Clinical Use of Bulk Drug Substances Nominated for Use in Compounding by Outsourcing Facilities
The University of Maryland is collaborating with the Food and Drug Administration (FDA) to identify bulk drug substances ordered as compounded medications for patients or for “office stock”. In particular, we are interested in how bulk drug substances, after being compounded by outsourcing facilities, have been used or are currently being used (e.g. the bulk drug substance is made into eye drops to treat post-operative inflammation).
Using mHealth to measure Impact in Functionality Behavior, Activity and Sleep Patterns in Children and Adolescents Treated with Psychotropics
This project aims to leverage the power of mobile technology to address three primary objectives: (1) fill the gap in the capture of behavioral, functional and activity data; (2) ease the burden on patients, caregivers, and providers struggling to capture relevant and actionable data related to treatment and care management; (3) identify severity of behavioral changes after treatment initiation or change, rates of adverse events/secondary effects, along with patterns of medication use and adherence. The ultimate goal is to integrate this data with larger data systems and existing data sources to support changes in labeling or in practice patterns.
Biocompatibility Studies of 3D Printed Dental Devices
Additive manufacturing (3D printing) has begun to enable the fabrication of patient-specific medical devices, such as surgical guides used in dentistry. FDA and the University of Maryland are collaborating to verify that certain dental devices manufactured by 3D printing are biocompatible. This study will inform FDA reviews regarding the likelihood that novel 3D printing methods of medical (dental) devices will cause allergic, inflammatory or other toxicological reactions in patients. Furthermore, our work may assist FDA in guiding medical device manufacturers to prevent serious adverse events. These findings are expected to directly improve quality assessment and control of a new generation of medical device products manufactured right at the bedside that are designed to meet individual patient needs.
An Introduction to the Science of Clinical Outcomes Assessment (COA) A-COA Online Continuing- Education Series
The science of clinical outcomes assessment (COA) is of growing interest and has become important to medical product development. COA involves understanding the patient’s view of illness and treatment, and gathering how the patient feels and functions. To understand if, for example, a treatment improves a patient’s pain, ability to perform daily activities, or quality of life, measures must be rigorous, whether collected from the patient, clinician, or caregiver’s perspectives. Thus, FDA staff and reviewers, and industry staff must be well versed in the science of COA. However, most educational programs on COA are not easily accessible to working professionals.
Development of diagnostic biomarkers for determination of traumatic brain injury
The scope of the work will leverage preliminary data in the TBI model2,6 as well as already developed LC-MS/MS-based methodology to enable the characterization of our two priority biomarker candidates: PE(P-36:4) and PE(38:6) as diagnostic biomarkers of TBI. The group will provide critical information towards establishing a context of use for one or more lipid biomarkers to serve as minimally invasive diagnostic biomarkers to determine TBI and/or determine clinical trial inclusion for the drug development of therapeutics for TBI. At the conclusion of these studies, our culminating overall goal is to submit a letter of intent (LOI) for the biomarker qualification for one or more of our priority biomarker candidates (PE(P-36:4) and PE(38:6)) as diagnostic biomarker(s) for determination of TBI, which may also be used as inclusion criteria for clinical trials of therapeutics to mitigate TBI.
Improving efficacy and safety of pathogen inactivation strategies for platelet transfusion
Platelets are used to treat or prevent bleeding. Because platelets are usually stored at room temperature, they are associated with a higher risk of bacterial contamination compared to other blood products. Blood collection establishments and transfusion services must take measures to mitigate that risk. One of these measures can be the use of pathogen-reduced platelet products. Currently approved pathogen reduction methods involve incubation of the platelet bag with a chemical and illumination of the bag with ultra violet light. This treatment is intended to inactivate any potential pathogens in the platelet bag. This study will evaluate how well pathogen reduced platelets control bleeding when many blood products are needed to stop active bleeding. Specifically, the current study will evaluate how well pathogen treated platelets restore platelet function and control bleeding in patients undergoing open heart surgery on cardiopulmonary bypass. Cardiopulmonary bypass alters platelet function and the transfusion of functional platelets, together with other blood products, is often required to control bleeding post-operatively. The efficiency of patients’ blood coagulation will be compared in patients who received either a pathogen-reduced platelet product or a conventional platelet product.
Trace metals and their impact on protein, quality, safety, and efficacy
Trace metals, such as iron, copper, and zinc, can be found nearly everywhere to varying degrees. In pharmaceutical products, they are found as leachables from the container closure system, the buffer system used, and reactions in their presence can be catalyzed by exposure to light, heat, agitation or freeze/thaw cycles. These metals may damage biotechnology products via fragmentation and aggregation, and should therefore be analyzed as accurately as possible to ensure product quality. Aggregated proteins can trigger immunogenicity and serious adverse events, including death in patients. Trace metals also contribute to biological disease states and have been targets for various therapies. Therefore, we will analyze these metals in products and biological samples and determine their propensity for damage. This data will allow reviewers to better ensure product quality, safety, and efficacy, and contribute to science-based decision-making.
