DID - Oct. 12, 2009 - Issue

Vol. 8 No. 198

Safety Signals for 13 Medicines, Drug Classes Appear in FDA List

Manufacturers with products among the 13 drugs or classes of pharmaceuticals with potential safety signals of serious risks or new safety information that the FDA listed in a new report may face labeling changes, risk evaluation and mitigation strategy requests or more data gathering if the agency confirms a cause-and-effect link to adverse events.

The agency’s adverse event reporting system includes incidents ranging from gastrointestinal perforation to liver failure during the first three months of 2009.

A product’s inclusion on the list, which the agency issues quarterly, does not establish proof of danger, the FDA says. A potential safety signal, such as elevated liver enzymes, does not mean that the FDA has identified a causal relationship between the drug and the listed risk or that the agency is suggesting the product should not be prescribed or used.

However, if the agency confirms a causal connection, it may require changes to the product’s labeling, development of a risk evaluation and mitigation strategy or the gathering of more data to characterize the risk.

One prominent product on the list is Pfizer’s oncology drug Sutent (sunitinib malate), which is approved for advanced renal cell carcinoma and gastrointestinal stromal tumor (DID, Jan. 27, 2006). The FDA says it is continuing to evaluate the risk of liver failure for this drug to determine whether regulatory action should be taken.

Another prominent product on the list, Roche’s antibiotic Rocephin (ceftriaxone sodium), had the risk of hemolytic anemia added to the warnings section of its label in June.

An example of a class of drugs cited in the list is promethazine injection, previously sold under the brand Phenergan and discontinued by Wyeth Pharmaceuticals, which lost the product liability suit Wyeth v. Levine in the U.S. Supreme Court due to the drug's labeling (DID, March 5). A number of companies market generic formulations of the drug, which now must include a boxed warning (DID, Sept. 17).

The full list can be seen below. — Martin Berman-Gorvine

Potential Signals of Serious Risks/New Safety Information Identified

From January to March 2009

Product Name or Class

Potential Signal

Additional Information

Ceftriaxone (Rocephin)

Hemolytic anemia

Hemolytic anemia was added to the Warnings section of labeling in June 2009. Ceftriaxone (Rocephin) Label

Diclofenac epolamine patch (Flector)

Hypersensitivity reactions

The FDA is continuing to evaluate this issue to determine the need for any regulatory action.

Didanosine (Videx)

Portal hypertension

The FDA is continuing to evaluate this issue to determine the need for any regulatory action.

Entacapone (Comtan)


The FDA is continuing to evaluate this issue to determine the need for any regulatory action.

Gadolinium-based contrast agents


The FDA is evaluating this issue to determine if labeling for the various gadolinium-based contrast agents, which include descriptions of hypersensitivity reactions, is adequate.

Alpha interferon products

Pulmonary Hypertension

Pulmonary hypertension was added to the Warnings section of labeling for all alpha interferon products. See September 2009 FDA announcement: New Class Safety Labeling Updates for Alpha Interferon Products.

Mecasermin products (Increlex, Iplex)

Hypersensitivity reactions

The FDA is continuing to evaluate this issue to determine the need for any regulatory action.

Methylnaltrexone (Relistor)

Gastrointestinal perforation

The FDA is continuing to evaluate this issue to determine the need for any regulatory action.

Minocycline (Solodyn)

Autoimmune disorders in pediatric patients

The FDA is continuing to evaluate this issue to determine the need for any regulatory action.

Promethazine injection

Severe tissue injury including gangrene

In September 2009, the FDA informed manufacturers of promethazine injection to include a boxed warning in the labeling to highlight the risk of serious tissue injury when this drug is administered incorrectly. FDA Requires Boxed Warning for Promethazine Hydrochloride Injection

Sunitinib (Sutent)

Liver failure

The FDA is continuing to evaluate this issue to determine the need for any regulatory action.

Tenofovir (Viread)

Safety during pregnancy

The FDA decided that no action is necessary at this time based on available information. The FDA is continuing to monitor the issue.

Zoledronic acid (Reclast)

Renal impairment

Renal impairment was added to the Warnings and Precautions section of labeling in March 2009. Zoledronic acid (Reclast) Labeling

Source: FDA drug surveillance web page


FDA’s $3.2 Billion in FY 2010 Appropriations Waits on Obama Signature

The FDA’s 23 percent increase in appropriations to $3.2 billion for fiscal year 2010 is awaiting final approval from President Barack Obama as part of the appropriations bill Congress passed last week.

Prescription drug user fees also increased in the legislation, H.R. 2997, accounting for $578 million of the bill’s funding compared with $511 million last year.

The agency’s CDER received $880 million, 13 percent more than last year, no less than $51.5 million of which must be made available for the Office of Generic Drugs. CBER received $305 million, a 12.5 percent increase.

In congressional testimony last May, FDA Principal Deputy Commissioner Joshua Sharfstein said the agency would use the money to launch an initiative to improve the safety of medical products and pledged support for programs permitting follow-on biologics and drug importation from other countries (DID, May 22).

