Therapeutic innovation & regulatory science最新文献

Intracerebral hemorrhage (ICH) is a major health problem. It is one of the most common types of stroke and results in mortality in approximately half of patients. More than half of the fatalities occur in the first 2 days. In addition to the mass effect after ICH hemorrhage, complex pathophysiological mechanisms such as intracranial vessel vasospasm, microthrombosis, and inflammatory immune reaction also increase brain damage. Both resident (including microglia and astrocytes) and circulating immune cells (including neutrophils, macrophages, and lymphocytes) involved in the inflammatory process. The inflammatory response is especially harmful in the acute phase due to harmful substances secreted by infiltrating immune cells. The inflammatory response also has beneficial effects, especially in the later stages. Their role in pathophysiology makes immune cells important therapeutic targets. General immunosuppressive approaches and depleting cell groups such as neutrophils or keeping them away from the lesion site may not be sufficient to prevent poor outcomes after ICH. This is most likely because they suppress anti-inflammatory activities and pro-inflammatory effects. Instead, directing immune cells to the beneficial subpopulation seems like a more rational solution. The pro-inflammatory N1 subpopulation of neutrophils damages the tissue surrounding ICH. In contrast, the N2 subpopulation is associated with anti-inflammatory reactions and tissue repair. Studies show that when neutrophils are polarized toward the N2 subpopulation, clinical outcomes improve and the volume of the infarct decreases. However, more research is still needed. This study aims to evaluate the role of neutrophils as immunotherapeutic targets in ICH in light of current knowledge.

Under current bioequivalence guidelines in Japan, it is mandatory to establish bioequivalence using a single pivotal study. Clinical trials with limited resources usually have a pre-defined maximum permissible number of participants. In this manuscript, we considered a trial design that would allow for bioequivalence evaluation at an interim analysis in which the total number of participants takes into account the resource constraints. Then, available options at the interim analysis are group sequential designs and adaptive designs, A comparison of the performance of the two methods under same maximum participant number has not been conducted thus far. So we examined which method should be used by conducting a simulation study. Since bioequivalence is expected to be achieved at the interim analysis, a study design using a Pocock-type alpha spending function is preferrable. Simulation results using a Pocock-type alpha spending function showed similar performance between group sequential and adaptive designs. Consequently, due to statistical and operational complexity, it is preferable to choose group sequential designs for bioequivalence study in Japan.

Background: This report describes the U.S. Food and Drug Administration (FDA) experience in establishing a dedicated mailbox, and in publishing related guidance, to address concerns among interested parties regarding the conduct of clinical trials during the COVID-19 public health emergency (PHE).

Methods: Six hundred and thirty-four mailbox inquiries were received from March 2020 through February 2022. Qualitative methods were used to provide a structured description of, and identify common themes among, these inquiries.

Results: Most inquiries came from U.S.-based interested parties, including sponsors, industry trade associations, academic institutions, hospitals, clinics, research sites, trial participants, and individual persons. Approximately one-fifth of questions were related directly to COVID-19 (e.g., proposals for treatment); other inquiries were related to conduct of routine trial-related activities, and concerns were often focused on maintaining compliance with good clinical practice. In March 2020, FDA published a guidance titled Conduct of Clinical Trials of Medical Products During the COVID-19 Public Health Emergency; the document was subsequently revised eight times based in part on issues raised in mailbox inquiries.

Conclusions: The dedicated mailbox enabled expedited communication among invested parties during the COVID-19 PHE; FDA also provided updates of the aforementioned guidance. These efforts supported the continuance of ongoing trials and the initiation of new trials during the PHE in accordance with good clinical practice guidelines, thereby helping to ensure the safety of trial participants while maintaining the quality of trial data. By soliciting and responding to trial-related inquiries and addressing corresponding needs and concerns, FDA improved transparency and communication.

Introduction: Although oncology has seen large scientific and clinical advances over the last decade, it also has one of the lowest success rates for novel agents across therapeutic areas. Adaptive clinical trial design has been a popular option for increasing clinical trial efficiency and the chances of trial success. Seamless clinical trial design are studies in which two or more clinical trial phases are combined into a single study with a pre-specified transition between stages. This integration of phases may enhance efficiency.

