Drug-device Combination Products Research Articles

Cardiovascular safety of dihydroergotamine mesylate delivered by precision olfactory delivery (INP104) for the acute treatment of migraine.

To report the cardiovascular (CV) safety of dihydroergotamine mesylate (DHE) administered by precision olfactory delivery (INP104) from two clinical trials. Although the absolute risk is low, migraine is associated with an increased risk of CV events. DHE is a highly effective acute treatment for migraine, but due to its theoretical risk of promoting arterial vasoconstriction, DHE is contraindicated in patients with CV disease or an unfavorable risk factor profile. The INP104 is a novel drug-device combination product approved for acute treatment of migraine that delivers DHE to the upper nasal space using precision olfactory delivery (POD®). The STOP 101 was a Phase 1 open-label study that assessed the safety, tolerability, and bioavailability of INP104 1.45 mg, intravenous DHE 1.0 mg, and MIGRANAL (nasal DHE) 2.0 mg in healthy participants. The STOP 301 was a pivotal Phase 3, open-label study that assessed the safety, tolerability, and exploratory efficacy of INP104 1.45 mg over 24 and 52 weeks in patients with migraine. In both studies, active or a history of CV disease, as well as significant CV risk factors, were exclusion criteria. In STOP 101, 36 participants received one or more doses of investigational product. Treatment with intravenous DHE, but not INP104 or nasal DHE, resulted in clinically relevant changes from baseline in systolic blood pressure (BP; 11.4 mmHg, 95% confidence interval [CI] 7.9-15.0) and diastolic BP (13.3 mmHg, 95% CI 9.4-17.1) at 5 min post-dose, persisting up to 30 min post-dose for systolic BP (6.3 mmHg; 95% CI 3.0-9.5) and diastolic BP (7.9 mmHg, 95% CI 3.9-11.9). None of the treatments produced any clinically meaningful electrocardiogram (ECG) changes. In STOP 301, 354 patients received one or more doses of INP104. Over 24 weeks, five patients (1.4%) experienced a non-serious, vascular treatment-emergent adverse event (TEAE). Minimal changes were observed for BP and ECG parameters over 24 or 52 weeks. Off-protocol concomitant use of triptans and other ergot derivatives did not result in any TEAEs. In two separate studies, INP104 demonstrated a favorable CV safety profile when used in a study population without CV-related contraindications.

Regulatory Framework for Drug-Device Combination Products in the United States, Europe, and Korea.

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.

Pre-ANDA strategy and Human Factors activities to de-risk pharmaceutical companies ANDA submission of drug–device combination products: case study of a formative Comparative Use Human Factors study

ABSTRACT Background This article presents a strategy that a Drug Delivery Device Developer (DDDD) has adopted to support Abbreviated New Drug Application (ANDA) submissions of drug–device combination products. As per the related FDA guidance, a threshold analysis should be compiled. If ‘other differences’ between the Reference Listed Drug (RLD) and the generic drug devices are identified, a Comparative Use Human Factors (CUHF) study may be requested. Methods The DDDD performed task analysis and physical comparison to assess the pen injector design differences. Then, a formative CUHF study with 25 participants simulating injections using both RLD and the generic pen injectors was conducted. Results After each participant completed four simulated injections, similar type and rates of use error between the RLD (0.70) and generic (0.68) pen injectors were observed. Conclusion DDDDs can support pharmaceutical companies in the ANDA submission strategy of their drug–device combination product by initiating comparative task analysis and physical comparison of the device as inputs for the threshold analysis. If ‘other differences’ are identified, a formative CUHF study can be performed. As shown in our case study, this approach can be leveraged to support the sample size calculation and non-inferiority margin determination for a CUHF study with the final combination product.

VP-102 Tolerability Evaluated by Concomitant Analgesic Medication Usage in Two Phase 3 Trials for Molluscum Contagiosum

Background: Drug tolerability is the degree to which a patient can tolerate a drug's adverse effects. VP-102, a drug-device combination product containing cantharidin (0.7%), a vesicant, is approved for treatment of molluscum contagiosum (molluscum) in patients >2. Local skin reactions (LSRs) are expected, including pain. In Phase 3 trials, 97% of LSRs were mild to moderate. The discontinuation rate due to an adverse reaction was 2.3%:0.5% (drug:vehicle) treated subjects, respectively. This post-hoc analysis evaluated VP-102 tolerability based on analgesic usage over the study course.
 Methods: VP-102 or vehicle was applied to all baseline and new lesions once every 21 days until complete clearance, or up to a maximum of 4 applications. Acetaminophen or ibuprofen were permitted for application site pain and/or other Adverse Reactions.
 Results: Overall incidence of pain at any time for a VP-102 subject was 62.7% (195/311), with the majority [(60.5%),188/311] as mild to moderate. 18.6% (58/311) of VP-102 and 1.4% (3/216) of vehicle treated subjects received an analgesic, including 15.8% (49/311) for an LSR after the first VP-102 application.
 
