DID - May 11, 2009 Issue

Vol. 8 No. 91

FDA Plans Significant Increase in Import Examinations

The FDA plans to more than double the number of import field examinations for drugs in 2010, significantly increasing its surveillance of products at U.S. ports of entry.

The agency estimates that it will conduct 2,870 import field inspections in this fiscal year. But starting in October, the FDA expects to raise that number to 6,197, according to the agency’s congressional justification for the proposed budget for 2010.

The FDA is seeking an additional $130.6 million in funding for CDER in the proposed budget — comprised of $44.3 million in congressional appropriations and $86.2 million in user fees — bringing the total funding for the center to $908 million, the FDA says.

The increase would support the ability of the Office of Regulatory Affairs field components “to implement targeted import safety activities,” the FDA says.

CDER is planning a Supply Chain Security pilot program in which importers obtain voluntary certifications for expedited product entry but is waiting for Office of Management and Budget approval to start the program (DID, Jan. 15).

The number of import samples analyzed is expected to increase this year to 586 from 346 in fiscal 2008, the FDA says in its congressional justification. The number of samples analyzed in fiscal 2010 is expected to remain at 586.

In fiscal 2008, 1 percent of import lines were examined. In fiscal 2010, an estimated 2 percent of import lines will be examined, the FDA says.

Supply Chain Safety

The FDA highlights its Supply Chain Safety and Security program in its appropriations justifications. It says reliance on traditional approaches such as inspections and sampling at the U.S border should be used with new approaches that are risk-based and verification-focused, holding industries accountable for the safety of their medical products, the agency says.

“FDA will increase medical product safety and security by enhancing oversight of entities in the supply chain,” the agency says. “FDA will use traditional and innovative mechanisms that include FDA inspections and field exams, integrated federal-state oversight and greater access to inspection data and results acquired from trusted foreign regulatory authorities.” 

When problems occur, the agency will respond more effectively with rapid product tracing to more accurately identify companies responsible for problems, it says.


Domestically, the FDA will conduct an estimated 120 preapproval inspections for new drugs and 51 preapproval inspections for generic drugs this fiscal year, the agency says. In addition, 1,085 domestic good manufacturing practice (GMP) drug-processing inspections are estimated for this year. Those numbers are not expected to change in fiscal 2010.

Foreign inspections are not expected to change this year and next. The FDA expects to conduct 192 preapproval inspections for new drugs and 69 for generic drugs in fiscal 2009 and 2010. It plans to conduct 382 foreign GMP surveillance inspections in 2009 and 2010. In fiscal 2008, the agency conducted 268 foreign GMP surveillance inspections.

The 2010 budget proposes a manufacturing facility re-inspection fee, which under the FDA’s Safer Medical Products initiative would authorize the collection of $10.5 million. The inspections would be conducted in FDA-regulated facilities deemed noncompliant with GMPs.

Generic drug user fees also are proposed in the fiscal 2010 document. They would give the FDA an additional $36 million for generic drug reviews and preapproval inspections, as well as provide for more oversight of foreign manufacturing facilities, the agency says.

“With the globalization of drug manufacturing, generic drugs or their ingredients are more likely to be produced in countries such as India and China. In India alone, the number of facilities named in generic drug applications grew from eight in 1992 to 963 in 2008,” the FDA says.

“This dramatic growth imposes additional burdens on FDA. It is becoming increasingly difficult to conduct preapproval inspections of all foreign facilities in a timely way,” the agency adds. — Christopher Hollis


Wyeth Accuses Sun, Caraco of Deception in Protonix Suit

Sun Pharmaceutical Industries and its subsidiary Caraco Pharmaceutical Laboratories may be enjoined from selling their generic Protonix heartburn drug with its current product insert if Wyeth prevails in a suit alleging the companies engaged in false advertising.

In court documents filed May 5, Wyeth maintains that the companies made false statements about the pantoprazole sodium used in their product by claiming it is the same active ingredient used in Protonix (pantoprazole sodium). These practices have deceived consumers and illegally cut into Wyeth’s sales, the drugmaker alleges. 

Before Protonix lost patent protection, it was a blockbuster product for Wyeth, bringing in an estimated $2 billion in the U.S. alone, according to court documents.

“Despite expressly representing to the public that they are selling pantoprazole sodium sesquihydrate tablets, Sun and Caraco are actually selling tablets containing a different polymorphic form of pantoprazole sodium — pantoprazole sodium monohydrate,” Wyeth maintains in court documents.

Polymorphic forms share the same chemical formula and molecular structure but have different crystal forms and therefore can have different properties, including bioavailability, Wyeth adds.

Because the generic companies claim their pantoprazole sodium monohydrate tablets actually contain pantoprazole sodium sesquihydrate, they are violating the Lanham Act, Wyeth asserts.

Furthermore, because the FDA hasn’t approved the sale of pantoprazole sodium monohydrate, Sun and Caraco have not demonstrated that their product has the same stability, dissolution, bioavailability, quality, safety or efficacy as Protonix, the plaintiff alleges.

The drugmaker has asked the court to stop the generic companies from selling their product, in its current form, under a label and product insert for pantaprazole sodium sesquihydrate.

Last year, Wyeth and Nycomed, its partner on Protonix, launched the 20- and 40-mg tablets of an authorized generic product under an agreement with Prasco Laboratories. Sun began selling its generic Protonix 40-mg tablets in the U.S. through Caraco the same month (DID, Jan. 31, 2008).

