Specialty Pharma Industry News is provided by SPA Member Dr. Larry Boos
November 29
Food and Drug Administration (FDA) issued a  final guidance for industry entitled, "Adaptive Designs for Clinical Trials of Drugs and Biologics." 
Adaptive design clinical trials allow for prospectively planned modifications to one or more aspects of the design based on accumulating data from subjects in the trial. The guidance provides information to sponsors submitting investigational new drug applications (INDs), new drug applications (NDAs), biologics licensing applications (BLAs), or supplemental applications on the appropriate use of adaptive designs for clinical trials to provide evidence of the effectiveness and safety of a drug or biologic.  Control/Click on the colored words "final guidance" above to download.   This guidance cross-references advice from the newly published draft guidance on 
November 27
The U.S. Food and Drug Administration has ordered Gynecology, Reproductive Endocrinology and Fertility Institute of San Juan, Puerto Rico and its Medical Director and Owner, Dr. Rosa I. Cruz, to immediately cease manufacturing due to significant violations of FDA regulations.
 An FDA inspection and subsequent record review revealed significant violations of regulations regarding donor eligibility determinations, including donor screening and testing. The clinic's failure to fulfill these requirements puts patients at risk for exposure to communicable diseases, including HIV and hepatitis.

Warning Letters
FDA issued warning letters to 15 companies for illegally selling products containing cannabidiol (CBD) in ways that violate the Federal Food, Drug, and Cosmetic Act (FD&C Act). The FDA also published a revised Consumer Update detailing safety concerns about CBD products more broadly. Based on the lack of scientific information supporting the safety of CBD in food, the FDA is also indicating today that it cannot conclude that CBD is generally recognized as safe (GRAS) among qualified experts for its use in human or animal food.  These actions come as the FDA continues to explore potential pathways for various types of CBD products to be lawfully marketed. This includes ongoing work to obtain and evaluate information to address outstanding questions related to the safety of CBD products, while maintaining the agency's rigorous public health standards. The FDA plans to provide an update on its progress regarding the agency's approach to these products in the coming weeks.

Mr. Kreshnik Lohxa, President, Lohxa LLC, Worcester, MA 01608
  1. Your firm failed to establish and follow an adequate written testing program designed to assess the stability characteristics of drug products and to use results of stability testing to determine appropriate storage conditions and expiration dates 
  2. Your firm failed to clean, maintain, and, as appropriate for the  nature of the drug, sanitize and/or    sterilize equipment and utensils at appropriate intervals to prevent malfunctions or contamination that would alter the safety, identity, strength, quality, or purity of the drug product beyond the official or other established requirements
  3. Your firm failed to thoroughly investigate any unexplained discrepancy or failure of a batch or any of its components to meet any of its specifications, whether or not the batch has already been distributed.
November 26
FDA Approves Novel Treatment to Target Abnormality in Sickle Cell Disease.  the U.S. Food and Drug Administration granted accelerated approval to Oxbryta (voxelotor) for the treatment of sickle cell disease (SCD) in adults and pediatric patients 12 years of age and older.
November 22
Recently Posted Guidance Documents (Control/Click to view) Recently Posted Guidance Documents.
November 21
The U.S. Food and Drug Administration today approved XCOPRI (cenobamate tablets) to treat partial-onset seizures in adults.    "XCOPRI is a new option to treat adults with partial-onset seizures, which is an often difficult-to-control condition that can have a significant impact on patient quality of life," said Billy Dunn, M.D., director of the Office of Neuroscience in the FDA's Center for Drug Evaluation and Research. "Patients can have different responses to the various seizure medicines that are available. This approval provides an additional needed treatment option for people with this condition."   The recommended maintenance dose of XCOPRI, following a titration (medication adjustment) period, is 200 mg daily; however, some patients may need an additional titration to 400 mg daily, the maximum recommended dose, based on their clinical response and tolerability.

FDA is evaluating the results of a Danish study that concludes there is a possible increased risk of miscarriage with the use of oral fluconazole (Diflucan) for yeast infections.   They are also reviewing additional data and will communicate their final conclusions and recommendations when their review is complete.  Patients who are pregnant or actively trying to get pregnant should talk to their health care professionals about alternative treatment options for yeast infections.   Read Drug Safety Communication .
November 20
On November 20, 2019, the Food and Drug Administration approved givosiran (GIVLAARI, Alnylam Pharmaceuticals, Inc.) for adults with acute hepatic porphyria (AHP).     Efficacy was evaluated in ENVISION (NCT03338816), a randomized, double-blind, placebo-controlled, multinational trial enrolling 94 patients with AHP. Patients were randomized (1:1) to receive once monthly subcutaneous injections of givosiran 2.5 mg/kg or placebo during a 6-month double-blind period.    The primary efficacy outcome measure was the rate of porphyria attacks requiring hospitalizations, urgent healthcare visit, or intravenous hemin administration at home.   On average, patients with AHP on givosiran experienced 70% fewer porphyria attacks compared to placebo.

