Phase I Dosing for Cancer Drugs Detailed in New ICH Guidance

FDA News Source
FDA draft guidance

Phase I clinical trials of cancer drugs can include maximum tolerated doses and dose-limiting toxicity, an International Conference on Harmonisation (ICH) draft guidance says. The draft offers advice on conducting nonclinical studies of drugs intended for patients with advanced cancer and limited therapeutic options, along with suggestions for conducting Phase I clinical trials to assess drug safety. Comments are due April 20.

FDA and International Serious Adverse Events Consortium Release First Data on Genetic Basis of Adverse Drug Events

FDA News Source
International Serious Adverse Event Consortium
FDA’s Critical Path Initiative

The first data offering health care professionals a better look into the genetic basis of certain types of adverse drug events was released today by the FDA and the International Serious Adverse Event Consortium (SAEC). The data are focused on the genetics associated with drug-induced serious skin rashes, such as Stevens-Johnson syndrome and toxic epidermal necrolysis, and helps better predict an individual’s risk of developing these reactions.

Both skin conditions appear as allergic-like skin reactions associated with blistering and peeling, and are considered life-threatening. Medications causing these serious allergic reactions should be discontinued; and if such signs and symptoms are not quickly recognized, these reactions can be fatal.

“The SAEC has fulfilled a key goal of the Critical Path Initiative by providing the research community with public access to new genomic data on adverse drug events,” said Janet Woodcock, M.D., director, the FDA’s Center for Drug Evaluation and Research. “This consortium has taken a significant step forward by promoting open sharing of drug safety data. This type of cooperation has the potential to lead to more personalized approaches to medicine that can reduce a patient’s risk for experiencing an adverse drug event.”

The SAEC is a nonprofit partnership of pharmaceutical companies, the Wellcome Trust, and academic institutions focused on research relating to the genetics of drug-induced serious adverse events. The samples from the initial serious skin rash cases and matched controls were collected by GlaxoSmithKline plc, London, U.K., and donated to the consortium for this research.

By pooling these samples, the SAEC has identified numerous genetic associations that may contribute to an individual’s risk of developing serious drug-induced skin reactions. The data was compiled and analyzed just 16 months after the consortium was launched.

“We are pleased to be able to provide these invaluable data to the research community to both improve the productivity of drug development and to begin the critical process of developing validated biomarkers to forecast patients who may be at risk for drug-induced serious adverse events,” said Arthur Holden, founder and chairman of the SAEC. “We continue to believe the application of genomics to research the genetic basis of serious adverse events will prove to be one the most productive early applications of this technology.”

The consortium will publish its initial research results later this year.

Researchers who enter in to a data use agreement can obtain free access to the data to generate custom data inquiries and obtain immediate results on the genetic basis of adverse drug events.

FDA Takes New Regulatory Action Against Ranbaxy’s Paonta Sahib Plant in India

FDA Source

Agency halts review of drug applications from plant due to evidence of falsified data; invokes Application Integrity Policy

The U.S. Food and Drug Administration today announced that a facility owned by India-based Ranbaxy Laboratories falsified data and test results in approved and pending drug applications. The facility, Paonta Sahib, has been under an FDA Import Alert since September 2008.

The FDA is continuing to investigate this matter to ensure the safety and efficacy of marketed drugs associated with Ranbaxy’s Paonta Sahib site. To date, the FDA has no evidence that these drugs do not meet their quality specifications and has not identified any health risks associated with currently marketed Ranbaxy products.

In the meantime, the FDA recommends that patients not disrupt their drug therapy because this could jeopardize their health. Individuals who are concerned about their medications should talk with their health care professional.

The affected applications are for drugs that fall into three categories:

* Approved drugs made at the Paonta Sahib site for the U.S. market;

* Drugs pending approval at the FDA that are not yet marketed; and

* Certain drugs manufactured in the United States that relied on data from the Paonta Sahib facility.

“Companies must provide truthful and accurate information in their marketing applications,” said Janet Woodcock, M.D., director of the FDA’s Center for Drug Evaluation and Research (CDER). “The American public expects and deserves no less.”

To address the falsified data, the FDA has invoked its Application Integrity Policy (AIP) against the Paonta Sahib facility. The AIP is invoked when a company’s actions raise significant questions about the integrity of data in drug applications. This AIP covers applications that rely on data generated by the Paonta Sahib facility only.

Under the AIP, the FDA has asked Ranbaxy to cooperate with the agency to resolve the questions of data integrity and reliability. This would include implementing a Corrective Action Operating Plan (CAOP) to provide assurance of the integrity and reliability of data from the Paonta Sahib facility. A CAOP includes, but is not limited to, conducting a third-party independent audit of applications associated with Paonta Sahib.

When the AIP is implemented, the FDA stops all substantive scientific review of any new or pending drug approval applications that contain data generated by the Paonta Sahib facility.

