DID - May 16, 2008 Issue

Vol. 7 No. 97

Senate Subcommittee Approves $275 Million More For FDA

A Senate Appropriations Subcommittee passed a markup bill Thursday granting the FDA an immediate $275 million infusion, including $100 million for drugs, biologics and medical devices, as requested by Commissioner Andrew von Eschenbach in a May 5 letter to Sen. Arlen Specter (R-Penn.).

The money is included in an emergency supplemental appropriations bill that the subcommittee approved. It includes $265 million in funding for the FDA through the end of fiscal 2009 — $125 million for food safety activities, $100 million for drug, device and biologic safety activities and $40 million for modernizing FDA science and the FDA workforce. In addition, $10 million is budgeted for capital spending on FDA buildings and laboratory facilities outside the Washington, D.C., area.

The approved additional funding includes:

  • $48.5 million for CDER operations and related field activities of the Office of Regulatory Affairs (ORA);
  • $35 million for the Center for Devices and Radiological Health and related ORA activities;
  • $23.5 million for CBER and related ORA activities;
  • $6 million for the National Center for Toxicological Research; and
  • $21.8 million for other activities, including the FDA Office of the Commissioner, Office of Operations, Office of Scientific and Medical Programs, Office of International and Special Programs, and Office of Policy, Planning and Preparedness.

This funding comes on top of an increase of nearly $150 million provided in the 2008 Agriculture Appropriations bill, bringing the total FDA funding increase in 2008 to almost $425 million.

The additional money is intended to help the agency implement new drug safety initiatives, including pediatric drug and device safety, postmarketing study commitments and improved drug surveillance and labeling, as required by the Food and Drug Administration Amendments Act of 2007.

The money will also allow the FDA to open offices in two additional countries and conduct 120 more foreign medical product facility inspections, 575 more domestic medical product inspections, 10,000 additional medical product import exams and an additional 300 lab analyses of imported medical products, partly in light of the scandal over contaminated heparin from China, which has been implicated in 81 deaths so far.

Other purposes include improving the FDA’s IT systems to improve drug safety, including more rapidly identifying adverse events; hiring an additional 99 medical product safety inspectors; expanding science training for FDA employees; and strengthen the FDA’s science programs to allow the agency to effectively regulate new and complex products.

“With serious concerns about the FDA lacking the resources to do its job, this much needed increase in funding means the agency can hire more food inspectors, open offices overseas, expand data collection and take other necessary steps to prevent our food and drug safety being severely compromised,” Sen. Herb Kohl (D-Wisc.), said. He chairs the Senate Agriculture, Rural Development and Related Agencies Appropriations Subcommittee, which has jurisdiction over the FDA. He said he will hold the agency accountable for how it uses the money, and will require quarterly status reports.

Von Eschenbach’s letter can be accessed at www.fdanews.com/ext/files/Drug_Industry_Daily/vonEschenbachSpector.pdf. — Martin Gidron


Wyeth Launches Antidepressant Pristiq

Wyeth began full-scale sales and educational efforts this week for its serotonin-norepinephrine reuptake inhibitor (SNRI) Pristiq, recently approved for the treatment of major depressive disorder.

Pristiq (desvenlafaxine succinate) is expected to be a major product for Wyeth, replacing the firm’s Effexor (venlafaxine HCl) franchise, also an SNRI. Effexor and Effexor XR had sales of $1.02 billion during the first quarter of 2008, according to the company. The extended release formulation of the drug is expected to lose patent protection no later than July 2010, if not sooner. Wyeth began shipping Pristiq in April following its February approval.

An application for Pristiq to treat major depressive disorder is pending at the European Medicines Agency (EMEA). The company said European reviewers are concerned over the efficacy of the drug and the EMEA is not expected to issue an opinion until early 2009.

In the U.S., Pristiq will go up against Eli Lilly’s SNRI Cymbalta (duloxetine HCl), which had $605 million in sales during the first quarter of 2008, according to the company. Cymbalta is approved for the treatment of major depressive disorder, generalized anxiety disorder and diabetic peripheral neuropathic pain. Pristiq is in Phase III testing for neuropathic pain, Wyeth said.

