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Objective: The purpose of this report is to provide insight from pediatric stakeholders with a shared desire to facilitate a revision of the current United States regulatory pathways for the development of pediatric healthcare devices. Methods: On August 5, 2020, a group of innovators, engineers, professors and clinicians met to discuss challenges and opportunities for the development of new medical devices for pediatric health and the importance of creating a regulatory environment that encourages and accelerates the research and development of such devices. On January 6, 2021, this group joined regulatory experts at a follow-up meeting. Results: One of the primary issues identified was the need to present decision-makers with opportunities that change the return-on-investment balance between adult and pediatric devices to promote investment in pediatric devices. Discussion/Conclusion: Several proposed strategies were discussed, and these strategies can be divided into two broad categories: 1. Removal of real and perceived barriers to pediatric device innovation; 2. Increasing incentives for pediatric device innovation.

Decades ago, the United Nations declared that access to essential medicines was a key element of universal human rights. Accordingly, member states have been striving to address this issue through strategic policies and programs. Strengthening local pharmaceutical production has been a pivotal strategy adopted by many developing countries including Ethiopia. The government of Ethiopia identified local pharmaceutical production as a key industrial sector and has been implementing a ten-years strategic plan to improve capabilities and attract investment. Such support is needed because local production could satisfy only 15 to 20% of the national demand, typically from a limited portfolio of medicines in conventional dosage forms. The increasing prevalence of chronic diseases has accentuated the need for a more sustainable supply to reduce reliance on imports and increase access to essential medicines. A full understanding of the structure, constraints and complexities of the Ethiopian pharmaceutical market structure is vital to direct effective policies, target most impactful investments and exploit opportunities for leapfrogging. Hence, the purpose of this review was to assess the trends and challenges in access to essential medicines and local pharmaceutical production in Ethiopia. Literature search through major databases and review of policy documents and performance reports from relevant sector institutions were made to extract information for the review.

Background Talent acquisition in regulatory affairs has been a continuing challenge now exaggerated by demographic shifts and expansion of regulatory requirements nationally and globally. Methods Survey and interview methods were used to provide information on graduation rates, graduate characteristics, and enrollment trends in the 17 US regulatory programs that could be identified to offer graduate degrees in regulatory affairs or regulatory science. Results US programs graduated approximately 522 MS and 4 doctoral students in 2018. About 70% of students attended programs in the Northeast; the remaining students were evenly split between programs in the Northwest and Southeast/Southwest. About half of the programs provided content by distance only. About 127 students were new entrants to the workforce; enrollments for this group most commonly leveled or decreased over the last 3 years. The primary challenge identified by most programs was the high tuition that discouraged participation by qualified candidates for the programs. Challenges were also reported when attracting international students because of tightening visa restrictions and consequent reluctance of industry to hire students with a temporary visa status. Conclusions The small number of graduating regulatory professionals from US universities is alarming because it falls far short of needs estimates for positions in regulatory departments. The particularly low number of entry-level professionals seems unlikely to be adequate as unemployment rates tighten and experienced professionals become harder to attract. These shortfalls may be particularly hurtful to small companies unable to compete for experienced professionals.

Some international regulatory agencies require that companies develop a validation master plan (VMP) to govern their validation activities, but such a plan is not an explicit requirement of US regulations. This paper examines the progress that US pharmaceutical companies have made to implement VMPs for drug products manufactured and produced in accordance with the US FDA Good Manufacturing Practice for Finished Pharmaceuticals.A survey instrument was developed using an established framework with a focus on behavior and capability and disseminated electronically to midlevel and senior regulatory and quality professionals concentrated in the US.Responses from 42 senior regulatory professionals showed that VMPs are incorporated into the quality systems of most companies but approaches to implementation differ. Small companies typically employ centralized VMPs whereas larger companies commonly decentralize their VMPs. Companies of all sizes most commonly use paper rather than electronic tools to organize and track validations including validations of equipment.The fact that VMPs are commonly used even when they are not mandated suggests that the VMP is becoming an industry standard and may suggest that global standards are playing a significant role in the quality approaches of US-based companies.

