Vol. 7 No. 137
More than two years after withdrawing a final rule that would have exempted investigational drugs in Phase I testing from certain good manufacturing practice (GMP) regulations, the FDA is issuing a final rule to do just that.
The new rule, which amends the GMP regulation with the exact same language as the withdrawn rule, is scheduled to be published in Tuesday’s Federal Register. Slated to take effect Sept. 15, it will apply to small-molecule drugs and biologics, including vaccines and gene therapy products.
“FDA’s position is that the United States’ [GMP] regulations were written primarily to address commercial manufacturing and do not consider the differences between early clinical supply manufacture and commercial manufacture,” the agency says.
For example, the requirements for a fully validated manufacturing process, rotation of stock for drug product containers, repackaging and relabeling of drugs and separate packaging and production areas need not apply to investigational drug products made for use in Phase I trials, the agency says.
The FDA’s original direct final rule exempted Phase I investigational drugs from GMP regulations covered under 21 CFR 211, but the agency withdrew it under pressure from groups as varied as Public Citizen, the Biotechnology Industry Organization (BIO) and the Parenteral Drug Association (PDA) (DID, May 2, 2006).
Under the new regulations, drugs manufactured for Phase I clinical study are exempt from the GMP requirements under 21 CFR 211 if such products are not marketed or are not being studied in Phase II or III testing.
However, the rule would require such products to be made under conditions that meet “statutory GMP” rules, the FDA says. To ensure Phase I drugs are suitable for human use, the agency also is highlighting its authority to regulate them under INDs, which contain sections on chemistry, manufacturing and controls.
“In addition to the authority to put an IND on clinical hold or terminate an IND, FDA may initiate an action to seize an investigational drug or enjoin its production if its production does not occur under conditions sufficient to ensure the identity, strength, quality and purity of the drug, which may adversely affect its safety,” the agency says.
While noting this rule is intended to streamline the drug development process, the agency says it will help promote simple, innovative and less expensive approaches to complying with statutory GMP requirements.
The FDA estimates manufacturers that make their own drugs for Phase I study could realize substantial savings in areas such as testing and analysis of components and in-process materials, which range from $50 to $1,200 per component tested.
Another benefit for manufacturers is that use of standard operating procedures and methods validation might be greatly reduced, the FDA says. “We estimate that large drug manufacturers that manufacture in-house investigational drugs used in phase I clinical trials could potentially save between 24 to 40 hours per IND,” the agency adds.
The FDA also is considering additional regulations and guidance regarding GMP requirements for investigational drugs in Phase II and III testing.
Guidance on Phase I GMPs
In connection with the final rule on Phase I drug GMPs, the FDA issued a guidance recommending approaches to satisfy statutory GMP requirements for such drugs.
“During product development, the quality and safety of Phase I investigational drugs are maintained, in part, by having appropriate [quality control (QC)] procedures in effect,” the guidance states. “Using established or standardized QC procedures and following appropriate cGMP will also facilitate the manufacture of equivalent or comparable IND product for future clinical trials as needed.”
Having well-defined written procedures, adequately controlled equipment and production environments, and accurate and consistent manufacturing data are ways firms can comply with GMPs for Phase I drugs, the guidance says.
The FDA recommends a systematic evaluation of the manufacturing setting that includes an assessment of the product environment, equipment, process, personnel and materials. In addition, it encourages actions to mitigate potential hazards to ensure the quality of the drug.
“For example, of particular importance is the susceptibility of a phase I investigational drug to contamination or cross contamination with other substances (e.g., chemicals, biologicals, adventitious agents) that may be present from previous or concurrent research or manufacturing activities,” the guidance says.
Special considerations are needed for sterile drugs that require aseptic processing. The guidance calls for process simulations to demonstrate the processes can produce sterile drugs and environmental monitoring of aseptic workstations.
More information on the final rule can be accessed at www.fda.gov/OHRMS/DOCKETS/98fr/oc07114.pdf. A copy of the guidance, “CGMP for Phase 1 Investigational Drugs,” can be viewed at www.fda.gov/OHRMS/DOCKETS/98fr/FDA-2005-D-0157-gdl.pdf. — Christopher Hollis
Senator Chuck Grassley (R-Iowa) has asked the American Psychiatric Association (APA) to detail its policies on accepting contributions from drugmakers and to list annual amounts given by individual companies since January 2003.
