Locally acting dermatology drug products: Pharmaco-analytic considerations for bioequivalence.

Bioequivalence determinations for locally acting dermatology drug products rely on assessing product sameness thru physicochemical composition and structure comparison, comparing the concentration of the active ingredient at the putative site of action, or comparing the clinical performance of the test (would-be generic) and reference products. Topical product action on cutaneous disease may be confounded by the action of excipients and are also subject to the inherent variability of how product may interact with the skin, including thermodynamic factors such as evaporation, spreadability, and interaction with the local environment such as heat and light and skin moisture.

Determining topical product bioequivalence with stimulated Raman scattering microscopy.

Generic drugs are essential for affordable medicine and improving accessibility to treatments. Bioequivalence (BE) is typically demonstrated by assessing a generic product's pharmacokinetics (PK) relative to a reference-listed drug (RLD). Accurately estimating cutaneous PK (cPK) at or near the site of action can be challenging for locally acting topical products. Certain cPK approaches are available for assessing local bioavailability (BA) in the skin. Stimulated Raman scattering (SRS) microscopy has unique capabilities enabling continuous, high spatial and temporal resolution and quantitative imaging of drugs within the skin. In this paper, we developed an approach based on SRS and a polymer-based standard reference for the evaluation of topical product BA and BE in human skin ex vivo. BE assessment of tazarotene-containing formulations was achieved using cPK parameters obtained within different skin microstructures. The establishment of BE between the RLD and an approved generic product was successfully demonstrated. Interestingly, within the constraints of the current study design the results suggest similar BA between the tested gel formulation and the reference cream formulation, despite the differences in the formulation/dosage form. Another formulation containing polyethylene glycol as the vehicle was demonstrated to be not bioequivalent to the RLD. Compared to using the SRS approach without a standard reference, the developed approach enabled more consistent and reproducible results, which is crucial in BE assessment. The abundant information from the developed approach can help to systematically identify key areas of study design that will enable a better comparison of topical products and support an assessment of BE.

Sensitivity of Pharmacokinetics to Differences in the Particle Size Distribution for Formulations of Locally Acting Mometasone Furoate Suspension-Based Nasal Sprays.

To assess bioequivalence of locally acting suspension-based nasal sprays, the U.S. FDA currently recommends a weight-of-evidence approach. In addition to in vitro and human pharmacokinetic (PK) studies, this includes a comparative clinical endpoint study to ensure equivalent bioavailability of the active pharmaceutical ingredient (API) at the site of action. The present study aimed to assess, within an in vitro/in vivo correlation paradigm, whether PK studies and dissolution kinetics are sensitive to differences in drug particle size for a locally acting suspension-based nasal spray product. Two investigational suspension-based nasal formulations of mometasone furoate (MF-I and MF-II; delivered dose: 180 µg) differed in API particle size and were compared in a single-center, double-blind, single-dose, randomized, two-way crossover PK study in 44 healthy subjects with oral charcoal block. Morphology-directed Raman spectroscopy yielded volume median diameters of 3.17 µm for MF-I and 5.50 µm for MF-II, and dissolution studies showed that MF-II had a slower dissolution profile than MF-I. The formulation with larger API particles (MF-II) showed a 45% smaller Cmax and 45% smaller AUC0-inf compared to those of MF-I. Systemic bioavailability of MF-I (2.20%) and MF-II (1.18%) correlated well with the dissolution kinetics, with the faster dissolving formulation yielding the higher bioavailability. This agreement between pharmacokinetics and dissolution kinetics cross-validated both methods and supported their use in assessing potential differences in slowly dissolving suspension-based nasal spray products.

Effect of the Similarity of Formulations and Excipients of Approved Generic Drug Products on In Vivo Bioequivalence for Putative Biopharmaceutics Classification System Class III Drugs.

