FDA Proposes Mandatory Electronic Safety Reporting

The U.S. Food and Drug Administration is proposing to amend postmarket safety reporting regulations for three of its centers to require that manufacturers and other facilities subject to current reporting requirements submit their reports in an electronic format.

The agency issued two proposed rules today—one that applies to electronic medical device adverse event reporting and one that applies to electronic drug and biologic product adverse experience reporting. Today’s rules would not change what types of incidents are required to be reported to the FDA—it would require that the incidents be reported in an electronic format that the FDA can process, review and archive.

“Both proposed rules will improve the agency’s ability to obtain safety information more quickly, which will help lead to faster identification of potential safety problems,” said David Buckles, Ph.D., director of the Division of Postmarket Surveillance at the FDA’s Center for Devices and Radiological Health (CDRH). “Information obtained from these reports may be critical to future action that improves patient safety.”

Currently, CDRH receives most mandatory medical device adverse event reports on paper, which requires that reports are manually entered into the center’s adverse event database, called the Manufacturer and User Facility Device Experience (MAUDE) database, for further analysis. Not only is this step costly, but it hinders CDRH’s ability to review safety data quickly to uncover potential public health problems.

The proposed regulation for medical devices would require manufacturers, importers and user facilities to submit reports to the FDA in electronic format, which will be loaded into the MAUDE database.

The electronic medical device reporting system, known as eMDR, provides a choice of two electronic options for reporting postmarket safety information. Small manufacturers with a limited number of reports may prefer an application known as eSub, which runs on free software available from the FDA. Large manufacturers, which can submit hundreds of reports per year, may prefer to use a batch submission protocol, based on a widely recognized informatics standard.

The FDA’s Center for Drug Evaluation and Research (CDER) and Center for Biologics Evaluation and Research (CBER) currently receive adverse event reports on paper forms or electronically. Safety reporting data submitted on paper forms must be manually entered into the FDA’s Adverse Event Reporting System (AERS) before these data can be evaluated. Since 2000, CDER and CBER have allowed manufacturers (through a pilot program and FDA guidance) to submit adverse event reports electronically, which get quickly entered into AERS. This pilot program has enabled FDA staff to more rapidly review postmarketing safety data and identify emerging safety problems. Safety reports in electronic format can currently be submitted to the FDA either through the FDA’s Electronic Submission Gateway or on CD-ROM, digital tape, or floppy disk. International Conference on Harmonization (ICH) standards for data elements and technical specifications are used for these electronic submissions.

The proposed rule for drugs and biologics reporting would require manufacturers, packers and distributors to submit reports to the FDA in electronic format, which will eliminate manual processing of paper forms by both manufacturers and the FDA. Reports will be submitted to the FDA using either the ICH electronic standards or through an FDA safety reporting Web portal that is currently under development.

“Electronic reporting of serious and unexpected adverse experiences will reduce industry costs and encourage better communication with the FDA and other regulators,” said Gerald J. Dal Pan, M.D., director of CDER’s Office of Surveillance and Epidemiology.

The proposed rule for drugs and biologics reporting does not apply to safety reports filed under an investigational new drug application, annual reports that manufacturers submit to the FDA on approved drugs and biologics, biologic product deviation reports, reports of complications of blood transfusion and collection confirmed to be fatal, and certain reports on human cells, tissues and cellular and tissue-based products.

The proposed rule for medical devices does not apply to reports submitted on a voluntary basis.

Manufacturers submitting reports under either rule would be required to obtain an electronic certificate to use the FDA Electronic Submissions Gateway. Information on how to prepare and send postmarket safety reports for devices and for drugs and biologics is contained in draft guidance documents. Draft guidance for device reports is available today—draft guidance for drug and biological product reports has been available since June 2008.

