9.
J Biopharm Stat ; 24(5): 994-1010, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25013971

RESUMO

Due to the special nature of medical device clinical studies, observational (nonrandomized) comparative studies play important roles in the premarket safety/effectiveness evaluation of medical devices. While historical data collected in earlier investigational device exemption studies of a previously approved medical device have been used to form control groups in comparative studies, high-quality registry data are emerging to provide opportunities for the premarket evaluation of new devices. However, in such studies, various biases could be introduced in every stage and aspect of study and may compromise the objectivity of study design and validity of study results. In this article, challenges and opportunities in the design of such studies using propensity score methodology are discussed from regulatory perspectives.


Assuntos
Aprovação de Equipamentos , Equipamentos e Provisões , Estudos Observacionais como Assunto/métodos , Projetos de Pesquisa , Grupos Controle , Aprovação de Equipamentos/normas , Humanos , Estudos Observacionais como Assunto/estatística & dados numéricos , Pontuação de Propensão , Tamanho da Amostra , Amostragem , Resultado do Tratamento
10.
J Biopharm Stat ; 22(5): 1001-18, 2012 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-22946946

RESUMO

Multiregional clinical trials provide the potential to make safe and effective medical products simultaneously available to patients globally. As regulatory decisions are always made in a local context, this poses huge regulatory challenges. In this article we propose two conditional decision rules that can be used for medical product approval by local regulatory agencies based on the results of a multiregional clinical trial. We also illustrate sample size planning for such trials.


Assuntos
Estudos Multicêntricos como Assunto/métodos , Projetos de Pesquisa/estatística & dados numéricos , Tamanho da Amostra , Algoritmos , China , Tomada de Decisões Gerenciais , Aprovação de Drogas , Interações de Medicamentos , Tratamento Farmacológico , Humanos , Japão , Estudos Multicêntricos como Assunto/estatística & dados numéricos
11.
Trends Amplif ; 16(2): 67-82, 2012 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-22790392

RESUMO

The present article reports on the perceptual weighting of prosodic cues in question-statement identification by adult cochlear implant (CI) listeners. Acoustic analyses of normal-hearing (NH) listeners' production of sentences spoken as questions or statements confirmed that in English the last bisyllabic word in a sentence carries the dominant cues (F0, duration, and intensity patterns) for the contrast. Furthermore, these analyses showed that the F0 contour is the primary cue for the question-statement contrast, with intensity and duration changes conveying important but less reliable information. On the basis of these acoustic findings, the authors examined adult CI listeners' performance in two question-statement identification tasks. In Task 1, 13 CI listeners' question-statement identification accuracy was measured using naturally uttered sentences matched for their syntactic structures. In Task 2, the same listeners' perceptual cue weighting in question-statement identification was assessed using resynthesized single-word stimuli, within which fundamental frequency (F0), intensity, and duration properties were systematically manipulated. Both tasks were also conducted with four NH listeners with full-spectrum and noise-band-vocoded stimuli. Perceptual cue weighting was assessed by comparing the estimated coefficients in logistic models fitted to the data. Of the 13 CI listeners, 7 achieved high performance levels in Task 1. The results of Task 2 indicated that multiple sources of acoustic cues for question-statement identification were utilized to different extents depending on the listening conditions (e.g., full spectrum vs. spectrally degraded) or the listeners' hearing and amplification status (e.g., CI vs. NH).


Assuntos
Implante Coclear/instrumentação , Implantes Cocleares , Correção de Deficiência Auditiva/psicologia , Sinais (Psicologia) , Pessoas com Deficiência Auditiva/reabilitação , Percepção da Fala , Estimulação Acústica , Adulto , Idoso , Análise de Variância , Audiometria da Fala , Estudos de Casos e Controles , Compreensão , Feminino , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Pessoas com Deficiência Auditiva/psicologia , Processamento de Sinais Assistido por Computador , Acústica da Fala , Adulto Jovem
12.
Audiol Neurootol ; 14(5): 327-37, 2009.
Artigo em Inglês | MEDLINE | ID: mdl-19372651

