Vol. 8 No. 230
A French active pharmaceutical ingredient (API) maker received a warning letter for failing to take appropriate action on API lots shipped to the U.S. that may be affected by a cross-contamination problem.
Although Zach System, based in Avrille Cedex, France, discovered the cross-contamination in March 2008, it did not notify customers until after a June FDA inspection and its investigation has not defined the extent of the contamination, according to the Oct. 23 letter posted Nov. 24 to the FDA website.
As of Sept. 23, the company had tested only a limited number of potentially affected API batches, the letter says. The agency is concerned that while the investigation is open, customers may still be manufacturing products with the affected API lots.
The FDA urgently needs to discuss additional corrective actions related to the API lots found with traces of cross-contamination that were shipped to the U.S., the letter says. It recommends arranging a teleconference within five days of receipt.
It also requests that Zach inform the agency of the action it intends to take on API lots with detected cross-contamination that were shipped to the U.S. The company should include a copy of its standard operating procedure requiring it to notify U.S. customers of quality problems when they occur.
The company discovered the cross-contamination issue during an investigation of a March 2008 complaint about metallic foreign material found in its pioglitazone HCl, a diabetes drug, the letter says. But it was not until Zach began investigating the source of the particles that it discovered a cross-contamination problem involving three different APIs and one intermediate product, the letter says.
The situation is similar to one faced recently by Genzyme when an FDA investigation following a bacterial contamination revealed foreign particles, including stainless steel fragments, in certain products (DID, Nov. 16).
After the FDA’s June 8 to 11 inspection, and during a Sept. 23 meeting at CDER’s Office of Compliance, Zach suggested that because its process validation demonstrated homogeneity, any cross-contamination would have been detected in its retained samples. The agency disagrees with this assessment because process validation is not intended to evaluate the uniformity or homogeneity of a cross-contamination, the letter says.
The company’s investigation also failed to recognize information in the impurity profile documentation for pioglitazone HCl batches manufactured between April 2007 and March 2008, the letter says. An unknown peak was detected but reported as 0.00 percent due to the small amount and the company’s procedures for rounding results.
The investigation also failed to recognize that the cross-contamination is not uniformly distributed throughout a batch, making the testing of retained samples from suspect batches inadequate to determine the safety of the batches in question. Therefore, Zach’s proposed corrective actions for developing a more sensitive method to detect cross-contamination in retained samples cannot alone support its position on the safety of the affected products, the letter says.
The company’s evaluation of out-of-specification results from related substances testing of a lot of pioglitazone HCl was cited as well. “We disagree with your decision to release this batch,” the letter says, adding the company’s practice of injecting and reinjecting new preparations of the sample solution until a passing result is achieved is unacceptable.
Zach also did not adequately monitor the effectiveness of its validation for cleaning procedures, the letter says.
The FDA notes Zach’s July 24 response to the post-inspection Form 483 lacked sufficient corrective actions.
Zach did not respond to a request for comment by press time. The warning letter is available at www.fdanews.com/ext/files/ZachSystem-WL.pdf. — April Hollis
The FDA has warned an independent institutional review board (IRB) for significant violations, including providing inaccurate minutes from its meetings and protocol inconsistencies on pediatric participation.
The Tulsa, Okla.-based IRB was cited for omitting serious adverse event reports and investigations from meeting minutes that it gave to an FDA investigator. The agency discovered that violation and several other inconsistencies by comparing Teneo’s minutes with another set of minutes from a redacted source.
The minutes given to the investigator lacked information on the IRB’s review and approval of studies, the Nov. 10 letter says. They also lacked documentation that Teneo conducted a full range of activities, the agency concluded, including approving protocols and consent forms, conducting continuing reviews, granting emergency approvals, evaluating adverse event reports, revising standard operating procedures (SOPs), and discussing the enrollment, treatment and consent of pediatric subjects.
