Caroline Hroncich was associate editor for Pharmaceutical Technology, Pharmaceutical Technology Europe, and BioPharm International from 2015 to 2017.

Caroline Hroncich

	A federal judge has entered an order of permanent injunction on behalf of FDA against Paul W. Franck, the owner and operator of numerous compounding pharmacies in Florida over the past 20 years, FDA said in an April 29, 2016 

. Franck allegedly “manufactured and distributed drug products that were adulterated and misbranded in violation of the Federal Food, Drug, and Cosmetic Act (FD&C Act),” FDA said. The order issued by the US Department of Justice prohibits Franck from distributing sterile drug products until he complies with the FD&C Act.

	Franck owned and operated several compounding pharmacies including Franck’s Lab Inc., which did business as Franck’s Compounding Lab and Trinity Care Solutions. FDA said Franck manufactured drugs that were considered adulterated because they contained “filthy, putrid, or decomposed substances; were prepared, packed, or held under insanitary conditions; and fell below the quality and/or purity standards they purported to possess.” FDA also asserts Franck’s drug products were misbranded, because “drugs purporting to be sterile contained bacterial contamination.”

	FDA has cited Franck’s compounding pharmacies in the past for compromising drug sterility. Trinity Care Solutions issued a recall and halted compounding activities in 2014 after inspection revealed multiple violations. FDA said its inspection of the Trinity facility revealed the presence of “dead spiders, beetles, ants, wasps, and cockroaches in the ceiling panel directly above the area where employees prepare for sterile processing.”

 to Franck’s Compounding Lab after contaminated ophthalmic drugs from the lab were linked to 47 cases of eye infections. At least 39 of those cases were linked to temporary or permanent vision loss. As a result, the lab issued a recall of all sterile products.  

	The injunction against Franck is just one of 

 FDA has had in the past over ensuring quality in compounding pharmacies. In a 

 to the Senate Special Committee on Aging in December 2015, Alan Coukell, senior director of The Pew Charitable Trusts, notes that in 2012 FDA increased its oversight of compounding facilities, which included conducting more than 200 inspections and issuing 60 warning letters that year alone. Coukell says that while oversight may have increased, compounded drugs may not meet the same approval standards for manufacturing safety and quality as new and generic drugs approved by FDA.

 related to the compounding of human drugs under section 503A in the FD&C Act. Section 503A in the FD&C Act describes the proper CGMP conditions for compounding drugs in a state-licensed pharmacy, a federal facility, or a licensed physician. In the guidance documents, FDA described its policies for compounding drugs based on prescription requirements, hospital pharmacies, and outsourcing facilities.

Articles

A federal judge entered an order of permanent injunction against Paul W. Franck, the owner and operator of several compounding pharmacies in Florida.

Federal Judge Enters Order of Permanent Injunction Against Compounding Pharmacy Owner

	AbbVie announced on April 28, 2016 that it has plans to acquire Stemcentrx, a biopharma company focused on developing cancer treatment therapies. Stemcentrx was founded in 2008 and currently has five investigational oncology drugs in human clinical trials. AbbVie will acquire Stemcentrx for approximately $5.8 billion, with $2 billion paid in cash and the remaining in stock. In a press announcement, AbbVie said it would acquire the San Francisco-based company’s lead late-stage asset rovalpituzumab tesirine (Rova-T), a novel biomarker-specific therapy derived from cancer stem cells, for the treatment of small cell lung cancer (SCLC).

	Rova-T is currently under investigation as a third-line treatment in SCLC, and has been submitted to FDA for Breakthrough Therapy designation. Stemcentrx has four other drugs in its pipeline including treatments for triple negative breast cancer, ovarian cancer, and non-small cell lung cancer.

	The move is strategic for AbbVie, who is looking to expand its oncology pipeline. In March 2015, 

, a California-based biopharmaceutical company focused on the development and commercialization of novel therapies for the treatment of cancer. AbbVie purchased the company for $21 billion, and acquired Imbruvica (ibrutinib), a treatment indicated for three types of blood cancer including chronic lymphocytic leukemia, mantle cell lymphoma, and Waldenstrom’s macroglobulinemia. 

	In the press announcement, AbbVie said its existing oncology pipeline currently consists of more than a dozen assets. The company has five programs in late-stage development, including 200 clinical trials with more than 19 types of tumors.

AbbVie will acquire Stemcentrx and its lead late-stage asset rovalpituzumab tesirine (Rova-T), a novel biomarker-specific therapy derived from cancer stem cells.

AbbVie to Acquire Stemcentrx

	The National Institutes of Health (NIH) released a statement on April 19, 2016 saying that it plans to suspend research in two laboratories after preliminary results found the labs not in compliance with CGMP practices.

, NIH said it has hired Work Buildings and Clinical IQ, companies specializing in quality assurance for manufacturing and compounding, to review quality procedures in its Clinical Center Pharmaceutical Development Section (PDS) facilities. Preliminary findings by the companies determined that NIH’s PDS facilities are not in compliance with quality standards for the production or sterile or infused products. In response, NIH has suspended production in a national Institute of Mental Health facility producing positron emission tomography materials and a National Cancer Institute laboratory producing cell therapies.