One of the potential essential factors that restricts generic industry from applying the Biopharmaceutics Classification System (BCS) Class III biowaiver is adherence to the stringent formulation criteria for formulation qualitative (Q1) sameness and quantitative (Q2) similarity. The present study has investigated formulations and excipients from 16 putative BCS Class III drug substances in a total of 19 drug products via 133 approved abbreviated new drug applications (ANDAs) containing in vivo bioequivalence (BE) studies in human subjects during the time period from 2006 to 2022. We included the BCS Class III drugs in this study by referring to published literature, the World Health Organization (WHO) BCS Class I-IV list, FDA internal assessments, and physicochemical properties (high solubility and low permeability) of specific drug substances. Based upon all 133 approved generic formulations in this study, the highest amount of each different compendial excipient with a total of 40 is defined as its corresponding typical amount that has not shown any potential impact on in vivo drug absorption. In the present study, although only 30.08% of the investigated generic formulations met Q1 the same/Q2 similar formulation criteria for the BCS Class III biowaiver, and while approximately 69.92% failed to meet those criteria with non-Q1/Q2 similar formulations, all test/reference ratios (T/R) and 90% confidence intervals for all instrumental PK parameters (AUC0-t, AUC0-inf, and Cmax) met the bioequivalence (BE) criteria (80-125%). The results of formulation assessment suggest that the commonly used excipients without atypical amounts did not impact absorption of 16 putative BCS Class III drug substances. The rate and extent of absorption of drugs appears to be more dependent upon the biopharmaceutic and physiochemical properties of BCS Class III drug substance and less, or not dependent upon their formulations, excipients, and the excipients class. Our findings may lead to a more flexible formulation design space regarding the stringent BCS Class III formulation criteria.

Mechanistic modeling of generic orally inhaled drug products: A workshop summary report.

In silico mechanistic modeling approaches have been designed by various stakeholders with the goal of supporting development and approval of generic orally inhaled drug products in the United States. This review summarizes the presentations and panel discussion that comprised a workshop session concentrated on the use of in silico models to predict various outcomes following orally inhaled drug product administration, including the status of such models and how model credibility may be effectively established.

Scientific and regulatory activities initiated by the U.S. Food and drug administration to foster approvals of generic dry powder inhalers: Bioequivalence perspective.

Regulatory science for generic dry powder inhalers (DPIs) in the United States (U.S.) has evolved over the last decade. In 2013, the U.S. Food and Drug Administration (FDA) published the draft product-specific guidance (PSG) for fluticasone propionate and salmeterol xinafoate inhalation powder. This was the first PSG for a DPI available in the U.S., which provided details on a weight-of-evidence approach for establishing bioequivalence (BE). A variety of research activities including in vivo and in vitro studies were used to support these recommendations, which have led to the first approval of a generic DPI in the U.S. for fluticasone propionate and salmeterol xinafoate inhalation powder in January of 2019. This review describes the scientific and regulatory activities that have been initiated by FDA to support the current BE recommendations for DPIs that led to the first generic DPI approvals, as well as research with novel in vitro and in silico methods that may potentially facilitate generic DPI development and approval.

Scientific and regulatory activities initiated by the U.S. food and drug administration to foster approvals of generic dry powder inhalers: Quality perspective.

Regulatory science for generic dry powder inhalation products worldwide has evolved over the last decade. The revised draft guidance Metered Dose Inhaler (MDI) and Dry Powder Inhaler (DPI) Products - Quality Considerations [1] (Revision 1, April 2018) that FDA issued summarizes product considerations and potential critical quality attributes (CQAs). This guidance emphasizes the need to apply the principles of quality by design (QbD) and elements of pharmaceutical development discussed in the International Conference for Harmonisation of (ICH) guidelines. Research studies related to quality were used to support guidance recommendations, which preceded the first approval of a generic DPI product in the U.S. This review outlines scientific and regulatory hurdles that need to be surmounted to successfully bring a generic DPI to the market. The goal of this review focuses on relevant issues and various challenges pertaining to CMC topics of the generic DPI quality attributes. Furthermore, this review provides recommendations to abbreviated new drug application (ANDA) applicants to expedite generic approvals.

The History of Dermatology and Dermatologists at the US Food and Drug Administration.

In the United States, the Food and Drug Administration's (FDA's) regulatory authorities have significantly influenced the products available to treat dermatologic conditions, but at the same time, advances in dermatology have also influenced the FDA's approach, including the agency's evaluation of risks and its' communications to consumers, patients, and providers. This essay reviews significant milestones in the history of FDA's regulation of dermatologic products, with attention paid to significant products, impactful legal changes, and key personnel and organizational changes.

How Does the Food and Drug Administration Approve Topical Generic Drugs Applied to the Skin?

Approved generic drugs are therapeutically equivalent to a preidentified brand name product and are expected to have the same clinical effect and safety profile when administered to patients under conditions specified in the labeling. Availability of generic topical dermatologic drugs is expected to enhance patient access to such widely used drug products. Assessment of equivalence for a prospective generic product involves a systematic and rigorous comparative evaluation to ensure there is no significant difference in the rate and extent to which the active ingredients become available at the site of action for the prospective generic and corresponding brand name product.