RESUMO

Cochlear implant (CI) recipients have only limited access to fundamental frequency (F0) information, and thus exhibit deficits in speech intonation recognition. For speech intonation, F0 serves as the primary cue, and other potential acoustic cues (e.g. intensity properties) may also contribute. This study examined the effects of cooperating or conflicting acoustic cues on speech intonation recognition by adult CI and normal hearing (NH) listeners with full-spectrum and spectrally degraded speech stimuli. Identification of speech intonation that signifies question and statement contrasts was measured in 13 CI recipients and 4 NH listeners, using resynthesized bi-syllabic words, where F0 and intensity properties were systematically manipulated. The stimulus set was comprised of tokens whose acoustic cues (i.e. F0 contour and intensity patterns) were either cooperating or conflicting. Subjects identified if each stimulus is a 'statement' or a 'question' in a single-interval, 2-alternative forced-choice (2AFC) paradigm. Logistic models were fitted to the data, and estimated coefficients were compared under cooperating and conflicting conditions, between the subject groups (CI vs. NH), and under full-spectrum and spectrally degraded conditions for NH listeners. The results indicated that CI listeners' intonation recognition was enhanced by cooperating F0 contour and intensity cues, but was adversely affected by these cues being conflicting. On the other hand, with full-spectrum stimuli, NH listeners' intonation recognition was not affected by cues being cooperating or conflicting. The effects of cues being cooperating or conflicting were comparable between the CI group and NH listeners with spectrally degraded stimuli. These findings suggest the importance of taking multiple acoustic sources for speech recognition into consideration in aural rehabilitation for CI recipients.


Assuntos
Implantes Cocleares , Perda Auditiva/reabilitação , Audição , Fonética , Percepção da Fala , Estimulação Acústica , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Perda Auditiva/fisiopatologia , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Ruído , Psicometria , Teste do Limiar de Recepção da Fala , Adulto Jovem
13.
ILAR J ; 49(4): 23-30, 2008 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-18849588

RESUMO

This study measured the influence of three different environmental enrichment devices (EEDs) on the severity of osteoarthritis (OA) in a surgically induced murine model. The development of OA requires joint movement after surgical instability induced by destabilization of the medial meniscus at 10 weeks of age. We evaluated the hypothesis that animals behavioral activity levels may influence the severity of the disease by investigating the effect of different EEDs on mouse activity and correlating this to OA severity. Thirty male 129S6/SvEvTac mice were housed in groups of five and provided with nesting material and one of three different EEDs: a heavy plastic tube (CPVC), Shepherd Shack (SS), or Tecniplast Mouse House (TMH). We videorecorded the cages throughout the study and constructed an ethogram. Eight weeks after surgery we euthanized the mice and performed a histologic examination of the knees to score the severity of OA based on the different housing systems, correlating the scores with behavioral activity levels for each cage. OA was higher in the mice with CPVC and TMH devices in their cages, whereas the mice with SS devices exhibited less cartilage damage; however, although we observed increased behavioral activity in mice with the CPVC tube and TMH and less in mice with the SS, the statistical results were not significant. The histological results of OA and the ethogram correlated to support our hypothesis that the type of EED plays an indirect role in the severity of the disease by modifying the activity levels of mice. In activity-dependent studies, the impact of an EED needs to be evaluated before change the environment.


Assuntos
Comportamento Animal/fisiologia , Modelos Animais de Doenças , Osteoartrite do Joelho/patologia , Animais , Progressão da Doença , Masculino , Camundongos , Osteoartrite do Joelho/fisiopatologia
14.
J Speech Lang Hear Res ; 51(5): 1353-68, 2008 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-18695018

RESUMO

PURPOSE: This study characterized the development of speech sound production in prelingually deaf children with a minimum of 8 years of cochlear implant (CI) experience. METHOD: Twenty-seven pediatric CI recipients' spontaneous speech samples from annual evaluation sessions were phonemically transcribed. Accuracy for these speech samples was evaluated in piecewise regression models. RESULTS: As a group, pediatric CI recipients showed steady improvement in speech sound production following implantation, but the improvement rate declined after 6 years of device experience. Piecewise regression models indicated that the slope estimating the participants' improvement rate was statistically greater than 0 during the first 6 years postimplantation, but not after 6 years. The group of pediatric CI recipients' accuracy of speech sound production after 4 years of device experience reasonably predicts their speech sound production after 5-10 years of device experience. CONCLUSIONS: The development of speech sound production in prelingually deaf children stabilizes after 6 years of device experience, and typically approaches a plateau by 8 years of device use. Early growth in speech before 4 years of device experience did not predict later rates of growth or levels of achievement. However, good predictions could be made after 4 years of device use.


Assuntos
Implantes Cocleares , Surdez/reabilitação , Desenvolvimento da Linguagem , Fonética , Fala , Criança , Pré-Escolar , Feminino , Humanos , Modelos Lineares , Masculino , Valor Preditivo dos Testes , Medida da Produção da Fala
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