Solid State Properties of Spray Dried Dispersions
To yield sufficient oral drug bioavailability, poorly soluble drugs often require “enabling formulation technology”. Spray dried dispersions (SDDs) are one such enabling technology. SDDs exhibit poor flowability, small particle size, and low bulk density. Hence, capsules are often not viable, such that dry granulation is typically required to fabricate tablets from SDDs. Manufacturing tablets of SDDs requires powder compaction, at each the slugging (or roller compaction) stage and the tableting stage. Hence, compaction is a major unit operation for formulations of poorly soluble drugs that employ SDDs. However, emerging observations across the industry point towards high sensitivity of tablets from SDDs to compaction factors. There is a need to understand the solid state compaction properties of spray dried dispersions. Tablet compacts will be manufactured using a compaction simulator, where compacts will be made of SDDs or simple mixture of drug an polymer (i.e. not spray dried dispersions). Drug will be itraconazole. Polymer will be various grades of hydroxypropylmethylcellulose acetate succinate (HPMCAS). A full factorial design will be carried out to assess impact of polymer type, compaction speed, and compaction thickness on solid state properties of spray dried dispersions. Compacts will be characterized with respect to their solid state compaction properties, to elucidate the effect of spray drying. Results are expected to yield insight into compact integrity, including its sensitivity to compaction variables, which will contribute to product quality of these complex formulations.
Evaluation of Metal Ions in Electronic Cigarette Aersol Condensates and Determination of their Effects on Oral Keratinocytes
The goal of year 1 of the proposal is to develop a bioanalytical approach to identify the metal ions and HPHCs present in ECACs that are taken up by normal oral keratinocytes.Our bioanalytical strategy to measure the repertoire of EC hardware-derived metal ions and HPHCs present in ECACs and identify cellular uptake in oral keratinocytes will inform regulatory agencies charged with documenting the toxicological profile of new ECs prior to market authorization.
hERG Channel Pharmacology for CiPA
The scope of work is to perform applied regulatory research in ion channel pharmacology. The Trudeau lab will collaborate with the FDA as part of the Comprehensive in-vitro Proarrhythmia Assay (CiPA) initiative. Our part of the collaboration will be to measure dose-response curves of 7 different drugs (at 4 different concentrations) that inhibit hERG (KCNH2) potassium channels, expressed in stably transfected HEK293 cells using whole-cell patch-clamp electrophysiology at physiological temperatures. Dr. Matthew Trudeau of the University of Maryland, Baltimore is contributing to this research, along with FDA collaborators David Strauss, Ruth Barratt, Wendy Wu, and Zhihua Li.
Improving FDA Health Communications with Older Women Regarding FDA-Regulated Products
It is important that FDA effective reach out to older women, including considering the financial costs of effectively reaching women. The investigators will conduct twelve (12) exploratory focus groups among US women aged 50 years and older (8-10 women per group). The plan is to this study older women by age, in order to see how types of communication are preferred by older women of various ages. These focus groups will take place in the Washington, DC/Maryland/Virginia area at times that best accommodate participants’ availability. The investigators will strive for socioeconomic and demographic diversity among participants in these focus groups. Focus groups will respond to the research questions regarding perceptions, motivations, attitudes, and behavior concerning use of FDA-regulated materials. Some questions will also address the role some of these older women play as caregivers to help the investigators better understand whether the health information needs vary between older women who seek health information for self-care, compared with those who seek health information to care for others.
In vivo Pig-a gene mutation assay
A workgroup of the International Life Sciences Institute (ILSI) Health and Environmental Sciences Institute (HESI) is developing an Organisation for Economic Co-operation and Development (OECD) Test Guideline (TG) for the in vivo Pig-a gene mutation assay. The TG will foster regulatory acceptance of the assay for conducting safety assessments.
Development and characterization of an animal model of perinatal infection with Zika virus: assessment of long-term neurological deficits
Zika virus (ZIKV) is an emerging mosquito-borne pathogen. Between 2014 and 2017 Zika spread over 84 countries infecting >2 million people. In the US alone, over 35,000 people were infected by Zika virus including 3500 pregnant women. Understanding and measuring the potential sequelae is critical to assessing the safety and efficacy of prospective therapies or vaccines, particularly as therapies may not clear immunoprivileged sites such as the CNS effectively. This study will support animal modeling of long term consequences of disease, which may help alert clinicians to possible sequelae and help provide timely support to minimize the long-term neurological consequences of infection. The results will provide guidance to the product developers as well as the reviewers reading the parameters that need to be monitored in animals to model product efficacy.
