Office of Generic Drugs
Office of Generic Drugs
News Article | May 10, 2017
America, you have a new commissioner at the Food and Drug Administration. Dr. Scott Gottlieb, a 44-year-old physician, was confirmed by the Senate this week in a 57-42 vote. Many Democrats expressed concern about Gottlieb’s financial ties to the pharmaceutical industry. Sen. Lamar Alexander (R-Tenn.), who chaired the panel that forwarded the nomination to the Senate floor, countered that Gottlieb’s extensive experience in the drug industry would be an asset in his regulatory role. Here are four things you’ll want to know about Gottlieb. In his Senate confirmation hearings in early April, Gottlieb told senators that the epidemic of opiate drug abuse in the United States "is a public health emergency on the order of Ebola and Zika." On average, 91 Americans die each day of an opioid overdose. But the FDA’s power to reduce opioid drug use is limited. The agency’s past decisions have clearly contributed to overdose deaths. The FDA does not regulate physicians’ prescribing of drugs — an important contributor to Americans’ widespread opioid drug use (and subsequent addiction). All it can do is enforce legal limits on the marketing of drugs once they’ve been approved — strictures that drug manufacturers, in their bid to build their markets, routinely flout. The FDA also reviews new pain medications and new formulations of opioid-based drugs for the U.S. market. In considering whether to approve them, the agency walks a fine line between keeping pain medication available to those who need it and not creating new addicts. Some of the abuse-resistant formulations of opioid pain relievers approved for the market in recent years have driven many addicts to cheaper, more readily available street drugs such as heroin. In his April confirmation hearings, Gottlieb sought to defuse concerns that speeding up the drug approval process would allow less-safe medications to come to market. He called it a “false dichotomy that it all boils down to a choice between speed and safety.” He repeatedly called the FDA’s review process “the gold standard.” And he stopped short of endorsing proposals that had been floated by other candidates for the job, including plans to approve drugs after they had been tested for safety but before their effectiveness had been established. But he also said the FDA should “lean forward” to modernize and speed the approvals process. Gottlieb has long been a fan of what are known in the clinical-trial business as “adaptive trials.” Such human experiments, which are already in limited use, depart from what many scientists define as the “gold standard” in that their design, their study populations, and even their objectives can be altered along the way in response to early results. A drug company running a clinical trial might be allowed to increase or decrease the number of subjects assigned to different “arms” of a trial, or change who gets assigned to those arms, or how those assignments are made. The idea is that researchers could shift a clinical trial’s focus in response to early signs of a drug’s strength in, for instance, treating one population (people with very early Alzheimer’s disease, for instance) over another (say, those whose dementia has already progressed). Rather than conducting a lengthy and expensive series of separate trials to discover which patients might benefit most from a drug, a single adaptive trial could come to the same conclusion after only one study that was allowed to “flex” along the way. Gottlieb has been critical of President Trump’s key proposal to drive down the cost of prescription drugs: allowing their importation from countries that impose price controls. In a March 2016 article in Forbes, Gottlieb wrote that while Trump’s plan is “perhaps good politics,” it will “offer consumers little relief.” Drug manufacturers would be unlikely to cooperate because increasing their output of production lines abroad would undermine their own interests. And it’s just as unlikely that other countries would stand for having their medications “skimmed off, only to create local shortages of important medicines,” he wrote. In its central mission of evaluating the safety and effectiveness of drugs and granting companies the right to market them in the United States, the FDA is not permitted to take price into consideration. But the FDA’s power over the approval of generic drugs is a key lever for bringing down the cost of drugs, and Gottlieb has said he wants to see improvements there. The company that makes a drug has exclusive rights to the U.S. market for three to seven years after it is granted FDA approval. But once that protection ends, any drug company can seek FDA approval to market a generic version by proving it can manufacture the active drug ingredient and package it for human use safely and reliably. The result: competition that typically drives drug prices down steeply. So driving down the cost of many