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Corticosteroid use has been associated with hypothalamic–pituitary–adrenal (HPA) axis suppression which can predispose the pediatric patient to multiple immune- and growth-related adverse effects. The objectives of this review were to identify the pediatric drug development programs involving corticosteroids and the associated pediatric HPA axis suppression studies submitted to the US Food and Drug Administration (FDA), capture FDA guidance topic related recommendations, and determine the consistency of HPA axis data in prescription corticosteroid labeling. A review of FDA submissions from January 2002 to July 2018 involving corticosteroid products and HPA axis testing in pediatric patients was conducted. The adrenal function testing methods, number of pediatric HPA axis dedicated studies, duration of these studies, and the labeling outcomes were assessed. Of the 437 total drug products that were submitted to FDA, only 36 products were corticosteroids or a corticosteroid combination product yielding a total of 83 pediatric clinical studies. Twenty-four of the 36 products included 37 HPA axis suppression dedicated studies which employed different measurement methods. The pediatric HPA axis suppression trial data collected did not necessitate any new actionable recommendations in the FDA labeling. Future pediatric drug development program goals would be to determine whether HPA axis suppression studies should be conducted, establish optimal testing methods if HPA axis testing is performed, continue to update guidances for industry, and actionable labeling recommendations. However, regulatory policy related to conducting pediatric HPA axis studies requires additional scientific research and discussion by the pediatric drug development community.

CONTEXT: On October 6, 2014, the United States Drug Enforcement Administration (DEA) implemented a regulatory change for hydrocodone combination products (HCPs), moving them from Schedule III to II, in an effort to decrease drug overdoses. Existing research suggests this regulatory action reduced HCP prescribing and dispensing; however, there is limited research assessing its possible effects on overdoses and accidental exposures. OBJECTIVE: To analyze the changes in opioid exposures reported to the California Poison Control System (CPCS) before and after DEA rescheduling of HCPs. METHODS: We collected monthly exposure data reported to CPCS from 2012–2019 and conducted interrupted time series analyses to assess changes in exposures after rescheduling for HCPs, tramadol, oxycodone, morphine, codeine, fentanyl, and heroin. Additional analyses were done to assess any changes in exposures resulting in severe outcomes (moderate or major health effects). For HCPs, we also conducted logistic regressions to identify characteristics of exposures resulting in severe outcomes before and after rescheduling. RESULTS: Overall monthly opioid exposures reported to CPCS decreased after DEA rescheduling of HCPs. These decreases were significant for HCP, tramadol, and morphine (p

Combination products (CPs), designated by the US Food and Drug Administration, continue to be on the rise, from the innovation of novel medicines and greater demand for injectable home and self-administration. CP qualification, its constituent parts or intended use, will depend upon the regulatory jurisdiction with reference to the product's primary mode of action. In the case of a drug product combined with a device, a consult or collaborative review process involving different Centers within the US Food and Drug Administration may be necessary. Policies and practices from different legislative branches of government will need to be merged for a single application. This presents a challenge for aligning information for the application dossier as it relates to a drug master file or drug-device CP design history file. A common objective for both pharmaceuticals and devices is to identify and evaluate patient risks to be mitigated, controlled, and managed across the drug product lifecycle. These concepts are reflected in the regulatory practices of pharmaceutical quality by design and device design controls. Early stakeholder engagement with this dynamic process between different regulatory paradigms becomes an advantage. This manuscript describes aspects for early planning for injectable drug-device development to facilitate time to market with patient centric solutions.

Introduction: With increasing use of biological products and devices, importance of human factor (HF) studies is increasing. The HF study ensures safe and effective use of the device by intended users, for intended uses, under intended use environments.Areas covered: This review compiles information of HF studies conducted for biological combination products (biological products plus device) approved by US FDA's Center for Drug Evaluation and Research between 21 June 2011 and 31 December 2018. Information regarding product, indication, device type, administration frequency, and various aspects related to HF studies was collected from published documents.Expert opinion: Learnings from HF studies and known use-related problems of similar devices should be incorporated in the design of the device and the HF validation study. User profile, group, subgroup, and sample size are important aspects of the HF validation study. Early engagement with US FDA can be helpful to integrate the HF program with the overall device development program. It may not be possible to eliminate all use errors or risks for the device. Any residual risk after an HF validation study should be evaluated, and benefits of the device use should outweigh the residual risk.Abbreviations: BCP: biological combination product; BLA: Biological License Application; CDER: Center of Drug Evaluation and Research; FDA: Food and Drug Administration; FDC: Food Drug and Cosmetic; HCP: healthcare professional; HF: human factor; IFU: instructions for use; NDA: New Drug Application; PFS: pre-filled syringe; PHS: Public Health Service; PI: prescribing information; US: United States.

This review presents the most common disease entities in which combinations of NSAIDs and spasmolytic drugs are used to reduce pain. The benefits of fixed-dose combination products (FDCs) are that they improve the response in people with insufficient monotherapy. Using the synergy or additive effect of drugs, it is possible to obtain a significant therapeutic effect and faster action with the use of smaller doses of individual drugs. In addition, one active ingredient may counteract adverse reactions from the other. Another essential aspect of the use of FDCs is the improvement of medical adherence due to the reduction in the pill burden on patients. It is also possible to develop a fixed-dosed combination product de novo to address a new therapeutic claim and be protected by patents so that the manufacturer can obtain exclusive rights to sell a particular FDC or a formulation thereof. The proposed fixed-dose combinations should always be based on valid therapeutic principles and consider the combined safety profile of all active substances included in the medicinal product. This review aims to identify which combinations of NSAIDs and spasmolytics have been developed and tested and which combinations are still under development.