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SAMHSA and FDA Join to Educate the Public on the Safe Use of Methadone

The U.S. Substance Abuse and Mental Health Services Administration (SAMHSA) and the U.S. Food and Drug Administration (FDA) today launched an initiative to help ensure the safe use of methadone. A prescription drug best known as a treatment for addiction and dependence on heroin and other narcotic pain medicines, methadone is also prescribed to treat moderate-to-severe chronic pain patients. The campaign responds to concerns about an escalating number of poisoning deaths linked to the improper use of this medication.

The public outreach effort, Follow Directions: How to Use Methadone Safely, is designed to inform consumers, health care professionals and treatment clinics about the safe use and misuse of the drug for both pain relief and drug addiction treatment.

Methadone is a synthetic opioid that has been used for decades to reduce drug withdrawal symptoms. Recently, it has been increasingly prescribed as a pain reliever for patients whose moderate-to-severe chronic pain does not respond to non-narcotic pain medications.

The percentage of all poisoning deaths linked to methadone has tripled in recent years, increasing from 4 percent in 1999 to 14 percent in 2004, according to the Centers for Disease Control and Prevention. Moreover, the number of poisoning deaths linked to methadone is rising faster than the number of poisoning deaths from any other narcotic drug.

Methadone may be best known for use as an addiction treatment medication, but the bigger problem and concern has been with the more recent use as an analgesic. The risk of methadone overdose is partly due to the way the drug metabolizes in the body. People who take methadone normally feel relief within four to eight hours. However, unlike other narcotic pain relievers a single dose of methadone can remain in the body anywhere from eight to 59 hours. As a result, the drug builds up to toxic levels if it is taken too often, in too high an amount, or with other medications.

“The methadone safety campaign materials provide simple instructions on how to use the medication correctly to either manage pain or treat drug addiction,” said H. Westley Clark, M.D., J.D., M.P.H., C.A.S., F.A.S.A.M., Director of SAMHSA’s Center for Substance Abuse Treatment. “Our goal for this training is to support the safe use of methadone by all patients and prescribing healthcare professionals.”

Methadone, when used for the treatment of narcotic addiction, must be dispensed by a program/clinic that is certified by SAMHSA and registered with the Drug Enforcement Administration (DEA). But when used as an analgesic, methadone may be prescribed by any healthcare professional registered to prescribe Schedule II controlled substances, and can be dispensed by any licensed and DEA-registered pharmacy.

“Methadone is an important and beneficial drug when prescribed and used properly,” said Douglas Throckmorton, M.D., Deputy Director of the FDA’s Center for Drug Evaluation and Research. “Educational efforts like the one we are announcing today can help prevent the tragedies that occur when methadone is used improperly.”

Outreach materials about methadone for the public and health care professionals include a brochure, a poster and a fact sheet, in English and Spanish. In addition, a point-of-sale information sheet will be distributed in pharmacies where methadone is dispensed to pain management patients.

SAMHSA and the FDA will continue to work collaboratively with other federal agencies, states, health professional societies, patient advocacy groups, and other interested parties to develop and implement practical steps to reduce avoidable methadone-associated deaths.

To learn more information about the campaign, visit www.dpt.samhsa.gov/methadonesafety.

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Federal Agents Seize more than $24 Million in Unapproved New Drugs

Representatives of the U.S. Food and Drug Administration and the U.S. Marshals Service today seized $24.2 million worth of unapproved new drugs from KV Pharmaceutical Company of St. Louis, Mo. Agents acted after United States Attorney Catherine L. Hanaway filed a civil forfeiture suit and obtained a warrant to seize the unapproved new drug products being made by KV Pharmaceutical.

"American consumers are entitled to have safe and effective drugs," said Hanaway.

The seizure followed an inspection of several of the company's plants where FDA investigators found that the company was not complying with an FDA enforcement notice as well as manufacturing unapproved new drugs such as products for cough, cold, topical wound healing, skin bleaching, and gastrointestinal conditions, as well as narcotic drug products.

