Evaluation of Excipient Risk in BCS Class I and III Biowaivers

The objective of this review article is to summarize literature data pertinent to potential excipient effects on intestinal drug permeability and transit. Despite the use of excipients in drug products for decades, considerable research efforts have been directed towards evaluating their potential effects on drug bioavailability. Potential excipient concerns stem from drug formulation changes (e.g., scale-up and post-approval changes, development of a new generic product). Regulatory agencies have established in vivo bioequivalence standards and, as a result, may waive the in vivo requirement, known as a biowaiver, for some oral products. Biowaiver acceptance criteria are based on the in vitro characterization of the drug substance and drug product using the Biopharmaceutics Classification System (BCS). Various regulatory guidance documents have been issued regarding BCS-based biowaivers, such that the current FDA guidance is more restrictive than prior guidance, specifically about excipient risk. In particular, sugar alcohols have been identified as potential absorption-modifying excipients. These biowaivers and excipient risks are discussed here.

Emerging trends in Abuse-Deterrent Formulations: Technological insights and Regulatory considerations

Background: Opioid medications are an integral part in the management of acute and chronic severe pain. However, non-medical practice of these prescription drug products is emerging as a serious public health problem. To control this opioid epidemic, USFDA is encouraging pharmaceutical companies to develop Abuse Deterrent Formulations (ADFs). Abuse Deterrent Formulations are much more difficult to manipulate and abuse when compared to their conventional formulations. This feature of ADFs is due to their ability to incumber extraction of active ingredients, to prevent administration through alternative routes and making abuse of altered product less rewarding. Objective: The main objective of this review is to abridge different ADFs and various laboratory-based in vitro manipulation and extraction studies, demonstrating that these approved ADFs have capabilities to deter abuse. Methods: The method includes collection of data from different search engines like PubMed, FDA guidance documents, ScienceDirect, Google Patents to get coverage of literature in order to get appropriate information regarding ADFs. Results: Various in vitro studies demonstrate that ADFs are effective in minimizing opioid drug abuse including opioid overdose. However, real impact of these ADFs on reducing the drug abuse can be concluded only after receiving the post marketing data. Conclusion: ADFs are embracing fundamentally different paradigm in management of severe pain. We believe that development of abuse deterrent technologies would shift the architype, deterring multipill abuse and can prove as a breakthrough strategy in controlling this opioid epidemic menace.

Challenges with Conducting an Investigational Drug Study in Older Adults in Nursing Homes During a Pandemic

In the early months of the pandemic, SARS-CoV-2 infected nursing home residents in explosive and deadly outbreaks. Nursing home residents disproportionately accounted for over 40% of COVID-19 mortality nationally. This national emergency drove scientific and public health experts to develop and implement administrative, clinical, and research programs to limit the pandemic’s impact, especially for high-risk individuals, such as those hospitalized or living in nursing homes. Nursing home policies, prompted by the Centers for Medicare & Medicaid Services (CMS) and the Centers for Disease Control and Prevention (CDC) guidance, severely restricted access beginning in March 2020 in an effort to limit disease exposure. In July 2020 we began the process to conduct an investigational SARS-CoV-2 post exposure prophylaxis study of nursing home residents, incorporating FDA guidance developed for conducting investigational drug trials in the context of COVID-19. Our research teams adapted our nursing home engagement, resident consenting and research data collection strategies accordingly. We remotely screened residents living in any of 28 nursing homes for eligibility to participate, ultimately consenting and randomizing individuals in 11 facilities. Of the 2,683 nursing home residents 65 years or older we screened, 48 (1.8%) agreed to consent individually or through proxy, most often a legally authorized representative. We will describe our research methods, with emphasis on how we addressed challenges presented due to performing all research tasks remotely and identify strategies that can qualitatively improve the remote nursing home research experience.