FDA announced today the availability of a draft guidance for industry entitled " Transdermal and Topical Delivery Systems - Product Development and Quality Considerations."
 This guidance provides recommendations to applicants and manufacturers of transdermal and topical delivery systems (TDS) regarding the pharmaceutical development and quality information to include in new drug applications (NDAs) and abbreviated new drug applications (ANDAs).   Control/Click to download.
November 15
FDA has issued a warning letter  to Greenbrier International, Inc., doing business as Dollar Tree, for receiving over-the-counter (OTC) drugs produced by foreign manufacturers found to have serious violations of federal law. The warning letter outlines multiple violations of current good manufacturing practices at contract manufacturers used to produce Dollar Tree's  Assured Brand OTC drugs as well as other drug products sold at Dollar Tree and Family Dollar stores.  The warning letter also details Dollar Tree's use of contract manufacturers that also received warning letters for similar issues between 2016 and 2019.  The warning letters sent to the contract manufacturers used by Dollar Tree show a pattern of serious violations of the law, such as not testing raw materials or finished drugs for pathogens and quality.

More Products Containing Undeclared Sildenafil Are Being Recalled.    SILVER BULLET 10 Male Enhancement Capsules by Nature's Rx: Recall - Due to undeclared sildenafil, the active ingredient in Viagra.    MAN ERECT, a product promoted for sexual enhancement was identified during an examination of international mail shipments.  It also contains sildenafil.   SHENGDA, a product promoted for sexual enhancement, was also identified to contain sildenafil during an examination of international mail shipments.   Med Man Distribution is voluntarily recalling all lots of UP2 DIETARY SUPPLEMENT THERE IS NO OTHER ALL-NATURAL DIETARY SUPPLEMENT to the consumer level due to presence of sildenafil.

The FDA has  granted accelerated approval to zanubrutinib (BRUKINSA, BeiGene, Ltd.) for adult patients with mantle cell lymphoma (MCL) who have received at least one prior therapy.  Efficacy was evaluated in BGB-3111-206 (NCT03206970), a phase 2 open-label, multicenter, single-arm trial of 86 patients with MCL who received at least one prior therapy.  FDA granted this application priority review and zanubrutinib received orphan product and breakthrough therapy designations for treatment of MCL.