"The FDA is committed to taking enforcement action against firms that circumvent the drug approval process," said Janet Woodcock, M.D., director of FDA's Center for Drug Evaluation and Research (CDER). "Consumers need to be confident that the drugs and medical products they use are safe and effective, and the FDA will take the necessary measures to ensure safety and effectiveness throughout the lifecycle of the product, including keeping the product from reaching the marketplace."

In a routine inspection of KV Pharmaceutical's facilities in early 2008, the FDA found the company was violating its May 29, 2007, notice (72 FR 29517) requiring companies to stop manufacturing all timed-release drug products containing guaifenesin, including combination drug products in which guaifenesin is in immediate release form, but another ingredient in the combination drug product is in timed-release form, because they are unapproved new drugs. FDA took the action as part of its effort to ensure that all drugs marketed in the United States have the required FDA approval and that they are safe, effective, of good quality, and are appropriately labeled. For products in timed-release form, FDA approval is also necessary to make sure that the product releases its active ingredients at the correct rate. Improperly manufactured timed-release products may release the active ingredients too quickly, too slowly, or not at all, making the product unsafe or ineffective.

The FDA required companies to stop manufacturing the affected products before August 27, 2007, and to stop shipping the products before November 26, 2007. KV Pharmaceutical continued to manufacture and ship these unapproved new drugs after the cessation dates.

The inspection also exposed the company's manufacturing and distribution of other unapproved drug products. Today's action addresses numerous unapproved drug products manufactured and distributed by the company.

The following drug products were seized and will be destroyed:

• PhenaVent Capsules
• PhenaVent LA Capsules
• PhenaVent PED Capsules
• Ethezyme Papain-Urea Ointment
• Ethezyme 650 Papain-Urea Ointment
• Ethezyme 830 Papain-Urea Ointment
• Hista-Vent DA Tablets
• Meperidine/Promethazine Capsules
• Pseudovent Capsules
• Pseudovent 400 Capsules
• Pseudovent PED Capsules
• Tri-Vent DM Syrup
• Tri-Vent DPC Syrup
• Hydro-Tussin DM Liquid
• Hydro-Tussin CBX Syrup
• Hydro-Tussin DHC Syrup
• Hydro- Tussin EXP Syrup
• Hydro-Tussin HD Syrup
• Hyoscyamine Sulfate Sublingual Tablets
• Hydroquinone 4% Cream
• Hydroquinone 4% Cream with Sunscreen
• Bromfenex Extended Release Capsules
• Bromfenex PD Extended Release Capsules

The seized drugs had been held under embargo by the state of Missouri. Since the time of the embargo, KV Pharmaceutical has been cooperating with FDA officials.

"The FDA will take action against companies that continue to manufacture or market an unapproved product after the marketing or distribution cessation date," said Deborah M. Autor, director of the FDA's Office of Compliance within CDER. "When a company does not heed a cessation date relating to a specific product, the FDA will take enforcement action relating to the company's other unapproved drugs."

In June 2006, the FDA issued a guidance document titled, "Marketed Unapproved Drugs—Compliance Policy Guide (CPG)." This CPG makes clear that companies may not market drugs that require approval without first establishing, through applications for approval, that the products are safe and effective.

The FDA encourages consumers who may have these products to contact their health care professional about FDA-approved treatments and discard these products.

FDA Reaches Settlement with California Hearing Device Maker

The U.S. Food and Drug Administration (FDA) has reached a settlement with California hearing device manufacturer Advanced Bionics LLC and its president and CEO Jeffrey Greiner over alleged violations of federal law. The alleged violations involved the failure to notify the FDA of a change of outside supplier or vendor, which may have exposed patients to unnecessary health risks, such as device failure and surgery.

Under the terms of the settlement, agreed to on July 14, 2008, Advanced Bionics will pay a civil money penalty of $1.1 million. Greiner will pay $75,000.