Human Epidermal Zinc Concentrations after Topical Application of ZnO Nanoparticles in Sunscreens

Zinc oxide nanoparticle (ZnO NP)-based sunscreens are generally considered safe because the ZnO NPs do not penetrate through the outermost layer of the skin, the stratum corneum (SC). However, cytotoxicity of zinc ions in the viable epidermis (VE) after dissolution from ZnO NP and penetration into the VE is ill-defined. We therefore quantified the relative concentrations of endogenous and exogenous Zn using a rare stable zinc-67 isotope (67Zn) ZnO NP sunscreen applied to excised human skin and the cytotoxicity of human keratinocytes (HaCaT) using multiphoton microscopy, zinc-selective fluorescent sensing, and a laser-ablation inductively coupled plasma–mass spectrometry (LA-ICP-MS) methodology. Multiphoton microscopy with second harmonic generation imaging showed that 67ZnO NPs were retained on the surface or within the superficial layers of the SC. Zn fluorescence sensing revealed higher levels of labile and intracellular zinc in both the SC and VE relative to untreated skin, confirming that dissolved zinc species permeated across the SC into the VE as ionic Zn and significantly not as ZnO NPs. Importantly, the LA-ICP-MS estimated exogenous 67Zn concentrations in the VE of 1.0 ± 0.3 μg/mL are much lower than that estimated for endogenous VE zinc of 4.3 ± 0.7 μg/mL. Furthermore, their combined total zinc concentrations in the VE are much lower than the exogenous zinc concentration of 21 to 31 μg/mL causing VE cytotoxicity, as defined by the half-maximal inhibitory concentration of exogenous 67Zn found in human keratinocytes (HaCaT). This speaks strongly for the safety of ZnO NP sunscreens applied to intact human skin and the associated recent US FDA guidance.

1433. Impact of 2019 US Food and Drug Administration (FDA) Guidance on Developing Drugs for Urinary Tract Infection (UTI) on the Perceived Efficacy of Antibiotics for the Treatment of Uncomplicated UTI (uUTI)

Background In 2019, the FDA issued guidance on drug development for treatment of UTIs. To explore the impact of this guidance, we compared clinical and microbiological outcomes of the fluoroquinolones norfloxacin and ciprofloxacin and the β-lactams pivmecillinam and sulopenem for treatment of uUTIs from original publications versus recent analyses conducted in accordance with the FDA guidance. Methods The efficacy of pivmecillinam 400 mg twice daily (BID), 3 days (3d) versus norfloxacin 400 mg BID, 3d was reported in a 2002 publication. Patient-level data were used to re-analyze clinical and microbiological outcomes in the microbiological intent-to-treat population in accordance with the 2019 FDA guidance. For descriptive comparison, we present the efficacy of ciprofloxacin 250 mg BID, 3d vs sulopenem 500 mg BID, 5d in the 2020 SURE-1 trial (also conducted in accordance with FDA guidance) alongside historical efficacy data for ciprofloxacin. Results Re-analysis of data from the trial of pivmecillinam and norfloxacin showed microbiological responses for pivmecillinam and norfloxacin of 64% and 79%, respectively. Microbiological responses were higher, 75% for pivmecillinam and 91% for norfloxacin, in the original analysis. For clinical response, re-analysis showed 75% for pivmecillinam and 88% for norfloxacin, while historical data were 82% and 88%, respectively. In the SURE-1 trial, the microbiological response of patients assessed at Day 12 was 76.6% for sulopenem and 79.1% for ciprofloxacin. In a 2002 publication, bacterial eradication at 4 to 11 days after treatment was 93.7% for ciprofloxacin 250 mg, a higher response rate than that reported in SURE-1. For clinical response, rates were 78.7% for ciprofloxacin in SURE-1 and 92.7% for the historical ciprofloxacin data. Conclusion When assessed in accordance with the 2019 FDA guidance, clinical and microbiological efficacy of both fluoroquinolones and β-lactam antibiotics appears lower than has been published in the past. Healthcare providers should be aware that newer antibiotics may appear to have a lower efficacy than older antibiotics due to the application of more stringent definitions in the FDA guidance. Disclosures Anne Santerre Henriksen, MS, Advanz (Consultant)Shionogi BV (Consultant)UTILITY Therapeutics (Consultant) Lindsay Nicolle, MD, Entos (Consultant)GSK (Consultant)Iterum (Consultant)Utility Therapeutics (Consultant) Anita F. Das, PhD, Adagio Therapeutics, Inc. (Consultant)