BACKGROUND/AIMS: Children with congenital cochleovestibular abnormalities associated with profound hearing loss have few treatment options if cochlear implantation does not yield benefit. An alternative is the auditory brainstem implant (ABI). Regulatory authority device approvals currently include a structured benefit-risk assessment. Such an assessment, for regulatory purposes or to guide clinical decision-making, has not been published, to our knowledge, for the ABI and may lead to the design of a research program which incorporates regulatory authority, family, and professional input. METHODS: Much structured benefit-risk research has been conducted in the context of drug trials, here we apply this approach to device studies. A qualitative framework organized benefit (speech recognition, parent self-report measures) and risk (surgery- and device-related) information to guide the selection of candidates thought to have potential benefit from ABI. RESULTS: Children with cochleovestibular anatomical abnormalities are challenging for appropriate assessment of candidacy for a cochlear implant or an ABI. While the research is still preliminary, children with an ABI appear to slowly obtain benefit over time. A team of professionals, including audiological, occupational, and educational therapy, affords maximum opportunity for benefit. CONCLUSIONS: Pediatric patients who have abnormal anatomy and are candidates for an implantable auditory prosthetic require an individualized, multi-systems review. The qualitative benefit-risk assessment used here to characterize the condition, the medical need, potential benefits, risks, and risk management strategies has revealed the complex factors involved. After implantation, continued team support for the family during extensive post-implant therapy is needed to develop maximum auditory skill benefit.

Academic biobanks face challenges that call for continuity and disaster planning. However, current regulations do not require such planning, so it is unclear if and how biobanks have prepared themselves to deal with future crises. This exploratory study used mixed methods to understand the state of continuity planning in U.S. biobanks. It first reviewed the current state of regulatory and implementation requirements that drive and challenge continuity planning. A survey instrument was then developed and critiqued by a focus group of experienced practitioners in biobanking. The refined survey was disseminated to a targeted group of respondents employed at biobanks across the United States. Most respondents were associated with relatively mature biobanks in operation for more than 6 years and these typically had some form of continuity plan in place. More commonly, continuity planning was reported to be focused on countering natural disasters rather than organization- or personnel-related crises. Respondents identified their most common limitation to be financial resources affecting all phases of implementation. Although many respondents appeared to be aware of some guidance documents and standards for continuity planning, many reported that they did not use or reference them when constructing their biobank continuity plans. Furthermore, nearly 25% of surveyed biobanks did not have a continuity plan and 61% indicated concern in having a mandated continuity plan. Results suggested academic organizations would benefit from a continuity plan template and best practice guidelines for plan development and implementation.

The footprint of drug distribution is multinational, but the regulatory frameworks supporting drug development, review, and approval remain largely regional. As a result, industry faces regulatory standards that may be complementary, additive, or contradictory, resulting in global regulatory dissonance (GRD). Global regulatory dissonance was explored through a case study of drug development (postmenopausal osteoporosis) using survey methodology. In the feedback received, respondents generally agreed that GRD increases the complexity, timelines, and size of registration studies. Dissonant regulatory feedback on proposed labeling, applications, and benefit-risk assessments was also reported. Multiple causes of GRD were identified, including dissonant drug regulatory authority advice, guidelines, benefit-risk assessments, drug approval precedents, medical standards of care, and health technology assessments. Harmonization of guidelines, scientific advice, benefit-risk procedures, and expanded use of mutual recognition agreements were identified as mechanisms thought to reduce GRD. The results suggest that global access to new drugs may be enhanced through a greater understanding of GRD.

Medical devices are typically marketed globally. In the descriptions that follow, the regulation of devices in the United States will be discussed in detail and comparative systems in a few example constituencies elsewhere will be described more briefly.