Pain, a severe public health problem, can affect patient quality of life when inadequately controlled. Considering that pain pathophysiological mechanisms are complex, combining active pharmaceutical ingredients (APIs) with multiple and synergistic mechanisms of action represents a potentially more effective therapeutic approach than conventional monotherapy treatments. In turn, topical drug delivery has clear advantages over other routes of administration, such as high levels of efficacy, better safety profile and great patient compliance. In this context, the combination of two or more APIs in a single dosage form - fixed-dose combination product (FDC) - for topical administration may represent a promising therapeutic option in the field of pain management. Considering the above mentioned, the purpose of this manuscript is to address an overview of some general aspects regarding pain management and FDCs, as well as the regulatory environment that has to be taken into consideration during their development. Special emphasis will be given to fixed-dose combinations for topical administration with analgesic and/or anti-inflammatory activity. Market drivers of the topical FDC currently approved are ultimately pointed out, and new opportunities in pain management highlighted.

Instructions for use (IFU) are part of the medical device interface. As such, it is critical that they are designed to facilitate safe use and prevent use-errors. To ensure that IFUs are designed to support the end user needs, abilities, and scenarios of use, they must be developed using a human-centered design (HCD) process. We introduce a framework that models human interaction with IFUs and provides guidance for their design solutions: Find, Comprehend, Apply. IFUs designed for users will reduce opportunities for device use-related errors and increase capacity to provide safe patient care.

Advanced Therapeutic Medicinal Products (ATMP) are a heterogenous group of investigational medicinal products at the forefront of innovative therapies with direct applicability in respiratory diseases. ATMPs include, but are not limited to, stem cells, their secretome, or extracellular vesicles, and each have shown some potential when delivered topically within the lung. This review focuses on that subset of ATMPs. One key mode of delivery that has enabling potential in ATMP validation is aerosol-mediated delivery. The selection of the most appropriate aerosol generator technology is influenced by several key factors, including formulation, patient type, patient intervention, and healthcare economics. The aerosol-mediated delivery of ATMPs has shown promise for the treatment of both chronic and acute respiratory disease in pre-clinical and clinical trials; however, in order for these ATMP device combinations to translate from the bench through to commercialization, they must meet the requirements set out by the various global regulatory bodies. In this review, we detail the potential for ATMP utility in the lungs and propose the nebulization of ATMPs as a viable route of administration in certain circumstances. Further, we provide insight to the current regulatory guidance for nascent ATMP device combination product development within the EU and US.

Background and Aims Distal renal tubular acidosis (dRTA) is a rare disorder leading to impaired net acid excretion by the kidney inducing hyperchloremic metabolic acidosis and hypokalemia. The therapeutic effect of the standard of care is of short duration and requires multiple day and night administrations; it is also often accompanied by gastrointestinal discomfort and poor palatability impacting medication adherence. ADV7103, the first advanced therapy for dRTA, consists of a combination of prolonged-release potassium citrate and prolonged-release potassium bicarbonate granules providing round-the-clock alkali and potassium coverage with twice daily administration. Long-term adherence with ADV7103 is reported, along with acceptability of the product. Method B22CS is a multicentre, open-label long-term extension study, evaluating safety, tolerability, acceptability and efficacy of ADV7103 in adult and paediatric patients with dRTA. Adherence was assessed at each study visit up to 24 months, based on accountability of study drug retrieval, laboratory results, and interview of the patients in a diary and expressed as the proportion of patients that presented adherence lower than 50%, between 50% and 74%, between 75 and 90%, and higher than to 90%. Treatment acceptability as well as quality of life of the patients and their parents were assessed using a 100-mm visual analogue scales (VAS). Results Table 1 shows the evolution of compliance between Month 6 and Month 24. Overall, of the 29 patients remaining in the study after 24 months, 18 (62%) had adherence rates >90%, 5 (17%) had adherence rates of 75-90%, 6 (21%) had adherence rates of 50-74%, and there were no patients with adherence Compared to the alkalising treatments they had before the study, more than 80% of the patients perceived both the improvement of the formulation and of the number of daily doses at scores ≥ 75 mm. The overall improvement of quality of life reported by the patients was of 89 ± 19 mm and that reported by their parents was of 90 ± 14 mm after 24 months of treatment. Conclusion Adherence to treatment was maintained at a high level throughout the 24 months of the study confirming the good acceptance of ADV7103 therapy.

Background: From 1999 to 2010, the annual number of US deaths due to opioid overdose increased about 400% as the number of opioids prescribed yearly also increased by approximately 400%. Over this period, hydrocodone combination products drove the opioid epidemic, as they became the most frequently prescribed medication in the United States. Our objective was to determine if the Drug Enforcement Administration's (DEA) 2014 policy change - which made it more difficult to prescribe hydrocodone combination products by moving them from Schedule III to Schedule II - reduced the total amount of opioid prescriptions as intended. Methods: We conducted a longitudinal analysis of the 10 most populous US states, beginning at the time each state began collecting data on opioid prescribing, and concluding at the end of 2016. The exposure was the DEA-mandated October 6, 2014 hydrocodone combination product schedule change. Results: After the DEA's schedule change for hydrocodone combination products, the total number of opioids prescribed each year per 100 people did not substantially change in California, Florida, Michigan, or New York. Although prescription rates dropped for hydrocodone combination products (CA: 43.2, 35.0; MI: 66.8, 55.6; NY: 20.8, 15.1), the reduction was commensurately counteracted by increased rates for tramadol (CA: 0.2, 9.9; MI: 0.1, 17.3; NY: 0.0, 7.6) and oxycodone (CA: 8.7, 9.7; MI: 10.3, 11.9; NY: 18.1, 18.8). Surprisingly, the other 6 states assessed had no viable mechanism in place for assessing state-wide opioid prescription totals, routinely expunged collected data, or only instituted a reporting mechanism toward the end of our study. Conclusion: Total opioid prescriptions were relatively unchanged following the 2014 DEA-mandated schedule change, however, physicians did change their prescribing habits by substituting tramadol for hydrocodone combination products. This substitution of similar medications for hydrocodone suggests alternative approaches are needed to reduce total US opioid prescription rates. Additionally, the current lack of standardized prescription reporting by states makes detailed opioid prescription analysis alarmingly difficult and insufficient to guide policy or monitor the impact of policy changes.

