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Vasoactive intestinal peptide (VIP) is a neuropeptide that is produced by the lymphoid cells and plays a major role in immunological functions for controlling the homeostasis of the immune system. VIP has been identified as a potent anti-inflammatory factor, in boosting both innate and adaptive immunity. Since December 2019, SARS‐Cov‐2 was found responsible for the disease COVID‐19 which has spread worldwide. No specific therapies or 100% effective vaccines are yet available for the treatment of COVID‐19. Drug repositioning may offer a strategy and several drugs have been repurposed, including lopinavir/ritonavir, remdesivir, favipiravir, and tocilizumab. This paper describes the main pharmacological properties of synthetic VIP drug (Aviptadil) which is now under clinical trials. A patented formulation of vasoactive intestinal polypeptide (VIP), named RLF-100 (Aviptadil), was developed and finally got approved for human trials by FDA in 2001 and in European medicines agency in 2005. It was awarded Orphan Drug Designation in 2001 by the US FDA for the treatment of acute respiratory distress syndrome and for the treatment of pulmonary arterial hypertension in 2005. Investigational new drug (IND) licenses for human trials of Aviptadil was guaranteed by both the US FDA and EMEA. Preliminary clinical trials seem to support Aviptadil’s benefit. However, such drugs like Aviptadil in COVID‐19 patients have peculiar safety profiles. Thus, adequate clinical trials are necessary for these compounds.

Background aims Cell-based regenerative medicine is an innovative field that can potentially alter the overall survival and quality of life of patients with devastating diseases. Several cell therapy products (CTPs) have been approved within the last two decades, and more are under development. The establishment of an effective developmental strategy in accordance with the regulatory bodies of each country/region is crucial for fast delivery of each respective CTP. In particular, facilitating investigational new drug (IND) approval is important for accelerating the transition from non-clinical to clinical research/trial phases. Methods Here the authors compared the non-clinical prerequisites for initiating clinical studies in five Asian countries/regions (India, China, Korea, Taiwan and Japan) from an industry viewpoint. The authors first identified the differences and tried to clarify the perspectives/considerations underpinning the different requirements. Results The authors’ findings revealed that differences in regulations and development experiences, especially with CTPs, have led to clear differences in the non-clinical study package and its corresponding study design. Conclusions By sharing experiences of the research and development of CTPs among Asian countries/regions and including not only industry but also regulatory authorities, we will be able to expedite cross-border IND approval and eventually contribute to the early delivery of innovative CTPs to many Asian patients.

PURPOSE The purpose of the studies described in this mini review article was to identify nontoxic compounds that could prevent or suppress the radiation induced malignant transformation of cells and be useful as human cancer preventive agents. CONCLUSIONS (1) Many different types of potential anticarcinogenic substances were evaluated initially for their abilities to prevent or suppress radiation induced malignant transformation in vitro, and certain anticarcinogenic protease inhibitors (APIs) were observed to be the most powerful anticarcinogenic agents at suppressing this surrogate endpoint biomarker of radiation carcinogenesis. (2) Within the category of APIs, those that inhibited the activity of chymotrypsin were effective at far lower molar concentrations than other APIs. The soybean-derived protease inhibitor known as the Bowman-Birk inhibitor (BBI) is a particularly powerful chymotrypsin inhibitor that is able to prevent radiation induced transformation in vitro (at concentrations down to nanomolar levels) as well as radiation induced carcinogenesis in vivo without toxicity. (3) There were many other unusual characteristics of APIs that led to the selection of one of these APIs, BBI, as the most appropriate compound for us to develop as a human cancer preventive agent. As one example, the APIs have an irreversible effect on carcinogenesis, while the effects are reversible for most anticarcinogenic agents when they are removed from carcinogenesis assay systems. (4) Numerous studies were performed in attempts to determine the potential mechanisms by which the APIs could prevent or suppress radiation induced carcinogenesis in in vitro and in vivo systems, and the results of these studies are described in this review article. The APIs and the proteases which interact with them appear to play important roles in radiation carcinogenesis. (5) Preparations for human trials using BBI began decades ago. The cost of preparing purified BBI was far too high to consider performing human trials with this agent, so BBI Concentrate (BBIC), a soybean extract enriched in BBI, was developed for the specific purpose of performing human trials with BBI. BBIC achieved Investigational New Drug (IND) Status with the Food and Drug Administration in April,1992, and human BBIC trials began at that time. (6) Several human trials were performed using BBIC and they indicated many potentially beneficial health effects produced by BBIC administration to people in various forms (e.g. tablets). 7) It is hypothesized that BBI takes the place of α-1-antichymotrypsin, an important regulatory compound in the human body, and helps to maintain homeostasis.