Methods: To understand the precedent for the use of seamless designs, this working group was formed to conduct a comprehensive literature search on seamless clinical trials conducted with confirmatory intent in oncology. Trial design features were extracted into a database and analyzed with descriptive statistics.

Results: A literature search identified 68 clinical trials meeting inclusion and exclusion criteria. The most common design feature was a gate on treatment efficacy, where the trial would only proceed to the second stage if sufficient efficacy was observed in the first. The next most common feature was a selection of a dose or treatment regimen. Inferentially and operationally seamless designs were approximately equally represented.

Discussion: Key statistical considerations for seamless phase II/III designs include optimizing design choices by evaluating and comparing operating characteristics across design alternatives as well as showing control of overall Type I error rates. Executing the transition between phases should be evaluated for issues related to accrual, drug production, and procedures to maintain trial integrity.

Conclusions: While there are unique statistical, regulatory, and operational considerations for seamless designs they are also uniquely suited to many development settings. These include, for example, addressing dose selection under FDA's Project Optimus and addressing the growing use of biomarkers and personalized medicine approaches in cancer treatment.

The Prescribing Information (PI) in the United States (US) and the Summary of Product Characteristics (SmPC) in the European Union (EU) are approved by the US Food & Drug Administration (FDA), and the European Medicines Agency (EMA), respectively. The inclusion of overdosage information in these documents is a regulatory requirement in both regions. This research evaluates the content of the overdosage section of US and EU labeling. The overdosage sections of labels for drugs approved in the US in three time periods were analyzed: 2000-2001, 2010-2011, and 2020-2021. EU labels for these same products were also reviewed if registered through the Centralized Procedure. Data collection and analyses were performed using a predefined questionnaire, focusing on adherence to regulatory requirements and identifying areas where additional regulatory guidance may be beneficial. The findings indicate that the content of the overdosage sections largely comply with the regulatory requirements of their respective regions. Fewer than half of the labels included information on supratherapeutic doses observed from clinical studies, risk factors for overdose or population specific data associated with overdose. Inconsistencies were noted concerning the incorporation of animal data when human data were available, in addition to the referencing of Poison Centers. The overall utility of non-specific treatment recommendations, in addition to gastric lavage is discussed. While the content of the overdosage section generally aligns with regulatory expectations, additional regulatory guidance could enhance consistency in how this section of labeling is presented and clarify expectations to improve its usefulness for health care professionals (HCPs).

Background: Little is known about patient and the public perspectives on decentralized and hybrid clinical trials in Canada.

Methods: We conducted an online survey (English and French) promoted on social media to understand perspectives of people in Canada about decentralized and hybrid clinical trials. The survey had two sections. We co-produced this project entirely with patient, caregiver, and family partners.

Results: The survey had 284 (14 French) individuals who started or completed Section 1, and 180 (16 French) individuals who started or completed Section 2. People prefer to have options to participate in clinical trials where aspects are decentralized or hybridized. 79% of respondents preferred to have options related to study visits. There were concerns about handling adverse events or potential complications in decentralized trials, however, communication options such as a dedicated contact person for participants was deemed helpful. Most respondents were amenable to informed consent being done at a satellite site closer to home or via technology and were split on privacy concerns about this. Most preferred travel to a site within an hour, depending on what the trial was for or its impact on quality of life. Due to the response rate, we were unable to explore associations with gender, age, health status, geography, ethnicity, and prior clinical trial participation.

Conclusion: Our findings indicate an openness in Canada to participating in trials that decentralize or hybridize some aspects. These trials are perceived to provide benefits to participants and ways to increase equity and accessibility for participants.

Seamless study designs have the potential to accelerate clinical development. The use of innovative seamless designs has been increasing in the oncology area; however, while the concept of seamless designs becomes more popular and accepted, many challenges remain in both the design and conduct of these trials. This may be especially true when seamless designs are used in late phase development supporting regulatory decision-making. The Innovative Design Scientific Working Group (IDSWG) Oncology team conducted a survey to understand the current use of seamless study designs for registration purposes in oncology clinical development. The survey was designed to provide insights into the benefits and to identify the roadblocks. A total of 16 questions were included in the survey that was distributed using the ASA Biopharmaceutical Section and IDSWG email listings from August to September 2022. A total of 51 responses were received, with 39 (76%) respondents indicating that their organizations had seamless oncology studies in planning or implementation for registration purposes. Detailed survey results are presented in the manuscript. Overall, while seamless designs offer advantages in terms of timeline reduction and cost saving, they also present challenges related to additional complexity and the need for efficient surrogate clinical endpoints in oncology drug development.