On July 7, 2003, Advanced Bionics received FDA approval to market the HiRes90k Implantable Cochlear Stimulator, an implant surgically placed under the skin behind the ear to treat profound hearing loss in some adults and children. The FDA regulates cochlear implants as Class III devices—the most stringent regulatory category for medical devices.

The FDA’s complaint against Advanced Bionics, filed November 2007 and amended July 7, 2008, alleges that Advanced Bionics shipped cochlear implants to customers in the United States without first filing appropriate supplemental information with the FDA, including notice of a change of a component supplier. The failure to submit supplemental information prevented the FDA from being able to evaluate the potential impact of the changes on the safety and effectiveness of the device.

As a result, the FDA considered those devices—shipped to health care providers across the country after the company changed suppliers—to be adulterated, as they were no longer covered by the agency’s original product approval, granted in 2003.

In March 2006, Advanced Bionics conducted a recall of the unimplanted devices containing components from the unapproved supplier, because of excessive moisture that could leak into the devices and cause device failure and possible surgery.

The FDA’s complaint also stated that two devices containing the component from the unapproved supplier were shipped by Advanced Bionics after the March 2006 recall and subsequently implanted in patients.

Advanced Bionics and Greiner agreed to settle the complaint without admitting liability, and must remit payment to the U.S. Treasury within 10 days of settlement.

Advanced Bionics LLC, is based in Sylmar, Calif.

FDA, European Medicines Agency to Consider Additional Test Results When Assessing New Drug Safety

In the first use of a framework allowing submission of a single application to the two agencies, the Food and Drug Administration (FDA) and the European Medicines Agency (EMEA) worked together to allow drug companies to submit the results of seven new tests that evaluate kidney damage during animal studies of new drugs. The tests measure the levels of seven key proteins or "biomarkers" found in urine that can provide additional information about drug-induced damage to kidney cells, also known as renal toxicity.

The new biomarkers are KIM-1, Albumin, Total Protein, β2-microglobulin, Cystatin C, Clusterin, and Trefoil Factor-3. For decades, both FDA and EMEA have required drug companies to submit the results of two blood tests, called blood urea nitrogen (BUN) and serum creatinine, to evaluate renal toxicity. In addition to those tests, the FDA and EMEA will now consider results from the seven new tests as part of their respective drug review processes. Although a decision by the sponsor to collect information using the new tests is voluntary, if collected, it must be submitted to FDA.

"The development of these and other biomarkers can result in important tools for better understanding the safety profile of new drugs," said Janet Woodcock, M.D., director of FDA's Center for Drug Evaluation and Research. "We hope these biomarkers will lead to human tests that detect drug-induced kidney injury in people earlier than is now possible, and help health care professionals better manage potential kidney damage from drugs."

Woodcock added that such human tests could one day open the door to the approval of more powerful drugs, especially for diseases where renal toxicity currently prevents promising experimental drugs from being approved. With more sensitive tests for renal toxicity, FDA could approve such drugs because health care professionals could closely monitor patients and halt the drug if early signs of renal toxicity appear.

Development of the new biomarkers was led by the Predictive Safety Testing Consortium (PSTC), whose members include scientists from 16 pharmaceutical companies. The PSTC was organized and led by the Critical Path Institute, a nonprofit organization that works to support FDA research collaborations that improve the development of medical products.

Researchers from Merck & Co., Whitehouse Station, N.J., and Novartis AG, Basel, Switzerland, identified the new biomarkers, tested them to prove their accuracy and usefulness, and then shared their findings with the other consortium members for further study. The consortium then submitted applications for use of the biomarkers to FDA and EMEA.

The project is the first in which a group of drug companies has worked together to propose and qualify new safety tests and then present them jointly to the FDA and EMEA for consideration. The FDA and EMEA laid the groundwork for these specific joint-agency biomarker reviews in 2004 when they developed a framework called the Voluntary Exploratory Data Submission review process.