prescription drugs will require the FDA’s Office of Generic Drugs to be staffed adequately to speed approval of drug applications. That’s a tall order against the backdrop of the Trump administration’s proposed budget cuts to the Department of Health and Human Services, the FDA’s parent agency. Also, many drugs — including a broad new category of drugs known as “biologics” — are less simple to copy. The FDA’s cautious approach to approving generic versions of many of these drugs — widely used to treat cancers and autoimmune diseases — threatens to create “monopolies in perpetuity,” Gottlieb has said. If prescription drug prices are to drop, he said, the rules for approving those complex generic drugs need to be rewritten. Gottlieb is a cancer survivor, having been successfully treated for Hodgkin’s lymphoma. That experience prompted Gottlieb to become a cancer policy advisor for the National Coalition for Cancer Survivorship. The coalition, in turn, strongly endorsed his nomination to head the FDA. In a statement issued when Trump nominated him in mid-March, the coalition said that Gottlieb “understands the human toll cancer takes on individuals and families, during both treatment and long-term survivorship. He is open to a wide range of perspectives, including those of the patients whose lives depend on a strong FDA.” Gottlieb is a physician. He trained at Mount Sinai School of Medicine in New York and completed his residency in internal medicine at Mount Sinai Hospital. But his interest in the business and economics of medicine has been a more salient and recurring theme in his career than direct patient care. After graduating from Wesleyan University in Connecticut, Gottlieb worked as a healthcare analyst at the investment bank Alex. Brown & Sons in Baltimore, and then went to medical school. Between 2003 and 2007, Gottlieb served the Bush administration in a wide range of positions at the FDA and in the Centers for Medicare and Medicaid Services. Among his titles: deputy FDA commissioner for medical and scientific affairs. At the FDA, he helped develop standards for drug cocktails to be used for HIV treatment. He also helped draft strategic plans for U.S. biodefense countermeasures as a member of the White House Biodefense Interagency Working Group. Since 2007, he has been a venture partner at New Enterprise Associates, focusing on healthcare and medical devices investments, and a resident fellow at the American Enterprise Institute, a conservative think tank. He’s also been a clinical assistant professor at New York University School of Medicine and practiced medicine as an attending physician at Stamford Hospital in Connecticut. He has said he'd divest himself of medical company stocks and recuse himself for a year from decisions involving nearly two dozen companies, including Tolero Pharmaceuticals, Daiichi Sankyo Inc. and GlaxoSmithKline. Speed up drug approvals at FDA? It's already faster than Europe's drug agency Dying patients want easier access to experimental drugs. Here's why experts say that's bad medicine The odds of a drug having a significant safety issue after winning FDA approval are nearly 1 in 3, study finds
Keire D.,OTR |
Lee S.,Office of Generic Drugs |
Raw A.,Office of Generic Drugs |
Yu L.,Office of Generic Drugs |
Habib M.J.,Howard University
AAPS Journal | Year: 2012
The purpose of this study was to characterize and evaluate differences of protamine sulfate, a highly basic peptide drug, obtained from five different sources, using orthogonal thermal and spectroscopic analytical methods. Thermogravimetric analysis and modulated differential scanning calorimetry showed that all five protamine sulfate samples had different moisture contents and glass transition and melting temperatures when temperature was modulated from 25 to 270°C. Protamine sulfate from source III had the highest residual moisture content (4.7∈±∈0.2%) at 105°C, resulting in the lowest glass transition (109.7°C) and melting (184.2°C) temperatures compared with the other four sources. By Fourier-transform infrared (FTIR) spectroscopy, the five sources of protamine sulfate had indistinguishable spectra, and the spectra were consistent with a predominantly random coil conformation in solution and a minor population in a β-sheet conformation (~12%). Circular dichroism spectropolarimetry confirmed the FTIR results with prominent minima at 206 nm observed for all five sources. Finally, proton ( 1H) nuclear magnetic resonance spectroscopy showed that all five protamine sulfate sources had identical spectra with backbone amide chemical shifts between 8.20 and 8.80 ppm, consistent with proteins with predominantly random coil conformation. In conclusion, thermal analyses showed differences in the thermal behavior of the five sources of protamine sulfate, while spectroscopic analyses showed the samples had a predominantly random coil conformation with a small amount of β-sheet present. © 2012 American Association of Pharmaceutical Scientists.