Clinical research data management in the United States: Where we've been and where we're going

With the focus of the COVID-19 pandemic, we wanted to reach all stakeholders representing communities concerned with good clinical data management practices. We wanted to represent not only data managers but bio-statisticians, clinical monitors, data scientists, informaticians, and all those who collect, organize, analyze, and report on clinical research data. In our paper we will discuss the history of clinical data management in the US and its evolution from the early days of FDA guidance. We will explore the role of biomedical research focusing on the similarities and differences in industry and academia clinical research data management and what we can learn from each other. We will talk about our goals for recruitment and training for the CDM community and what we propose for increasing the knowledge and understanding of good clinical data practice to all – particularly our front-line data collectors i.e., nurses, medical assistants, patients, other data collectors. Finally, we will explore the challenges and opportunities to see CDM as the hub for good clinical data research practices in all of our communities.We will also discuss our survey on how the COVID-19 pandemic has affected the work of CDM in clinical research.

Method to determine particle release during long-term loading for assessment of coating durability of cardiovascular stents

Many catheters and vascular implants are coated to increase biocompatibility or to reduce friction during catheter based implantation. Several regulations require assessment of coating durability over the implant’s life time. An in vitro method for stent testing is presented to measure released particulate matter at defined inspection intervals. The method was validated using polystyrene microspheres with a size of 10, 25 and 50 μm to check for particle recovery (n=6). Two cleaning steps followed. Particle counting was performed by light obscuration method. The recovery rate was 103±5% (10μm), 94±4% (25 μm) and 78±12% (50 μm), respectively, meeting the requirements of FDA guidance documents (i.e. FDA 1545). Less than 3% of the particles were found in the cleaning solutions. The method using a fixed volume during stent loading can be adapted to all durability testers where tubes are used to fix the stents (radial pulsatile, bending, axial compression, torsion).

A 15 Year Review (2006-2020) of Patient-Reported Outcomes (PRO) in United States Oncology Product Labeling and Trends in Sponsor Size and Oncology Experience

BackgroundDespite wide use of patient reported outcomes (PRO) tools in clinical development, resulting data is rarely incorporated into the US label. This study reviewed oncology product labels approved by the Food and Drug Administration (FDA) between 2006 and 2020 to determine if the rate of PRO inclusion in labeling has meaningfully changed. Sponsors were assessed to identify demographic trends in achieving PRO label success. MethodsFDA-approved drugs were searched utilizing the Drugs@FDA database by month from January 2006 to December 2020 for novel drug and biologic approvals. Labels and product summary basis of approval (SBA) were reviewed for inclusion of PRO data. Sponsor size and experience were determined for each product in the year of initial approval. Results155 oncology products received initial approval between 2006-2020, of which only 7 contained PRO data in the label. More than half (53.5%) of products had PRO data described in the SBA. Over time, PRO information increasingly been included in the product marketing application. Sponsors utilizing PRO data tend to be experienced in oncology development and larger in size. ConclusionsThere has been no meaningful change in inclusion of PRO data in oncology product labeling over the past 15 years. Recent FDA guidance and initiatives may provide additional clarification to support appropriate PRO tools to support label inclusion as well as another forum for distributing PRO data publicly.

Selection of Filovirus Isolates for Vaccine Development Programs

The continuing outbreaks of ebola virus disease highlight the ongoing threat posed by filoviruses. Fortunately, licensed vaccines and therapeutics are now available for Zaire ebolavirus. However, effective medical countermeasures, such as vaccines for other filoviruses such as Sudan ebolavirus and the Marburg virus, are presently in early stages of development and, in the absence of a large outbreak, would require regulatory approval via the U.S. Food and Drug Administration (FDA) Animal Rule. The selection of an appropriate animal model and virus challenge isolates for nonclinical studies are critical aspects of the development program. Here, we have focused on the recommendation of challenge isolates for Sudan ebolavirus and Marburg virus. Based on analyses led by the Filovirus Animal and Nonclinical Group (FANG) and considerations for strain selection under the FDA Guidance for the Animal Rule, we propose prototype virus isolates for use in nonclinical challenge studies.