 Median VP-102 analgesic use for LSR pain (range) was 2 (1-14) days for the entire study, and 2 (1-9) days after the first application. 29% of participants who reported analgesic usage took medication ≤1 day. Analgesic usage for AEs other than LSR pain (≥ 5% of participants) included 6% (19/311) for application site vesicles. There were no treatment-related SAEs reported.
 
 Conclusions: In this largely pediatric population, VP-102 was well-tolerated, with a short duration of elective analgesic use.

Digital Therapeutics for Improving Effectiveness of Pharmaceutical Drugs and Biological Products: Preclinical and Clinical Studies Supporting Development of Drug + Digital Combination Therapies for Chronic Diseases.

Limitations of pharmaceutical drugs and biologics for chronic diseases (e.g., medication non-adherence, adverse effects, toxicity, or inadequate efficacy) can be mitigated by mobile medical apps, known as digital therapeutics (DTx). Authorization of adjunct DTx by the US Food and Drug Administration and draft guidelines on "prescription drug use-related software" illustrate opportunities to create drug + digital combination therapies, ultimately leading towards drug-device combination products (DTx has a status of medical devices). Digital interventions (mobile, web-based, virtual reality, and video game applications) demonstrate clinically meaningful benefits for people living with Alzheimer's disease, dementia, rheumatoid arthritis, cancer, chronic pain, epilepsy, depression, and anxiety. In the respective animal disease models, preclinical studies on environmental enrichment and other non-pharmacological modalities (physical activity, social interactions, learning, and music) as surrogates for DTx "active ingredients" also show improved outcomes. In this narrative review, we discuss how drug + digital combination therapies can impact translational research, drug discovery and development, generic drug repurposing, and gene therapies. Market-driven incentives to create drug-device combination products are illustrated by Humira® (adalimumab) facing a "patent-cliff" competition with cheaper and more effective biosimilars seamlessly integrated with DTx. In conclusion, pharma and biotech companies, patients, and healthcare professionals will benefit from accelerating integration of digital interventions with pharmacotherapies.

Cantharidin Topical Solution 0.7%: First Approval.

Cantharidin (YCANTH™) is a proprietary drug-device combination product containing a formulation of cantharidin 0.7% topical solution (a vesicant naturally derived from blister beetles) delivered via a single-use applicator that has been developed by Verrica Pharmaceuticals Inc. for the treatment of molluscum contagiosum and is also being developed for the treatment of warts. In July 2023, YCANTH™ (cantharidin 0.7% topical solution) was approved for the topical treatment of molluscum contagiosum in adult and pediatric patients 2years of age and older in the USA. This article summarizes the milestones in the development of cantharidin 0.7% topical solution leading to this first approval for the topical treatment of molluscum contagiosum in adult and pediatric patients 2years of age and older.

Biocompatibility Considerations for Orally Inhaled and Nasal Drug Products and Other Drug--Device Combination Products.

Biocompatibility considerations have historically been important for orally inhaled and nasal drug products (OINDPs) and other drug-device combination products, because finished device components and packaging in these products are often in direct contact with formulation and the patient. The International Pharmaceutical Aerosol Consortium on Regulation and Science (IPAC-RS) discusses, in this article, the current regulatory landscape associated with biocompatibility and how biocompatibility is typically assessed for OINDPs, including risk management considerations and navigation of regulatory requirements. The article also describes current challenges related to alignment of regulatory expectations, particularly for drug-device combination products, and proposes some questions and topics for further discussion with regulatory agencies and other stakeholders to help advance alignment. To further illustrate current challenges and industry approaches to meeting biocompatibility requirements, we also present results of an IPAC-RS benchmarking survey and case studies.

Self-Entrapment of Antimicrobial Peptides in Silica Particles for Stable and Effective Antimicrobial Peptide Delivery System.