The clinical trial agreement (CTA) is a key but often underappreciated document governing the relationship between a study site and a sponsor. Previous anecdotal materials have suggested that investigators may not often be involved in the review or negotiation of the CTA and may attach little importance to it. To provide more systematic current information, survey methods were used to explore the level of engagement, knowledge, and perceptions of investigators in the United States. The survey was distributed to more than 700 investigators-university affiliated and nonaffiliated-and/or related study staff, of whom 167 responded. Most respondents identified that they did not manage the clinical trial agreement process but were actively engaged in its review. Most were encouraged by their institutions to participate. However, some respondents expressed concerns with regard to their satisfaction with the content of the CTA, particularly with respect to issues such as financial negotiations and payments, indemnification, and subject injury language. The majority of investigators either strongly agreed or agreed that it was important for the investigator to be actively involved in the CTA process. Data from this survey provide the first systematic look at the current practices of US investigators, possible issues, and areas for improvement from the investigator's point of view.

Survey methods were used to explore the expectations and recommendations of senior business development professionals with respect to the roles, activities, and interactions with US universities in the development of new medical products. This target group was chosen because it was judged to be most likely to interact with university faculty and technology transfer services and seek and acquire university assets. The survey instrument was first reviewed by a focus group of individuals with experience both in technology transfer and in academic or industry policy, then distributed to a selected subset of 80 business development professionals, of whom 72 responded. Serious concerns were expressed over the current mechanisms for technology transfer and university support of commercialization. When asked if they believed that there is a need for a change in the way that universities interact with industry in the US, 86% of the respondents replied that they either strongly agreed or agreed that there was, indeed, a need for change. Among several areas that might be improved, the availability of proof-of-concept facilities and funds for early-stage feasibility studies were most often identified as important.

This study evaluated drug-registration transparency in 3 Pharmerging markets, South Korea, China and India, using the US as a comparator. Focus group methods were used to identify factors perceived by regulatory experts as important in defining transparency in regulatory agencies. This input was used to guide the development of a survey to evaluate drug-registration transparency, which was administered to 64 regulatory professionals responsible for international drug registration. Respondents viewed the US as most transparent, South Korea as intermediate in transparency, and China and India as least transparent. The survey instrument appears to provide a novel way to study regulatory transparency, based on 3 key aspects of transparency: clarity, accessibility, and accountability. With minor change, it could be adapted to study the transparency of more countries and product categories including medical devices and in vitro diagnostics.

Summary of the BION Shoulder Subluxation and Knee Osteoarthritis Studies. Subacute Shoulder Subluxation Knee OsteoarthritisLocation Kingston, Canada Milan, ItalyDesign Randomized, cross-over Longitudinal, repeated measuresBaseline No Yes, 12 weeksStimulation period 6 weeks 12 weeksOff-stim. period 6 weeks NoStimulation frequency 5 Hz 2 HzAssessment Subluxation, active/passive ROM, strength, arm function, VAS pain, muscle thickness (ultrasound).WOMAC, Knee Function, VAS pain,muscle cross-sectional area (MRI).# subjects (July 2002) 10 (5 TES; 5 control initially) 5# control subjects 3 (out of 5, above) N/Acrossed-over to TES# total TES 8 (5 initial; 3 cross-over from control) 5# noncompliant TES 3 (out of 8, above) 0Final subject distribution 5 compliant TES; 3 noncompliant N/ATES; 5 control# BIONs implanted (July 2002)17 (8 TES subjects—one has two BIONs in the supraspinatus because of technical failure)8 (subjects 1–3 have 2 BIONs each; subjects 4–5 have one BION each) Fig. 3. Top: BION being removed from Subject 1 in theshoulder subluxation study (trapezius). Bottom: histologicsection of excised muscle (left: muscle cells; right: scar tissuearound device).