The agency plans to hire additional safety experts to analyze adverse events associated with drugs, biologics and medical devices to address patient-product interactions that generally do not relate to manufacturing flaws, Sharfstein said, and will rely on the principle of supply-chain safety and security to protect patients from contamination or other manufacturing flaws.

H.R. 2997 can be found at thomas.loc.gov/cgibin/cpquery/T?&report=hr279&dbname=111&. — David Belian


Eli Lilly Paid Faculty Physicians $22 Million in the First Quarter

Eli Lilly paid 3,339 physicians, excluding clinical investigators, a total of $22 million in the first three months of 2009 for healthcare professional education, patient education, advising and consulting, according to the company’s online “faculty registry.”

The registry lists payments by individual, including physicians in 32 group practices or hospitals, an analysis by DID shows. The company made the first-quarter results available July 31, and it will post second-quarter figures this month, a Lilly representative  told DID.

Of the three categories for which it details payments, Lilly spent the most — $18.4 million — on physicians to provide healthcare professional education, which includes programs “intended to enhance a healthcare professional’s knowledge and patient care expertise,” according to the registry website. Areas covered include:

  • Symptom identification, patient presentation and diagnosis;
  • Disease state information, epidemiology and disease management;
  • Medication dosage, frequency of administration and duration of use; and
  • Data from clinical trials on the efficacy and safety of the company’s drugs, and application of these data in clinical practice.

The company spent $1.8 million on physicians’ advising and consulting services, which include such areas as development of marketing materials; data analysis, interpretation and insights on clinical implications; treatment issues in specific patient populations; and healthcare professional education program development and training, according to Lilly’s registry.

Lilly also paid physicians $1.8 million for patient education, helping to educate patients on use of the company’s medicines at the request of their treating physicians.

Five individual physicians and one multi-person practice earned more than $60,000 from Lilly in the first quarter, approaching the company’s self-imposed annual ceiling of $75,000 per individual. Their names, medical specialties and the services they provided to Lilly are listed in the following table:

Eli Lilly’s Top Six Faculty Earners in 2009 First Quarter



Manoj Waikar, psychiatrist, San Jose, Calif.

$67,050 for healthcare professional education and $3,000 for advising and consulting

Roueen Rafeyan, psychiatrist, Kenilworth, Ill.

$68,400 for healthcare professional education

Manuel Suarez-Barcelo, internal medicine, Miami, Fla.

$65,100: $60,600 for healthcare professional education and $4,500 for advising and consulting

Scott Hoopes, psychiatrist, Meridian, Id.

$64,000 for healthcare professional education

Healthcare Technology Systems, Madison, Wis. (John Greist, James Jefferson and David Katzelnick, psychiatrists)

$61,769: $52,300 for healthcare professional education and $9,469 for advising and consulting

Fred Viren, endocrinologist, Spokane, Wash.

$60,500 for healthcare professional education

In addition, 40 individual physicians and one two-person practice were paid between $40,000 and $60,000 by Lilly during the first quarter.

DID tried to contact each of the top six earners for comment. Healthcare Technology Systems declined to comment, and Waikar, Rafeyan and Suarez-Barcelo did not respond by press time. Waikar is an adjunct clinical instructor in Stanford University’s Department of Psychiatry and Behavioral Sciences.

His position is not paid by the university, and his name does not appear on the its registry of payments made to faculty physicians, university spokeswoman Ruthann Richter told DID.

Stanford’s School of Medicine adopted a policy last year to prohibit new commercial funding for specific continuing medical education (CME) courses or programs (DID, Aug. 27, 2008). CME programs are independently accredited by the Accreditation Council for Continuing Medical Education, the American Academy of Family Physicians, the American Medical Association and other organizations.

Almost half of the $2.51 billion a year spent on CME in the U.S. comes from the industry, Hilary Schmidt, associate vice president of medical education at Sanofi-Aventis, said last year at the Food and Drug Law Institute’s conference on advertising and promotion in Washington, D.C. More than 14.7 million people participated in CME in 2007, collectively receiving more than 740,000 hours of instruction, she added (DID, Sept. 10, 2008).

The question of whether it is a conflict of interest for academic medical instructors to consult for drug companies has been high on the public agenda recently, with Sen. Chuck Grassley (R-Iowa) spearheading investigations into such figures as Charles Nemeroff, the former chair of the Department of Psychiatry and Behavioral Sciences at the Emory University School of Medicine (DID, Dec. 29, 2008).

Nemeroff agreed to step down from his post last December. Separately, Grassley’s office had revealed that he had received more than $800,000 from GlaxoSmithKline for more than 250 speaking engagements between January 2000 and January 2006.

Waikar does not receive NIH grants and is therefore exempt from its conflict-of-interest reporting regulations required for grant recipients, which is a particular concern of the senator’s, Jill Kozeny, a spokeswoman for Grassley, told DID.

