3 results
3570 The Regulatory Landscape of Products to Treat Opioid Overdose
- Pooja Singh, Kaylene Okada, Amelia Spinrad, Nancy Pire-Smerkanich, Eunjoo Pacifici
-
- Journal:
- Journal of Clinical and Translational Science / Volume 3 / Issue s1 / March 2019
- Published online by Cambridge University Press:
- 26 March 2019, pp. 58-59
-
- Article
-
- You have access Access
- Open access
- Export citation
-
OBJECTIVES/SPECIFIC AIMS: Since 1971, Naloxone has been the only FDA approved opioid antagonist indicated for use after opioid overdose. New formulations of Naloxone have been introduced into the market, including an injectable, auto-injector, and nasal spray. However, Naloxone is short-acting and as such often requires multiple doses and may induce severe withdrawal symptoms. This study examines the regulatory framework to understand the evolution of products indicated to treat opioid overdose and the landscape of therapies in development. Furthermore, this study examines how the Food and Drug Administration (FDA) and other government agencies have approached the opioid crisis. METHODS/STUDY POPULATION: A PubMed search of “naloxone AND opioid overdose” with the filter “humans” was conducted to understand Naloxone’s regulatory framework. The term “naloxone” was searched on the Drugs@FDA: Approved Drug Products database. Additionally, “nalmefene” was searched on ClinicalTrials.gov. To examine the opioid antagonist market landscape, a PubMed search of “opioid antagonist AND opioid overdose” with the filters “humans” and “clinical trial,” and a ClinicalTrials.gov search of “opioid antagonist and opioid overdose,” were conducted. Government agency reports were reviewed and cataloged. RESULTS/ANTICIPATED RESULTS: Preliminary findings suggest a lack of innovation in the development of novel opioid antagonists. Most literature review findings focused on already-marketed Naloxone products, including the original injectable approved in 1971, the 2014 Evzio Auto-Injector, and the 2015 Narcan Nasal Spray (Figure 1). For example, there were 14 results yielded from the FDA approvals database, but none of these results represented a new opioid antagonist molecule. A longer-acting opioid antagonist, Nalmefene injectable, was approved in 1995 but has since been removed from the market due to low sales. Our initial ClinicalTrials.gov search using condition “opioid overdose” and other terms “opioid antagonist”,revealed no new studies being conducted on alternative opioid antagonist treatments for opioid overdose. Findings only focused on the distribution, co-dispensing, intervention, pharmacokinetics/pharmacodynamics (PK/PD) of Naloxone (Figure 2). However, a Google search yielded one new trial with an opioid antagonist by Opiant Pharmaceuticals, almost fifty years after FDA’s approval of Naloxone. A ClinicalTrials.gov search was then performed using the search term “nalmefene” to find whether Opiant Pharmaceuticals’ trial was in the ClinicalTrials.gov database. However, the Opiant trial is phase I, and as such does not require reporting on ClinicalTrials.gov. In 2017, the National Institutes of Health (NIH) launched an initiative for longer-acting opioid antagonist formulations. In 2018, Opiant Pharmaceuticals announced positive phase I results for intranasal Nalmefene. The potential return of Nalmefene in intranasal form may play a significant role in reducing overdoses, especially in cases where a longer-acting opioid antagonist is necessary. Opiant Pharmaceuticals’ trial commenced after the NIH announced their initiative; furthermore, the NIH’s National Institute on Drug Abuse granted the company $7.4 million to further the investigation of this drug. We will continue to research drugs that have previously been studied for the indication of treating opioid overdose in the United States and abroad and catalog them. DISCUSSION/SIGNIFICANCE OF IMPACT: The abuse and misuse of opioids in the United States has caused an epidemic accounting for over 115 opioid-overdose deaths each day, devastating our nation, both socially and economically. The United States spends $78.5 billion annually to combat the misuse of these drugs. Due to the severity of the opioid crisis, efforts to better understand approved therapies and investigational products in development to treat opioid overdose will be of significance moving forward. This research can inform agencies who are developing strategies to reduce opioid overdoses and pharmaceutical product developers about the current opioid antagonist landscape.