The regulatory environment is one of the key factors in successfully bringing an innovative medical product, like a drug-device combination product, to market. This paper offers insight into the experiences of those involved in obtaining regulatory approval of drug-device combination products in the European Union and the United States.The research consisted of two phases, qualitative data collection (through semi-structured interviews) and analysis, followed by quantitative data collection (through an online survey) and analysis.A conceptual model was developed that depicted the facilitating factors for obtaining regulatory approval of a drug-device combination product, relevant to the European Union and United States systems, respectively.This model provides, for the first time, a comprehensive understanding of these factors, providing a foundation that could be adapted to reflect specific drug-device combination products. This research demonstrated originality of approach in interviewing thought leaders in the life sciences sector as well as conducting a survey that spans two of the largest jurisdictions for drug-device combination products in the world.

Medical devices and medicinal products have many similarities in their nature, scope or specific medical purposes, and despite the differences in their principal means of action, they are often used in combination. Indeed, many medicinal products depend on medical devices for their administration, and it is increasingly common for medical devices to contain medicinal substances to support their action. Therefore, the combination of medicinal products and medical devices provides additional benefits for patients. However, their higher technical complexity requires a strengthening of their authorisation and certification requirements. In this regard, more comprehensive requirements and classification rules are introduced by a new European regulation on medical devices that fully applies from May 26th 2021. On account of their therapeutic significance, this review aims at gaining insight into the borderline between medical devices and medicinal products in this new 2021 regulatory framework. For the first time, any item containing a medical device and a medicinal product will have both parts evaluated. Through exemplification of both marketed and investigational devices incorporating medicinal substances and drug-device combinations, the new European requirements and their implications are thoroughly illustrated herein.

The consortium RESPONSE is a cooperation of partners from science and industry within the BMBFProgram “Twenty20 - Partnership for Innovation”, 2014- 2021. Current efforts are being made towards the transfer of new products, technologies and processes in the field of medical devices. Here, RESPONSE is focusing on novel concepts of implantable medical devices for cardiovascular, ophthalmologic and otolaryngologic application. Platform technology approaches, such as drug delivery systems for responsive functionalized implants or smart implant technologies, are being used to enable new applications.

The US Food and Drug Administration recently granted an approved indication for the first fixed-dose combination antihypertensive (amlodipine) and nonsteroidal anti-inflammatory drug (celecoxib) for treatment of comorbid hypertension and osteoarthritis. This review summarizes available data on this combination product, to be marketed as Consensi (Kitov Pharmaceuticals, Ltd, Tel Aviv, Israel), and discusses its potential place in therapy.

Biologic-device combination products using prefilled syringes (PFSs) and autoinjectors (AIs) are popular for biological products administered subcutaneously. Pharmacokinetic (PK) comparability studies commonly provide the scientific data to support introduction of AI presentations via bridging with PFS. A survey of biological products approved by FDA's Center for Drug Evaluation and Research identified 17 biologics license applications (BLAs) with both PFS and AI presentations for subcutaneous (SC) administration, including 16 approved on February 1, 2018, and one with AI presentation under review. A systematic review on the device parameters and the PK comparability studies bridging the two presentations was conducted. Subsequently, whether device parameters or the PK study design may have influenced the PK comparability study results was evaluated. The reported device parameters for AI and PFS are generally consistent across BLAs, whereas the approach to assess PK comparability varied, including the study design. Most PK comparability studies met bioequivalence (BE) criteria. Upon inspection of the studies that did not meet BE criteria, injection depth of AI and the injection site for either AI or PFS were identified as potential influencing factors to the outcome of PK comparability study. This study represents an initial attempt to identify the potential influencing factors on device bridging, including the characteristics of the device and the clinical pharmacology study. These findings may inform the combination product development strategy, specifically design considerations for device and PK comparability studies.

Human factors engineering is an important part of combination product development, and regulatory bodies expect certain human factors standards to be met for successful pre-market submissions that demonstrate a product is safe and effective in the hands of end users. This chapter identifies US and international human factors standards for combination products and examines best practices used to develop use-related product documentation that forms the framework of a sponsor’s human factors program, for example, use-related risk analyses (URRA). In addition, strategic implementation of human factors methodologies are discussed in terms of how to (1) start the human factors process early, (2) leverage applicable prior work, (3) keep the global market in mind, and (4) collect labeling-focused data. Challenges that sponsors often encounter during human factors validation testing are also explored, which can include accounting for negative transfer, cautiously relying on training or labeling as a mitigation, providing data-driven design decisions, creating quick reference guides, and determining how to confirm delivery of a full dose.

New patient treatment options continue to drive the need for the development of combination products. Sterility assurance innovation is critical to bring these combination products to market. This innovation requires sterility assurance professionals to collaborate across the broad spectrum of the demands of the health-care industry. Not only does a successful sterility assurance professional need to be an expert in their field, but also they need to be aware of the broad challenges and opportunities associated with bringing a combination product to the market. This book provides an overview as well as introduces exciting new opportunities in each industry sector. The sectors addressed include combination products and their design, terminal sterilization, aseptic processing, packaging, health-care practices as well as the worldwide regulatory environment. The topics associated with each sector are introduced with the perspective of facilitating the development of innovative new combination products.

Core to managing a combination product’s life cycle is a quality system outlining robust design controls and risk management processes. Competent monitoring processes and a multidisciplinary governance structure providing oversight empower efficient and patient-centric product development while facilitating accountability and management awareness throughout.

Competent and timely development of drug delivery systems designed for self-administration requires a thoughtful organizational model, dedicated and centralized engineering project management, global design verification standards, and regulatory engagement. Advances in sensors, wireless communication technologies, mobile medical applications (MMA), and cloud-based data paradigms are empowering patients and healthcare providers. However, these opportunities are not without risk.

