DID - July 14, 2009 Issue

Vol. 8 No. 135


Guidance: Add Labels to Unapproved OTC Drug Adverse Event Reports

The FDA has given manufacturers of OTC products without approved applications more information on the minimum data elements that should be included in an adverse event report in a final guidance.

“Postmaketing Adverse Event Reporting for Nonprescription Human Drug Products Marketed Without an Approved Application” in today’s Federal Register tells manufacturers where to submit the reports and gives information about the label to be included and reporting formats for paper and electronic submissions.

A manufacturer, packer or distributor whose name appears on the label of a nonprescription drug marketed in the U.S. without an approved application — known as the responsible person — must submit to the FDA any report of a serious adverse event associated with the drug’s use, accompanied by a copy of the label on or within the retail package of the drug.

An initial individual case safety report (ICSR) should include four elements:

  • A suspect drug;
  • An identifiable patient;
  • An identifiable person who reported the adverse event; and
  • A serious adverse event or fatal outcome.

To identify the suspect drug, the responsible person should have information on the active ingredient in the product. The report should describe known product attributes, such as dosage form, strength, color and lot number.

The ICSR must be submitted within 15 business days of the receipt of the report of a serious adverse event, according to the guidance. Each ICSR must be accompanied by a copy of the label on or in the retail package of the drug according to the guidance.

In addition, the responsible person must submit follow-up reports of new medical information related to a submitted serious adverse event report within one year of the initial report, according to the guidance. These reports must be submitted no later than 15 business days after the receipt of new information.

The guidance finalizes a draft published in the Oct. 15, 2007, Federal Register. The final guidance is available at www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM171672.pdf. — Elizabeth Jones


Bedford: Cancer Treatment Shortage to Last Until Fall

Bedford Laboratories has four lots of the cancer treatment methotrexate scheduled for release this fall to help alleviate a shortage caused by insufficient manufacturing capacity to meet demand for the company’s products.

Bedford is one of five companies approved to manufacture the injectable methotrexate sodium, company spokesman Jason Kurtz told DID, citing IMS Health data. The company released one lot of freeze-dried 1-gram injectable methotrexate last month.

The FDA drug shortage database posted a July release date for additional lots of Bedford’s injectable methotrexate drug.

Kurtz said that date represents the deadline by which the products will be manufactured and they will be released in September or October, The 2-, 4-, 8- and 10-ml lots to be released in the fall are liquid forms of the treatment.

In recent months, manufacturing delays have led to interruptions in the supply of Bedford’s products (DID, Feb. 20).

Bedford is the generic arm of Boehringer Ingelheim’s contract manufacturing subsidiary Ben Venue Laboratories, which is building a 240,000 square foot, $140 million facility that will provide additional production capacity for cytotoxic-genotoxic drugs, Kurtz said. Completion of the facility is expected by the end of the year. “We could have production there by year-end,” he added.

GeneraMedix has been able to meet its demand so far, and has increased production of the drug, spokesman David Ritchie told DID. Ritchie noted that the company believes a change in reimbursement for larger vials of the treatment this year led to increased demand for 2-ml vials.

Ebewe Parenta Pharmaceuticals, Hospira and APP also manufacture methotrexate for injection, according to the FDA. — April Hollis


IRB Registration Outlined in Q&A Document

The FDA is seeking complete information about institutional review boards (IRBs) that oversee industry-sponsored clinical trials, according to an agency question-and-answer (Q&A) document on IRB registration procedures.

Beginning today, IRBs are required to register with the FDA (DID, July 10). But IRBs overseeing clinical trials that receive federal government funding must register with the HHS Office for Human Research Protections (OHRP) instead of the FDA. The same electronic registration system is available for both types of IRBs.

The FDA says it lacks information on IRBs that oversee certain drug and device studies that are exempt from the IND and investigational device exemption requirements. Such trials are conducted without FDA involvement, as are nonsignificant risk device studies and many in vitro diagnostic studies, which are conducted with only IRB approval.

The Q&A includes an FDA explanation for the new rule, the type of IRB that is subject to it, what information is required and what happens if IRBs don’t comply.

If an IRB is registered in the OHRP system, it must update its listing to include all information required by the FDA, the guidance says. The information includes:

  • Contact information for the IRB, the institution operating the IRB, the IRB chairman or chairwoman, and the senior institutional officer responsible for overseeing the IRB’s activities;
  • The approximate number of active study protocols involving FDA-regulated products the IRB reviews. Active protocols are any for which the IRB conducted an initial or continuing review during the preceding 12 months; and
  • A description of the types of FDA-regulated products involved in the protocols the IRB reviews.

