Amy Ritter was Scientific Editor, BioPharm International.

Amy Ritter, PhD

New drug approvals sometimes come in class-specific clusters, as drug makers competing for the same indication race to get to market first. In the US, the year 2011 was notable for approvals of drugs to treat hepatitis C. Merck’s protease inhibitor, Victrelis (boceprevir), was the first in its class to be approved in May 2011, followed later that month by Incivek (telaprevir) from Vertex Pharmaceuticals. Both compounds promised substantially greater benefit than previously available therapies, and touched off a wave of acquisitions as companies 

 sought to add hepatitis C treatments to their portfolio of products.

		This year appears to be the year of the diet pill. In June, FDA approved a weight-loss pill for the first time in more than 10 years, with a second approval following in July. Belviq (lorcaserin hydrochloride), a serotonin 2C agonist developed by Arena Pharmaceuticals, was 

 on Jun. 27, 2012 and Vivus’s Qsymia (phentermine and topiramate extended-release) was 

 on Jul. 17, 2012. Both drugs are indicated for overweight or obese adults who also have at least one weight-related condition such as hypertension or diabetes.

		Both drugs faced intense safety scrutiny on their way to approval, and both manufacturers are required to perform an extensive set of postmarketing safety studies to monitor, among other things, cardiovascular risk. With respect to weight-loss drugs, FDA’s risk-benefit analysis had to take into account not only the risks posed by these drugs, but also the prevalence of obesity and obesity-related diseases and the fact that few treatment options are available apart from diet and exercise and bariatric surgery. The danger, of course, is that the drugs will be irresponsibly prescribed and not used as intended, which is as an adjunct to diet and exercise. Weight-loss experts caution that there’s no such thing as a magic pill, but there are always those willing to believe in magic.

Articles

New drug approvals sometimes come in class-specific clusters, as drug makers competing for the same indication race to get to market first. In the US, the year 2011 was notable for approvals of drugs to treat hepatitis C. Merck’s protease inhibitor, Victrelis (boceprevir), was the first in its class to be approved in May 2011, followed later that month by Incivek (telaprevir) from Vertex Pharmaceuticals.

The Year of the Diet Pill

Sandoz announced it has completed the acquisition of Fougera Pharmaceuticals, a maker of generic dermatology products, for $1.525 billion in an all-cash transaction. According to a company 

, the acquisition will complement Sandoz’s existing pipeline of biosimilars and generic injectables, ophthalmics, and antibiotics. Sandoz plans to use its global reach to expand Fougera’s dermatology portfolio into new markets.

Currently, Fougera Pharmaceuticals employs approximately 700 people across its US sites. It operates two main businesses: Fougera, specializing in dermatology development and manufacturing, with expertise in the area of semi-solid forms such as creams and ointments, and PharmaDerm, a branded specialty pharma business.

Fougera will be integrated into Sandoz’s US business based in Princeton, New Jersey, but will continue to exist as a separate legal entity. Fougera’s site in Melville, New York, will be home to a new center of excellence for generic dermatology development and manufacturing within the global Sandoz network.

Sandoz announced it has completed the acquisition of Fougera Pharmaceuticals, a maker of generic dermatology products, for $1.5 billion.

Sandoz Completes Acquisition of Generic Dermatology Company Fougera for $1.5 Billion

 that it has entered into an agreement to be acquired by an affiliate of the private investment firm, TPG. The transaction has an equity value of $1.9 billion. Under the terms of the agreement, Par shareholders will receive $50 per share of common stock, which represents a premium of 37% over the closing price of the stock on July 13, 2012.

In addition, Par may solicit offers of greater value from third parties through Aug. 24, 2012. If no superior offer is forthcoming, the transaction is expected to close in 2012, subject to customary approvals and closing conditions.

Par Pharmaceuticals is a maker of generic drugs based in the US, and contains two operating divisions, Par Pharmaceutical and Strativa Pharmaceuticals. The company develops, manufactures, and markets high-barrier-to-entry generic drugs and niche, innovative proprietary pharmaceuticals. Par’s agreement with TPG follows a period of growth through acquisition by Par over the past year. Par acquired the Chennai, India-based solid-dosage manufacturer, Edict Pharmaceuticals, in February 2012 for approximately $24 million, and specialty pharmaceutical company Anchen in November 2011 for approximately $410 million.

Par Pharmaceuticals, a maker of generic drugs, has entered into an agreement to be acquired by the private investment firm, TPG, for $1.9 billion.

Par Pharmaceuticals to be Acquired by TPG for $1.9 Billion

On July 9, 2012, FDA approved a risk evaluation and mitigation strategy (REMS) for extended-release and long-acting opioid medications. The REMS is part of a federal initiative to address the potential for misuse and abuse of prescription drugs, and will affect more than 20 companies that produce extended-release or long-acting opioid drugs. Companies will be required to make educational programs available to prescribers based on a blueprint provided by FDA. In addition, companies will be required to make FDA-approved patient education materials available, and to perform periodic assessments of the implementation of the REMS.

There are three key components to the initiative:

Training for prescribers that includes information on the risks and benefits of opioid therapy, choosing patients appropriately, monitoring patients, and counseling patients on the safe use of these types of opioids

An updated medication guide and patient counseling document

Assessment and auditing, to determine whether companies have achieved FDA-established goals for the percentage of prescribers completing the training, and to assess whether the REMS is adversely affecting the ability of patients to access necessary pain medication. 