Antimicrobial peptides (AMPs) have emerged as a promising solution to tackle bacterial infections and combat antibiotic resistance. However, their vulnerability to protease degradation and toxicity towards mammalian cells has hindered their clinical application. To overcome these challenges, our study aims to develop a method to enhance the stability and safety of AMPs applicable to effective drug-device combination products. The KR12 antimicrobial peptide was chosen, and in order to further enhance its delivery and efficacy the human immunodeficiency virus TAT protein-derived cell-penetrating peptide (CPP) was fused to form CPP-KR12. A new product, CPP-KR12@Si, was developed by forming silica particles with self-entrapped CPP-KR12 peptide using biomimetic silica precipitability because of its cationic nature. Peptide delivery from CPP-KR12@Si to bacteria and cells was observed at a slightly delivered rate, with improved stability against trypsin treatment and a reduction in cytotoxicity compared to CPP-KR12. Finally, the antimicrobial potential of the CPP-KR12@Si/bone graft substitute (BGS) combination product was demonstrated. CPP-KR12 is coated in the form of submicron-sized particles on the surface of the BGS. Self-entrapped AMP in silica nanoparticles is a safe and effective AMP delivery method that will be useful for developing a drug-device combination product for tissue regeneration.

Challenges Associated with Biological Safety Assessments for Drug-Device Combination Products.

Biological safety assessments for drug-device combination products involve evaluation of the drug container closure and the device constituent part. When the device constituent part is the drug delivery system as well as the drug container closure system, both device and drug-based packaging standards have been deemed applicable. Approaches used for the biological safety assessment of medical devices differ from those used for pharmaceutical packaging/delivery systems. One area of difference is the extent to which chemical characterization with toxicological assessment is used either in addition to, or in place of, biological in vivo or in vitro tests. Differences also exist in the way nonclinical studies are used to evaluate the safety of medical devices or drug delivery systems. The lack of alignment in standards and guidance has resulted in confusion over what combination of tests and methods of evaluation constitute a biological safety assessment that will meet regulatory expectations for a drug-device combination product. The intent of this article is to discuss the challenges created when the packaging or delivery system is also a device constituent part of a drug-device combination product. Suggestions are offered regarding approaches that may be useful for conducting suitable biological safety assessments for drug-device combination products.

Generic substitution of epinephrine autoinjectors: Patient and caregiver perceptions and attitudes

It is important to understand and address patient and caregiver perceptions about and attitudes toward generic substitution of drug-device combination products. The goal of this study was to explore how differences in design and usability features of epinephrine autoinjectors (EAIs) affect patients' and caregivers' views of product quality, efficacy, and device usability in an emergency setting and to better understand attitudes about and perceptions of EAI substitution. This qualitative, enhanced focus group study was conducted in the United States among adult and adolescent EAI users. Ajourney mapping exercise was used to explore patient and caregiver perceptions of and barriers to switching to a generic EAI. Discussion topics also focused on questions participants would ask, challenges they would face, and actions they would take if they were switched to a generic EAI. While patients and caregivers were interested in the potential cost savings and increased access to treatment offered by generic EAIs, they wanted to be informed by their prescriber or pharmacist about generic substitution before or when it occurs. In terms of design differences, participant feedback most often related to differences in look and feel (eg, size, force to execute user tasks, hand grip) or functionality and design differences (eg, the generic version has a twist-off cap at the needle end, and the brand-name EpiPen does not). Outcomes from these focus groups suggest opportunities for the US Food and Drug Administration, health care professional organizations, and patient advocacy organizations to improve generic drug literacy among adults, adolescents, and health care providers.

Durable benefit after treatment of obstructive benign prostatic hyperplasia with a novel drug-device combination product: 2-year outcomes from the EVEREST-I study.

To evaluate the safety and efficacy of the Optilume BPH Catheter System for the treatment of lower urinary tract symptoms (LUTS) secondary to benign prostatic hyperplasia (BPH). This open-label, single-arm study enrolled eighty subjects with LUTS secondary to BPH who were treated with the Optilume BPH Catheter System. Symptoms were recorded utilizing the International Prostate Symptom Score (IPSS) and Benign Prostatic Hyperplasia Impact Index (BPH-II). Functional improvement was measured utilizing peak urinary flow rate (Qmax) and post-void residual urine volume (PVR). Adverse events were systematically captured and reported at each follow-up visit. Subjects treated with the Optilume BPH Catheter System experienced a significant improvement in LUTS from baseline through 2years of follow-up, as measured by IPSS (22.3 vs 8.2, p < 0.001) and BPH-II (6.9 vs 2.3, p < 0.001). Functional improvement was also significant, with Qmax improving from an average of 10.9mL/s at baseline to 17.2mL/s at the 2-year follow-up and PVR improving from 63.1 to 45.0mL. Treatment-related adverse events were typically minor, with none occurring between 1- and 2-year post-treatment. The Optilume BPH Catheter System is a unique minimally invasive surgical therapy that combines mechanical and pharmaceutical aspects for the treatment of BPH. The functional and symptomatic improvements seen after treatment are significant and have been sustained through 2years in this early feasibility study. NCT03423979, registered February 6, 2018.