The Production Assistance for Cellular Therapies (PACT) Program, is funded and supported by the US Department of Health and Human Services’ National Institutes of Health (NIH) National Heart Lung and Blood Institute (NHLBI) to advance development of somatic cell and genetically modified cell therapeutics in the areas of heart, lung, and blood diseases. The program began in 2003, continued under two competitive renewals, and ended June 2021. PACT has supported cell therapy product manufacturing, investigational new drug enabling preclinical studies, and translational services, and has provided regulatory assistance for candidate cell therapy products that may aid in the repair and regeneration of damaged/diseased cells, tissues, and organs. PACT currently supports the development of novel cell therapies through five cell processing facilities. These facilities offer manufacturing processes, analytical development, technology transfer, process scale‐up, and preclinical development expertise necessary to produce cell therapy products that are compliant with Good Laboratory Practices, current Good Manufacturing Practices, and current Good Tissue Practices regulations. The Emmes Company, LLC, serves as the Coordinating Center and assists with the management and coordination of PACT and its application submission and review process. This paper discusses the impact and accomplishments of the PACT program on the cell therapy field and its evolution over the duration of the program. It highlights the work that has been accomplished and provides a foundation to build future programs with similar goals to advance cellular therapeutics in a coordinated and centralized programmatic manner to support unmet medical needs within NHLBI purview.

China has been criticized for the long drug delay for a long time. There was little understanding of Chinese drug lag formation from the investigational new drug (IND) submission to the new drug application (NDA) approval. Therefore, we analyzed the problem of drug lag in China cumulating from the clinical trial starting lag to the lags formed during the regulatory process and discerned the key underlying factors. After investigating the availability in China of new molecular entities (NMEs) approved by the Food and Drug Administration (FDA) between 1999 and 2019, we find that even though cutting regulatory process could reduce the approval lag, the clinical trial starting time in China is more important in drug lag reduction than shortening development time and review time. The reduction of the regulatory process also needs continuous efforts by defining the clinical value based on the medical needs, regulatory procedure harmonization, and intensive discussions between applicants and regulators during the drug development process. Meanwhile, proactive approaches should be taken to encourage developing the first generics in China. More importantly, enhancing domestic research and development capabilities is still the key to cutting the drug lag. Moreover, the China National Medical Product Administration (NMPA) should attach importance to the accumulation of regulation experience on innovative drugs and transform the style of regulating generics to new drugs.

The FDA IND safety reporting Final Rule (21CFR 312.32) applies to all human drugs and biological products being studied under an Investigational New Drug (IND). A sponsor must file an IND safety report for any serious unexpected suspected adverse reaction (SUSAR) of a medicinal product being investigated. Some events may be obviously drug-related (e.g., agranulocytosis, anaphylactic reaction, drug-induced hepatic injury, Stevens-Johnson Syndrome). For serious adverse events that are not interpretable as individual occurrences, additional processes and procedures need to be employed for identifying and assessing risks in the accumulating safety data. The approaches shared in this manuscript apply principally to safety reporting of events that are anticipated to occur in the patient population-regardless of study participation. For these events, the study sponsor should periodically review the data in the aggregate and make a judgment as to whether there is a reasonable possibility of an event having been caused by the study drug rather than the underlying condition of the patient or a concomitant therapy. Factors cited for consideration are the size and consistency of the difference in event frequency between the test and control groups, supportive preclinical findings, evidence of a dose response relationship, plausible mechanism of action, known class effect and occurrence of other related adverse events. Examples are provided that demonstrate the flexibility sponsors have in meeting the spirit of the Final Rule; some combination and variation of methods from the examples could be employed. The important thing, as expressed by Jacqueline Corrigan-Curay (Director of the Office of Medical Policy, Center for Drug Evaluation and Research, FDA), is to have a thoughtful process; a system in place to look for clinically important imbalances, applying the best clinical and quantitative judgment, while maintaining trial integrity (Ball et al. in Interdisciplinary aggregate assessments for IND safety reporting: a dialogue among colleagues from industry, Academia and the FDA. ASA biopharmaceutical section regulatory-industry statistics workshop, 2018).