“The FDA’s investigations revealed a pattern of questionable data raising significant questions regarding the reliability of certain applications, and this warrants applying the Application Integrity Policy,” said Deborah Autor, director of CDER’s Office of Compliance. “Today’s action reflects the FDA’s continued vigilance and its steadfast commitment to safeguarding the public’s health.”

On Sept. 16, 2008, the FDA issued two warning letters and instituted an Import Alert barring the entry of all finished drug products and active pharmaceutical ingredients from Ranbaxy’s Dewas, Paonta Sahib and Batamandi Unit facilities due to violations of U.S. current Good Manufacturing Practices requirements. That action barred the commercial importation of 30 different generic drugs into the United States and remains in effect.

FDA Requires Boxed Warning and Risk Mitigation Strategy for Metoclopramide-Containing Drugs

FDA Source

Agency warns against chronic use of these products to treat gastrointestinal disorders

The U.S. Food and Drug Administration announced today that manufacturers of metoclopramide, a drug used to treat gastrointestinal disorders, must add a boxed warning to their drug labels about the risk of its long-term or high-dose use. Chronic use of metoclopramide has been linked to tardive dyskinesia, which may include involuntary and repetitive movements of the body, even after the drugs are no longer taken.

Manufacturers will be required to implement a risk evaluation and mitigation strategy, or REMS, to ensure patients are provided with a medication guide that discusses this risk.

“The FDA wants patients and health care professionals to know about this risk so they can make informed decisions about treatment,” said Janet Woodcock, M.D., director of the FDA’s Center for Drug Evaluation and Research. “The chronic use of metoclopramide therapy should be avoided in all but rare cases where the benefit is believed to outweigh the risk.”

Current product labeling warns of the risk of tardive dyskinesia with chronic metoclopramide treatment. The development of this condition is directly related to the length of time a patient is taking metoclopramide and the number of doses taken. Those at greatest risk include the elderly, especially older women, and people who have been on the drug for a long time.

Tardive dyskinesia is characterized by involuntary, repetitive movements of the extremities, or lip smacking, grimacing, tongue protrusion, rapid eye movements or blinking, puckering and pursing of the lips, or impaired movement of the fingers. These symptoms are rarely reversible and there is no known treatment. However, in some patients, symptoms may lessen or resolve after metoclopramide treatment is stopped.

Metoclopramide works by speeding up the movement of the stomach muscles, thus increasing the rate at which the stomach empties into the intestines. It is used as a short-term treatment of gastroesophageal reflux disease in patients who have not responded to other therapies, and to treat diabetic gastroparesis (slowed emptying of the stomach’s contents into the intestines). It is recommended that treatment not exceed three months.

Metoclopramide is available in a variety of formulations including tablets, syrups and injections. Names of metoclopramide-containing products include Reglan Tablets, Reglan Oral Disintegrating Tablets, Metoclopramide Oral Solution, and Reglan Injection. More than two million Americans use these products.

Recently published analyses suggest that metoclopramide is the most common cause of drug-induced movement disorders. Another analysis of study data by the FDA showed that about 20 percent of patients in that study who used metoclopramide took it for longer than three months. The FDA has also become aware of continued spontaneous reports of tardive dyskinesia in patients who used metoclopramide, the majority of whom had taken the drug for more than three months.

Consumers and health care professionals are encouraged to report adverse events to the FDA's MedWatch program at 800-FDA-1088, by mail at MedWatch, HF-2, FDA, 5600 Fishers Lane, Rockville, Md. 20852-9787, or online at: www.fda.gov/medwatch/report.htm

Elite Announces Drug Application Filing For Synthetic Narcotic Analgesic Accepted by FDA

Globes News Wire Source

Elite Pharmaceuticals, Inc. ("Elite" or the "Company") (AMEX:ELI) in collaboration with ThePharmaNetwork, LLC., announced today the acceptance by the U.S. Food and Drug Administration (FDA) of the Abbreviated New Drug Application (ANDA) for a generic equivalent of a synthetic narcotic analgesic drug product. The product had annual sales of approximately $36 million in 2007. Elite will manufacture the product and will receive a share of the profits from the sale of the product upon commercialization.