Wen H.,Office of Generic Drugs |
Jung H.,Office of Generic Drugs |
Li X.,Office of Pharmaceutical Quality
AAPS Journal | Year: 2015
Various drug delivery approaches can be used to maximize therapeutic efficacy and minimize side effects, by impacting absorption, distribution, metabolism, and elimination (ADME) of a drug compound. For those drugs with poor water solubility or low permeability, techniques such as amorphous solid dispersion, liposomes, and complexations have been used to improve their oral bioavailability. Modified release (MR) formulations have been widely used to improve patient compliance, as well as to reduce side effects, especially for those drugs with short half-lives or narrow therapeutic windows. More than ten drugs using sterile long-acting release (LAR) formulations with clear clinical benefit have been successfully marketed. Furthermore, drug delivery systems have been used in delaying drug clearance processes. Additionally, modifying the in vivo drug distribution using targeted delivery systems has significantly improved oncology treatments. All the drug delivery approaches have their advantages and limitations. For both brand and generic drugs, the achievement of consistent quality and therapeutic performance using drug delivery systems can also pose serious challenges in developing a drug for the market, which requires close collaboration among industry, academia, and regulatory agencies. With the advent of personalized medicines, there will be great opportunities and challenges in utilizing drug delivery systems to provide better products and services for patients. © 2015, American Association of Pharmaceutical Scientists.
Xu X.,U.S. Food and Drug Administration |
Gupta A.,U.S. Food and Drug Administration |
Faustino P.,U.S. Food and Drug Administration |
Sathe P.M.,Office of Generic Drugs |
And 2 more authors.
AAPS PharmSciTech | Year: 2013
To assay the dissolution samples of a drug product from several sources, a simple but broadly applicable analytical method is always desired. For the liquid-filled cyclosporine capsules, while analyzing the dissolution samples, the current compendial and literature HPLC methods have been found to be inadequate to provide satisfactory separation of the drug and the excipient peaks. Accordingly, a suitable isocratic reverse-phase HPLC method was developed for the analysis of dissolution samples of liquid-filled cyclosporine capsules. The method successfully separated the cyclosporine peak from the interfering chromatographic peaks of the excipients. The method was validated according to the ICH and FDA guidelines. Specificity, selectivity, linearity, accuracy, precision, and robustness were established over 3 days as part of method validation. Additionally, the degradation kinetics of cyclosporine in dissolution media was determined. Cyclosporine degradation followed a zero-order kinetics in the dissolution media with the respective rate constants of -3.5, -1.5, and -0.3%/h at 37 C, 25 C, and 10 C. © 2013 American Association of Pharmaceutical Scientists.
Sun W.,U.S. Food and Drug Administration |
Zhou L.,George Washington University |
Grosser S.,U.S. Food and Drug Administration |
Kim C.,Office of Generic Drugs
Statistics in Biopharmaceutical Research | Year: 2016
Missing data and noncompliance data questions are especially important in evaluating locally acting generic drugs because primary equivalence analyses in clinical endpoint bioequivalence (BE) studies are based on the per-protocol (PP) population (generally, completers and compliers). A meta-analysis using six clinical endpoint BE studies for topical drugs reveals the following: (1) An average of 22% (95% CI: 15–29%) of randomized subjects are excluded from the PP population. (2) Of these excluded subjects, half (10.6%, 95% CI: 8.3–12.8%) dropped out. Most who dropped out (6.9%, 95% CI: 5.0–8.8%) did not specify reasons. (3) Noncompliance categories include out-of-window visits (7.7%, 95% CI: 5.5%–9.8%), dosing noncompliance (<75% or >125% of dose) (5%, 95% CI: 2.7%–7.4%), and restricted medication use (3.2%, 95% CI: 1.8%–4.7%). (4) Drop out and noncompliance are not completely at random: a better treatment effect is associated with less drop out and less noncompliance. (5) Drop out and noncompliance are correlated: noncompliers are more likely to drop out, and vice versa. These results will help regulators better understand the extent and pattern of drop out and noncompliance and shed light on designing appropriate analysis population, endpoints, estimands, and investigating primary and sensitivity methods for equivalence in clinical endpoint BE studies in presence of missing and noncompliance data. © 2016 American Statistical Association.