	This comes after an FDA inspection in May 2015 citing several safety concerns with the facilities’ aseptic processes. In June 2015, 

, saying it planned to hire a contracting firm and organize an outside group of advisors experienced in CGMP regulations in order to evaluate PDS operations and recommend potential improvements. NIH also submitted a corrective action plan to FDA, in response to an inspection of NIH facilities completed by the agency in late May 2015.

, NIH responded to 17 of FDA’s investigational observations. Some of these observations include an inadequately designed air system in aseptic processing areas, a deficient system for monitoring environmental conditions in aseptic processing areas, and an improper system for cleaning and disinfecting the equipment to produce aseptic conditions.

	As a result of the shutdown, several companies had to pause clinical trials being conducted in NIH laboratories.

 issued a statement saying that their trials were among those suspended.

	No patients have been harmed as a result of the quality issues, NIH said in its statement. NIH said it plans to undergo a “rigorous review” of the facilities and no new patients will be enrolled until all issues are resolved.

The National Institutes of Health (NIH) released a statement on April 19, 2016 saying that it plans to suspend research in two laboratories after preliminary results found the labs not in compliance with CGMP practices.

NIH Suspends Research in Sterile Production Facilities

	The European Medicines Agency’s (EMA) Pharmacovigilance Risk Assessment Committee (PRAC) says it has plans to review the safety of canagliflozin, a sodium-glucose co-transporter 2 (SGLT2) inhibitor 

 in patients with Type 2 diabetes. The committee will also extend the review of several direct-acting antivirals for the treatment of hepatitis C, PRAC said in an April 15, 2016

 of canagliflozin, the active substance used in Invokana and Vokanamet, after CANVAS, an ongoing clinical trial, showed a slight increase in the incidence of lower limb amputations, specifically toe amputations, in patients taking the medications. Another clinical study, CANVAS-R, showed a similar small increase in amputations, PRAC notes. This is particularly evident for patients with poorly controlled diabetes and preexisting heart and blood vessel issues. PRAC said it plans to review data from the drugs, as well as from other SGLT2 inhibitors, to determine if canagliflozin causes an increase in lower limb amputations.

 to Type 2 diabetes medications containing saxagliptin and alogliptin. Review from FDA determined that the drugs may increase the risk of heart failure, particularly in patients with kidney or heart diseases. Canagliflozin is also 

 in the United States to treat Type 2 diabetes. 

 that SGLT2 inhibitors, including canagliflozin, can lead to blindness, nerve and kidney damage, and heart disease. However, FDA has not made any comment on the possible increase in lower limb amputations. 

	In March 17, 2016, PRAC said it would review several direct-acting antivirals for the treatment of hepatitis C including Daklinza, Exviera, Harvoni, Olysio, Sovaldi, and Viekirax. Until recently, Direct-acting antivirals were part of treatment regiments for hepatitis B and C, which may be simultaneously present in a patient, PRAC notes. The committee decided to review use of antivirals after hepatitis B reactivation occurred in some patients.

 after new data became available in April 2016. The committee says data “became available regarding the risk of liver cancer (hepatocellular carcinoma) coming back in patients who were treated with direct-acting antivirals for hepatitis C.” According to PRAC, the study suggests patients treated with direct acting antivirals were at risk of cancer coming back earlier, than those not treated with the antivirals.

PRAC said it has plans to review both canagliflozin and several direct-acting antivirals, after new study data showed potential risks associated with the drugs.

PRAC to Review Canagliflozin and Direct-Acting Antivirals

	The IMS Institute for Healthcare Informatics released its annual 

report, a review of 2015 and outlook to 2020 of the medicines market. The report, officially released on April 14, 2016, analyzed medicine use in the United States, focusing specifically on spending, drivers of growth, major market segments, prescription volume, patient costs, and healthcare delivery changes.

According to IMS Institute, spending on pharmaceuticals reached $424.8 billion, based on invoice prices, in 2015, up 12.2% from 2014. After adjusting for price concessions and rebates, net spending on medicines increased 8.5% from 2014, topping off at $309.5 billion. IMS Institute says this is the second year spending on medicines has increased by double digits.

	IMS Institute attributes the increase in spending growth on an invoice and net basis to five major areas including generics, new brands, protected brands prices, protected brands volume, and patent expirations. According to the report, a large contributor to spending in 2015 was protected brands. Spending on these drugs increased to $28.3 billion in 2015, including volume growth and price increases. This is up from the IMS Institute reported spending growth of $26 billion on protected brands in 2014. Although protected brands played a large role in spending growth, IMS Institute estimates invoice based price growth slowed for protected brands, declining to 12.4% from 14.3% in 2014. Net price growth declined from 5.1% in 2014 to 2.8% in 2015. This is mainly due to rebates and other price concessions that may have offset price growth calculations in previous years.