"We are pleased to reach this milestone and look forward to working with ThePharmaNetwork in this venture," commented Bernard Berk, Chairman and CEO for Elite. "With the revenue generated from the Lodrane(r) products along with the proceeds of our recent capital raise, Elite continues to move forward with the development of our two lead pain products, ELI-216, our abuse resistant oxycodone, and ELI-154, our once daily oxycodone product and will complete the work necessary for initiating Phase III clinical studies. Prescription drug abuse is a national crisis and abuse resistant drugs, like those being developed by Elite, are aimed at making a significant impact on this problem. ELI-216 is differentiated from other abuse resistant products in development by being the only once daily oxycodone using a pharmacological approach for abuse resistance. The pharmacological approach, we believe, compared to other technologies can provide a higher barrier for those recreational drug users trying to use these prescription drugs inappropriately to achieve a euphoric high and the once daily delivery provides a more consistent blood levels of the drug for these chronic indications as compared to the current sustained release oxycodone products. Elite will continue to prosecute the patents it has filed for this product and is preparing to file additional patents to strengthen our intellectual patent estate. Elite has also improved its financial condition by restructuring its workforce which, together with the growth in Elite's Lodrane revenues (approximately $1.3 million in last 6 months), is expected to significantly reduce Elite's operating losses. Lodrane 24(r) and Lodrane 24D(r) are products manufactured by Elite and sold and distributed by our partner ECR Pharmaceuticals. We will continue to seek out additional partnering prospects and other venture opportunities to leverage our proprietary opioid abuse technology and our unique drug delivery systems."

FDA Offers Advice on End of Phase IIa Meetings

FDA Source

The FDA is recommending that IND sponsors meet with the agency at the end of Phase IIa clinical trials to discuss dose estimation and selection for late-stage efficacy trials and whether novel trial designs would be useful, according to a new CDER draft guidance. The meeting also would allow sponsors to discuss critical data on drug interactions, studies in special populations defined by genetic characteristics or other biomarkers, and other pharmacokinetic or pharmacodynamic relationships.

The FDA is also recommending that IND sponsors meet with the agency at the end of Phase IIa clinical trials to discuss dose estimation and selection for late-stage efficacy trials and whether novel trial designs would be useful, according to a draft guidance from the Center for Drug Evaluation and Research.

Comments on the draft are due Nov. 25.

U.S. Food & Drug Administration Approved the use of REYATAZ® (atazanavir sulfate) Boosted with Ritonavir, in Combination Therapy, for Previously Untreated HIV-1 Infected Adult Patients

Business Wire Source

Bristol-Myers Squibb Company (NYSE: BMY) announced today that the U.S. Food & Drug Administration (FDA) approved the use of REYATAZ® (atazanavir sulfate) 300 mg once-daily boosted with ritonavir 100 mg as part of combination therapy in previously untreated (treatment-naive) HIV-1 infected patients. REYATAZ boosted with ritonavir (REYATAZ/r) taken once daily with food is recognized by the U.S. Department of Health and Human Services (DHHS) as a preferred component of combination HIV therapy for treatment-naive patients1.

For treatment-naive patients who are unable to tolerate ritonavir, REYATAZ 400 mg (without ritonavir), taken once daily with food, is recommended.

This use of once-daily REYATAZ/r in HIV-1 infected treatment-naive adult patients is based on 48-week results from the CASTLE study, which demonstrated similar antiviral efficacy of REYATAZ/r to twice-daily lopinavir/ritonavir (lopinavir/r), each as part of HIV combination therapy, in treatment-naive HIV-1 infected adult patients.

Within the CASTLE study, the REYATAZ/r arm was associated with low increases from baseline in total cholesterol (13 percent), LDL cholesterol (14 percent), HDL cholesterol (29 percent), and triglycerides (15 percent). The lopinavir arm was associated with 25 percent increase in total cholesterol, 19 percent increase in LDL cholesterol, 37 percent increase in HDL cholesterol, and 52 percent increase in triglycerides. Two percent of patients in the REYATAZ® (atazanavir sulfate)arm and eight percent of patients in the lopinavir arm required lipid-lowering therapy in the study, compared to 1 percent in each arm at baseline.

Safety events in this study were consistent with prior experience. Grade 2-4 treatment-related adverse events that occurred in two percent or greater of patients in the CASTLE study included jaundice (4 percent and zero percent), nausea (4 percent and 8 percent), diarrhea (2 percent and 11 percent) and rash (3 percent and 2 percent) in the REYATAZ/r and lopinavir/r arms, respectively. Grade 3–4 increases in total bilirubin were seen in 34 percent of patients in the REYATAZ/r arm and in less than 1 percent of patients in the lopinavir/r arm.

"Bristol-Myers Squibb is committed to developing medicines that enhance the care of people living with HIV and AIDS," said Elliott Sigal, M.D., Ph.D., Executive Vice President, Chief Scientific Officer and President, Research and Development, Bristol-Myers Squibb. "Boosted REYATAZ provides health care professionals a newly approved, once-daily dosing option as part of combination therapy for patients naive to HIV therapy."

Process Validation Guidance to Focus on Testing Upfront

FDA News Source

The FDA will emphasize more oversight and batch testing in the early stages of drug commercialization in its revised guidance on process validation, according to Brian Hasselbalch, a consumer safety officer in CDER’s Division of Manufacturing and Product Quality.