Charging that “money from the pharmaceutical industry can shape the practices of nonprofit organizations which purport to be independent in their viewpoints and actions,” the request is the most recent action by lawmakers investigating potential conflicts of interest for physicians, medical centers and continuing medical education (CME) activities.
Last week, PhRMA revised its marketing code for drugmakers, asking them to stop distributing non-educational gifts to physicians and to require that consultants disclose their corporate relationships (DID, July 11). A few days before that, Pfizer said it will no longer fund CME programs provided by medical education and communication companies (DID, July 7).
Merck agreed in a May court settlement to follow Accreditation Council for Continuing Medical Education standards for commercial support, which are intended to ensure CME activities are independent (DID, May 21).
Grassley asks the APA to provide by July 24 a chart detailing the funding, including, for each donation, the year, name of the donor company, amount of the funding and reasons it was provided.
“Specifically, it is alleged that pharmaceutical companies give money to nonprofits in an attempt to garner favor in ways that increase sales of their products,” Grassley writes in his letter to James Scully, the APA’s medical director and CEO.
Grassley also asks the APA to explain its policies on accepting industry funding and to answer whether it allows donor companies to place restrictions or provide guidance on how funding will be spent. If the APA allows such restrictions, Grassley requests details of them for all donations since January 2003.
“We have received the request and are going to respond to it,” an APA spokeswoman told DID.
Grassley’s letter can be viewed at finance.senate.gov/press/Gpress/2008/prg071008h.pdf. — Martin Gidron
The Justice Department has asked a Maryland court to order Ranbaxy and its consultant Parexel to turn over subpoenaed documents in an ongoing investigation over alleged fraud and conspiracy involving applications for generic drugs and distribution of AIDS therapies.
Ranbaxy replied Monday to the court, saying it would turn over all subpoenaed materials.
Justice, through the U.S. State Attorney’s Office for the District of Maryland and the Civil Division, Office of Consumer Litigation, maintains the company submitted false information about stability and bioequivalence to support ANDAs and for anti-retrovirals distributed by the President’s Emergency Plan for AIDS Relief, a five-year, $15 billion program aimed at combating HIV and other disease in 114 countries.
The government is probing whether Ranbaxy used active pharmaceutical ingredients (API) from unapproved sources, blended approved with unapproved API and put less API in drugs approved by the FDA. It had subpoenaed certain documents, some of which the company had made available but some of which it refused to provide.
In Monday’s response, Ranbaxy asserted that it waived all privileges for the remaining information and that it knows of no proof supporting allegations that it had committed fraud or conspiracy.
Roots of the Case
The government’s case stems from a February 2006 inspection of Ranbaxy’s Paonta Sahib, India, plant that resulted in a warning letter detailing “significant deviations” from current good manufacturing practices at the facility. The violations ranged from missing data and documentation to an insufficient number of personnel testing products for stability (DID, June 27, 2006). The FDA subsequently imposed a compliance hold on agency approval of ANDAs originating from the plant.
After the inspection, Buc & Beardsley, the law firm representing Ranbaxy, retained Parexel Consulting, which audited the processes and procedures in the company’s stability and quality control laboratories. Ranbaxy subsequently released information about the Parexel audits — and portions of the audits themselves — to persuade the FDA to lift the hold on the facility.
However, the company continued to assert privilege on some of the requested audit documents, which hampered the government’s investigation, Justice alleged in court documents, adding that by releasing portions of the audits, the company waived any privilege that was attached to the documents.
Ranbaxy Answers Allegations
Ranbaxy “strongly denies the allegations” in the government’s motion, a company spokesman said, adding that no charges have been filed against it during the three-year investigation.
The company’s response Monday says it has been cooperative, especially after a February 2007 raid of its U.S. facilities. While it continued to assert privilege on a few of the audits after the raid, the company concluded that it must waive privilege to assuage the fears of the government. It has asked Parexel to waive privilege on the remaining documents. Parexel says it can produce these documents within a month, according to court documents.
Last month, Japan’s Daiichi Sankyo bought a majority stake in Ranbaxy in a deal potentially worth up to $4.6 billion. This deal “remains on track,” the spokesman added.
Biotechnology start-ups nationwide will be able to use an incentive for capital investments if a provision in the housing bill passed last Friday by the Senate becomes law, according to the Biotechnology Industry Organization (BIO).