This chapter tracks the relatively short, but fairly robust, history of combination product regulation in the USA. It starts with an overview of the legislation, regulations, and key policy events that have shaped the regulatory environment for combination products since the 1970s, when these products first started coming on the scene. It covers events such as the enactment of the Safe Medical Devices Act in 1990, which expressly recognized the existence of combination products and created an avenue for FDA to develop a framework for assigning these products for regulatory review, as well as the creation of the Office of Combination Products in 2002. Additionally, the chapter outlines the Agency’s combination product initiatives leading up to the enactment of the 21st Century Cures Act (“Cures Act”) in 2016, an overview of the impact of the Cures Act on combination products and a summary of the Agency activities that have occurred following the enactment of the Cures Act. The middle portion of the chapter provides an overview of the increasing technical and regulatory expectations for combination products. This includes an in-depth discussion of 21 CFR 4 and how these requirements affect product development. Additionally, this portion of the chapter focuses on the technical considerations relating to container closure systems, injection products, inhalation products, human factors, and bridging. The final portion of the chapter provides regulatory submission and life cycle management considerations, including eCTD structure, use of master files, postapproval changes, and postmarket safety reporting. The chapter concludes with perspectives for the future of combination product regulation in the USA.

Launching a new or improvement to a combination product can bring the patient satisfaction and confirmation but also the potential for an unexpected surprise as they may not be familiar with the combination product or changes made to the on-market product. In addition to planned changes, normal variation in combination product constituent parts may be perceived as a difference to the user and impact their experience with the product. These types of use experiences come back in the form of customer appreciation, complaints, and/or testimonies, through direct access via company product support channels, social media, as well as health care givers. In this chapter, lessons learned from the launch and sustaining engineering of the Humira Autoinjector will be discussed, including examples of design/process improvements based on an understanding of the key functional attributes of the design and constituent parts required to deliver robust autoinjector performance.

Therapeutics known as combination products because they combine drug, device, and/or biologic elements can offer important advantages relative to single‐modality products. However, regulatory policy in this arena has lagged relative to increases in product submissions and complexity of these products. In this article we describe how the US Food and Drug Administration (FDA) applied Lean Management methods to improve and streamline the process by which different FDA centers and offices coordinate review of combination products. Therapeutic products that combine drug, device, and/or biologic elements account for an increasing share of medical products. The global market for these combination products is expected to grow at a compound annual rate of 5.6% from 2012–2017,1 higher than rates projected for medical devices2 or prescription drugs.3 Combination products such as drug‐eluting stents, prefilled infusion pumps and inhalers, transdermal patches, antibody‐drug conjugates, and even some digital health technologies comprise approximately one‐third of all medical products under development.4 Combination product submissions to the FDA including new technologies increased 17% in 2015 vs. the previous 5‐year average. Combination products offer potential advantages relative to single‐modality products, including fewer adverse effects, improved adherence, controlled drug release, and targeted delivery. However, regulatory policies have not kept pace with the growing number and complexity of these products.5

Modern-day treatment regimens for human immunodeficiency virus (HIV) are not only highly effective, but are now more often available as convenient fixed-dose combination products. Furthermore, as medication adherence is of utmost importance in this setting, national guidelines endorse the use of such products. Transplant providers of HIV-infected patients will undoubtedly encounter these products, some of which contain medications known to drastically alter the metabolism of certain immunosuppressants. Herein, we describe an instance of drug interaction-induced calcineurin inhibitor (CNI) nephrotoxicity in a renal transplant recipient being started on a cobicistat-containing combination product for HIV. CNI toxicity, in turn, was resolved with the aid of phenytoin as an inducer of drug metabolism. This case underscores the importance of familiarity with newer combination products on the market and constant communication with HIV-positive transplant recipients and their providers.

Compared with single-entity treatments, multientity or combination products have the potential to provide enhanced therapeutic utility. Because they involve components that would normally be overseen by different branches of health authorities (eg, different FDA centers), they raise numerous scientific, regulatory, policy, and review management challenges. This article summarizes the current status of the evolving combination product development landscape and potential options to address key challenges facing combination product developers. Continued collaboration and transparency among regulators, combination product developers, and other stakeholders is essential to streamlining the global combination product development and review process to ensure the availability of high-quality new products that are being used in a way that is safe and effective.