Prescription Drug Advertising Subject of New FDA Web Site for Consumers

PR News Wire Source

EthicAd, a nonprofit organization devoted to improving public health through consumer education, announces the launch of a new FDA Web site created to help the general public better understand direct-to-consumer (DTC) advertising of prescription medications. The site, "Be Smart About Prescription Drug Advertising," is hosted by the FDA's Center for Drug Evaluation and Research and was developed by the FDA in partnership with EthicAd. For details, visit EthicAd.

Michael S. Shaw, M.D., executive director of EthicAd, notes that the primary goal of the new site is to help the public obtain accurate, science-based information about prescription drugs and to understand the role and nature of DTC advertising.

"People are often confused about DTC advertising, which is one of the most controversial areas of pharmaceutical marketing," Shaw says. "FDA's new Web site helps clarify the issues by outlining the different types of DTC advertising, explaining what information people should expect to see in DTC ads, and what additional information they should seek out about advertised products."

The easy-to-navigate site includes a practical "Ask Yourself" checklist summarizing information consumers should obtain in order to have knowledgeable conversations with their physicians about advertised products. The new Web site also includes a section for public feedback, which will be used to shape the direction of future FDA consumer-oriented initiatives.

"We share the FDA's commitment to developing innovative and relevant education programs," Shaw says. "By helping consumers obtain factual and reliable information about prescription drugs and have empowered conversations with their healthcare providers about treatment options, EthicAd and the FDA hope to improve individual patient outcomes as well as improve the public health at large."

EthicAd is a volunteer nonprofit organization whose goal is maximizing the public health benefits of DTC advertising by promoting the development of ads that provide substantive, understandable and reliable information about pharmaceutical products. The organization was founded by noted heart surgeon and Congressional Gold Medal recipient Dr. Michael E. DeBakey.

EthicAd does not receive any funding from the pharmaceutical industry.

FDA to List Drugs Under Review for Safety Issues

Wall Street Journal Source Wave 3 Source

Conference with Gerald Dal Pan, M.D., M.P.H., director, Office of Surveillance and Epidemiology, CDE and Paul Seligman, M.D., M.P.H., associate director of Safety Policy and Communication, CDER, both with U.S. FDA

The U.S. Food and Drug Administration has started listing on its Web site drugs being evaluated for potential safety issues, the agency said Friday.

"If a drug appears on a quarterly report, it means we have begun analysis to determine whether there is a safety problem that requires further evaluation," Dr. Gerald Dal Pan, director of the FDA's Office of Surveillance and Epidemiology, Center for Drug Evaluation and Research, said during a Friday teleconference.

This information is being posted as part of the 2007 Food and Drug Administration Amendments Act. Under the act, the agency must post quarterly information on potential drug risks, based on the agency's review of adverse-event reports submitted by doctors.

The list contains only the drug's name and the potential problem associated with it; it doesn't reveal the extent of the problem or how many adverse reports have been filed.

The list also doesn't include all the drugs the FDA is currently reviewing for safety problems, Dal Pan said. "This list is derived from issues identified in the adverse-event reporting system," he said.

The current list covers January to March 2008. The appearance of a drug on the list doesn't mean the FDA has concluded that there's a problem with it. A drug only appears on the list because the agency has identified a potential safety problem, Dal Pan said.

The initial list, released Friday on the Web site, includes 20 drugs. The drugs range from the anesthetic Desflurane, which has been linked to cardiac arrest, to nitroglycerin (Nitrostat) which is used to treat angina. A confusing label could result in overdose, the agency said. Other drugs on the list include natalizumab (Tysabri), which is used to treat multiple sclerosis and Crohn's disease and has been linked to melanoma, and telbivudine (Tyzeka), which treats hepatitis B and has been linked to damage to the nervous system, the FDA said.

The list includes a wide array of drugs, from Eli Lilly & Co.'s antidepressant Cymbalta to Purdue Pharma LP's painkiller Oxycontin. It also addresses a range of adverse reactions, including cardiac arrest, cancer and Purple Glove Syndrome, which can result in patients having their arms amputated. (See the FDA's list of drugs that are under investigation.)

Drugs under investigation before 2008 or after March aren't included on the current list. Dal Pan said he wasn't sure when an updated list would be posted.

FDA officials emphasized that people taking drugs on the list should not overreact and stop taking them.

"As always, we are very sensitive to the potential misinterpretation or over-interpretation of any potential unintended consequences because the drug is on the list," Dr. Paul Seligman, the associate director of Safety Policy and Communication at the FDA's Center for Drug Evaluation and Research, said during the teleconference.

"There is always the risk that anytime you put something in writing and post it on an official FDA Web site that people will read into it more than that we are just conducting a review," Seligman said. "We are expecting people not to take actions simply based on the fact that we are evaluating a particular drug."

In addition to providing the public with more information, the agency thinks the list will encourage more reporting of adverse events.