An NDA for the drug as a treatment of vasomotor symptoms associated with menopause is pending at the FDA with an approvable letter (DID, July 25, 2007). The agency wants additional clinical data, and the company plans to provide it through an 18-month study expected to start in mid-2008, pending the agency’s agreement on the trial’s protocol, the company said.

In March, Wyeth withdrew the drug’s application for vasomotor symptoms in Europe. It said additional data is necessary to address questions raised by the European reviewers, which could be provided by the study planned to gain FDA approval. — Christopher Hollis


Bayer Pulls Remaining Trasylol From Hospitals

Bayer Pharmaceuticals is removing all remaining supplies of its clotting drug Trasylol from hospital pharmacies and warehouses after a study was published showing an increased risk of death with the drug.

Bayer had suspended global marketing of Trasylol at the FDA’s request last November while waiting for additional data from the study (DID, Nov. 6, 2007). The BART study compared Trasylol (aprotinin) with lysine analogues in patients undergoing high-risk cardiac surgery. At 30 days, patients receiving aprotinin had an increased risk of death of more than 50 percent.

Enrollment was halted after a data safety monitoring board observed an increased risk of all-cause mortality in patients receiving Trasylol compared with the control arms. Results were published May 14 in the New England Journal of Medicine (NEJM).

“In all likelihood, this is the end of the aprotinin story,” Wayne Ray and C. Michael Stein of Vanderbilt University School of Medicine wrote in an editorial accompanying the study.

Under a limited-use agreement, Trasylol will be restricted to investigational use according to a special treatment protocol, the FDA said. The protocol allows certain patients at increased risk of blood loss and transfusions during coronary artery bypass graft surgery to use the drug if they have no acceptable alternative therapy. Physicians using the drug must verify that the benefits of the drug clearly outweigh the risks for their patients.

A Bayer spokeswoman told DID that the company expects to receive redacted data from the BART trial and will have independent experts review and analyze it. Then, Bayer will work with health authorities to determine the data’s impact on Trasylol’s benefit-risk profile.

Bayer said it will share the BART findings, the NEJM editorial and its initial interpretation of these materials with all physicians and investigators who have been using or will use Trasylol under the programs. — April Astor


BIO Backs Biosimilars Bill

The Biotechnology Industry Organization (BIO) has sent a letter to two lawmakers in support of a bill that would allow follow-on products to be approved as interchangeable with brand biologics and provide 12 years of data exclusivity for innovator products.

BIO’s President and CEO Jim Greenwood sent the letter to Rep. Anna Eshoo (D-Calif.) and Rep. Joe Barton (R-Texas), the ranking member of the House Energy and Commerce Committee, who introduced the Pathway for Biosimilars Act, H.R. 5629, in March. The bill subsequently was referred to the committee for consideration.

In the letter, Greenwood says the bill respects principles that BIO, which represents the biotechnology industry, has developed to create a regulatory pathway for follow-on biological products.

Under the proposed pathway, the FDA could request data from studies assessing pharmacokinetics or pharmacodynamics from biosimilar applicants. Immunogenicity testing would be mandatory unless the applicant obtains a waiver.

Although BIO has reservations about the waiver provision, “the required guidance process for certain clinical trials in the bill would provide important patient protections and allow stakeholder input before such a waiver could be made,” Greenwood writes.

The bill would permit the FDA to determine that a biosimilar product is interchangeable with the reference product. Data would have to show that the follow-on is expected to produce the same result as the reference product.

Greenwood says the interchangeability provision is important and stresses that patients should not be given a follow-on unless their physician prescribes it.

BIO also supports a 14-year period of exclusivity. The act provides 12 years of data exclusivity for innovator products and an additional two years if they are approved for new indications, plus an additional six months for pediatric approval (DID, March 17).

H.R. 5629 is available at eshoo.house.gov/images//pathway%20for%20biosimilars%20act.pdf. — Elizabeth Jones


FDA Expected to Be Tough on Chinese Importers 

The FDA plans to be more vigilant in inspecting overseas active pharmaceutical ingredient (API) production facilities in the wake of the heparin contamination, according to a counterfeiting expert.