VC-01 is a novel cell replacement therapy being developed as a potential long-term diabetes therapy to more effectively control glycemia, reduce hypoglycemia risk and mitigate diabetes-related complications. VC-01 is derived from directed differentiation of human embryonic stem cells to pancreatic progenitor cells, which are loaded into a durable, retrievable delivery device and then implanted subcutaneously. Once implanted and matured, the cells secrete insulin and other islet hormones in response to blood glucose levels. The delivery device is immunoprotective to implanted cells. VC-01 is currently being evaluated in a 24-month open-label, dose-escalating Phase 1/2 study in T1D patients with minimal insulin-producing β-cell function. Cohort 1 has evaluated product at a subtherapeutic dose to assess initial safety and tolerability and establish implantation techniques. To date, 19 subjects have been implanted and evaluated throughout implantation duration until final product explant. Product has been safe and well tolerated; adverse events have been relatively minor and generally related to the surgical procedure. The delivery device has provided protection against the host adaptive immune system with no evidence of allogeneic or autoimmune rejection or sensitization based upon a sensitive panel of immune function tests. No off-target growth of donor cells has been detected. The potential for prolonged cell survival has been demonstrated, as long as 24 months, but has been inconsistent among subjects and primarily limited by a foreign body response to the device component. Positive immunohistochemical staining for pancreatic islet cell markers NKX6-1, insulin, and glucagon has been observed. These preliminary results demonstrate the immune-protective nature of the encapsulation device and safety of this human stem cell-derived product, but also indicate the ongoing requirement for optimization of the host response to device materials. Disclosure R.R. Henry: Consultant; Self; Abbott, Alere Inc., AstraZeneca. Research Support; Self; AstaReal. Advisory Panel; Self; Boehringer Ingelheim Pharmaceuticals, Inc.. Consultant; Self; Bristol-Myers Squibb Company. Advisory Panel; Self; Elcelyx Therapeutics, Inc.. Research Support; Self; Eli Lilly and Company, Hitachi, Ltd.. Advisory Panel; Self; AstraZeneca. Consultant; Self; Boehringer Ingelheim Pharmaceuticals, Inc.. Advisory Panel; Self; Intarcia Therapeutics, Inc.. Consultant; Self; Intarcia Therapeutics, Inc., Ionis Pharmaceuticals, Inc., Janssen Pharmaceuticals, Inc.. Advisory Panel; Self; Johnson & Johnson Services, Inc.. Research Support; Self; Lexicon Pharmaceuticals, Inc.. Consultant; Self; Ligand Pharmaceuticals, Inc.. Advisory Panel; Self; Merck & Co., Inc.. Consultant; Self; Merck & Co., Inc.. Research Support; Self; Viacyte, Inc.. Consultant; Self; Sanofi-Aventis. Advisory Panel; Self; Sanofi-Aventis. J. Pettus: Advisory Panel; Self; Sanofi, Novo Nordisk Inc.. Consultant; Self; MannKind Corporation. Advisory Panel; Self; Insulet Corporation. Consultant; Self; Senseonics. J. Wilensky: None. A. Shapiro: Consultant; Self; Viacyte, Inc., Protokinetix. P.A. Senior: Consultant; Self; Abbott, AstraZeneca. Research Support; Self; AstraZeneca, Prometic Life Sciences Inc., Novo Nordisk Inc., Sanofi. Consultant; Self; Eli Lilly and Company. Speaker's Bureau; Self; Eli Lilly and Company, Novo Nordisk Inc.. Consultant; Self; Novo Nordisk Inc., Janssen Pharmaceuticals, Inc.. Speaker's Bureau; Self; Janssen Pharmaceuticals, Inc.. Consultant; Self; Boehringer Ingelheim Pharmaceuticals, Inc.. Speaker's Bureau; Self; AstraZeneca, Merck & Co., Inc., Abbott. Research Support; Self; Viacyte, Inc. B. Roep: Consultant; Self; Viacyte, Inc.. Research Support; Self; Viacyte, Inc. R. Wang: Employee; Self; Viacyte, Inc.. Stock/Shareholder; Self; Sanofi. E.J. Kroon: Employee; Self; Viacyte, Inc. M. Scott: Stock/Shareholder; Self; Viacyte, Inc.. K. D'Amour: None. H.L. Foyt: Employee; Self; Viacyte, Inc.. Stock/Shareholder; Self; Viacyte, Inc..

The US Food and Drug Administration (FDA) put out a call for comments on new draft guidance for industry “Comparative Analyses and Related Comparative Use Human Factors Studies for a Drug-Device Combination Product Submitted in an ANDA.” This call for comments elicited 7 submissions from various organizations in the field of health care products. This article reports on a review conducted on these 7 submissions. The purpose of this review was to identify any commonalities across the different submissions and determine if there was consensus on any point or aspect of the draft guidance. To identify any commonalities, a heat map plotting the lines of the draft guidance that had raised a comment/suggestion was produced. Also, a thematic analysis was conducted on the comments/suggestions. In total the 7 submissions produced 137 suggestions. The heat map revealed that these suggestions did not focus on any single part of the guidance but were spread throughout the guidance. The thematic analysis conducted on the suggestions found a number of distinct trends. These trends were grouped into 10 primary themes, each with a number of subthemes. It was concluded that guidance from the FDA on this matter is warranted and would be appreciated. However, it was also concluded that based on the distinct trends identified in the suggestions, there are issues that the FDA may wish to consider before publishing their final guidance.

Resistant hypertension (RH) is defined as a condition in which blood pressure remains above 140/90 mm Hg despite the use of at least three antihypertensive drugs, correctly combined and in full doses (including a diuretic). In Poland, the percentage of people suffering from RH is estimated at 10–13% relative to the total number of patients with hypertension. On the other hand, in recent years we have seen a significant increase in the importance of combination products both in Europe and in the United States. Several studies have shown that therapy that includes an average of 3 antihypertensive agents (in the form of combination products) having different mechanisms of action, such as blockers of the renin-angiotensin-aldosterone system (RAAS) in combination with a calcium channel blocker (CCB) or a diuretic, provides blood pressure control in the majority of patients, not only through increased efficacy and tolerability of drugs, but also owing to the simplification of the therapeutic regimen, which promotes the compliance with medical recommendations. In this paper we present the case of a patient with resistant hypertension, whose blood pressure normalised only after the use of a combination product.

Delivery of therapeutic agents directly to the central nervous system can be critical to address a number of diseases. Intraventricular administration of drugs has been used for over 50 years. Despite a substantial number of drugs routinely administered to the central nervous system in the course of medical practice, very few medical devices are appropriately cleared in the US for this route of administration. This review explores the regulatory challenges, the supplementary testing and more stringent acceptance criteria required for combination products and medical devices intended for CNS therapies. A case study of the recent Brineura® combination product approval is also presented.

The number of pulmonary diseases that are effectively treated by aerosolized medicine continues to grow.These diseases include chronic obstructive pulmonary disease (COPD), lung inflammatory diseases (e.g., asthma) and pulmonary infections. Dry powder inhalers (DPIs) exhibit many unique advantages that have contributed to the incredible growth in the number of DPI pharmaceutical products. To improve the performance, there are a relatively large number of DPI devices available for different inhalable powder formulations. The relationship between formulation and inhaler device features on performance of the drug-device combination product is critical. Aerosol medicine products are drug-device combination products. Device design and compatibility with the formulation are key drug-device combination product aspects in delivering drugs to the lungs as inhaled powders. In addition to discussing pulmonary diseases, this review discusses DPI devices, respirable powder formulation and their interactions in the context of currently marketed DPI products used in the treatment of COPD, asthma and pulmonary infections.There is a growing line of product options available for patients in choosing inhalers for treatment of respiratory diseases. Looking ahead, combining nanotechnology with optimized DPI formulation and enhancing device design presents a promising future for DPI development.