Xu X.,U.S. Food and Drug Administration |
Gupta A.,U.S. Food and Drug Administration |
Sayeed V.A.,Office of Generic Drugs |
Khan M.A.,U.S. Food and Drug Administration
Journal of Pharmaceutical Sciences | Year: 2013
Various adverse events including esophagus irritations have been reported with the use of alendronate tablets, likely attributed to the rapid tablet disintegration in the mouth or esophagus. Accordingly, the disintegration of six alendronate tablet drug products was studied using a newly developed testing device equipped with in-line sensors, in addition to the official compendial procedure for measuring the disintegration time. The in-line sensors were used to monitor the particle count and solution pH change to assess the onset and duration of disintegration. A relatively large variation was observed in the disintegration time of the tested drug products using the compendial method. The data collected using the in-line sensors suggested that all tested drug products exhibited almost instantaneous onset of disintegration, under 2s, and a sharp drop in solution pH. The drop in pH was slower for tablets with slower disintegration. The in-house prepared alendronate test tablets also showed similar trends suggesting rapid solubilization of the drug contributed to the fast tablet disintegration. This research highlights the usefulness of the newly developed in-line analytical method in combination with the compendial method in providing a better understanding of the disintegration and the accompanying drug solubilization processes for fast disintegrating tablet drug products. © 2013 Wiley Periodicals, Inc.
Wu G.K.,Office of Generic Drugs |
Casey E.,Purdue University |
Read E.,Office of Biotechnology Products |
Lute S.,Office of Biotechnology Products |
Brorson K.A.,Office of Biotechnology Products
International Journal of Pharmaceutics | Year: 2012
The purpose of this study was to use QbD approaches to evaluate the effect of several variables and their interactions on quality of a challenging model murine IgG3κ monoclonal antibody (mAb), and then to obtain an optimized formulation with predefined quality target product profile. This antibody was chosen because it has a propensity to precipitate and thus represents a challenge condition for formulation development. Preliminary experiments were conducted to rule out incompatible buffer systems for the mAb product quality. A fractional factorial experimental design was then applied to screen the effects of buffer type, pH and excipients such as sucrose, sodium chloride (NaCl), lactic acid and Polysorbate 20 on glass transition temperature (T′g), monoclonal antibody concentration (A280), presence of aggregation, unfolding transition temperature (Tm) of the lyophilized product, and particle size of the reconstituted product. A Box-Behnken experimental design was subsequently applied to study the main, interaction, and quadratic effects of these variables on the responses. Pareto ranking analyses showed that the three most important factors affecting the selected responses for this particular antibody were pH, NaCl, and Polysorbate 20. The presence of curvature in the variables' effects on responses indicated interactions. Based on the constraints set on the responses, a design space was identified for this mAb and confirmed with experiments at three different levels of the variables within the design space. The model indicated a combination of high pH (8) and NaCl (50 mM) levels, and a low Polysorbate 20 (0.008 mM) level at which an optimal formulation of the mAb could be achieved. Moisture contents and other analytical procedures such as size exclusion chromatography, protein A analysis and SDS-PAGE of the pre-lyophilized and final reconstituted lyophilized products indicated an intact protein structure with minimal aggregation after formulation and lyophilization. In conclusion, experimental design approach was effective in identifying optimal concentrations of excipients and pH for this challenging monoclonal antibody formulation. © 2012 Published by Elsevier B.V.