Application of implementation science framework to develop and adopt regulatory science in different national regulatory authorities.

The purpose of developing and adopting regulatory science (RS) for drug regulatory authorities (DRAs) is to enhance regulatory capacity by advancing the scientific approach for the evaluation of health-related products. While many DRAs around the world advocate the concept of RS, the implementation approaches of RS vary according to local needs and have not been systemically examined. This study aimed to systematically identify the evidence about how RS was developed, adopted, and advanced by the selected DRAs, and analyzed and compared the implementation experiences of RS development under the guidance of an implementation science framework. Documentary analysis of government documents and a scoping literature review were conducted, and data analysis was performed under the guidance of the PRECEDE-PROCEED Model (PPM). DRAs in the United States, the European Union, Japan, and China had officially launched RS initiatives and were therefore selected as the target countries in this study. There is no common consensus on the definition of RS among the DRAs. However, these DRAs shared the same goal of developing and adopting RS, which was used to develop new tools, standards, and guidelines that could improve the effectiveness and efficiency of the risk and benefit assessment of the regulated products. Each DRA had decided its own priority areas for RS development and thus set specific objectives that might be technology-based (e.g., toxicology and clinical evaluation), process-based (e.g., partnership with healthcare systems and high-quality review/consultation services), or product-based (e.g., drug-device combination products and innovative emerging technologies). To advance RS, considerable resources had been allocated for staff training, advancing information technology and laboratory infrastructure, and funding research projects. DRAs also took multifaceted approaches to expand scientific collaborations through public-private partnerships, research funding mechanisms, and innovation networks. Cross-DRA communications were also reinforced through horizon scanning systems and consortiums to better inform and assist the regulatory decision-making process. The output measurements might be scientific publications, funded projects, DRAs interactions, and evaluation methods and guidelines. Improved regulatory efficiency and transparency leading to benefits to public health, patient outcomes, and translation of drug research and development as the key primary outcomes of RS development were anticipated but not yet clearly defined. The application of the implementation science framework is useful for conceptualizing and planning the development and adoption of RS for evidence-based regulatory decision-making. Continuous commitment to the RS development and regular review of the RS goals by the decision-makers are important for DRAs to meet the ever-changing scientific challenges in their regulatory decision-making process.

INP104: a drug evaluation of a nonoral product for the acute treatment of migraine.

Migraine is a highly prevalent, disabling neurological disorder that is also associated with gastrointestinal symptoms, autonomic dysfunctionand allodynia. Despite the availability of multiple acute agents for migraine, an unmet need remains for effective, well-tolerated drugs that are nonoral and noninvasive. Here, we provide a drug evaluation of INP104, a novel drug-device combination product of dihydroergotamine (DHE) mesylate -a molecule with a long history of efficacy familiar to headache specialists -which is delivered to the difficult-to-reach upper nasal space where it is rapidly and consistently absorbed via Precision Olfactory Delivery (POD®). In clinical trials, INP104 exhibited favorable pharmacokinetics, a well-tolerated safety profile, and rapid symptom relief, highlighting its potential as a suitable acute therapy for migraine.

Pre-Clinical Requirements for Drug-Eluting Stents for CE Certification

Abstract: Drug Eluting Stents (DES) are small, expandable tubes that are implanted into a diseased, blocked peripheral or coronary artery through angioplasty to widen and increase the blood flow by slowly releasing the drug from device. They are covered in a medication that stops scar tissue from expanding upon that artery. In medical practice DES are frequently used for vascular disorders, exhibiting adequate potency and suitability within the acceptable range. Medical device regulations in European Union (EU) are covered by Directives 93/42/EEC, 98/79/EEC and 90/385/EEC which were recently replaced by new regulations (EU) 2017/745 on medical devices and (EU) 2017/746 on In vitro diagnostic medical devices. Across all the EU legislation, “CE Mark” or “Certificate of Compliance” has become a recognised term. The Competent authority’s (CA) certifies that a product conforms to required standards of EU, then the manufacturer display the “CE mark” on the label. The DrugDevice combination products like DES are included in Class-III high risk active implantable medical devices. The pre-clinical investigations of drug eluting stents often follow International Organization for Standardization (ISO) requirements, these vascular stents are covered under ISO 25539-2: 2020 - Cardiovascular Implants - Endovascular Devices, ISO 10993:2018- Biological Evaluation of Medical Devices and ISO 10555-1: 2013 – Intravascular catheters, sterile and single use medical devices.