	IMS Institute notes that patent expirations impacted branded drug spending in 2015. Branded drug spending decreased more in 2015 than in 2014. Due to patent expirations in 2015, brand spending decreased $14.2 billion, whereas in 2014, spending decreased only $12.1 billion. While the 2015 figure may reflect an increased reduction of spending due to the loss of patent exclusivity, it is nowhere near the record high brand spending decrease of $32.6 billion in 2012. IMS Institute notes the biggest patent expirations in 2015 included Abilify (aripiprazole), Nexium (esomeprazole), and Namenda (memantine).

	IMS Institute says the loss of exclusivity for Suboxone (buprenorphine), Neupogen (filgrastim), and Copaxone (glatiramer acetate injection) did not result in a decline in brand spending. 

, a biosimilar to filgrastim, was approved in 2015, and subsequently the first biosimilar approved by FDA. The minor effect Neupogen’s patent loss had on brand spending in 2015 may reflect early uncertainty surrounding the interchangeability of biosimilars.

	IMS Institute calls specialty drugs one of the “most dynamic market segments of the total market.” In total, spending on specialty drugs reached $121 on a net price basis in 2015, up more than 15% from 2014. Cancer drugs saw an 18% increase in spending during 2015, with a $6.0 billion jump from 2014, to $39.1 billion. The institute says the fastest growing segments of oncology drugs include monoclonal antibodies and protein kinase inhibitors. Diabetes drugs also saw spending increase, increasing by $1.6 billion, estimated 8.2% on a net basis, in 2015. The report notes, “invoice spending on DPP-IV inhibitors increased $1.4 billion, or 21.6%, to $8.1 billion.”

According to IMS Institute, a total of 73 new active substances (NASs) were launched in 2015, a third of which received orphan drug designation from FDA. Oncology drugs accounted for 35% of the new medicines in 2015 and represent the “greatest share of launches by therapeutic area over the past 10 years.” IMS says some notable advances in 2015 were in the areas of precision medicines, rare disease treatments, and chronic disease medicines.

	IMS Institute also notes that 2015 was an important year for biosimilars. The US market saw the first biosimilar approval in March 2015 with Sandoz’s Zarxio (filgrastim-sndz). The price difference between biosimilar and reference product was 16% on an invoice price basis, according to the report. By the end of 2015, there were seven applications pending via FDA’s biosimilar pathway. IMS Institute says the biologics with the greatest number of biosimilar candidates include filgrastim, adalimumab, rituximab, etanercept, bevacizumab, trastuzumab, pegfilgrastim, and infliximab. 

, a biosimilar to infliximab, in early April 2016. J&J subsidiary, Janssen Biotech said it plans to defend its patents for Remicade (infliximab). It is still uncertain how the approval of a Remicade biosimilar will affect the biologics market in upcoming years.

IMS Institute predicts that US spending on medicines will reach $610-640 billion by 2020 on an invoice price basis. The institute predicts that $282 billion of the growth in the next five years will come from branded medicines and $91 billion will result from new medicines, the majority of which will be for oncology. In total, IMS Institute predicts 2320 novel products and 43-49 NASs currently in the pipeline will launch over the next five years.  

The IMS Institute for Healthcare Informatics report examines spending on medicine in the US, drivers of growth, major market segments, prescription volume, patient costs, and healthcare delivery changes.

IMS Institute Report Examines Medicine Use and Spending in 2015

	On April 5, 2016, FDA said that it would be adding 

 to the labels of Type 2 diabetes medicines containing saxagliptin and alogliptin. An FDA safety review determined saxagliptin and alogliptin might increase the risk of heart failure, particularly in patients with heart or kidney disease.

	Saxagliptin and alogliptin are part of a class of dipeptidyl peptidates-4 (DPP-4) inhibitor drugs, which are used to lower blood sugar in adults with Type 2 diabetes. FDA cited the following medications as containing saxagliptin and alogliptin: Onglyza (saxagliptin), Kombiglyze XR (saxagliptin and metformin extended release), Nesina (alogliptin), Kazano (alogliptin and metformin), and Oseni (alogliptin and pioglitazone).

	In February 2014, FDA said it was planning to review the heart failure risk associated with saxagliptin after a study published in the 

 observed a “higher incidence of hospitalization for heart failure among patients treated with saxagliptin.” In 2014, FDA said it considered the findings to be preliminary but found the risk serious enough to continue investigation. In April 2015, FDA held an Endocrinologic and Metabolic Drugs Advisory Committee meeting to discuss the results of the trial and determine if both drugs had a significant effect on the risk of heart failure.

	FDA said it evaluated “two large clinical trials” both of which “showed that more patients who received saxagliptin- or alogliptin- containing medicines were hospitalized for heart failure compared to patients who received an inactive treatment.” FDA references the information from these clinical trials as the reasoning for adding the 

label to diabetes medications containing both DPP-4 inhibitors. In a trial with saxagliptin, 3.5% of patients who received the drug were hospitalized for heart failure, compared with 2.8% of patients receiving the placebo treatment. In the alogliptin trial, 3.9% of patients were hospitalized for heart failure, compared with 3.3% of those taking the placebo.

FDA added warning labels to medications containing saxagliptin and alogliptin after clinical trials linked the drugs to increased risk of hospitalization for heart failure.