The Federal Register notice of the FDA’s IRB registration rule can be viewed at edocket.access.gpo.gov/2009/E9-682.htm, and the Q&A can be seen at www.fda.gov/downloads/RegulatoryInformation/Guidances/UCM171256.pdf. — Martin Berman-Gorvine


FDA Advises on Physical-Chemical Anti-Counterfeit Identifiers

The FDA has issued a draft guidance on the use of pigments, flavors and other physical-chemical identifiers (PCIDs) in drug products to make them more difficult to counterfeit.

The identifiers may be used to authenticate products or code the product identity in the solid oral dosage forms (SODFs). The FDA anticipates that many of the ingredients manufacturers will use as PCIDs are being used as food additives, colorants or excipients with established safety profiles. 

“We look forward to working with industry to help ensure that consumers are not exposed to products containing unknown, ineffective or harmful ingredients,” FDA Commissioner Margaret Hamburg says in an emailed statement Monday.

The guidance recommends contacting the appropriate clinical review division for more information on assessing the safety of proposed PCIDs.

To ensure the least toxicological risk, the FDA recommends using permissible direct food additives, including those generally recognized as safe, or ingredients listed in the FDA’s inactive ingredient guide. If an applicant incorporates a PCID, the agency recommends its ingredients be pharmacologically inactive so they can be treated as excipients.

Ensure Least Risk

Manufacturers also should add a PCID at the lowest level that ensures identification of the dosage unit and should use a PCID that is relatively inert.

Placing a PCID inside a core section of the SODF may increase the chances of it interacting with the drug substance, which could cause degradation, the guidance notes. Manufacturers also may want to avoid incorporating the PCID into a section of the SODF that contains release-controlling excipients.

The draft guidance gives recommendations on design considerations for incorporating PCIDs, documentation to be submitted in NDAs and ANDAs, documentation to be submitted for incorporating a PCID after approval and procedures for reporting or requesting approval to incorporate PCIDs after a drug’s approval. It also gives recommendations for evaluating the safety of PCIDs incorporated into packaging and labeling, and procedures for reporting or requesting approval to add PCIDs to packaging and containers postapproval.


The following information should be included in premarket or postapproval regulatory submissions proposing the incorporation of a PCID in an SODF:

  • Chemical composition of the PCID;
  • Relevant physical attributes of the PCID;
  • An illustration showing the location of the PCID;
  • Information on possible impurities;
  • Justification for safety of the PCID, including any toxicological assessment;
  • Information on product development pertaining to incorporation of the PCID;
  • Description of manufacturing steps and controls associated with incorporation;
  • Rationale for selection and incorporation of the PCID, and a description of how it is integrated into the design;
  • Assurance and verification of quality, performance and stability of the drug product containing the PCID; and
  • A summary of product quality and performance risk assessment associated with the incorporation.

When an applicant proposes incorporating a PCID into an SODF that has been approved and marketed without the PCID, the FDA expects the applicant will be able to conduct certain assessments comparing the product with and without the PCID.

Evaluations of the drug product containing the PCID should ensure there is no significant increase in previously detected impurities. Additionally, toxicological assessments may be warranted if the impurity profile of the drug is altered significantly by the PCID.

If the addition has the potential to significantly affect drug-release rates, the guidance also recommends evaluating dissolution profiles. Sponsors should use long-term and accelerated stability studies to evaluate impurity formulation and the effect of the PCID on the dissolution. Such stability studies should be conducted through the drug product expiration date although the studies do not need to be completed prior to submission of the change.

The draft guidance, “Incorporation of Physical-Chemical Identifiers into Solid Oral Dosage Form Drug Products for Anticounterfeiting,” does not apply to manufacturing or formulation changes that go beyond inserting the PCID into a blending or mixing operation.

To search the FDA’s website for inactive ingredients, go to www.accessdata.fda.gov/scripts/cder/iig/index.cfm. The draft guidance is available at www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM171575.pdf. — April Hollis

Federal Court Won’t Dismiss Alpharma Patent Case

A federal court has kept alive a case brought by Alpharma in an effort to introduce the drugmaker’s abuse-resistant opioid pain product.

The drugmaker is seeking to invalidate patents Purdue Pharma plans to use to keep Alpharma from selling its ALO-01 product, an opioid pain medicine containing naltrexone. Alpharma has asked U.S. District Court for the Western District of Virginia Judge James Jones to declare invalid a number of patents that Purdue may claim are infringed by ALO-01.