Further, minutes were missing for three meetings that discussed communication between the IRB and investigator, compensation for research subjects, providing subjects with copies of informed consents, changes to an SOP, and review of informed consent forms. Other meeting minutes fail to show the IRB discussed pediatric consent forms and the hiring of pediatric specialists.
Teneo also failed to resolve inconsistencies on inclusion and exclusion criteria for patients under age 18 before approving research, the letter says.
During a March 12 to 18 inspection, the IRB told the FDA it did not review studies involving children, that it received no adverse event reports and that the minutes provided to the investigator were complete, the letter says. The FDA has requested an explanation from the IRB.
Teneo also did not maintain copies of approval letters it issued, and its minutes omit that it reviewed and approved several studies. Additionally, it did not maintain documentation of requests for emergency approvals or the action taken on those requests.
The IRB initiated several corrective actions at the close of the inspection, the letter says. It provided an updated membership roster to the investigator and revised an SOP to change the monthly meeting requirement to an annual requirement, with additional meetings scheduled by the chair as needed. It also revised an approval letter to show expiration of approval to occur at one year, rather than three years.
The company did not respond to a request for comment by press time. The warning letter is available at www.fdanews.com/ext/files/Teneo-IRB-WL.pdf. — April Hollis
Drugmakers may eventually see more detailed and knowledgeable reviews of NDAs as the result of a contract for a new professional development program that the FDA has awarded to the National Institute for Pharmaceutical Technology and Education (NIPTE).
The program, which begins this year and is expected to finish by September 2011, is supposed to help drug reviewers apply state-of-the-art manufacturing and technology issues to their review, research and policymaking activities, according to a NIPTE statement last week.
The two-year, $652,000 program will assess the needs of the FDA’s Office of Pharmaceutical Science staff and develop recommendations for training areas.
NIPTE represents 11 U.S. universities with leading pharmaceutical science and engineering programs.
Last month, the FDA awarded NIPTE a $1.19 million contract to develop quality by design guidance on design space specifications, according to a previous statement by the nonprofit. That contract’s goal is to formulate best practices and develop science-based guidance documents that the FDA can use to evaluate new and generic drug applications, Prabir Basu, NIPTE’s executive director, says in the statement. — David Belian
Idera Pharmaceuticals has renewed its exclusive license and research collaboration with Merck for a fourth year and ended its four-year asthma and allergy R&D agreement with Novartis, effective Feb. 21.
The agreement with Merck, initiated in December 2006, employs Idera’s experimental agonist compounds targeting toll-like receptors (TLRs) 7, 8 and 9 and tests them in treatment areas including cancer, infectious diseases and Alzheimer’s disease, Idera says in a statement last week. The collaboration also uses Merck’s chemistry and adjuvant formulation advances.
The agreement includes a two-year R&D effort to develop novel agonists targeting TLR7 and TLR8 for use in vaccines for diseases such as cancer, the statement says. Merck can renew the arrangement for two one-year periods.
Tim Sullivan, vice president of development programs at Idera, says in the statement that the companies plan “continued studies with selected TLR agonist candidates as vaccine adjuvants.”
The termination of Idera’s agreement with Novartis allows Idera to regain sole rights to QAX935 (IMO-2134), a new agonist of TLR9 identified during the collaboration, Idera says in a separate statement Nov. 25. Idera will be free of restrictions on its right to develop its TLR-targeted compounds, including those that target respiratory diseases, the company says.
Novartis paid Idera a total of $6 million during the collaboration that began in 2005, including a $1 million milestone payment associated with initiation of a Phase I clinical trial of IMO-2134 by intranasal delivery for respiratory diseases. — Meg Bryant
Novartis has cut a licensing deal with Incyte that gives the Swiss firm exclusive U.S. rights to a potentially first-in-class oral agent to treat myelofibrosis and another investigational oral therapy to treat various blood disorders.