Interest in human factors usability testing has seen a sharp increase from manufacturers bringing new injectable pharmaceutical combination products to market and from regulators reviewing and approving submissions. This paper highlights the special regulatory considerations in the planning, execution, and reporting of human factor usability studies for injectable combination products. The paper describes recent human factors examples that capture and convey important sponsor learning for drug/device combination products. Special emphasis is placed on the recent focus across U.S. Food and Drug Administration centers, offices, and divisions in issuing new draft guidance outlining expectations in the execution and reporting of usability testing. Insight is provided into how the new guidance has been put into practice in the development and review of injectable combination products, and some of the unwritten recommendations/expectations that have been gleaned from these regulatory interactions are identified. The paper also describes future areas of opportunity for regulatory guidance based on reflections from over two dozen recent combination product human factor studies covering from early design development and testing through to the reporting of human factors results in the final submission. LAY ABSTRACT: Human factors is the study of the interaction of people and technology to ensure the safety and effectiveness of that interaction and to improve human/device compatibility, including the user interface, instructions, and training programs to avoid use error. The enhanced focus on human factors usability assessments for injectable combination products is an acknowledgement by regulators and industry that the device mechanics are typically quite reliable and that device risk hazards are likely due to device usability. Use errors can occur when the device is not being used as intended or the design features are less than optimal. Human factors testing, analysis, and validation helps to identify and eliminate use errors by informing appropriate mitigation strategies to ensure the device design provides the optimum use of injectable drug/device combination products.

Background & Aim Regulatory approval from federal health agencies is a requirement to begin most phase 1 clinical trials with investigational agents. Enabling this approval requires evidence of previous human experience or, in the case of novel, fist-in-human treatments, significant preclinical data to support initial approval for use. Proof of concept, method of action and the penultimate safety studies are highly scrutinized and regulatory agencies often seek specific types of studies to provide this data. While a typical battery of pharmacological, pharmacodynamic, and toxicological tests are often used by the pharmaceutical industry, investigator-initiated trials by academic institutions need not always follow that route. In addition, the intricacies that surround cellular and gene therapy treatments make this data difficult to obtain or lacking in clinical relevance, thus dictating changes to the traditional IND-enabling roadmap. In addition to navigating the complex regulatory framework that is the US Food and Drug Administration, trial operation, product manufacturing, oversight and IND maintenance represent considerable hurdles which must be overcome. Despite these challenges, cellular and gene therapy INDs present unique opportunities to foremost provide lifesaving treatments but also do so without many conventional IND requirements. Careful consideration of these factors can lead the development of a successful and efficient implementation of a clinical research plan, so we have established a cell therapy IND algorithm and implemented a planning team to support investigators with a uniform and centralized process to ensure application success. Methods, Results & Conclusion Here we present our initial experience with this process in a new cell therapy program, discussing the pathway towards IND activation focusing on the intricacies that cellular and gene therapy trials present. We also provide our experience with over 20 active, under review and in preparation cellular therapy, gene therapy and combination product submissions. We further discuss type, quality (GLP, non-GLP), depth and breadth of studies required to enable investigator-initiated clinical studies, and challenges and opportunities in operationalizing cellular therapy clinical trials, both from a single- and multi-institution approach.

FDA on July 7 announced the approval of sacubitril–valsartan oral tablets to reduce the risk of cardiovascular death and hospitalization for heart failure in patients with the chronic form of that condition. Novartis will market the combination product as Entresto. Labeling for Entresto states

Background Topical treatments are usually effective in mild psoriasis. However, the complexity of their use may result in low patient adherence with treatment. Combination of a vitamin D analog and a corticosteroid into a two-compound topical formulation has increased efficacy compared with either drug administered alone. Once-daily application of such a product would likely improve adherence. The purpose of this study was to determine whether twice-daily application of a calcipotriene + betamethasone topical formulation can provide improved clinical outcomes compared with once-daily treatment with the same product. Methods A review of the literature was performed seeking clinical trials comparing once-daily versus twice-daily application of calcipotriene + betamethasone topical formulations for the treatment of psoriasis. Results We found only one relevant clinical trial. This study showed similar efficacy and safety with once-daily versus twice-daily application of a topical calcipotriene + betamethasone formulation in the treatment of psoriasis vulgaris. Conclusion Once-daily application of a topical calcipotriene + betamethasone formulation may offer increased patient convenience and potentially increased patient adherence with long-term treatment, compared with twice-daily use, without reducing the efficacy. In order to enhance adherence, patient preference regarding frequency of application of topical treatments should be considered when prescribing medications.

In 2014, the US Food and Drug Administration limited the production of prescription acetaminophen-opioid combination products to 325 mg per dose unit. The goal of this mandate was to decrease the likelihood of unintentional acetaminophen hepatotoxicity. This study was designed to determine if this federal regulation has succeeded in reducing unintentional acetaminophen-induced hepatotoxicity from opioid combination products. Using data from the National Poison Data System (NPDS), we analyzed all calls to US Poison Control Centers in the years 2013 and 2015 for acetaminophen-opioid combination product exposures. We then excluded cases that were classified as intentional and those aged 12 years and younger. We used a primary endpoint of N-acetylcysteine administration; secondary endpoints included evidence of hepatotoxicity as aspartate aminotransferase elevation, opioid antagonist administration and severity of overall medical outcome. A total of 18,259 calls between the two yearlong periods met inclusion criteria. 5.16 and 5.01% of calls resulted in N-acetylcysteine administration in 2013 and 2015, respectively. 3.63 and 4.02% received naloxone in 2013 and 2015, respectively, and 0.9% in each year developed hepatotoxicity. Rates of N-acetylcysteine administration, naloxone administration, and hepatotoxicity did not differ significantly between 2013 and 2015. Severity of medical outcome was worse in 2015 as compared to 2013 with more cases being categorized as “major effect” and fewer cases being categorized as “no effect.” The Food and Drug Administration limitation on acetaminophen content per dose unit in opioid combination products did not reduce the occurrence of unintentional acetaminophen-induced hepatotoxicity or N-acetylcysteine administration as reported to NPDS.