Background Single patient Investigational New Drug (IND) applications are one mechanism through which experimental therapies are accessed for children with cancer. The landscape of use, outcomes, and toxicity from single patient INDs remains unknown in pediatric oncology. Methods We performed a retrospective analysis of all single patient INDs requested and prescribed at a single institution between 1/1/2007 and 5/1/2019. We report aggregate data from the US Food and Drug Administration (FDA) on single patient IND applications over the final two years of the study (2017–2019). We report an overview of all IND applications, as well as clinical descriptions of patients, treatments, outcomes, and toxicity. Results Over the 2‐year period, the FDA approved all 171 submitted single patient IND requests for pediatric oncology. We identified 56 requests from our center during the 12‐year study period, and all were approved (median time from FDA submission to approval: 1 day (range 0–12)). 71% of requests were based on disease histology. Lack of pediatric clinical trial (65%) was the most common reason for use. 48 approved requests were ultimately administered. The median duration of treatment was 84 days (range: 4–1590), with 3 patients remaining on treatment at time of analysis. Only 7% discontinued treatment due to toxicity. Three‐year overall survival was 50% (95% CI, 35–64). Conclusions Single patient INDs in pediatric oncology were universally approved in our national and single‐center analysis. In our cohort, single patient INDs were primarily utilized based on disease histology, rather than genomics, for agents that lacked a clinical trial., Single patient Investigational New Drug (IND) applications in pediatric oncology are universally approved in a timely fashion in our analysis. Single patient IND therapy is pursued for a range of reasons, with few patients discontinuing therapy due to toxicity.

Synthetic nucleotides that utilize RNA‐centric pharmacology can target diseases at the RNA level, thus altering protein expression in ways previously inaccessible to small molecules and therapeutic biologics. Recognizing that the unique pharmacology of oligonucleotides may require specific considerations in pre‐approval assessment, clinical and nonclinical pharmacology studies being conducted for a selected set of oligonucleotide therapies in a 6‐year period were assessed. This investigation focused primarily on the four following areas: (i) drug‐drug interaction (DDI) potential, (ii) organ impairment (i.e., renal and hepatic impairment), (iii) immunogenicity, and (iv) cardiac safety. Data were summarized and assessed from 14 Investigational New Drug programs and 7 New Drug Applications submitted to the US Food and Drug Administration (FDA) from the period of January 2012 to August 2018, encompassing 152 unique studies. The assessment of DDI potential was largely consistent with the recommendations of current DDI‐relevant guidances. Limited data were available to provide recommendations across organ impairment categories. Limited data on immunogenicity indicate impact on pharmacokinetic, the impact on safety and efficacy, although not extensively evaluated, appeared negligible. Cardiac safety evaluation indicated a potential for discordant translation of risk from nonclinical studies to clinical findings. Continued experience with synthetic oligonucleotide therapies will help inform the development of best practices to support their development and regulatory approval.