“As a whole, the FDA is going to be much more aggressive in inspecting and approving Chinese [drugs], particularly APIs, coming into the United States,” Donald deKieffer, a principal at the deKieffer & Horgan law firm, said. An expert on international counterfeiting and diversion, he said there are probably 30–40 counterfeiting rings operating in the U.S., some of which have substantial operations.

The FDA has been criticized by Congress for not conducting a preapproval inspection of the China-based heparin API facility that distributed contaminated product to Baxter, leading to a large-scale recall and drug shortage (DID, April 22). The impurity, which is synthetic and cheaper to make than genuine heparin, has been implicated in 81 patient deaths and was likely introduced into the drug supply intentionally, CDER Director Janet Woodcock has said.

Counterfeiter Case Study

DeKieffer detailed a Florida counterfeiting ring led by Michael Carlow, who set up wholesale distribution companies, established relationships with wholesalers and sold them stolen medicines at discounted prices.

He then started buying medications in foreign countries at substantial discounts and shipping them to the U.S. for distribution. He used counterfeit pedigrees to authenticate the product, which he sold to wholesalers that then sold the drugs to other wholesalers. The counterfeit product ended up in warehouses of the big three distributors: McKesson, Cardinal Health and AmerisourceBergen.

Carlow also counterfeited drugs, including Pfizer’s Lipitor (atorvastatin calcium). It was manufactured in Costa Rica using API sourced from China. He also diluted or relabeled such injectable drugs as Amgen’s Epogen (epoetin alfa), claiming they contained more active ingredient than they contained.

What Companies Can Do

Firms need to know their suppliers and customers. Checking to make sure customers are not in any databases of known diverters or counterfeiters is essential. “It’s always been astonishing to me that some very large and sophisticated manufacturers … continue to do business with known crooks … to whom they’re selling, both in this country and overseas. They’re selling lots and lots of product,” deKieffer said.

One of the most difficult aspects of employing an anti-diversion policy is finding alternative ways to compensate sales representatives, considering the pressures to meet profit expectations, deKieffer said. Representatives should not get credit for sales to diverters.

Firms can check Nelson point-of-sales data and match it against internal sales data. A 4 percent to 5 percent differential between the data sets over an extended period of time indicates a problem, deKieffer said. Although this technique is difficult because manufacturers often do not know how much drug is dispensed at a particular pharmacy, the sales data can be manipulated to provide some useful information, he added.

If a leak in the distribution channel is detected, companies need to increase surveillance. For example, firms can convince pharmacies to authenticate drugs by checking for certain convert markers on products.

When considering track-and-trace methods, manufacturers need to consider whether the technology allows company representatives to identify suspect product immediately without sending the drug to a lab for verification. Counterfeiters can change locations quickly, deKieffer said.

He noted the pharmaceutical industry has been slow to adopt these technologies although the high-end cosmetics and apparel industries have been using these technologies for years.

Firms need to establish internal task forces and have counterfeiting and diversion policies in place. For example, companies should designate a person to be responsible for handling recalls.

In addition, having an exclusive wholesaler distributor, as Pfizer does in the UK, will help prevent diversion by shorting the supply chain. However, deKieffer said he could not speak about any business-related implications for using an exclusive distributor. — Christopher Hollis


Biologics Adverse Experience Reports Take 88 Hours Annually

It takes biologics manufacturers 88 hours on average to file and maintain all the information required for adverse experience reports (AERs), according to the FDA.

Those hours include the time spent filing 15-day postmarketing alerts required by 21 CFR Part 600. The alerts enable the FDA to recommend labeling changes, start removing biological products from the market if needed and assure that manufacturers take appropriate corrective action when necessary. The hours do not include time spent to file MedWatch forms.

The agency calculated the annual burden of recordkeeping based on the annual average of lots released (5,291), number of recalls made (1,841) and number of 15-day and other AERs received (45,707) in fiscal 2006 from 303 firms.

The data was part of an information collection approval request the FDA sent to the Office of Management and Budget for review and clearance. In it, the agency estimates the total annual reporting burden will be 636,436 hours. A copy of the agency’s notice is available at www.fda.gov/OHRMS/DOCKETS/98fr/FDA-2008-N-0073.pdf. — Elizabeth Jones

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Reporters: Martin Gidron, April Astor, Christopher Hollis, Elizabeth Jones

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