Bai J.P.F.,Office of Generic Drugs |
Bai J.P.F.,U.S. Food and Drug Administration |
Hausman E.,Office of Pharmacovigilance and Epidemiology |
Lionberger R.,Office of Generic Drugs |
Zhang X.,Office of Generic Drugs
Molecular Pharmaceutics | Year: 2012
Prolonged use of proton pump inhibitors has reportedly caused rare clinically symptomatic hypomagnesemia. A review of the literature suggests PPI drugs may impair intestinal magnesium absorption. With the goal of preventing PPI-induced hypomagnesemia, an oral absorption-centric model was developed by referencing literature data. Our modeling with human data reveals that magnesium absorption is substantial in the distal intestine. We then perform simulations by referring to the reported reduction in mid to distal intestinal pH caused by one week of oral esomeprazole, and to reported reduction of the divalent cation-sensitive current when the carboxyl side chains of glutamic and aspartic residues in the binding channels of TRPM6/TRPM7 were neutralized. Our simulations reveal that short-term PPI therapy may cause a very small reduction (5%) in the serum magnesium level, which is qualitatively consistent with the reported 1% reduction in magnesium absorption following 1 week of omeprazole in humans. Simulations provide insight into the benefit of frequent but small dose of magnesium supplementation in maintaining the serum magnesium level when magnesium deficiency occurs. © This article not subject to U.S. Copyright. Published 2012 by the American Chemical Society.
Roudier B.,CITES |
Roudier B.,University of Auvergne |
Davit B.M.,Office of Generic Drugs |
Davit B.M.,Merck And Co. |
And 2 more authors.
Pharmaceutical Research | Year: 2014
Purpose In vitro in vivo correlation (IVIVC) is a biopharmaceutical tool recommended for use in formulation development. When validated, IVIVC can be used to set dissolution limits and, based on the dissolution limits, as a surrogate for an in vivo study. The purpose of this paper is to study the various methods used to fix dissolution limits. Methods Fixing dissolution limits is not a straightforward process; various approaches exist. The classical ±10% of dissolution limits was compared to the recommended ±10% of Cmax and AUC and to an innovative back calculation of the 90% CI. Based on simulated values the influence of the calculation method as well as of the variability of the results and pharmacokinetic processes was investigated. Results Depending upon the method, the results are different and their comparison leads to possible rules. It appears that the usage of a back calculation of a 90% CI is an accurate and advantageous method when intra-individual variability associated with the drug is low. Those findings are in accordance with the current practice of IVIVC, which is not recommended for highly variable drugs. Conclusions The approach of using a 90% CI allows the intra-subject variability to be taken into account and fixes limits that ensure a greater chance to show acceptable BE, in case of reasonable intra-subject variability, leading to setting broader in vitro dissolution limits compared to classical solutions. © 2014 Springer Science+Business Media New York (outside the USA).
PubMed | Office of Pharmaceutical Quality and Office of Generic Drugs
Type: Journal Article | Journal: The AAPS journal | Year: 2015
Various drug delivery approaches can be used to maximize therapeutic efficacy and minimize side effects, by impacting absorption, distribution, metabolism, and elimination (ADME) of a drug compound. For those drugs with poor water solubility or low permeability, techniques such as amorphous solid dispersion, liposomes, and complexations have been used to improve their oral bioavailability. Modified release (MR) formulations have been widely used to improve patient compliance, as well as to reduce side effects, especially for those drugs with short half-lives or narrow therapeutic windows. More than ten drugs using sterile long-acting release (LAR) formulations with clear clinical benefit have been successfully marketed. Furthermore, drug delivery systems have been used in delaying drug clearance processes. Additionally, modifying the in vivo drug distribution using targeted delivery systems has significantly improved oncology treatments. All the drug delivery approaches have their advantages and limitations. For both brand and generic drugs, the achievement of consistent quality and therapeutic performance using drug delivery systems can also pose serious challenges in developing a drug for the market, which requires close collaboration among industry, academia, and regulatory agencies. With the advent of personalized medicines, there will be great opportunities and challenges in utilizing drug delivery systems to provide better products and services for patients.