Background In March 2020, the Food and Drug Administration (FDA) approved use of COVID‐19 convalescent plasma (CCP) as an investigational new drug for treatment of COVID‐19. Since then, collection of CCP from COVID‐19–recovered patients has been implemented in donor centers nationwide. Childrenʼs Hospital Colorado rapidly put into practice a CCP collection protocol, necessitating development and implementation of assays to evaluate SARS‐CoV‐2 antibodies in CCP units. Study Design and Methods We evaluated 87 units of CCP collected from 36 donors over two to four sequential donations using both antigen‐binding assays for SARS‐CoV‐2 nucleoprotein and spike antigens and a live virus focus reduction neutralization test (FRNT50). Results Our data show that the majority of donors (83%) had a FRNT50 titer of at least 80, and 61% had a titer of at least 160, which met the FDAʼs criteria for acceptable CCP units. Additionally, our data indicate that analysis of antibodies to a single SARS‐CoV‐2 antigen is likely to miss a percentage of seroconverters; however, these individuals tend to have neutralizing antibody titers of less than 80. There was considerable variability in the short‐term, sustained antibody response, measured by neutralizing antibody titers, among our donor population. Conclusion The correlation of neutralizing activity and antigen‐binding assays is necessary to qualify CCP for therapeutic use. Since SARS‐CoV‐2 antibody levels decline in a percentage of donors, and such a decline is not detectable by current qualitative assays implemented in many laboratories, robust, quantitative assays are necessary to evaluate CCP units best suited for therapeutic infusion in COVID‐19 patients.

High doses of total-body or partial-body radiation exposure can result in a life-threatening acute radiation syndrome as manifested by severe morbidity. Entolimod (CBLB502) is effective in protecting against, and mitigating the development of, the hematopoietic and gastrointestinal subsyndromes of the acute radiation syndrome in rodents and nonhuman primates. Entolimod treatment reduces radiation-induced apoptosis and accelerates the regeneration of progenitors in radiation-damaged tissues. The drug has been evaluated clinically for its pharmacokinetics (PK), toxicity, and biomarkers. The US Food and Drug Administration (FDA) has granted investigational new drug, fast-track, and orphan drug statuses to entolimod. Its safety, efficacy, and animal-to-human dose conversion data allowed its progression with a pre-emergency use authorization application submission.

Introduction: The Investigational New Drug (IND) committee advises the Drug Controller General of India on matters pertaining to clinical trials (CTs) of IND for clinical development. An audit of the minutes of this committee's meetings would shed light on the drug discovery in India. Methods: Minutes of the IND committee meetings available in the public domain (2-year period) were evaluated. The applications which were postponed were excluded from the study. Outcome measures were therapeutic areas of IND, purpose of the applications, status of registration with the CT Registry of India (CTRI), and the innovator country. Results: The minutes of N = 7 meetings were available in the public domain for the period January 2017–December 2018 with N = 45 agenda items. One agenda item was excluded, and n = 44 agenda items were finally analyzed. The total number of therapeutic agents discussed was N = 29, of which n = 7/29 and n = 6/29 belonged to infectious diseases (ID) and oncology, respectively. The total number of purposes of these applications was N = 46, of which n = 35/46 (76%) were to seek permission to conduct a CT, and n = 31/35 (88.6%) were found registered with CTRI as on April 01, 2019. Of the N = 46 purposes, n = 33/46 (71.7%) were approved. Of the n = 29 INDs discussed, n = 19/29 (65.52%) were of the Indian origin. Conclusions: Although a majority (65%) of INDs discussed in the meetings were of the Indian origin, the drug discovery was not in line to tackle the top ten causes of years of life lost prematurely (barring ID).

In response to a rapid increase in drug development activity during the past two decades, the Food and Drug Administration's Center for Drug Evaluation and Research launched a multi-year effort in 2017 to modernize the program by which new drug products are regulated, known as the New Drugs Regulatory Program. Following a detailed analysis of FDA activities in new drug development, premarket review, and postmarket monitoring, the Office of New Drugs was restructured to therapeutically align its clinical offices and to add new cross-functional offices for regulatory support. An interdisciplinary review process for new drug and biologics applications was rolled out to reduce redundancy and produce review documents that effectively communicate the scientific basis for the regulatory decision. The investigational new drug (IND) review process was also streamlined. During the next 2 years, the modernization initiative will seek to attract and retain new scientific and regulatory staff, improve postmarket safety monitoring, increase efficiency of drug review via technology-enabled workflows, and standardize the capture and use of scientific data to inform future regulatory decisions. The modernization effort will position the New Drugs Regulatory Program to continually improve and adapt to innovations in science, technology, and drug development.