Of note, the REMS applies only to extended-release and long-acting opioid medications, not to immediate release formulations, because FDA has concluded that there is a disproportionate safety problem (i.e., abuse, misuse, and overdose potential) associated with these products that must be addressed. At this time, prescriber training is voluntary, and not a precondition for prescribing extended-release or long-lasting opioids to patients. However, according to the FDA 

, the Obama Administration is pursuing legislation that would make opioid prescriber training mandatory and link training to registration with the Drug Enforcement Agency.

On July 9, 2012, FDA approved a risk evaluation and mitigation strategy for extended-release and long-acting opioid medications.

FDA Introduces New Safety Measures for Opioid Medications

This week, KV Pharmaceuticals filed a lawsuit against FDA to force the agency to stop compounded versions of their synthetic progesterone drug, Makena (hydroxyprogesterone caproate), from being produced. Makena was granted approval in February 2011 to reduce the risk of premature birth, and was granted seven years of market exclusivity under the Orphan Drug Act. At approval, KV set the price of Makena at $1500 per dose, but before Makena was approved, physicians had been able to prescribe synthetic progesterone prepared by compounding pharmacies at a cost of $10–$20 per dose. The resulting outcry over the huge price tag prompted KV to drop the price to $690 per dose and implement a patient assistance plan, but apparently the company is still encountering difficulty in persuading prescribers and payers that the GMP product is worth the considerable upcharge.

		When the price of $1500 per dose was originally set, FDA took the unusual position of declining to specifically enforce Makena’s exclusivity. In a 

 issued in March 2011 the agency stated, “In order to support access to this important drug, at this time and under this unique situation, FDA does not intend to take enforcement action against pharmacies that compound hydroxyprogesterone caproate based on a valid prescription for an individually identified patient unless the compounded products are unsafe, of substandard quality, or are not being compounded in accordance with appropriate standards for compounding sterile products.”

		KV’s response was to try to convince FDA that compounded versions of the drug presented a safety risk, but without success. FDA acquired 16 samples of hydroxyprogesterone caproate API and 13 compounded versions of hydroxyprogesterone caproate and tested them for purity and potency. Although some deviations from the purity and potency standards specified in the Makena NDA were found, no major safety issues were identified. After the analysis, FDA 

 that it makes its enforcement decisions about compounded products on a case-by-case basis after considering the particular facts at issue, and that compounding of any product, including hydroxyprogesterone caproate should not exceed the scope of traditional pharmacy compounding. In other words, the agency declined to issue a blanket ban on compounding, but also left the door open for enforcement if warranted by safety concerns or if pharmacies were found to be producing drugs in bulk.

		Risk-based, limited enforcement makes sense in a resource-constrained environment. Chasing down pharmacies compounding hydroxyprogesterone caproate requires resources that could be better spent investigating more serious safety breaches. This type of reality is not to KV Pharma’s liking, hence the lawsuit. If KV Pharma wins its suit, one company, in essence, would be dictating enforcement priorities for the agency.

This week, KV Pharmaceuticals filed a lawsuit against FDA to force the agency to stop compounded versions of their synthetic progesterone drug, Makena (hydroxyprogesterone caproate), from being produced.

Limited Enforcement

GlaxoSmithKline has agreed to plead guilty and pay $3 billion to resolve criminal and civil liability resulting from unlawful promotion of certain drugs, failure to report safety data, and alleged false price reporting practices. According to the Justice Department 

, the settlement is the largest healthcare fraud settlement in US history, and the largest payment ever by a drug company.

GSK agreed to plead guilty to three criminal counts, including two counts of introducing misbranded drugs, Paxil and Wellbutrin, into interstate commerce and one count of failing to report safety data about the drug Avandia to FDA. Under the terms of the plea agreement, GSK will pay a total of $1 billion, including a criminal fine of $956,814,400 and forfeiture in the amount of $43,185,600. The guilty plea and sentence are subject to final acceptance by the US District Court. 

In addition, GSK agreed to pay $2 billion to resolve its civil liabilities with the federal government under the False Claims Act, as well as the states.  The civil settlement resolves claims relating to Paxil, Wellbutrin, and Avandia, as well as additional drugs, and also resolves pricing fraud allegations.

GSK’s criminal liability stems from off-label promotion of two drugs.  According to the Justice Department, from April 1998 to August 2003 GSK unlawfully promoted the antidepressant Paxil for treating depression in patients under age 18, even though the FDA has never approved the drug for pediatric use.  The Justice Department also alleges that, from January 1999 to December 2003, GSK promoted Wellbutrin, a drug approved at that time only for major depressive disorder, for weight loss, the treatment of sexual dysfunction, substance addictions, and attention deficit hyperactivity disorder, among other off-label uses.

GSK also pled guilty to criminal charges of withholding safety data for the diabetes medication, Avandia, from 2001–2007. The missing information included data regarding certain postmarketing studies, as well as data regarding two studies undertaken in response to European regulators’ concerns about the cardiovascular safety of Avandia. FDA has since added two black-box warnings for Avandia for cardiovascular safety.

The civil liabilities that GSK has agreed to resolve in this settlement include off-label promotion of the drugs Paxil, Wellbutrin, Advair, Lamictal, and Zofran, and paying kickbacks to physicians to prescribe those drugs as well as the drugs Imitrex, Lotronex, Flovent, and Valtrex; making false and misleading statements concerning the safety of Avandia; and reporting false best prices and underpaying rebates owed under the Medicaid Drug Rebate Program.  According to the Justice Department, except to the extent that GSK has agreed to plead guilty to the three-count criminal information, the claims settled by these agreements are allegations only, and there has been no determination of liability.

GlaxoSmithKline has agreed to plead guilty and pay $3 billion to resolve criminal and civil liability resulting from unlawful promotion of certain drugs, failure to report safety data, and alleged false price reporting practices.