Amy Ritter was Scientific Editor, BioPharm International.

Amy Ritter, PhD

	In the wake of the meningitis outbreak caused by contaminated compounded medications produced by the New England Compounding Center (NECC), both the government and the public have been wrestling with the question of how this happened-how did a company producing substandard medicines slip through regulatory oversight?

	Regulatory authority over compounding pharmacies is murky. In general, compounders are regulated by state pharmacy boards, but FDA has maintained that it can intervene when compounders exceed their role as producers of specialty doses for individual patients and engage in activities that can be construed as manufacturing. According to a background 

 released by the House Energy and Commerce Committee, both FDA and the Massachusetts Board of Pharmacy were aware of problems at NECC in the years leading up to the outbreak. The memo indicates that FDA conducted three series of inspections of NECC, each based on a separate set of allegations or events, issued two Form 483s in 2002 and 2003, and issued a Warning Letter in 2006. In addition, the Massachusetts Board of Pharmacy had investigated at least twelve separate complaints concerning NECC or its president, Barry J. Cadden, issued four advisory letters and/or informal reprimands, and entered into a consent agreement with the company in 2006. By any measure, NECC was engaging in manufacturing rather than compounding, distributing tens of thousands of doses across state lines, yet FDA did not intervene, nor did the Massachusetts Board of Pharmacy, despite a long list of infractions.

	This week, FDA will be called to testify before the 

 on Health, Education, Labor and Pensions. After all the finger pointing is over, one hopes that legislators will better define the roles and responsibilities of the regulatory authorities, both state and federal, to ensure that unsafe medicines can’t slide by under the radar.

Articles

In the wake of the meningitis outbreak caused by contaminated compounded medications produced by the New England Compounding Center (NECC).

Will FDA Gain More Oversight Over Compounders?

Boehringer Ingelheim (BI) has agreed to pay $95 million to settle allegations that it improperly promoted the stroke-prevention drug Aggrenox (aspirin and extended-release dipyridamole), the chronic obstructive pulmonary disease drugs Atrovent (ipratropium) and Combivent (ipratropium and albuterol), and the hypertension drug Micardis (telmisartan).

According to an Oct. 25, 2012, US Justice Department press 

, the government alleges that BI improperly promoted each of the drugs for uses that were not medically accepted indications and that were not covered by federal healthcare programs. Specifically, the settlement resolves allegations that BI promoted Aggrenox for certain cardiovascular events such as myocardial infarction and peripheral vascular disease; that Combivent was marketed for use before another bronchodilator in treating COPD; and that Micardis was marketed for treatment of early diabetic kidney disease.

In addition, the settlement resolves allegations that BI promoted the sale and use of Combivent and Atrovent at doses that exceeded those covered by federal healthcare programs and that BI made unsubstantiated claims about the efficacy of Aggrenox. Finally, the agreement resolves allegations that the company paid kickbacks to healthcare professionals to induce them to prescribe Aggrenox, Atrovent, Combivent, and Micardis.

As a result of the settlement, the federal government will receive $78,455,048, and state Medicaid programs will receive $16,544,952. BI has also agreed to enter into a corporate integrity agreement that provides for procedures and reviews to be put in place to avoid and detect conduct similar to that which gave rise to the settlement. According to the Justice Department, the claims settled by this agreement are allegations only; there has been no determination of liability.

Boehringer Ingelheim has agreed to pay $95 million to settle allegations that it improperly promoted four of its drugs.

Boehringer Ingelheim Settles False Claims Act Allegations for $95 Million

Watson Pharmaceuticals has received clearance from the Federal Trade Commission (FTC) for its acquisition of generic drug manufacturer Actavis. The $5.6-billion deal was first announced in April 2012, and will result in Watson becoming the third largest global generic-drug company.

The FTC identified 21 drugs either currently marketed or under development for which competition would be reduced as a result of the merger. The FTC’s consent order requires Watson or Actavis to sell assets related to 14 drugs to Par Pharmaceuticals. Watson has indicated in a 

 that Par will acquire the following products:

Watson's morphine sulfate      extended release  capsules 

Actavis' nifedipine extended      release tablets 

Actavis' metoclopramide      hydrochloride tablets 

Actavis' diltiazem      hydrochloride extended release capsules 

Watson's pending application      for adapalene/benzoyl peroxide gel 

Watson's pending application      for oxymorphone hydrochloride ER tablets 

Watson's pending application      for amphetamine salts ER tablets 

Actavis' pending application      for rivastigmine patch 

Actavis' pending application      for glipizide extended release tablets 

Actavis' pending application      for varenicline tartrate tablets 

Actavis' pending application      for oxycodone hydrochloride extended release tablets 

Actavis' pending application      for ursodiol tablets

Sandoz, the generic pharmaceuticals division of Novartis, will acquire the following four products:

Actavis' bupropion      hydrochloride 150-mg. extended release tablets 

Watson's pending application      for dextromethorphan hydrobromide/quinidine sulfate

The FTC expects that Sandoz and Par will be able to replicate the competition that otherwise would have been lost through the acquisition. For the remaining three drugs, different steps have been taken to address the competition concerns. To remedy the FTC’s concerns related to one drug product, the combined firm is required to end Actavis’s existing development and manufacturing agreement with Pfizer and transfer the manufacturing rights back to Pfizer. For two other drugs, Watson and Actavis must relinquish the marketing rights to another firm.

, some products being divested have been identified by FDA as being in short supply. The FTC evaluated whether the proposed transaction would exacerbate any of those shortages, and concluded that the manufacture of those products would not likely be altered in a way that could affect their continued availability.

Watson Pharmaceuticals to Acquire Actavis for $5.6 Billion

Watson Pharmaceuticals has received clearance from the Federal Trade Commission for its acquisition of generic drug manufacturer, Actavis.