The new process allowed the PSTC to submit a single biomarker data application to both regulatory agencies, and then to meet jointly with scientists from both agencies to discuss it in detail and to address additional scientific questions posed by the regulators. Each regulatory agency then reviewed the application separately and made independent decisions on use of the new biomarkers.

FDA scientists believe that the seven new tests may provide important advantages over the BUN and creatinine tests. For example, in experiments using rats, the two traditional tests can only detect kidney damage a week after it has begun to occur. The new tests, however, are more sensitive and can detect cellular damage within hours. And while BUN and serum creatinine show that damage has occurred somewhere in the kidneys, the new tests can pinpoint which parts of the kidney have been affected.

The seven new tests were developed and will be carried out initially in rats. These tests were selected because other studies have shown that identical biomarkers are produced in human kidney cells. While the FDA and EMEA will consider these biomarkers in rat studies initially, the PSTC has begun work to further qualify the biomarkers for use in human studies. If successful, the PSTC will present a new biomarker data application to the two agencies to seek acceptance of the human biomarkers.

FDA Announces New Labeling Changes for Regranex

The U.S. Food and Drug Administration today announced the addition of a boxed warning to the label of Regranex Gel 0.01% (becaplermin) to address the increased risk of cancer mortality in patients who use 3 or more tubes of the product. Regranex is a topical cream indicated for the treatment of leg and foot ulcers that are not healing in diabetic patients.

The warnings section of the product has been updated to include a boxed warning and a description of the epidemiologic data that is the basis for the revised label. These data come from a retrospective study that compared cancer incidence and cancer mortality among 1,622 patients exposed to Regranex to 2,809 otherwise similar patients who were not exposed. The results were consistent with no overall increase in cancer incidence among the patients exposed to Regranex. However, there was a five-fold increased risk of cancer mortality in the group exposed to three or more tubes of Regranex.

"In announcing this label change, FDA still cautions health care professionals to carefully weigh the risks and benefits of treating patients with Regranex," said Susan Walker, M.D., director of the Division of Dermatological and Dental Products. "Regranex is not recommended for patients with known malignancies."

In late March FDA issued an Ongoing Safety Review Communication on Regranex notifying the public that it was conducting a safety review. This follow-up communication is in keeping with FDA’s commitment to notify the public of any regulatory changes with this FDA approved product.

Regranex is a medicine that is a recombinant form of human platelet-derived growth factor which is applied directly to diabetic foot and leg ulcers that are not healing. The recombinant form of platelet growth factor has a biologic activity that is much like that produced naturally by the body. Growth factors cause cells to divide more rapidly. It is for this reason that the manufacturer continued to monitor studies begun before Regranex was approved in December 1997 for any evidence of adverse effects such as increased numbers of cancers. In a long term safety study completed in 2001, there were more deaths from cancer in people who used Regranex than in those who did not use it.

Following the report of the study completed in 2001, an additional study was performed using a health insurance database that covered the period from January, 1998 through June, 2003. This study used the database to identify two groups of patients with similar diagnoses, drug use, and use of health services, one of which used Regranex and one group that did not. The results of this study showed that deaths from cancer were higher for patients who were given three or more prescriptions for treatment with Regranex than those who were not treated with Regranex. No single type of cancer was identified, but rather deaths from all types of cancer, combined were observed.

To read about Regranex and FDA's follow-up communication go to:

Becaplermin (marketed as Regranex) Information

Update of Safety Review: Follow-up to the March 27, 2008, Communication about the Ongoing Safety Review of Regranex (becaplermin)

The FDA urges healthcare professionals to promptly report serious and unexpected adverse reactions associated with Regranex to the FDA MedWatch reporting program, as described below.

• online at www.fda.gov/medwatch/report.htm
• by returning the postage-paid FDA form 3500 (available in PDF format at www.fda.gov/medwatch/getforms.htm) to 5600 Fishers Lane, Rockville, MD 20852-9787
• faxing the form to 1-800-FDA-0178
• by phone at 1-800-332-1088