Background: Medical-product companies often outsource research and manufacturing needs to contracting or partnering organizations but then must manage a challenging patchwork of regulatory activities. A standalone regulatory agreement could clarify the relationships and responsibilities between companies working jointly on a single regulated product. This study explored the need for and current use of standalone regulatory agreements.

Methods: A survey instrument was developed using an implementation framework and disseminated to mid- to senior-level employees and consultants for sponsor and vendor companies in the medical products sector.

Results: Of 294 respondents, about half, primarily from companies with more than 200 employees, were familiar with standalone regulatory agreements, and half of this subgroup had moved forward to implement them. Such agreements were considered beneficial to clarify regulatory roles and responsibilities, standardize regulatory expectations between the companies, and stimulate earlier discussion about joint regulatory strategies. However, the development of regulatory agreements appears challenged by the fact that such agreements are not required by regulatory agencies overseeing medical products and have no standardized templates, agency or industry guidance. Respondents whose organizations do not now use regulatory agreements either had not considered or did not see a need for a standalone agreement.

Conclusions: Standalone regulatory agreements are becoming more common but are not yet implemented fully by most companies. Their usefulness and content appeared to depend upon the type of partner, the complexity of the relationship and the availability of internal expertise and support.

Combination products (CPs) combine two or more product types such as drugs, devices, and/or biological products for increased safety and clinical effectiveness. The emergence of innovative CPs poses new challenges for regulatory agencies in assigning jurisdiction for premarket review and oversight. In US, the 1990 Safe Medical Devices Act defines and provides classification criteria for CPs, and the US government has developed a regulatory process through multiple acts, including the 21st Century Cures Act of 2016. Meanwhile, regulators in the European Union (EU) and the Republic of Korea have recently recognized the importance of premarket pathways for CPs. The European Medicines Agency (EMA) has issued guidelines and explanations on compliance issues related to drug-device CPs under MDR. EMA doesn't have the definitions of CPs, but uses the term drug-device combination products (drug-device CPs). CPs are categorized as drugs or medical devices, which follow their relevant regulatory framework. The Ministry of Food and Drug Safety (MFDS) in Korea has legal definitions of CPs under the Notice of the MFDS. CPs are designated as drugs or medical devices according to their primary mode of actions (PMOA) and follow regulatory processes through the framework of drugs or medical devices. This study aims to comprehensively summarize the regulatory oversight of CPs by analyzing the regulatory policies and legal frameworks in the US, the EU, and Korea. The regulatory challenges encountered when developing CPs are also discussed. With specific emphasis on the combination of drugs and devices, this study provides in-depth insights into the regulatory landscape, shedding light on the unique challenges associated with the development of CPs for this particular intersection of drugs and devices.

Background: Risk-based quality management is a regulatory-recommended approach to manage risk in a clinical trial. A key element of this strategy is to conduct risk-based monitoring to detect potential risks to critical data and processes earlier. However, there are limited publicly available tools to perform the analytics required for this purpose. Good Statistical Monitoring is a new open-source solution developed to help address this need.

Methods: A team of statisticians, data scientists, clinicians, data managers, clinical operations, regulatory, and quality compliance staff collaborated to design Good Statistical Monitoring, an R package, to flexibly and efficiently implement end-to-end analyses of key risks. The package currently supports the mapping of clinical trial data from a variety of formats, evaluation of 12 key risk indicators, interactive visualization of analysis results, and creation of standardized reports.

Results: The Good Statistical Monitoring package is freely available on GitHub and empowers clinical study teams to proactively monitor key risks. It employs a modular workflow to perform risk assessments that can be customized by replacing any workflow component with a study-specific alternative. Results can be exported to other clinical systems or can be viewed as an interactive report to facilitate follow-up risk mitigation. Rigorous testing and qualification are performed as part of each release to ensure package quality.

Conclusions: Good Statistical Monitoring is an open-source solution designed to enable clinical study teams to implement statistical monitoring of critical risks, as part of a comprehensive risk-based quality management strategy.