3567 An Analysis of Current Trends in Inclusion of Historically Underrepresented Populations in Clinical Trials: Women and Geriatrics
- Jacqueline Chen, Kaitlyn Park, Sun Young Uhm, Amelia Spinrad, Apurva Uniya, Nancy Pire-Smerkanich, Eunjoo Pacifici
-
- Journal:
- Journal of Clinical and Translational Science / Volume 3 / Issue s1 / March 2019
- Published online by Cambridge University Press:
- 26 March 2019, pp. 83-84
-
- Article
-
- You have access Access
- Open access
- Export citation
-
OBJECTIVES/SPECIFIC AIMS: Clinical trials (CTs) play an important role in developing new treatments, expanding or refining treatments that are already available, and/or identifying behavioral changes that can prolong or improve the lives of subjects. CTs are also conducted to understand normal human physiology, pathophysiology, and factors associated with health outcomes. Results from CTs are then used to determine the safety and efficacy of medications or treatment. CT participants should reflect the diversity of those receiving the treatments because, exclusion of specific populations in CTs may potentially result in knowledge gaps for clinicians and regulators. Historically, women and geriatrics have been underrepresented as CT participants. For women, this is the result of Food and Drug Administration (FDA) action in 1977 which restricted women with childbearing potential from participating in phase I and early phase II CTs after thousands of birth defects resulted from thalidomide usage during pregnancy. While the U.S. Government Accountability Office’s 1992 and 2001 reports documented an increased female inclusion in later stages of CTs, earlier phases of CTs were still lacking. Likewise, older adults and geriatrics have been excluded in CTs arbitrarily or to avoid adverse events associated with drug-drug interactions and comorbidities. Over the past few decades, the FDA has worked to address this issue and increase diversity and transparency in CTs. In 2015, the FDA’s Action Plan for Food and Drug Administration Safety and Innovation Act (FDASIA) Section 907 called for improved CT inclusion and reporting of demographic subgroups (sex, age, race, and ethnicity), highlighting three priority areas: quality, participation, and transparency. This research examines the current state of female inclusion in phase I and II CTs (2016 to 2017) and geriatric inclusion in phase III CTs (2010 to 2017). METHODS/STUDY POPULATION: To assess female representation in phase I and II CTs, data from 2016 CTs was extracted from clinicaltrials.gov. The average percentage of male and female participation in trials recruiting for males and females was determined; CTs conducted in only males or females (due to sex specific disease states) were excluded. The data was further differentiated into investigator-initiated and industry-sponsored trials to determine any differences in sex representation. Data from 2017 CTs on clinicaltrials.gov will be extracted and analyzed as well as 2016 to 2017 data from FDA novel drug approvals. To assess geriatric representation in phase III CTs, geriatric subsections of drug labels from novel drug applications approved between 2010 to 2017 were assessed for geriatric-specific information based on four areas: 1) reporting of CT including geriatrics, 2) reporting of percentage of CT participants ages 75+, 3) providing geriatric dosage recommendations, 4) determining product safety and efficacy for geriatrics. RESULTS/ANTICIPATED RESULTS: It is mandatory that all US CTs are registered on clinicaltrials.gov with the exception of Phase I studies, and results posted within 1 year of CT completion. In 2016, 916 phase I and 713 phase II CTs were registered on clinicaltrials.gov. Of these registered CTs, 4% of phase I and 9% of phase II CTs posted results. Of these, phase I studies included more males than females. Of these, phase I studies showed higher percentage of males (58%) than females (42%). In phase I/II, phase II, and phase II/III CTs, females were represented at a higher levels than males by 8-20% (Table 1). Phase I industry-sponsored and investigator-initiated trials and phase II/III investigator-initiated trials included less females than males (Table 2); all other types of CTs had more female than male subjects (Table 2). Preliminary findings will be expanded to include 2017 CTs and a wider pool of clinical trials will include all those associated with FDA novel drugs approved in 2016 and 2017. Of the 250 labels of novel drugs approved from 2010 to 2017 assessed for geriatric inclusion, 74% reported a CT including geriatrics, and 55% reported including CT participants ages 75+. Further, 31% provided geriatric dosage recommendations and 62% indicated insufficient evidence to determine product safety/efficacy for geriatrics (Figure 1). There was no consistent increase following the 2015 implementation of FDASIA section 907 in any of the four areas examined (Figure 2). Labels providing geriatric dosage recommendations were consistently the least fulfilled area across all years analyzed (Figure 3). DISCUSSION/SIGNIFICANCE OF IMPACT: A lack of inclusion of specific populations in CTs can lead to serious complications. For example, in 2013, the FDA required a lower recommended dose for women for drugs containing the sedative-hypnotic zolpidem (i.e. Ambien) due to persisting next morning drowsiness; the FDA arbitrarily recommended the dosage be halved from 10 mg to 5 mg as it found that women appeared to eliminate zolpidem from their bodies more slowly than men. Additionally, $35.7 million is spent annually on hospitalization from adverse drug reactions in the elderly. And, although government acts and initiatives have called for greater inclusion of certain populations like females and geriatrics in CTs, there is no penalty for exclusion. Problems like these may be avoided if these specific populations are included in CTs so that drugs can be properly studied. It may be preliminary to make conclusions about