When muscles lose neural drive, they atrophy rapidly. Neuromuscular electrical stimulation (NMS) has been used in attempts to prevent or reverse the atrophy, but optimal stimulation programs and parameters are not well defined. In this study, we investigated the effects of four different stimulation patterns on disuse atrophy produced in the tibialis anterior, lateral gastrocnemius, and soleus muscles of rats paralyzed with tetrodotoxin for seven days. Stimulation paradigms differed from one another by their stimulation frequency (2 or 10 pulses/s) and by their stimulation period (2 or 10 h a day). Results showed that stimulation with 2 pulses/s, paradigms were more effective at preventing disuse muscle atrophy than higher-frequency stimulation. The most marked difference was in the slow soleus muscle, which had only 10% mean atrophy when stimulated at 2 pulses/s for 10 h, compared to 26% atrophy when stimulated at 10 pulses/s for either 2 or 10 h and 32% atrophy in unstimulated, paralyzed controls. The level of atrophic change was not correlated with the levels of serum creatine kinase, used as an index of muscle damage. Results suggest that remediation of disuse atrophy may be accomplished using unphysiologically low rates of motor-unit activation despite the relatively low force produced by such unfused contractions. This may have significant implications for the design of therapies for muscle paralysis consequent to upper-motoneuron lesions.

Previous studies have shown that immobilization causes muscle atrophy and that the rate of atrophy depends on the length at which the muscle is immobilized. However, most studies have been carried out in neurologically intact animals that were capable of generating at least some voluntary muscle activation. In this study, tetrodotoxin was applied chronically to the rat sciatic nerve to produce complete paralysis of distal muscles for seven days, and the ankle was immobilized to hold the muscles at long or short lengths. Paralysis without immobilization resulted in relative weight losses of 36% for soleus, 19% for tibialis anterior (TA), and 17% for lateral gastrocnemius (LG) muscles. Casting the ankle in plantarflexion stretched TA and reduced its weight loss to 10%. Soleus and LG were shortened by this intervention and had increased losses of 43% and 28%, respectively. Fixing the limb in dorsiflexion resulted in a posture similar to that adopted by the unrestrained rats and had no significant effect on the amount of muscle atrophy compared to that in unrestrained paralyzed animals.

Physiological experiments in primates have identified a region of the midbrain tegmentum, the central mesencephalic reticular formation (cMRF), which plays a role in gaze control.1 Specifically, stimulation of this region produces horizontal saccades; recordings from this region reveal neurons with saccade-related activity; and chemical inactivation of this region produces contralateral head tilt and spontaneous saccades. More rostral regions of the midbrain reticular formation (MRF), just lateral to the interstitial nucleus of Cajal (InC), have neurons with vertical movement fields, and chemical inactivation of this region produces hypometric vertical saccades.2 In the macaque, there is an extensive overlap of tectoreticular terminals and reticulotectal cells in the region corresponding to the cMRF.3 The present study explored whether an area similar to the cMRF is present in the cat by analyzing the distribution of MRF neurons targeting the superior colliculus (SCol) and cervical spinal cord. These studies were carried out in eight adult cats under approved protocols adhering to the NIH guidelines. In the single-injection animals, 0.1-0.5 μl of a 10% BDA was injected into either the SCol or cervical cord. The SCol was approached dorsally, by aspirating the overlying cortex, while the cervical cord (C1) was approached through the foramen magnum. In the dual-tracer animals, both approaches were used to inject 5% Fast Blue into the SCol and 5% Fluoro-Gold into C1 (0.5 μl each). Standard perfusion and processing techniques were used.

We are using percutaneous electrical stimulation to simulate BION/spl trade/ activation of posterior genioglossus during sleep to prevent occurrences of obstructive sleep apnea (OSA). Patients with OSA due to tongue prolapse are recruited in this ongoing clinical study for an overnight session in a sleep laboratory. Bipolar hooked wires are inserted percutaneously into the tongue muscle, from under the chin at midline, and used for neuromuscular stimulation. Data are collected with polysomnography and analyzed to compare the efficacy of proposed treatment to conventional CPAP or the untreated state. Encouraging preliminary results from the first study participant are described.