The clinical, molecular, and genetic heterogeneity of uterine cervix cancers makes the discovery of effective therapies a challenge. Optimal evaluation of effective radiotherapy-agent combinations requires sophisticated trial strategies from the United States National Cancer Institute and its pharmaceutical collaborators. One strategy involves the phase 0 trial, which falls under the United States Food and Drug Administration Exploratory Investigational New Drug Guidance, or xIND. As currently envisioned for radiotherapy-based trials, the phase 0 trial provides a platform for study of pharmacodynamic effects linked to pharmacokinetic exposures, designed to screen a new experimental agent's dose or schedule, in combination with standard radiotherapy regimens, in a very small number (10-15) of subjects. In the phase 0 trial, radiotherapy-agent combinations are intended to be biologically active, but a new experimental agent's low dose or infrequent schedule is considered nontoxic and nonbeneficial. The phase 0 trial primary endpoint is an individual subject's pharmacodynamic response. Regimens move on from phase 0 trial development if and when a predetermined all-subject pharmacodynamic response rate is crossed. An initial safety experience during and after the radiotherapy-agent combination determines future feasibility. For this article, the clinical example of women with abdominopelvic lymph node-positive uterine cervix cancer is used to elaborate the phase 0 trial approach to the discovery of novel radiosensitizing oncological agents. It is expected that phase 0 radiotherapy-agent trials will become more prevalent in near-term clinical development.

The world is on the cusp of a post-antibiotic era, but researchers and medical doctors have found a way forward-by looking back at how infections were treated before the advent of antibiotics, namely using phage therapy. Although bacteriophages (phages) continue to lack drug approval in Western medicine, an increasing number of patients are being treated on an expanded-access emergency investigational new drug basis. To streamline the production of high-quality and clinically safe phage preparations, we developed a systematic procedure for medicinal phage isolation, liter-scale cultivation, concentration and purification. The 16- to 21-day procedure described in this protocol uses a combination of modified classic techniques, modern membrane filtration processes and no organic solvents to yield on average 23 mL of 1011 plaque-forming units (PFUs) per milliliter for Pseudomonas, Klebsiella, and Serratia phages tested. Thus, a single production run can produce up to 64,000 treatment doses at 109 PFUs, which would be sufficient for most expanded-access phage therapy cases and potentially for clinical phase I/II applications. The protocol focuses on removing endotoxins early by conducting multiple low-speed centrifugations, microfiltration, and cross-flow ultrafiltration, which reduced endotoxins by up to 106-fold in phage preparations. Implementation of a standardized phage cultivation and purification across research laboratories participating in phage production for expanded-access phage therapy might be pivotal to reintroduce phage therapy to Western medicine.

A veterinarian and pet owner survey (Project Jake) examined the use and safety of isoxazoline parasiticides given to dogs. Data were received during August 1–31, 2018 from a total of 2,751 survey responses. Forty‐two percent (1,157) reported no flea treatment or adverse events (AE), while 58% (1594) had been treated with some parasiticide for flea control, and of those that received a parasiticide, the majority, or 83% (1,325), received an isooxazoline. When any flea treatment was given, AE were reported for 66.6% of respondents, with no apparent AE noted for 36.1%. Project Jake findings were compared to a retrospective analysis of publicly available Food and Drug Administration (FDA) and European Medicines Agency (EMA) reported AE. The number of total AE reported to FDA and EMA were comparable, although a 7 to 10 times higher occurrence of death and seizures was reported from the EMA or from outside the United States (US). Serious AE responses for death, seizures and neurological effects reported in our survey were higher than the FDA but moderately lower than the EMA reports. These sizable global data sets combined with this pre‐ and post‐parasiticide administration survey indicated that isoxazoline neurotoxicity was not flea‐ and tick‐specific. Post‐marketing serious AE were much higher than in Investigational New Drug (IND) submissions. Although the labels have recently been updated, dogs, cats and their caregivers remain impacted by their use. These aggregate data reports support the need for continued cross‐species studies and critical review of product labelling by regulatory agencies and manufacturers., A veterinarian and pet owner survey (Project Jake) examined the use and safety of isoxazoline parasiticides given to dogs during August 1‐31, 2018 from 2751 survey responses. When any preventive treatment was given, AE were reported for 66.6% of respondents, with no apparent AE noted for 36.1%. These survey data support the need for continued cross‐species studies and critical review of product labeling by regulatory agencies and manufacturers.