Abstract 1812: ROS-dependent activation of immunogenic glioblastoma cell death &amp; release of immunogenic particles by an autologous cell-based immunotherapeutic platform

Abstract Background: Imvax is developing a novel personalized immunotherapy platform that combines whole-tumor derived cells with an antisense oligonucleotide against insulin-like growth factor 1-receptor in implantable biodiffusion chambers (BDCs; 0.1 μm pore-size). The lead product, IGV-001, was evaluated in newly diagnosed glioblastoma (GBM) patients in a phase 1b clinical trial. Median overall survival of highest exposure IGV-001-treated ‘Stupp-eligible patients (n=10) was 38.2 months compared with 16.2 months in current standard-of-care-treated patients (p=0.044) (Andrews 2021). Imvax also reported anti-tumor activity of the murine variant of this product, mIGV-001, in the GL261 GBM mouse model and detected mIGV-001-induced immune responses in BDC-draining lymph nodes. Since reactive oxygen species (ROS) overproduction can result in immunogenic cell death, we investigated the role of ROS formation as a mediator of cell death in mIGV-001 as well as the generation of subcellular particles that, when released from the BDCs, may provide a tumor antigen payload with potential anti-tumor activity. Methods: Mouse (m) or human (h) variants of IGV-001 were prepared using mouse GL261 or human T98G GBM cells, respectively, and BDCs were incubated for 24-48 h. ROS levels were detected by flow cytometry and fluorescence microscopy via oxidation of H2DCF (a fluorescein analog used to quantify ROS in cells) in the presence or absence of the antioxidant N-acetyl-cysteine (NAC). m/hIGV-001 viability was assessed by flow cytometry using Annexin V/7-AAD staining. Particle size distribution in hIGV-001 BDC contents was analyzed using a Nanosight NS300. The transport of subcellular particles (25-90 nm) across the BDC membrane was modeled under dynamic and static conditions using MATLAB® 2022a and confirmed by in vitro studies. Results: After 24 h in vitro, ROS levels in mIGV-001 were significantly increased along with overt cell death. ROS scavenging with NAC resulted in a cell viability rescue of approximately 50% (from ~40% to ~60% viable cells). Similar trends, although of reduced magnitude, were observed in hIGV-001. Particle analysis within hIGV-001 BDCs showed that after 48 h in culture, dead cells produced particles small enough to diffuse through the BDC membrane. Computational models corroborated that under static conditions, particle equilibrium inside and outside BDCs was achieved after 40 h, 80 h, and 260 h for 25 nm, 50 nm, and 90 nm particles, respectively. Under dynamic conditions, equilibrium was reached in less than 5 h irrespective of particle size. Conclusions: The use of a surgically implantable drug-device combination product induces ROS-associated immunogenic cell death and generation of a tumor-derived immunogenic payload that can be taken up by local DCs, which travel to the proximal draining lymph nodes to activate anti-tumor T cells. Citation Format: Christopher Cultrara, Kenneth Kirby, Essam Elrazaq, Christopher Uhl, Amelia Zellander, Lorenzo Galluzzi, Mark Exley, Jenny Zilberberg. ROS-dependent activation of immunogenic glioblastoma cell death &amp; release of immunogenic particles by an autologous cell-based immunotherapeutic platform [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1812.

Industry update, December 2022.

Industry update, December 2022.

An Overview and Discussion of N-nitrosamine Considerations for Orally Inhaled Drug Products and Relevance to Other Dosage Forms.

The presence of N-nitrosamines in drug products are currently an area of high regulatory and industry scrutiny, having been detected above acceptable regulatory levels in several solid oral drug products. For over 20years, there has been an expectation that N-nitrosamines be eliminated or controlled to acceptable levels in orally inhaled and nasal drug products (OINDP). As a result, the OINDP industry has developed and implemented risk management processes and considerations to address N-nitrosamines in final drug product, including management and understanding of upstream supply particularly for OINDP device and container closure systems. We provide an overview of N-nitrosamine formation, discuss key current regulatory expectations worldwide for N-nitrosamines in drug products, discuss risk management approaches relevant for drug device combination products, and share analytical "tips" with respect to handling N-nitrosamines chemical assessments.