Considerations for the Forced Expiratory Volume in 1 Second-Based Comparative Clinical Endpoint Bioequivalence Studies for Orally Inhaled Drug Products.

Herein, we present the US Food and Drug Administration (FDA) Office of Research and Standards' current thinking, challenges, and opportunities for comparative clinical endpoint bioequivalence (BE) studies of orally inhaled drug products (OIDPs). Given the product-associated complexities of OIDPs, the FDA currently uses an aggregate weight-of-evidence approach to demonstrate that a generic OIDP is bioequivalent to its reference listed drug. The approach utilizes comparative clinical endpoint BE or pharmacodynamic BE studies, pharmacokinetic BE studies, and in vitro BE studies to demonstrate equivalence, in addition to formulation sameness and device similarity. For the comparative clinical endpoint BE studies, metrics based on forced expiratory volume in the first second (FEV1 ) are often the recommended clinical endpoints. However, the use of FEV1 can pose a challenge due to its large variability and a relatively flat dose-response relationship for most OIDPs. The utility of applying dose-scale analysis was also investigated by the FDA but often not recommended, due to either flat dose-response relationships or insufficient clinical study data. As a potential way to reduce sample size, we found adapting covariate analysis only explained a limited portion of the variation based on further investigation. The FDA continues to develop alternative methods to make BE assessment of OIDPs more cost- and time-efficient. Prospective generic drug applicants and academia are encouraged to participate in this effort by proposing new approaches in pre-abbreviated new drug application meeting requests and collaborating in the form of grants and contracts under the Generic Drug User Fee Amendments (GDUFA) Regulatory Science and Research Program.

Medication Cost-Savings and Utilization of Generic Inhaled Corticosteroid (ICS) and Long-Acting Beta-Agonist (LABA) Drug Products in the USA.

BACKGROUND: In the USA, drug costs associated with the inhaled corticosteroid (ICS) and long acting ß agonist (LABA) combination products have been increasing since 2001. In January 2019, the first generic ICS/LABA drug product was approved by the U.S. Food and Drug Administration. METHODS: We investigated retrospectively the effects of the first approved generic ICS/LABA drug from 2019 to 2020 on the wholesale cost-savings and prescription dispensing using the IQVIA data system in the USA. RESULTS: The marketing of the first generic for fluticasone propionate and salmeterol xinafoate dry powder inhaler was associated with $941 million in drug cost-savings during the first year for this class of medications. Although the brand-name drug manufacturer concurrently introduced its authorized generic, these cost-savings were driven by the averaged unit cost of the approved generic at $115, compared to $169 for the authorized generic and $334 for the branded product. Generic initiation and substitution with the first generic were, respectively, higher compared to those with authorized generics; however, overall dispensing of the first generic was lower than that of its branded product. As in the case of budesonide and formoterol fumarate dry powder inhaler, marketing of authorized generics alone was not associated with any noticeable change in sales or prescription cost-saving. CONCLUSION: We estimated that more than 20% of prescription cost-saving was achieved for the ICS/LABA dry powder inhalers in the first year following the introduction of the first approved generic, even though generic utilization remained lower than that of the branded counterpart.

Particle size affects pharmacokinetics of milled oxycodone hydrochloride tablet products following nasal insufflation in nondependent, recreational opioid users.

This study assessed the impact of product particle sizes (fine: 106-500 µm; coarse: 500-1000 µm) on oxycodone pharmacokinetics (PK) following nasal insufflation of milled oxycodone extended-release (ER) abuse-deterrent (AD) tablets using immediate-release (IR) non-AD product as reference. Additionally, this study assessed the effects of different excipient to drug ratio (EDR) by comparing two products with fine particle size but different EDRs, again using IR non-AD as the control. Thirty milligrams of oxycodone were administered in each treatment. Coarsely milled 30 mg ER tablets demonstrated significantly lower maximum plasma concentration (Cmax ) and partial areas under the concentration-time curve (AUCs) than those of the finely milled IR tablets. Finely milled ER tablets demonstrated similar Cmax and partial AUCs but higher total systemic exposures than those of finely milled IR tablets. Finely milled 80 mg ER tablets were bioequivalent to IR tablet on all parameters. The finely milled 30 mg ER tablet was not bioequivalent to the coarsely milled 30 mg ER tablet and had higher values for all parameters. The finely milled 30 mg ER tablets (EDR 6.9) showed no PK differences with finely milled 80 mg ER tablets (EDR 4.9). No serious adverse events were reported. The study demonstrated a significant effect of particle sizes (106-1000 µm) on PK of milled and insufflated oxycodone ER AD tablets. EDR difference did not have any significant effects on the PK of finely milled oxycodone ER AD tablets. Particle size distribution should be considered when nasal AD properties of opioid drug products are investigated during drug development.