Sencils™ (sensory cilia) are chemical sensors that are minimally invasive, disposable and easily readable to make frequent measurements of various analytes in vivo over a period of 1-3 months. A percutaneous optical fiber permits precise, reliable photonic measurement of chemical reactions in a nano-engineered polymer matrix attached to the internal end of the fiber. The first Sencils sense interstitial glucose based on measurement of fluorescence resonance energy transfer (FRET) between fluorophores bound to betacyclodextrin and Concanavalin A (Con A) in a polyethylene glycol (PEG) matrix. In vitro experiments demonstrate a rapid and precise relationship between the ratio of the two fluorescent emissions and concentration of glucose in saline over the physiological range of 0-500mg/dl. Chronic implantation in pigs has demonstrated biocompatibility. The Sencil platform can be adapted to detect other analytes in interstitial fluids.

Sencilstrade (sensory cilia) are chemical sensors that are minimally invasive, disposable and easily readable to make frequent measurements of various analytes in vivo over a period of 1-3 months. A percutaneous optical fiber permits precise, reliable photonic measurement of chemical reactions in a nano-engineered polymer matrix attached to the internal end of the fiber. The first Sencils sense interstitial glucose based on measurement of fluorescence resonance energy transfer (FRET) between fluorophores bound to betacyclodextrin and Concanavalin-A in a polyethylene glycol (PEG) matrix. In vitro experiments demonstrate a rapid and precise relationship between the ratio of the two fluorescent emissions and concentration of glucose in saline over the physiological range of 0-500 mg/dl. Chronic implantation in pigs has demonstrated biocompatibility. The materials and fabrication methods to produce Sencil implants are robust and inexpensive. Systematic nano-engineering of binding affinities, fluorophore attachment, reactant entrapment and matrix structure provides the key to a wide range of clinical applications

BIONs/spl trade/ are individually addressable, single channel electrical stimulators that can be injected into one or more muscles through a 12-gauge hypodermic needle. They receive power and command signals from an externally worn RF transmission coil. Two clinical trials are underway to determine their safety and efficacy for strengthening atrophic muscles associated with stroke (7 patients accrued; 6 implanted) and chronic osteoarthritis of the knee (5 patients accrued; 3 implanted). In both studies, BIONs/spl trade/ have proven easy for the clinician to implant and for the patients to use. Thresholds for recruitment of muscle contractions have remained stable and no adverse effects have been reported. Patients generally like the stimulation and most have elected to continue stimulation after the prescribed study period. Stimulation at low frequencies for a total of about 1 hour/day has produced demonstrable reversals of muscle atrophy as measured by imaging. In patients with radiological subluxation of the shoulder, the subluxation has been reduced. Preliminary indications suggest also that chronic pain has been reduced and locomotor function has improved in patients with knee osteoarthritis.

Virtually all bodily functions are controlled by electrical signals in nerves and muscles. Electrical stimulation can restore missing signals but this has been difficult to achieve practically because of limitations in the bioelectric interfaces. Wireless, injectable microdevices are versatile, robust and relatively inexpensive to implant in a variety of sites and applications. Several variants are now in clinical use or under development to perform stimulation and/or sensing functions and to operate autonomously or with continuous coordination and feedback control.