The European Society for Biomaterials 2015 Translational Research Symposium focused on 'Innovating in the Medical Device Industry - Challenges & Opportunities' from different perspectives, i.e., from a non-profit research organisation to a syndicate of small and medium-sized companies and large companies. Lecturers from regulatory consultants, industry and research institutions described the innovation process and regulatory processes (e.g., 510K, PMA, combination product) towards market approval. The aim of the present article is to summarise and explain the main statements made during the symposium, in terms of challenges and opportunities for medical device industries, in a constantly changing customer and regulatory environment. Innovation and new product development in the medical device industry have largely been technology driven in the last decades but always to solve clinical needs. Advancements have been often rapid and significant. Today's biomaterial implants have reached high standards; consequently, the state of art treatment generally supports acceptable return to daily activities and quality of life. Nonetheless, today's product development occurs in a complex healthcare environment, with multiple stakeholders involved. Each of these stakeholders can have different and sometimes conflicting requirements and expectations. While technological innovation to solve current clinical needs may still be the driving force behind new product development, in many cases it is not sufficient to reach the clinic. Innovation in the medical device industry can take many forms. From an entrepreneurship perspective, it does not require inventing something completely new; it can simply involve applying an existing idea in a new way or to a new situation. Innovation includes (i) rapid cadence of market release of new devices or services; (ii) scientific communication on a company's latest products with key opinion leaders support; (iii) clinical education of care providers; (iv) skilled communication channels; and (v) brand equity or the value of the brand name. Those are the five pillars of success in medical devices business. Innovation is greatly influenced by the patients, the care providers, the physicians, the payers, the policymakers and the producers who can all influence real-world healthcare decision-making. Putting on the market innovative products also depends on the fulfillment of regulatory requirements (which vary from continent to continent and even between countries), which are difficult but are in place to attempt to guarantee the safety and efficacy of any market approved products. This is a crucial bottleneck in time and cost for a biomaterial-based device and therapy. This topic was specifically addressed at the European Society for Biomaterials 2015 in Krakow, where the Translational Research Symposium focused on 'Innovating in the Medical Device Industry - Challenges & Opportunities' from different perspectives. This was from a non-profit translational research organisation to a syndicate of small and medium-sized companies (SMEs) and large companies. Lecturers from regulatory consultants, industry and research institutions described the innovation process and regulatory processes (e.g., 510K, Pre-market approval [PMA], combination product) towards market approval. The customer and the constantly changing regulatory environment represented both innovation challenges and opportunities for medical device industries.

Drug-device combination products introduced a new dynamic on medical product development, regulatory approval, and corporate interaction that provide valuable lessons for the development of new generations of combination products. This paper examines the case studies of drug-eluting stents and transdermal patches to facilitate a detailed understanding of the challenges and opportunities introduced by combination products when compared to previous generations of traditional medical or drug delivery devices. Our analysis indicates that the largest barrier to introduce a new kind of combination products is the determination of the regulatory center that is to oversee its approval. The first product of a new class of combination products offers a learning opportunity for the regulator and the sponsor. Once that first product is approved, the leading regulatory center is determined, and the uncertainty about the entire class of combination products is drastically reduced. The sponsor pioneering a new class of combination products assumes a central role in reducing this uncertainty by advising the decision on the primary function of the combination product. Our analysis also suggests that this decision influences the nature (pharmaceutical, biotechnology, or medical devices) of the companies that will lead the introduction of these products into the market, and guide the structure of corporate interaction thereon., MIT-Portugal Doctoral Program. Bioengineering (SFRH/BD/39444/2007), MIT Portugal Program

Fixed-dose combinations (FDCs) dominating the global market because of better compliance. However, irrational combination can lead to human-made menace in terms of development of resistance, tolerance, drug abuse, and economy encumbrance. The US Food and Drug Administration defines a combination product as "a product composed of any combination of a drug and a device or a biological product and a device or a drug and a biological product or a drug, device, and a biological product." Unfortunately, many FDC being introduced in India are usually irrational. The need for the present study arises as the Indian drug regulatory system has been oscillating between central drug authorities versus state drug regulatory authorities. To assess the same fifty-six regulators and 70 other stakeholders including researchers, clinician, and industry people have exposed to 14 questions, and the same are used to get the insights of FDC among producers and consumers. All data were analyzed using Sigma plot Software. Data was presented in the form of percentage of response (responders vs. nonresponders, agree vs. disagree, yes vs. no). Most of the stakeholders (99%) stressed on Rule 122 to be strictly followed and same should be disseminated among all the stakeholders. Similarly, it was emphasized by more than 95% stakeholders that FDC contents should be tested as per official pharmacopoeia.

Medical device developers are always looking for an optimized method to translate a clinical need or a problem into a device, service, or combination product. Established companies are searching for methods to improve this transition, and newer companies, in general, do not have this capability in any form. Using a Voice of the Customer (VOC) process on a new problem or just to improve on an existing product is a systematic and effective way to listen to the stakeholders and glean information that allows a team to be truly innovative in the solution and ultimately better meet the stakeholders' needs. Battelle's Medical Device Solutions (MDS) team has developed a standardized, scalable approach to performing VOC as part of our medical device design and development process.

The global pharmaceutical industry is facing unprecedented challenges that are increasingly influenced by financial, political, demographical and ecological issues. As shown by the significant reduction of new drug applications or NDAs (U.S. Food and Drug Administration-approved new molecular entities) in recent years, the industry is profoundly affected by the increasing cost of development of new drugs, the large number of existing drugs that have begun to go off patent (reduced revenues), increasingly stringent regulations and corresponding increased development time. As a response, we have created a technological platform aimed at accelerating the development of new drug treatments for central nervous system indications. It allows a rapid identification of leads and drug candidates suitable for clinical development based upon a novel in vivo drug screening and hypothesis-driven approach that reduces the time of drug discovery and development. Furthermore, the platform is adapted to specifically identify synergistic (or new) effects induced by combination products with known molecular entities rather than with new molecular entities which reduces risks and costs of development. In less than five years, we have identified with minimal investment, two (2) combination product candidates for functional recovery after spinal cord injury that are suitable for preclinical and clinical development. These results provide evidence suggesting that it is feasible with alternative approaches and small research facilities to efficiently identify leads and drug candidates and, thus, to provide the industry with new drug treatments suitable for clinical development.