Jim Greenwood, BIO’s president and CEO, said the provision will put biotech companies whose products have not reached the market “in a stronger position to carry out clinical trials and product development.”
It would allow companies to use accumulated alternative minimum tax or R&D credits in lieu of a bonus depreciation. “On behalf of the thousands of patients who can benefit from these therapies, we strongly encourage the House to include this provision when it considers the bill,” Greenwood added.
The provision is part of H.R. 3221, the American Housing Rescue and Foreclosure Prevention Act, offered by Sens. George Voinovich (R-Ohio) and Debbie Stabenow (D-Mich.) earlier this year. Sponsored in the House by Rep. Nancy Pelosi (D-Calif.), the bill passed the Senate by a 63–5 vote. There is no separate Senate bill.
After the Senate vote, Pelosi expressed confidence that the two chambers would be able to “arrive at a bipartisan, bicameral compromise” and deliver a bill for the president to sign. — Elizabeth Jones
Genentech is recommending that its cancer agent Avastin not be used in combination with Pfizer’s kinase inhibitor Sutent after several cases of microangiopathic hemolytic anemia (MAHA) were observed during an investigator-sponsored study.
The FDA issued a MedWatch report to oncologists regarding the potential safety problem Monday, and Genentech issued a July 11 “dear healthcare professional” letter alerting physicians to the cases of MAHA.
trial was a Phase I dose-escalation study testing the drugs against renal cell carcinoma. It included 25 patients who were given a fixed dose of Avastin (bevacizumab) and escalating doses of Sutent (sunitinib malate). Of the 12 patients who received the highest Sutent doses, five had laboratory findings consistent with MAHA, according to Genentech.
“Two of these cases were considered severe with evidence of thrombocytopenia, anemia, reticulocytosis, reductions in serum haptoglobin, schistocytes on peripheral smear, modest increases in serum creatinine levels, and severe hypertension, reversible posterior leukoencephalopathy syndrome (RPLS) and proteinuria,” Genentech says in the letter.
“The findings in these two cases were reversible within three weeks upon discontinuation of both drugs without additional intervention,” the company adds.
Based on information from the study, Genentech halted the SABRE-R trial, a Phase II study with a similar design testing Avastin in combination with Sutent.
Genentech told DID that it first announced the discontinuation of SABRE-R during its earnings call in January. When the company became aware of the results from the investigator-sponsored trial, it looked at data from SABRE-R and discovered two cases of MAHA out of a total of seven enrolled patients.
The letter notes that two additional Phase II trials were closed as well, SABRE-L and SABRE-B. Both trials tested Avastin in combination with Sutent and chemotherapy — the “L” trial in patients with lung cancer and the “B” trial in patients with metastatic breast cancer. Those trials were closed because of poor tolerability, primarily due to myelosuppression, fatigue and gastrointestinal complications, not MAHA, the company says.
Genentech emphasized that the cases of MAHA were observed in patients on higher doses of Sutent and that Avastin doses were fixed.
Sutent, which had worldwide sales of $190 million during the first quarter of 2008, is indicated for use against advanced renal cell carcinoma as well as gastrointestinal stromal tumors after patients fail on Novartis’ Gleevec (imatinib mesylate). — Christopher Hollis
GlaxoSmithKline (GSK) may pay Actelion up to $2.7 billion in milestone payments for the right to jointly develop and commercialize the Swiss biopharma company’s insomnia drug almorexant.
The two companies have agreed on exclusive worldwide collaboration, excluding Japan, on the drug, an orexin receptor antagonist now in Phase III clinical trials that has first-in-class potential. Orexins, previously referred to as hypocretins, are proteins produced by the hypothalamus that play an important role in controlling the sleep-wake cycle.
Actelion will receive an upfront payment of $147.6 million and will be eligible for milestone payments of up to $408.4 million if almorexant is successfully developed and approved for treating primary insomnia. The $2.7 billion figure would depend on the drug’s approval for two other indications for which it has not yet undergone clinical trials.
The RESTORA Phase III clinical trial of almorexant for primary insomnia in adult and elderly patients began late last year, with first findings expected in the second half of 2009. Pivotal studies required for registration in the U.S. are scheduled to start later this year. — Martin Gidron
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