Quantification of Surface Defects that Complicate Cleaning of 3D Printed Medical Devices
A key goal is to study AM printed products and develop process controls for safe manufacture and confirm chemical and mechanical structure. Additively manufactured products are now being manufactured as dental surgery guides, for use as cell culture expansion scaffolds and for drug-release combination products. AM can be conducted without qualification of feedstock materials, quality systems management over final finished products or premarket regulatory review. Uncertainties about post processing of AM parts can affect product chemistry and mechanical integrity. Our work will inform FDA reviewers about potential hazards or practices likely to be safe.
Biocompatibility in Additive Manufacturing
Some medical devices not subject to premarket review by FDA are being fabricated by clinicians at the point-of-care using consumer grade 3D printers. However, any medical device in physical contact with a patient should be biocompatible to insure safety. No studies have been published that relate specific 3D manufacturing process parameters to standard industry measures of biocompatibility. Recognizing this, Dr. Lex Schultheis and his research team investigated whether a specific ABS feedstock that was expected to be biocompatible for permanent contact with skin and mucosal membranes would be altered by 3D printing, and thereby change biocompatibility in the final finished medical device.
Transdermal Drug Delivery Systems-Fentanyl: In Vitro Studies
Dr. Audra Stinchcomb is building on upon the currently FDA-funded project grant NIPTE-U01-MD-2015-001 titled, "Transdermal Drug Delivery Systems-Fentanyl" (program officer representative: Caroline Strasinger). This currently funded project is focused on human in vivo testing. The goal is to understand ways to label drug delivery rates from patches, as current dose labeling is not consistent among patch products. In vivo human studies employ fentanyl patches to determine delivery rates from pharmacokinetic parameters, as well as the residual drug amount left in the patch at the end of the wear time. This research team is creating a database of controlled human studies. In vitro studies are proposed here in order to assess if in vitro studies can mimic ongoing in vivo studies, in terms of delivery rates. In vitro studies would employ the same products that are being evaluated in vivo in humans. This correlation analysis will help develop in vitro tests to predict patch delivery rates.
Water proton NMR to analyze sub-visible particulates in solutions
In this project, Dr. Bruce Yu is developing a simple and noninvasive technique to analyze sub-visible particulates in solutions. The method is based on the water proton NMR signal and can be carried out using desktop instruments without even taking the drug solution out of its vial. Sub-visible particulates formed by proteins is a safety concern for biologic products. Current analytics for such particulates are complex and invasive. A simple noninvasive analytical technology has the potential to enable effective regulation and control of sub-visible particulates in biologics.
Impact of Dose on In Vitro Dissolution Predictability
This projects extends on-going work by Dr. James Polli to develop an in vitro dissolution test that predicts the absorption and pharmacokinetics of poorly soluble drugs that have been formulated via amorphous solid dispersion technology. In vitro dissolution is an important test of pharmaceutical quality. However, products of low solubility drugs that employ amorphous solid dispersion technology are complex. Results of these formulation and human pharmacokinetic studies aim to yield an in vitro test that others can rely upon.
Improving pre-clinical assessments of safety and efficacy
"Improving pre-clinical assessments of safety and efficacy" focuses on membrane transporters in drug development. Membrane transporters allow nutrients to move throughout the body, and also move drugs throughout the body. However, these doorways can be the basis for drug-to-drug interactions, where a “perpetrator drug” interferes with how a second “victim drug” normally uses a transporter. The University of Maryland is conducting experiments in collaboration with FDA scientists in order to aid FDA to develop decision trees. FDA decision trees will help industry and FDA scientists identify what membrane transporters are most important, in terms of the potential to cause drug-to-drug interactions. FDA decision trees will also provide guidance about how cell culture studies can be used to avoid or require human clinical testing, in order to advise health care professionals and patients about transporter-based drug-to-drug interactions. University of Maryland faculty contributing to the research are Drs. Yan Shu, James Polli, Peter Swaan, and Hongbing Wang.
Ensuring readiness to evaluate innovative and emerging technologies
Ensuring readiness to evaluate innovative and emerging technologies is an important goal for the M-CERSI, focusing on new technologies that will contribute to the scientific underpinning of two device-related product areas: (1) laser-based therapeutic devices; and (2) tissue engineering constructs.
Harnessing diverse data through information sciences to improve health outcomes
This project focuses on patient prescriber agreements (PPAs) of prescription opioid analgesic drugs. In recent years, FDA has started to employ strategies to reduce misuse and abuse of opioid pain medications. PPAs are contracts between prescribers and their patients to at least list expectations of each the prescriber and the patient. With pain drugs a serious health issue, and opioids having abuse potential, there are several PPAs for various opioid pain medications. These PPAs often outline terms of treatment, patient responsibilities, education issues, addiction treatments, emergency issues, goals, and prescription limitations. University of Maryland faculty are conducting a review of PPAs currently in use, determining which healthcare professionals are using PPAs and the conditions of use. The researchers are also examining different formats and types of PPAs. University of Maryland faculty contributing to the research are Drs. Frank Palumbo, Francoise Pradel, Gail Rattinger, and Ilene Zuckerman.