Purpose of Review Emergency physicians generally have limited exposure to internationally acquired illnesses. However, travelers can present quite ill, and delays in recognition and treatment can lead to increased morbidity and mortality. This paper aims to summarize typical presentations of common international diseases and provide the emergency physician with a practical approach based on current guidelines. Recent Findings In the treatment of traveler’s diarrhea, azithromycin has become the treatment of choice due to the growing antibiotic resistance. Intravenous artesunate was approved in 2019 under investigational new drug protocol for the treatment of severe malaria, and artemisinin-based combination therapies (ACTs) have become the first-line treatment for most cases of uncomplicated malaria. Since the 2015 outbreak, Zika has become a concern to many travelers, but the current treatment is supportive. Summary Clinicians should be aware of a few noteworthy updates in the treatment of internationally acquired illnesses, but more importantly, they must recognize warning signs of severe illness and treat promptly. Future research on workup and disposition could help emergency physicians identify which patients need admission in well-appearing febrile travelers.

BACKGROUND The use of bone marrow concentrate (BMC) for treatment of musculoskeletal disorders has become increasingly popular over the last several years, as technology has improved along with the need for better solutions for these pathologies. The use of cellular tissue raises a number of issues regarding the US Food and Drug Administration's (FDA) regulation in classifying these treatments as a drug versus just autologous tissue transplantation. In the case of BMC in musculoskeletal and spine care, this determination will likely hinge on whether BMC is homologous to the musculoskeletal system and spine. OBJECTIVES The aim of this review is to describe the current regulatory guidelines set in place by the FDA, specifically the terminology around "minimal manipulation" and "homologous use" within Regulation 21 CFR Part 1271, and specifically how this applies to the use of BMC in interventional musculoskeletal medicine. METHODS The methodology utilized here is similar to the methodology utilized in preparation of multiple guidelines employing the experience of a panel of experts from various medical specialties and subspecialties from differing regions of the world. The collaborators who developed these position statements have submitted their appropriate disclosures of conflicts of interest. Trustworthy standards were employed in the creation of these position statements. The literature pertaining to BMC, its effectiveness, adverse consequences, FDA regulations, criteria for meeting the standards of minimal manipulation, and homologous use were comprehensively reviewed using a best evidence synthesis of the available and relevant literature. RESULTS/Summary of Evidence: In conjunction with evidence-based medicine principles, the following position statements were developed: Statement 1: Based on a review of the literature in discussing the preparation of BMC using accepted methodologies, there is strong evidence of minimal manipulation in its preparation, and moderate evidence for homologous utility for various musculoskeletal and spinal conditions qualifies for the same surgical exemption. Statement 2: Assessment of clinical effectiveness based on extensive literature shows emerging evidence for multiple musculoskeletal and spinal conditions. • The evidence is highest for knee osteoarthritis with level II evidence based on relevant systematic reviews, randomized controlled trials and nonrandomized studies. There is level III evidence for knee cartilage conditions. • Based on the relevant systematic reviews, randomized trials, and nonrandomized studies, the evidence for disc injections is level III. • Based on the available literature without appropriate systematic reviews or randomized controlled trials, the evidence for all other conditions is level IV or limited for BMC injections. Statement 3: Based on an extensive review of the literature, there is strong evidence for the safety of BMC when performed by trained physicians with the appropriate precautions under image guidance utilizing a sterile technique. Statement 4: Musculoskeletal disorders and spinal disorders with related disability for economic and human toll, despite advancements with a wide array of treatment modalities. Statement 5: The 21st Century Cures Act was enacted in December 2016 with provisions to accelerate the development and translation of promising new therapies into clinical evaluation and use. Statement 6: Development of cell-based therapies is rapidly proliferating in a number of disease areas, including musculoskeletal disorders and spine. With mixed results, these therapies are greatly outpacing the evidence. The reckless publicity with unsubstantiated claims of beneficial outcomes having putative potential, and has led the FDA Federal Trade Commission (FTC) to issue multiple warnings. Thus the US FDA is considering the appropriateness of using various therapies, including BMC, for homologous use. Statement 7: Since the 1980's and the description of mesenchymal stem cells by Caplan et al, (now called medicinal signaling cells), the use of BMC in musculoskeletal and spinal disorders has been increasing in the management of pain and promoting tissue healing. Statement 8: The Public Health Service Act (PHSA) of the FDA requires minimal manipulation under same surgical procedure exemption. Homologous use of BMC in musculoskeletal and spinal disorders is provided by preclinical and clinical evidence. Statement 9: If the FDA does not accept BMC as homologous, then it will require an Investigational New Drug (IND) classification with FDA (351) cellular drug approval for use. Statement 10: This literature review and these position statements establish compliance with the FDA's intent and corroborates its present description of BMC as homologous with same surgical exemption, and exempt from IND, for use of BMC for treatment of musculoskeletal tissues, such as cartilage, bones, ligaments, muscles, tendons, and spinal discs. CONCLUSIONS Based on the review of all available and pertinent literature, multiple position statements have been developed showing that BMC in musculoskeletal disorders meets the criteria of minimal manipulation and homologous use. KEY WORDS Cell-based therapies, bone marrow concentrate, mesenchymal stem cells, medicinal signaling cells, Food and Drug Administration, human cells, tissues, and cellular tissue-based products, Public Health Service Act (PHSA), minimal manipulation, homologous use, same surgical procedure exemption.