Under the agreement, Novartis will pay Wilmington, Del.-based Incyte $150 million upfront for exclusive rights to the experimental therapies for patients with a range of serious blood disorders and cancers that have not been managed by existing therapies, the Swiss drugmaker says in a statement last week. Incyte remains eligible for future milestone payments and royalties for the product.
The agreement gives Novartis exclusive U.S. rights to Incyte’s Janus kinase inhibitor INCB18424, which is in Phase III clinical studies to treat myelofibrosis, a life-threatening tissue disorder characterized by bone marrow failure, enlarged spleen and debilitating symptoms.
In addition, the licensing arrangement gives Novartis worldwide rights to mesenchymal-epithelial transition factor kinase (MET) inhibitor INCB28060, one in a group of compounds that are potential agents to fight cancers, the statement says.
According to Novartis, the MET inhibitor works by blocking molecular signals that can lead to the growth, survival and metastases of tumor cells. They also may decrease resistance to targeted therapies, such as geftinib, in nonsmall cell lung cancer. INCB28060 currently is entering Phase I development.
The agreement also includes a first milestone payment of $60 million to Incyte for initiation of the European Phase III trial of INCB18424 in July 2009. — Meg Bryant
Drugmakers that have been selling allergen products in Germany under the “named-patient” basis must now get a German marketing authorization by submitting applications in Germany no later than Dec. 1, 2010, that include dedicated pediatric clinical trials.
The applications must include a pediatric investigation plan (PIP) approved by the European Medicines Agency (EMEA), the agency says in a draft PIP standard released last week. Germany requested the recommendations from the EMEA.
The named-patient basis allows physicians access to medicines that are approved for investigational use. About 60 percent of allergen products marketed in Germany for specific immunotherapy under a named-patient basis do not have marketing authorizations, the EMEA draft says.
European pediatric regulation requires drugmakers applying for pediatric product marketing authorizations to submit study results governed by a PIP or receive an EMEA decision on a waiver or deferral.
The draft, which includes a template appropriate only for a product indicated for allergic rhinitis/rhinoconjunctivitis, defines measures that must be included in PIP applications. Products for Type I allergies must have dedicated studies in children, and products in homologous groups, including birch, grass and mites, must have:
The EMEA notes that the template should be read in light of a Committee for Medicinal Products for Human Use (CHMP) Nov. 20, 2008, guideline on allergies.
In the pediatric trials, one member of a homologous group can be selected as the representative allergen for the purpose of quality, efficacy and safety, the EMEA says. The choice should be justified, taking into consideration factors such as geographical differences in the sensitization patterns and other relevant factors. Separate PIPs must be submitted for each product within one homologous group.
Among other general requirements, the agency will allow drugmakers to receive a waiver for the trials in children younger than 5 years of age; however, patients eligible for sublingual immunotherapy should be enrolled from age 3, the EMEA says.
The pediatric trials also should be described and justified in detail, including explaining the choice and use of diagnostic tests, the interrelation of the development and results compared with the products’ use in adults and the study design.
If an applicant chooses to extrapolate data from dose-finding studies in adults instead of conducting a separate study in the pediatric population, the approach should be justified, the EMEA says.
The EMEA proposes a phased-in approach, saying drugmakers should defer pediatric trials until long-term efficacy of the drugs has been established in adults, and once this is established, should require only short-term trials in children.
If a drugmaker wishes to claim long-term efficacy in post-treatment years and a disease-modifying effect, a proposal for a long-term study in children, including a follow-up with patients two years after treatment, should be included.
The EMEA’s draft Standard PIP for Allergen Products for Specific Immunotherapy can be found at www.emea.europa.eu/pdfs/human/paediatrics/73760509en.pdf. The CHMP “Guideline on the Clinical Development of Products for Specific Immunotherapy for the Treatment of Allergic Diseases” is available at www.emea.europa.eu/pdfs/human/ewp/1850406enfin.pdf. — David Belian
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