Hoopes said that the entire question of conflict of interest is overblown. “There is potential for conflicts of interest in any relationship we have,” he told DID.

PhRMA’s view dovetails with Hoopes’ opinion. “Efforts to restrict physicians from serving as faculty for CME if they provide services to biopharmaceutical manufacturers are misguided,” PhRMA Senior Vice President Ken Johnson says in July statement. “Physicians who are involved in CME and who sit on committees that draft guidelines explaining best practices often are leaders in their field. … There is no evidence that a company’s funding of CME or other physician educational activities, when provided within appropriate guidelines, creates bias.”

However, Hoopes distinguished between the healthcare professional education he does for Lilly, which has a promotional purpose, and CME, which does not. He said he is on the company’s speakers’ bureau for the psychiatric drugs Cymbalta (duloxetine HCl), Zyprexa (olanzapine) and Strattera (atomoxetine HCl), which entails annual training in the marketing status of the product and information on new clinical trials of the drugs.

The guidelines he uses when speaking to physician groups are “to know and address the data in a thoughtful way, including its limitations, and don’t make outrageous statements,” he added.

The FDA’s attempts to regulate this field are hamstringing speakers, Hoopes said. For example, when asked a question during a presentation, he can no longer answer it himself but has to refer the questioner to Lilly, he noted.

Viren, the endocrinologist, is paid for presentations on Lilly’s osteoporosis drugs Evista (raloxifene HCl) and Forteo (teriparatide recombinant). He said he is “very happy” the company is posting its registry of physician payments online.

Lilly’s faculty registry is available at www.lillyfacultyregistry.com/lilly-registry-report.jsp. Stanford University’s registry is at med.stanford.edu/profiles. — Martin Berman-Gorvine


Pfizer Halts Figitumumab Study Enrollment to Investigate Deaths

Pfizer has suspended new patient enrollment in a Phase III clinical trial of its investigational compound figitumumab in nonsmall cell lung cancer (NSCLC) patients because of a higher number of deaths and other adverse events in the drug arm compared with another treatment arm.

Pfizer has notified all clinical trial investigators and regulatory agencies and will work closely with the data safety monitoring committee to conduct a thorough analysis, according to a company statement Friday.

The decision follows a routine review of serious adverse events by the committee that indicated an apparent imbalance between the treatment arms in which more events, including fatalities, were reported in patients receiving figitumumab, Pfizer says. Patients enrolled in the trial were randomized to receive either figitumumab combined with carboplatin and paclitaxel or the carboplatin-paclitaxel combination alone.

Patients who have already been enrolled may continue their treatment in consultation with their physicians, the company says. A separate Phase III study evaluating figitumumab in combination with erlotinib or erlotinib alone in patients with refractory non-adenocarcinoma NSCLC will continue to enroll new patients, Pfizer added. — Elizabeth Jones


Fusilev Gets Complete Response Letter From FDA

Spectrum Pharmaceuticals has received a complete response letter from the FDA regarding its sNDA for Fusilev to treat patients with advanced, metastatic colorectal cancer.

The FDA says in the letter that Spectrum has failed to show that Fusilev (levoleucovorin calcium) is not inferior to leucovorin and recommended a meeting to discuss the company’s options. Spectrum says in a statement Friday that it will make the request soon.

Fusilev is approved for “rescue” use after high-dose methotrexate therapy in osteosarcoma patients to diminish the toxicity of methotrexate and counteract the effects of impaired methotrexate elimination and inadvertent overdosage of folic acid antagonists. — Elizabeth Jones


Drugmakers to Get Parallel Scientific Advice From FDA, EMEA

Makers of drugs to be sold in the U.S. and Europe can nominate products to the FDA and the European Medicines Agency (EMEA) to receive development guidance under a new parallel scientific advice program launched by the agencies.

The program is designed to give drugmakers a better understanding of regulatory decisions, improve drug development and avoid unnecessary testing replication and methodologies, the EMEA says in a statement Friday.

The program will focus on sharing information rather than harmonizing regulatory requirements, the EMEA says. The parallel advice meetings should yield a clear idea for drugmakers of the respective requirements and perspectives of the two agencies with regard to the development program discussed, and if necessary, reasons for any divergence.

Because resources are limited, the program will focus on breakthrough drugs, especially those being developed for indications for which there are no development guidelines or recommendations from the EMEA and the FDA that differ.

Safety areas of interest also will be a focus of the program, the EMEA says, including: oncology, anti-infectives, orphan drugs, drugs for pediatric use, nanotechnology and advanced therapies.

Drugmakers that wish to nominate a product for parallel scientific advice should address a letter to Emer Cooke at the EMEA and Janice Soreth at the FDA. The letter should explain why a discussion with assessors of both agencies would help product development, list specific questions for clarification and the desired goals for the meeting.

The drugmaker letter also should explicitly authorize the comprehensive exchange between the two agencies of all information relevant to the subject product, specifically trade secret information, the EMEA says. — David Belian

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