FDA Approving Drugs at Breakneck Speed, Raising Alarm    The U.S. is approving new drugs so fast that companies are now preparing for a green light months in advance of the scheduled decision date, a pace that's helping patients with rare or untreatable diseases but raising alarm among consumer advocates.  "We're allowing drugs come to market sooner, faster without having sufficient information about their safety," said Michael Carome, health research group director at the consumer advocacy group Public Citizen. "Over the last few decades the FDA's standards for approving drugs have weakened, which has led to faster drug approval."  A  growing number of breakthrough products have beaten their FDA deadlines by weeks and sometimes months. For normal medicines, the agency typically has 10 months to issue a ruling. For those with exceptional benefits, or that treat conditions with few existing therapies, it offers a priority review that takes just six months. From mid-October to mid-November, the agency approved five medicines in as little as eight weeks.  Studies show medicines approved on a faster time line are more likely to have safety problems emerge after they become broadly available, while other treatments offer fewer benefits than anticipated.  
November 14
The U.S. Food and Drug Administration today approved Fetroja (cefiderocol), an antibacterial drug for treatment of patients 18 years of age or older with complicated urinary tract infections (cUTI), including kidney infections caused by susceptible Gram-negative microorganisms, who have limited or no alternative treatment options.    The safety and effectiveness of Fetroja was demonstrated in a study of 448 patients with cUTIs. Of the patients who were administered Fetroja, 72.6% had resolution of symptoms and eradication of the bacteria approximately seven days after completing treatment, compared with 54.6% in patients who received an alternative antibiotic. The clinical response rates were similar between the two treatment groups.
November 13
More recalls of Ranitidine Tablets generic for Zantac brand.
1. Amneal Pharmaceuticals is recalling their 150mg and 300mg tablets, and their Ranitidine Syrup (Oral Solution), 15 mg/mL l - Due to Possible Presence of N-nitrosodimethylamine (NDMA) Impurity. NDMA is classified as a probable human carcinogen (a substance that could cause cancer) based on results from laboratory tests.
2. Ranitidine Capsules 150 mg and 300 mg by Golden State Medical Supply: Recall - Due to an Elevated Amount of Unexpected Impurity, N-Nitrosodimethylamine (NDMA)
3. Aurobindo Pharma USA, Inc. is conducting a voluntary recall of 1 lot of Ranitidine Tablets 150mg to the retail level and 37 lots of Ranitidine Capsules 150mg, Ranitidine Capsules 300mg and Ranitidine Syrup 15mg/mL for the same reason.
4. American Health Packaging is voluntarily recalling eight lots of Ranitidine Syrup (Ranitidine Oral Solution USP) 150 mg/10 mL Liquid Unit Dose Cups to the consumer level due to the detection of trace amounts of an unexpected impurity found in the finished drug product. The impurity detected in the finished drug product is N-nitrosodimethylamine (NDMA). This recall is being initiated in response to the recall by the manufacturer (Lannett Company, Inc.), which included affected lots that were repackaged by American Health Packaging.
5. Precision Dose Inc. is voluntarily recalling 5 lots of Ranitidine Oral Solution, USP 150 mg/10 mL to the consumer level.
6. Golden State Medical Supply, Incorporated (GSMS, Inc) based upon a manufacturer's recall by Novitium Pharma LLC (Novitium), is voluntarily instituting a recall of all quantities and lots, within expiry, of Ranitidine HCl 150mg and 300mg Capsules to the consumer level because of potential presence of N-Nitrosodimethylamine (NDMA) above levels established by the FDA.
November 8
Today, the FDA Approved the First Therapy to Treat Patients with a Rare Blood Disorder.  Today the U.S. Food and Drug Administration granted approval to Reblozyl (luspatercept-aamt) for the treatment of anemia (lack of red blood cells) in adult patients with beta thalassemia who require regular red blood cell (RBC) transfusions.  Beta thalassemia, also called "Cooley's anemia," is an inherited blood disorder that reduces the production of hemoglobin, an iron-containing protein in red blood cells that carries oxygen to cells throughout the body.  The approval of Reblozyl was based on the results of a clinical trial of 336 patients with beta thalassemia who required RBC transfusions, of which 112 received a placebo. Twenty-one percent of the patients who received Reblozyl achieved at least a 33% reduction in transfusions compared to 4.5% of the patients who received a placebo.
November 6
Today the U.S. Food and Drug Administration (FDA) posted a draft document on its website titled "Best Practices in Drug and Biological Product Postmarket Safety Surveillance for FDA Staff." This document is required under a provision of the 21st Century Cures Act. The Act includes a revision to a previous statutory requirement that generally required FDA to undertake routine safety analyses of drugs 18 months following approval or after 10,000 individuals have used the drug, whichever occurs later.  Many drugs and biological products for rare diseases never met the 10,000-individual use threshold triggering these analyses.   The 21st Century Cures Act replaced the previous 18-month/10,000 patient analyses with a new requirement that FDA make publicly available on the internet its best practices for drug safety surveillance activities for drugs approved under section 505 of the Federal Food, Drug, and Cosmetic Act or licensed as biological products under section 351 of the Public Health Service Act.  Control/Click on the colored title above to download the document.

Medication Adherence: Landscape, Strategies, and Evaluation Methods.    Medication adherence-the extent to which patients take medications as prescribed in agreement with their health care provider-is an ongoing public health priority.     This public meeting,   to be held at the Washington Marriott at Metro Center (775 12th St NW, Washington, DC 20005), is convened under a cooperative agreement between the Robert J. Margolis, MD, Center for Health Policy at Duke University and the U.S. Food and Drug Administration on December 10, will explore the state of the science of clinical research evaluating medication adherence involving FDA-regulated products.  For more information and to  register for the event,  please visit the Duke-Margolis website.
November 5
Biotin May Interfere with Lab Tests.    Many dietary supplements promoted for hair, skin, and nail benefits contain biotin levels up to 650 times the recommended daily intake of biotin. Physicians may also recommend high levels of biotin for patients with certain conditions such as multiple sclerosis.  For example, a falsely low result for troponin, a clinically important biomarker to aid in the diagnosis of heart attacks, may lead to a missed diagnosis and potentially serious clinical implications.  T he FDA issued a Safety Communication,  The FDA Warns that Biotin May Interfere with Lab Tests , that discussed concerns with biotin interference in certain laboratory tests.
November 1
The Food and Drug Administration (FDA) recently posted its first  Quarterly Inactive Ingredient Database (IID) Change Log. The IID provides information on inactive ingredients used in FDA-approved products.   You can view and download by Control Click on the colored title above.