Jones denied Purdue’s request to move the case to the U.S. District Court for the District of Connecticut, according to documents filed in Alpharma, Inc. v. Purdue Pharma L.P.

“Absent a declaration of invalidity and/or non-infringement, Purdue will continue to use its patents as a means to intimidate and threaten Alpharma from entering the market, and thereby cause Alpharma irreparable injury and damage,” the plaintiff maintains in its Nov. 17, 2008, complaint.

Purdue had sought a dismissal of Alpharma’s case, alleging there was no justiciable controversy. Jones disagreed, citing a Sept. 14, 2007, meeting between the two parties during which Purdue representatives maintained that the company’s patents encompassed Alpharma’s naltrexone technology. Alpharma said at the meeting that it had studied Purdue’s patents and concluded it has the freedom to practice in this area, Jones says in his ruling. 

In an email later sent to Alpharma representatives, Purdue offered to have its chief intellectual property counsel discuss the extent of its patents. “There would be no need for the lawyers to confer if the defendant did not believe that this difference in opinion did not touch the legal interests of the parties,” Jones says in court documents.

Based on this exchange between the two parties, there does seem to be “a dispute definite and concrete in nature,” Jones adds.

The judge also refused to transfer the case because Purdue had failed to show that Connecticut is a substantially more convenient venue than Virginia.

Multiple Lawsuits

Purdue has sued a number of companies, including Actavis Totowa and Mallinckrodt, for infringing patents related to OxyContin (oxycodone). It also filed a citizen petition last year asking the FDA to deny approval to Remoxy (oxycodone), an extended-release, tamper-resistant pain product being developed by Pain Therapeutics and King Pharmaceuticals, which recently acquired Alpharma.

King has taken over all development activities related to Remoxy. The company announced earlier this month it won’t resubmit their NDA for the long-acting oxycodone formulation until mid-2010, after a meeting with the FDA gave it a clear path to submitting six-month stability data on the drug (DID, July 8).

Alpharma had expected FDA approval of its product by Dec. 30, 2008, but a recent change in the FDA’s risk evaluation and mitigation strategy of opioid drugs has delayed the process, according to court documents.

The FDA told 16 drugmakers in February that it will require REMS to help prevent abuse of opioid pain products (DID, Feb. 10). Most of the affected products are transdermal patches or extended-release versions of drugs containing the active ingredients fentanyl, hydromorphone, methadone, morphine, oxycodone and oxymorphone.

The agency held a two-day meeting in May to get input from industry, healthcare providers, patient advocates and pharmacies on risk management for certain opioids and to assess whether the benefits of the painkillers outweigh their risks, which include addiction and death (DID, May 28). — Elizabeth Jones


Tarceva Improved Lung Cancer Patient Survival in Study

OSI Pharmaceuticals and Genentech’s Tarceva, when given immediately after initial chemotherapy, improved survival in patients with advanced nonsmall cell lung cancer (NSCLC) in a Phase III clinical trial.

“This study has now not only confirmed that immediate treatment with Tarceva [erlotinib] after initial chemotherapy delayed the progression of disease, but also importantly helped patients in the study live longer,” Federico Cappuzzo, principal investigator of the SATURN study, says in a statement Monday.

OSI spokeswoman Kim Wittig told DID that delaying disease progression was the primary endpoint of the study. She said those data were released last month, but specifics on the improvement in overall survival won’t be made available until they are released at the 13th World Conference on Lung Cancer, July 31–Aug. 4.

The improvement in survival, a secondary endpoint, was deemed statistically significant in a planned final analysis of the patient population. OSI and Genentech will submit the survival data to the FDA to support their sNDA to use Tarceva as a first-line maintenance treatment for patients with advanced NSCLC. The FDA Prescription Drug User Fee Act review deadline for the sNDA submitted March 17 is Jan. 18, 2010.

Roche, which is OSI’s international partner for Tarceva, will submit the survival data to support a parallel application submitted to the European Medicines Agency in March.

In May, the FDA, OSI and Genentech warned that patients taking Tarceva have died of gastrointestinal perforation and severe skin disorders (DID, May 11).

Tarceva is approved as a monotherapy to treat locally advanced or metastatic NSCLC after failure of at least one prior chemotherapy regimen. It also is indicated for use with gemcitabine as a first-line treatment for locally advanced, unresectable or metastatic pancreatic cancer. — Martin Berman-Gorvine

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