Regulating Generic Ophthalmologic Drug Bioequivalence-Envisioning Accessibility for Patients.

New, brand-name, ophthalmology drug products are developed, investigated, and submitted for marketing approval through premarket interactions with the Food and Drug Administration (FDA). These drug applications for novel drugs are reviewed by FDA for safety and effectiveness before being allowed on the market. Many brand-name drugs are allowed a period of marketing exclusivity and/or have patent protections that can delay generic competition. When these exclusivity periods or patents expire or are challenged (in the case of patents), generic competitors may then market equivalent products, as allowed by U.S. law (eg, Drug Price Competition and Patent Term Restoration Act, often referred to as "the Hatch-Waxman Act"). To be approved as a therapeutic equivalent, a generic product must demonstrate that it is both pharmaceutically equivalent and bioequivalent to the brand-name drug product, which can involve innovative analytical methods and study designs. To facilitate generic drug assessment and approval, the FDA has negotiated the Generic Drug User Fee Amendments (GDUFA) program that funds a rigorous generic drug development program that includes pre-Abbreviated New Drug Application (pre-ANDA) correspondence and meetings, targeted bioequivalence research, and publication of product-specific guidances (PSGs) to support generic drug research and development for manufacturers interested in developing generic drugs for the U.S. market. FDA's regulatory practices include the monitoring of quality and postapproval adverse events of all marketed products, including those for use in and around the eyes.

From Pharmacology Research, to Pharmacology Regulation, and Back-as Inspired by the Teachings of Dr. Gavril Pasternak.

Dr. Gavril Pasternak, M.D., Ph.D. was an inspiration to many of his students, including myself. It was with great sadness that I learned about the passing of Dr. Gavril Pasternak in February 2019 after his brief battle with pancreatic cancer. I worked with Dr. Pasternak while I was an undergraduate chemistry student and as one of his technicians, collaborating with Dr. Charles Inturrisi and Dr. Eliot F. Hahn on opiate agonists and antagonists for opioid receptor subtypes. Dr. Pasternak inspired me and set me on the road to a career in pharmacology and encouraged me to pursue the fruitful paradigm of moving therapeutics from bench to bedside.

The relationship between the number of available therapeutic options and government payer (medicare part D) spending on topical drug products.

The cost of prescription drugs has increased at rates far exceeding general inflation in recent history, with topical drugs increasing at a disproportionate rate compared to other routes of administration. We assessed the relationship between net changes in the number of therapeutic options, defined as any approved drug or therapeutic equivalent on the market, and prescription topical drug spending. Drugs were divided based on the category of use through pairing of Medicare Part D Prescriber Public Use and Food and Drug Administration (FDA) approved drug products databases. Across drug classes, we modeled the log of the ratio of total spending per unit in 2015 to total spending per unit in 2011 as a linear function of net number of topical therapeutic options over this time period. Primary outcomes include total Medicaid Part D spending on topical drugs and net change in the number of available therapeutic options within each category of use. Total spending on topical drugs increased by 61%, while the number of units dispensed increased by only 18% from 2011-2015. The greatest total spending increases were in categories with few new therapeutic options, such as topical corticosteroid and antifungal medications. Each net additional therapeutic option during 2011-2015 was associated with an reduction in how much relative spending per unit increased (95% CI 2.5%-14.4%, p = 0.013). Stimulating greater competition through increasing the net number of therapeutic options within each major topical category of use may place downward pressure on topical prescription drug spending under medicare Part D.

Medical device regulation: what a practicing dermatologist should know.

The practicing dermatologist uses many medical devices during his or her day-to-day practice. The authors present a broad overview of how such medical devices are reviewed for safety and reasonable assurance of effectiveness, and evaluated for classification prior to marketing in the United States by the Food and Drug Administration. The specific example of dermal fillers as a class III medical device is discussed together with its regulatory ramifications. This article is written by staff currently employed at the Center for Devices and Radiological Health and should provide information useful to the practicing dermatologist.