female representation in phase I clinical trials because it is not mandatory to register all phase I trials on clinicaltrials.gov, but further investigation will be conducted into FDA summary reports. Preliminary findings indicate that efforts to include female subjects may be effective in the subset of studies that reported their results. As of 2017, 51.3% of the U.S. population over 18 years old is female (U.S. Census Bureau). Early clinical trials often help to establish safety and dosing for phase III trials. Thus, it is pertinent that the inclusion rate is reflective of the general population at all clinical trial stages, not just pivotal, phase III trials. It would be prudent to monitor this trend as more studies report their results. Given that the average US life expectancy is now 78 years and that elderly population is expected to double in coming decades (NIH, 2016), there is an urgent need to include this population in current and future clinical research. Geriatrics, particularly those age 75+, use more than a third of total prescription and over-the-counter medications sold in US (Merck Institute, 2014), but is severely underrepresented in CTs. The effects of polypharmacy and changes in drug metabolism with age increase the need for specific drug dosage recommendations for geriatrics. As there was no discernable difference in drug labels fulfilling areas examined before and after 2015, FDASIA implementation may not have impacted geriatric inclusion in CT for drugs approved between 2010 to 2017. As many of these CTs began prior to FDASIA 2012 signing and 2015 implementation, the legislation’s full impact may occur in future years. Nonetheless, inadequate language currently found in geriatric drug labels can create challenges for clinicians when prescribing these medications for geriatric patients, potentially contributing to adverse drug events.
3080 Ensuring Quality in Investigator-Initiated Clinical Trials through Monitoring Concepts Training
- Amelia Spinrad, Nancy Pire-Smerkanich, Eunjoo Pacifici, Apurva Uniyal, Annie Xie, Annie Ly, Advaita Chandramohan
-
- Journal:
- Journal of Clinical and Translational Science / Volume 3 / Issue s1 / March 2019
- Published online by Cambridge University Press:
- 26 March 2019, p. 117
-
- Article
-
- You have access Access
- Open access
- Export citation
-
OBJECTIVES/SPECIFIC AIMS: Because clinical trial results are instrumental in the approval of a new drug or changes to the practice of medicine, ensuring the accuracy and validity of collected data is critical in the clinical trial process. This function, routinely carried out by clinical trial monitors in industry-sponsored trials, is often lacking in investigator-initiated trials (IITs) conducted in academia. To address this challenge, we have developed a self-study module that can be used to cross-train academic researchers in essential concepts and practical approaches to monitoring. Furthermore, we are applying a framework drawn from implementation science in the development and launch of this initiative. This framework, as used in other educational programs, is employed here to close the gap between initiative and practice, thereby effectively disseminating this training would improve the quality of clinical trials in academia. METHODS/STUDY POPULATION: This research project applied exploration, installation and implementation stages of the implementation science process by 1) exploring the need for a new initiative, 2) disseminating results, 3) engaging stakeholders, 4) creating standard operating procedures (SOPs) for installation and implementation, 5) studying user satisfaction and effectiveness, 6) addressing feedback and 7) conducting implementation. RESULTS/ANTICIPATED RESULTS: From literature review and internet searches we determined that although numerous GCP training resources exist, most are too broad and lack the practical approaches to meet the complex requirements of monitoring. Moreover, most of the offerings identified are costly or inaccessible. With only about 65% of IITs reported as being monitored (Figures 1 and 2), it appears that there is a clear need for training tools that are easily available to a broader audience. And because monitoring skills are substantially different from those associated with research coordination, it is not surprising that research professionals believed that they would need additional training to become proficient. To address this need, we began developing a monitoring module. We engaged key stakeholders from academia and industry to gain insights into their needs. The results indicated that although our training module was effective, supplementary information on the fundamentals of clinical trials should be included for those new to the field. After incorporating suggested changes and completing the module, we conducted user testing to determine if our module is ready to be broadly disseminated (Figures 3 and 4). Following positive feedback from the group, we are currently in the process of disseminating our module and studying its impact. DISCUSSION/SIGNIFICANCE OF IMPACT: IITs are instrumental in translating academic research into product development. Deficiencies in the quality control of these trials can lead to inadequacies in data accuracy and validity that could lead to significant delays in bringing innovative therapies to patients. Recent NIH policies require data and safety monitoring for all of the trials it supports. The latest addendum to ICH GCP, E6(R2), discusses a need for quality management across the clinical trial lifecycle. As we continue to disseminate and share information during the development of our self-study monitoring module, we are engaging key stakeholders from academia, government, and private institutions to understand and address quality challenges in conducting clinical trials. Finally, this research informs dissemination and implementation research, specifically for creating training for academic research professionals.