Wyeth’s Protonix franchise brought in $215 million in revenue during the quarter that ended March 31 — $123 million from the generic product and $92 million from the brand drug, the company says in its April 29 earnings statement.

The lawsuit, Wyeth v. Sun Pharmaceutical Industries Ltd. and Caraco Pharmaceutical Laboratories Ltd., was filed in the U.S. District Court for the Eastern District of Michigan. — Elizabeth Jones


GSK’s HPV Vaccine Bests Merck’s Gardasil in Clinical Trial

GlaxoSmithKline (GSK) says its human papillomavirus (HPV) vaccine Cervarix provoked a significantly greater immune response in patients than Merck’s Gardasil in a Phase III clinical trial.

The comparative study in women age 18–45 found that Cervarix triggered more than twice the level of neutralizing antibodies to HPV 16, a measure of immune response, than Gardasil, and the response was more than six times higher for HPV 18. These results were statistically significant, GSK says in a statement.

Compared with Gardasil, GSK’s vaccine also produced 2.7 times more memory B cells for HPV 16 and 18, another measure of immune response. Cervarix provided a high and statistically significant level of efficacy against precancerous lesions associated with HPV 16 and 18 and type-specific protection against precancerous lesions associated with some additional common cancer-causing HPV types.

Rates of serious adverse events and medically significant conditions were similar among the active and control groups.

In March, GSK gave the FDA the final data from the study (DID, March 31).

GSK also announced results of a separate, long-term follow-up study showing that Cervarix provided high and sustained antibody levels against HPV 16 and 18 for as long as 7.3 years after vaccination.

To date, Cervarix has been approved in 95 countries, including the 27 member states of the EU, Australia, Brazil, South Korea, Mexico and Taiwan. Licensing applications have been submitted in more than 20 additional countries, including Japan and the U.S. GSK also submitted the vaccine to the World Health Organization for prequalification in September 2007. — Martin Berman-Gorvine


EMEA Recommends Tamiflu Use After Expiration Dates

The European Medicines Agency (EMEA) has issued a guidance in response to the recent outbreak of influenza A (H1N1) recommending the use of Tamiflu capsules that have been distributed for as long as two years after their expiration dates.

The guideline released Friday effectively extends the shelf life of Tamiflu (oseltamivir) capsules from five to seven years.

Patients who have Tamiflu (oseltamivir phosphate) capsules that have expired recently should not dispose of them because they might be needed during an influenza A (H1N1) pandemic, the guidance says.

The agency’s Committee for Medicinal Products for Human Use (CHMP) looked at data on the condition of the capsules after seven years, in particular the impurities and degradation that products may develop during storage.

“Due to the public health emergency linked to the current risk of pandemic influenza, and based on data made available regarding the stability of Tamiflu (oseltamivir) 30-mg, 45-mg and 75-mg capsules for an additional period of two years, the CHMP recommends that boxes of Tamiflu should not be discarded where the expiry date has passed,” the committee says in a statement.

Storage conditions help determine the stability of pharmaceuticals. The boxes should be kept at temperatures below 25 degrees Celsius (77 degrees Fahrenheit), CHMP says.

A copy of the guidance can be found at www.emea.europa.eu/humandocs/PDFs/EPAR/tamiflu/28766209en.pdf. — David Belian


Lannett Gets Approval to Add Second Strength of Generic Salagen

Lannett has received FDA approval for its generic version of Eisai Pharmaceuticals’ Salagen 7.5-mg tablets, which are used to treat certain side effects associated with radiotherapy.

Salagen (pilocarpine HCl) is indicated to treat dry mouth caused by radiotherapy for head and neck cancer and in patients with Sjogren’s syndrome, an autoimmune disease. Lannett already markets pilocarpine HCl 5-mg tablets.

“This approval adds an important dosage strength to our Pilocarpine product offering,” Arthur Bedrosian, president and CEO of Lannett, says in a statement. “We are now able to offer our customers one stop shopping for both strengths.”

MGI Pharma, which became a subsidiary of Eisai last year, received approval for Salagen in March 1994, according to the FDA. — Elizabeth Jones


MedWatch Warns Doctors About Deaths Reported in Tarceva Patients

Patients taking Tarceva, the nonsmall cell lung and pancreatic cancer treatment, have died of gastrointestinal perforation and severe skin disorders, OSI Pharmaceuticals, Genentech and the FDA warned in a MedWatch alert and “dear healthcare professional” letter.

Neither the MedWatch alert issued Friday nor the letter this month state how many patients have died. The skin conditions are described as bullous, blistering and exfoliative, including cases suggestive of Stevens-Johnson syndrome/toxic epidermal necrolysis. Other reported adverse events include ocular disorders, such as corneal perforation or ulceration.

The new safety information comes from routine pharmacovigilance during clinical trials and postmarketing reports.

Doctors should discontinue prescribing Tarceva for patients who develop gastrointestinal perforation, and treatment should be interrupted or discontinued for those who develop the skin or eye disorders, the letter to healthcare professionals says.

Tarceva is used alone to treat patients with locally advanced or metastatic nonsmall cell lung cancer after failure of at least one prior chemotherapy regimen and in combination with gemcitabine for the first-line treatment of patients with locally advanced, unresectable or metastatic pancreatic cancer.

The MedWatch safety summary, including a link to the letter to healthcare professionals, can be found at www.fda.gov/medwatch/safety/2009/safety09.htm#Tarceva. — Martin Berman-Gorvine

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