Umbilical Cord Blood (UCB) transplant (UCBT) is a curative procedure for patients with hematologic malignancies and genetic disorders and expands access for non-Caucasian patients unable to find a fully matched unrelated donor. In 2011, the Food and Drug Administration (FDA) required that unrelated UCBT use either licensed UCB or unlicensed UCB via an Investigational New Drug (IND). The National Marrow Donor Program® (NMDP) manages an IND under which 2456 patients (1499 adults and 957 children (564 malignant disease and 393 non-malignant disease) received single or double UCBT between October 2011 and December, 2016. Median age was 31 years (

In patients undergoing total pancreatectomy for chronic pancreatitis, isolation, and infusion of autologous islets must comply with Good Manufacturing Practices standards established by the Food and Drug Administration (FDA) but does not standardly require an Investigational New Drug (IND) status. We report a case of a 4-year-old child with severe hereditary pancreatitis who developed clinical sepsis during total pancreatectomy (TP) surgery; subsequent pancreas, islet, and blood cultures were positive for Enterococcus. Because of clinical deterioration, planned islet infusion was aborted and islets were kept viable in a culture period while the patient was stabilized. Two days later, 38 000 islet equivalents (IEQ, 2808 IEQ/kg) were infused in a second procedure. Because maintaining the islets in culture met the FDA standard for "more than minimal" tissue manipulation, an emergency IND was obtained from the FDA to permit delayed infusion. The patient tolerated islet infusion well, and subsequently has partial islet graft function with normal glucoses and minimal insulin needs. This case highlights the possibility to delay islet infusion in an emergency, the potential for success with few islets in a young child, and the need to consider regulatory complexities of islet transplant in this situation.

Safe practices for dispensing investigational product (IP) during clinical trials are not standardized and information in this regard is often limited. ASPIRE was a Phase 3 safety and effectiveness trial of a vaginal matrix ring containing 25 mg of dapivirine for the prevention of HIV-1 in women. The study enrolled 2629 women at 15 clinical research sites in Malawi, Uganda, South Africa and Zimbabwe who were randomized in a 1:1 ratio to receive either a vaginal ring containing 25 mg of dapivirine or a matching placebo vaginal ring. The vaginal rings and packaging were identical in appearance in order to maintain the study blind. A real-time, documented second check of the dispensing process was conducted by a second pharmacy staff. Frequent inventory counts and real time accountability audits were also useful for rapidly identifying a dispensing error. A total of 52,625 vaginal rings were dispensed with only three documented pharmacy dispensing errors. There were zero dispensing errors at 13 of the 15 sites with an overall rate of