— Sencils™ (sen sory cilia) are chemical sensors that are minimally invasive, disposable and easily readable to make freque nt measurements of various analytes in vivo over a period of 1-3 months. A percutaneous optical fiber permits precise, reliable photonic measurement of chemical reactions in a nano-engineered poly mer matrix attached to the internal end of the fiber. The first Sencils sense interstitial glucose based on mea surement of fluorescence resonance energy transfer (FRET) between fluorophors bound to dextran and Concanavalin-A in a polyethylene glycol (PEG) matrix. In vitro experiments demonstrate a rapid and precise relationship be tween the ratio of the two fluorescent emissions and concentration of gluc ose in saline over the physiological range of 0-500mg/dl. Chronic implantation in pigs has demonstrated biocompatibility. The Sencil platform can be adapted to detect other analytes in interstitial fluids. Keywords — Optical fiber, chemical sensor, fluorescence resonance energy transfer, affinity-binding assay, glucose, Quantum dots 1 The Potential of Chemical Sensing in vivo Although biosensors have been used in clinical application for decades, most of the commercialized products are intended for in vitro assays of samples expelled or extracted from body (urine, blood, tissue etc.). These sensors have significant disadvantages for monitoring fluctuating physiological processes because it is impractical to obtain these samples more than once or twice a day. In order to manage certain diseases and conditions, it is important to make frequent measurements of specific analytes over an extended pe riod of time. These include diabet es, cancer chemotherapy treatment, and hormonal monitoring for fertility and complications of pregnancy. Continuous in vivo monitoring could reduce the complications of diabetes from hyperglycemia and hypoglycemia (insulin overdosage). Frequent monitoring could increase the safety and ef fectiveness of chemotherapy by measuring interstitial drug levels and detecting apoptosis of tumor cells in situ without sampling through biopsy. The technology can also benefit basic research in molecular biology, drug discovery and veterinary medicine. For example, some metabolites and secondary messengers in signaling transduction pathways can only be traced directly through in vivo detection (Harper et al.). Tracking such activity without requiring biopsies or sacrificing experimental animals wo uld expedite such research (Wiley et al.). Sencils can be implanted precisely in solid tumors and other tissues to provide highly localized information. 2 Challenges of chemical sensing in vivo Over the past twenty years, there have been many research projects to develop minimally invasive chemical sensors but relatively few products have been approved for clinical use. The requirements discussed below tend to compete with each other, making it difficult to develop and validate strategies that achieve useful tradeoffs among them.

We describe the design, fabrication method, biocompatibility test results, and first application of the novel chemical sensor technology that is under development. The sensor is designed to be minimally invasive, disposable and easily readable to make frequent measurements of various analytes in vivo over a period of 1-3 months. It uses photonic sensing of a chemical reaction that occurs in a polymer matrix bound to the internal end of a chronically implanted percutaneous optical fiber.

Injectable, wireless microstimulators have the potential to provide low-cost and easily administered electrical stimulation to a variety of neuromuscular sites for a variety of clinical disorders. We are studying one version of this new technology platform in several different clinical studies currently underway or in the final stages of preclinical development. Preliminary results suggest that the approach is safe and effective for muscle activation. They also suggest enhancements of the technology that should improve its ease and reliability of use.

Clinical application of neural prosthetic technology raises a multitude of questions about neuromuscular anatomy and physiology. Such knowledge can be used to identify efficient and effective sites at which to apply stimulation and to identify stimulation parameters that are likely to produce the desired therapeutic effects. The scientific literature is often surprisingly patchy when it comes to making such decisions, but recently developed methodologies provide many useful tools. These have led us to a number of novel approaches that are now being tested in preclinical and clinical trials.

Electromyographic (EMG) activity was recorded in ≤12 neck muscles in four alert monkeys whose heads were unrestrained to describe the spatial and temporal patterns of neck muscle activation accompanying a large range of head postures and movements. Some head postures and movements were elicited by training animals to generate gaze shifts to visual targets. Other spontaneous head movements were made during orienting, tracking, feeding, expressive, and head-shaking behaviors. These latter movements exhibited a wider range of kinematic patterns. Stable postures and small head movements of only a few degrees were associated with activation of a small number of muscles in a reproducible synergy. Additional muscles were recruited for more eccentric postures and larger movements. For head movements during trained gaze shifts, movement amplitude, velocity, and acceleration were correlated linearly and agonist muscles were recruited without antagonist muscles. Complex sequences of reciprocal bursts in agonist and antagonist muscles were observed during very brisk movements. Turning movements of similar amplitudes that began from different initial head positions were associated with systematic variations in the activities of different muscles and in the relative timings of these activities. Unique recruitment synergies were observed during feeding and head-shaking behaviors. Our results emphasize that the recruitment of a given muscle was generally ordered and consistent but that strategies for coordination among various neck muscles were often complex and appeared to depend on the specifics of musculoskeletal architecture, posture, and movement kinematics that differ substantially among species.