Watson Receives Clearance for Actavis Acquisition

 that it will be investing EUR 30 million ($39 million) to build what will be the world’s largest chromatography plant for the production of large volumes of commercial APIs. The plant will be built on Novasep’s existing site in Mourenx, France, and is expected to be operational and validated within 18 months. According to the company’s press release, the new plant, designed by an in-house engineering team, will contain Varicol continuous chromatography systems with 1200-mm diameter columns operated at up to 70 bars. The plant will enable the production of a highly purified API from a complex mixture. In addition, the systems will integrate sophisticated solvent recovery systems for the recycling of 99.9% of solvents.

According to the press release, the chromatography plant is the third in a string of global investments by Novasep. The first was the opening of a 2000-m

 facility in Shanghai, China and the second was a EUR three million ($3.9 million) investment to expand the highly potent API manufacturing capabilities at Novasep’s facility in Le Mans, France. “Demand for Novasep’s advanced, purification-based manufacturing capabilities in the life-science industries continues to increase as drugs in development and reaching the market become more complex and specific. This necessitates our third and largest global plant expansion in 2012,” said Patrick Glaser, president and CEO of Novasep, in the release. 

Novasep announced that it will be investing EUR 30 million ($39 million) to build what will be the world's largest chromatography plant for the production of large volumes of commercial APIs.

Novasep to Build the World's Largest Chromatography Plant

 in the New York Times, a trio of physicians from the Memorial Sloan Kettering Cancer Center in New York announced their decision to remove an expensive new cancer treatment from the hospital formulary, citing cost-benefit as their reason. The physicians said that because Zaltrap (ziv-aflibercept) made by Sanofi/Regeneron was no better at extending median survival in advanced metastatic bowel cancer patients than Avastin (bevacizumab) from Roche/Genentech but costs more than twice as much, it would no longer be given to patients at the hospital.

	While Avastin is expensive in its own right, costing around $5000 per month, the hospital decided that the $11,063 per month Zaltrap did not provide any additional benefit, and so they could not justify passing the additional cost along to their patients. According to the op-ed’s authors, Peter B. Bach, the director of the Center for Health Policy and Outcomes, Leonard B. Saltz, chief of the gastrointestinal oncology service and chairman of the pharmacy and therapeutics committee, and Robert E. Wittes the physician in chief, “Ignoring the cost of care, though, is no longer tenable. Soaring spending has presented the medical community with a new obligation. When choosing treatments for a patient, we have to consider the financial strains they may cause alongside the benefits they might deliver.”

	The authors admit that a single exclusion by a single hospital for a single drug is not likely to produce a major savings in the nation’s healthcare costs. However, the decision by the Sloan Kettering physicians to publicize and explain their decision in a Times op-ed is interesting because it reads a warning to drug companies. FDA does not factor cost into its approval decisions, nor can Medicare exclude cancer medications based on cost. If the government is prevented from directly controlling drug prices, it may be that greater price pressures will come from hospitals and individual prescribers.

In an op-ed in the New York Times, a trio of physicians from the Memorial Sloan Kettering Cancer Center in New York announced their decision to remove an expensive new cancer treatment from the hospital formulary.

More Cost Pressures for Pricey Drugs

The Nobel Prize for Physiology and Medicine was shared by two researchers: Sir John B. Gurdon of the Gurdon Institute, Cambridge, United Kingdom; and Shinya Yamanaka of Kyoto University, Kyoto, Japan and the Gladstone Institutes, San Francisco, CA, “

for the discovery that mature cells can be reprogrammed to become pluripotent.

” Gurdon was the first to demonstrate this property through a technique called nuclear transfer. In experiments published in 1962, he showed that transplanting the nucleus of a cell from a tadpole’s intestine into an enucleated frog egg resulted in reprogramming of the fully-differentiated nucleus (1). The transplanted nucleus behaved like a fertilized egg, differentiated into all the tissues an oocyte would normally produce, and generated a tadpole. At the time, cell differentiation was viewed as a one-way street, and Gurdon’s demonstration that it could be completely reversed changed the way scientists viewed cell determination and differentiation. Work in his laboratory continues to focus on identifying the factors within the egg that enable this transformation.

		Yamanaka’s seminal work was in the creation of induced pluripotent stem cells. In 2006, he and his coworker demonstrated that introducing genes for four transcription factors into an adult skin cell was sufficient to turn it into a stem cell capable of differentiating into multiple tissue types (2). Being able to reprogram adult cells has fueled the field of regenerative medicine, because it offers an avenue to create new tissues for disease research or therapy without the ethical concerns facing embryonic stem cells.

		The Nobel Prize in Chemistry was shared by Brian Kobilka at Stanford University School of Medicine in California and Robert Lefkowitz of Duke University Medical Center in Durham, North Carolina “

for studies of G-protein-coupled receptors

.” G-protein coupled receptors (GPCRs) are a large class of membrane-spanning receptors that include those for many hormones and neurotransmitters, such as adrenaline, serotonin, and dopamine. Around 30% of drugs on the market target GPCRs, making the study of their structure and function important for drug developers as well as physiologists. Kobilka continues to study the structural basis for the functional properties of GPCRs, while work in Lefkowitz’s laboratory is aimed at understanding pathways by which GPCR function can be modulated.

he Nobel Prize for Physiology and Medicine was shared by two researchers: Sir John B. Gurdon of the Gurdon Institute, Cambridge, United Kingdom; and Shinya Yamanaka of Kyoto University, Kyoto, Japan and the Gladstone Institutes, San Francisco, CA, “for the discovery that mature cells can be reprogrammed to become pluripotent.”