Drug-eluting stents (DES) are a preferred treatment modality for occlusive coronary artery disease. First-generation DES have demonstrated high levels of efficacy. However, concerns have been raised over late thrombotic events. XIENCE V™ everolimus-eluting coronary stent is a second-generation DES designed to be more deliverable and safe, while maintaining efficacy in a broad patient population compared with first-generation DES.1−3As a drug/device combination product, the overall performance of a DES is determined by its components and how well they are integrated. XIENCE V utilizes the MULTI-LINK VISION® stent, the antiproliferative drug everolimus, a fluorinated polymer drug carrier, poly(vinylidene fluoride-co-hexafluoropropylene) (PVDF-HFP), and a stent-specific delivery system. A DES coating must fulfill the multiple goals of biocompatibility, controlled drug release and maintenance of the coating durability through stent crimping, and expansion in vivo. The XIENCE V coating utilizes a two-layer coating system composed of an acrylate primer and a fluorinated copolymer drug reservoir. Fluorinated polymers have a long history of use in permanent vascular implant applications. The XIENCE V fluorinated copolymer offers in vivo biocompatibility combined with excellent chemical stability and high purity. Described in this article are the design rationale and polymer selection criteria. The hemocompatibility and biocompatibility of the fluorinated polymer coating are discussed. Characterization results on drug release control, possible drug release mechanism, coating integrity, coating uniformity, and fatigue resistance are also presented.

The Food and Drug Administration (FDA) regulates sunscreens as over-the-counter drugs. This article describes sunscreen actives available in the United States, new developments available elsewhere, and the amendment to the FDA 1999 sunscreen monograph, released on August 27, 2007, which proposes a new grading system for ultraviolet B protection, a cap of the sunburn protection factor to 50+, and a 4-star grading of ultraviolet A protection. In addition, current data on combination sunscreen and insect repellent products are discussed. Application of a combination product too frequently poses the risk of insect repellent toxicity, whereas application too infrequently invites photodamage. It may be prudent to follow the same approach of our Canadian colleagues of discontinuing combination products until more investigations are available.

Background We examined the use and acceptability of a combination product (diaphragm and gel) compared to a single product (gel) during a 6-month safety trial in Zimbabwe. Study Design Women were randomized to the use of a diaphragm with gel or the use of gel alone, in addition to male condoms. Ever use and use of study product on the last act of sexual intercourse were assessed monthly by Audio Computer-Assisted Self-Interviewing. Acceptability, correct use and consistent use (use at every sexual act during the previous 3 months) were measured on the last visit by face-to-face interview. Predictors of consistent use were examined using multivariate logistic regression analyses. Results In this sample of 117 sexually active, monogamous, contracepting women, rates of consistent use were similar in both groups (59.7% for combination method vs. 56.4% for gel alone). Product acceptability was high, but was not independently associated with consistent use. Independent predictors of consistent use included age [adjusted odds ratio (AOR)=1.08; 95% confidence interval (95% CI)=1.01–1.16], consistent condom use (AOR=3.85; 95% CI=1.54–9.63) and having a partner who approves of product use (AOR=2.66; 95% CI=1.10–6.39). Conclusions Despite high reported acceptability and few problems with the products, the participants reported only moderate product adherence levels. Consistent use of condoms and consistent use of products were strongly associated. If observed in other studies, this may bias the estimation of product effectiveness in future trials of female-controlled methods.

2015 was yet another dynamic year for Pharmaceuticals with the Pharma industry witnessing tremendous investment on drug development. The year saw 45 new molecular entity (NME) approvals from US FDA Centre for Drug Evaluation and Research (CDER), which is the highest number of approvals since 1996 [1]. NMEs are those products containing active moieties that have been never approved by FDA previously, either as a single ingredient drug or as a part of a combination product.

This research has been conducted in the Integrated Agro Industrial Area (TIP) Province of Gorontalo in November 2010 using the data and using linear programming models. The research aims to find the product combination of corn chips, nuts disco, peanuts eggs should be produced to achieve maximum profit, find out how much the maximum advantage can be achieved by TIPS, and TIPS determine the pattern of production, it is optimal or not. The results showed that the combination product should be produced (packaging / wrappers) sequentially from X1 to X13 are 2545, 314, 76.130, 344, 509, 331, 172, 7, 311, 180, 854, 7. The combination product is a combination of products that can provide maximum benefit. The maximum profit that can be achieved by following the TIP with the combination product that is equal to Rp8.770.206. This advantage is greater than the actual clappers TIPS. TIPS production pattern is not optimal, because for some products there is still a considerable difference between the optimal production and actual production in which the optimal production gives better results (large), and also there is no actual product produced equal to optimal production

Recognizing that the standard treatments for heart failure often do not benefit black patients, FDA on June 23 approved the marketing of a combination product expressly for use in those patients who identify themselves as black and need additional therapy. BiDil, by NitroMed Inc., combines 20 mg of

The concomitant use of medicinal products may trigger the development of a fixed combination product with the intention to facilitate for the user and improve compliance. At present, there is a lack of detailed regulatory guidance on the strategies for the non-clinical development of a fixed combination, and companies often seek scientific advice at the European Medicines Agency (EMEA) and its scientific committee, the Committee for Medicinal Products for Human Use (CHMP). Four main scenarios can be identified: combination of well known compounds already approved/used in combination; combination of approved/well known compounds not previously approved in combination; combination of one or more new chemical entity(ies) [NCE] with one or more well known compound(s); and combination of two or more NCEs. The level of knowledge and experience in these scenarios will differ markedly and, therefore, different strategies for the non-clinical development programme are justified.