Impact of drug loading on release from levonorgestrel intrauterine systems

Levonorgestrel intrauterine systems (LNG-IUSs) are polydimethylsiloxane (PDMS) based non-biodegradable complex drug-device combination products providing efficacy for up to several years based on the strength. A large amount of LNG (e.g., 52 mg in Mirena and Liletta) must be loaded in the LNG-IUS products to maintain the long-acting effect even though LNG is a potent hormone. However, the high amount of LNG not only poses the potential risk of dose dumping, but also leads to drug waste due to incomplete drug utilization close to the end of usage. It has been unclear whether the duration of usage of these products should be extended for full drug utilization or products with lower drug loading should be developed. Therefore, it is critical to understand the impact of strength (or drug loading) on drug release from LNG-IUSs. In the current study, drug reservoirs with a broad range of drug loading (from 0.5% w/w to 50% w/w) were prepared and assembled into LNG-IUSs. Different accelerated release conditions were used to perform release testing of LNG-IUSs with different drug loading. 5% to 10% variation in excipient of the LNG-IUSs did not significantly alter the drug release profiles of the LNG-IUSs. The release rate of LNG-IUSs is inversely proportional to their drug loading at high drug loading (10% w/w, 25% w/w and 50% w/w). Drug release was incomplete for LNG-IUS with low drug loading (2.5% w/w and 1% w/w) and no drug release could be detected for the LNG-IUS with 0.5% w/w drug loading. In addition, the burst effect of the LNG-IUSs with different drug loading was investigated. This is the first research report covering ultra-long duration (more than four years) of real-time drug release from LNG-IUSs with different drug loading (0.5%-50% w/w). The amount of excipient (PDMS) used in the reservoir of LNG-IUSs was determined to be not a critical quality parameter in the formulation design since LNG-IUSs (50% w/w drug loading) with up to 10% variation in excipient did not show significant differences in their release profiles. The drug release kinetics/mechanism remained the same for LNG-IUSs with drug loading ranging from 1% to 50%. In addition, the accelerated release testing methods were confirmed to be representative of the real-time release profiles and this can give confidence in extending the duration of usage for these products provided that the device remains physically intact (no tearing or damage in the outer membrane) and the release rate is within the therapeutic window. It is recommended to perform both real-time and accelerated release testing simultaneously for LNG-IUSs to understand the burst effect as well as the complete release characteristics. Lastly, drug/polymer interaction may play a role when designing LNG-IUS formulations with low drug loading (<5% w/w) since drug/polymer interaction is significant when only a small amount of drug present.

Advancements in the Design and Development of Dry Powder Inhalers and Potential Implications for Generic Development.

Dry powder inhalers (DPIs) are drug-device combination products where the complexity of the formulation, its interaction with the device, and input from users play important roles in the drug delivery. As the landscape of DPI products advances with new powder formulations and novel device designs, understanding how these advancements impact performance can aid in developing generics that are therapeutically equivalent to the reference listed drug (RLD) products. This review details the current understanding of the formulation and device related principles driving DPI performance, past and present research efforts to characterize these performance factors, and the implications that advances in formulation and device design may present for evaluating bioequivalence (BE) for generic development.

Advancing medical device regulatory reforms for innovation, translation and industry development in China.

The blossoming Chinese medical device market calls for a science-based regulatory system in China. Consistent efforts have been made to advance the medical device regulatory reforms for innovation, translation and industry development. In this article, we report both the latest regulatory requirements which aim to ensure safety and efficacy for patients while encouraging innovation of the medical device industry, and the key programs on medical devices covered in the Regulatory Science Action Plan (RSAP) of the National Medical Products Administration of China (NMPA). The main features of the revised regulations are first elucidated before the opportunities for translational research are interpreted, including those for additive manufacturing and customized devices, drug–device combination products, artificial intelligence-powered software and surgical robots, and nanomaterials for medical devices. Finally, a regulatory perspective is provided to researchers who expect to translate their technologies in the Chinese medical device market. Important issues including early attention to critical market and clinical needs, understanding the true principle and spirit underlying the changing regulations and standards, and protecting intellectual property rights with comprehensive measures, are discussed. These developments warrant further investigations into the distinct role of regulatory science in shaping medical devices research and development.