Vol. 7 No. 67
Firms opposing the FDA’s final rule modifying GMP regulations scored a victory this week when the agency withdrew the proposal after receiving significant adverse comments from industry.
The FDA proposed the changes in a direct final rule last year (DID, Dec. 4, 2007). At the time, the agency said the new regulations would take effect this month.
When the regulation was published, the FDA released an identical proposed rule so it could proceed with the standard rulemaking process in case significant adverse comments were received. The agency says it will consider the adverse comments as it codifies the proposed rule, according to a notice to be published in Friday’s Federal Register.
The FDA wanted to allow firms to use only one person to check critical manufacturing steps, such as adding materials to a batch, when the process is done by automated equipment. Current regulations call for a second individual to check such steps performed by another person, but the agency said the change in the regulation would only reflect current policy.
Both the Biotechnology Industry Organization (BIO) and the Parenteral Drug Association (PDA) expressed concern about that proposal in comments to the rule.
BIO says automated systems that are validated and equipped with real-time alarms do not require human intervention and should not require human verification. “The proposed revision requiring operator verification of automatic mechanical and electronic equipment … may hinder the implementation of process analytical technology [PAT],” the trade group says.
The PDA concurrs: “In instances where components are charged in a fully automated manner per a validated algorithm, there would not appear to be any value added in a manual verification of that component addition.”
The FDA’s proposed language apparently does not permit the operation of automated equipment where a check to ensure proper functioning of such equipment is performed by the operator at the beginning of a shift, PDA says.
Acceptance of a validated yield algorithm would not have been permitted either. “It would seem that each component addition would need to be witnessed/verified or that the calculation of the yield would need to be performed by hand following calculation by the system,” PDA added.
New Water Standard
Both Schering-Plough and PDA asked the FDA to change the rule’s language on water standards, which would remove a requirement that facilities use water complying with Environmental Protection Agency (EPA) standards. Instead, the regulation, 21 CFR 211.48, stipulates that water just be safe for human consumption.
Both organizations want more prescriptive requirements in the regulation — either a statement that pharmaceutical water conforms to applicable public health standards or meets European, Japanese, World Health Organization or U.S. standards. The FDA says it removed the EPA standard from the regulation to harmonize requirements with Europe and Japan.
The withdrawn rule also would have explicitly required manufacturers to validate aseptic processes, a stipulation for which there are no means to comply, Russell Madsen, former acting president of PDA and president of The Williamsburg Group consulting firm, says. “There is no method to directly measure the output of an aseptic process since it is not possible to determine the sterility of each manufactured unit.
“Aseptic processes are different than processes such as moist-heat sterilization, depyrogenation, lyophilization, blending, encapsulation and distillation to produce [water for injection]. Such processes can be validated because there are defined process inputs, control parameters and process outputs that can be measured accurately,” he adds.
Aseptic processing, however, uses microbiological methods to monitor environmental and decontamination processes. Such methods lack sensitivity, recoverability and accuracy of physical/chemical measurements associated with process validation, Madsen says. — Christopher Hollis
Potential participants in clinical trials may not care about the investigators’ financial interests in the study unless the researchers own stock in the sponsoring drug company, according to a survey presented in the Journal of General Internal Medicine.
“We found that the patients we surveyed rated most types of financial disclosures less important in influencing their decisions to participate than other factors, like the risks and benefits of the proposed treatment,” says Kevin Weinfurt, deputy director of the Duke Clinical Research Institute’s Center for Clinical and Genetic Economics.
The purpose of the study was more important to the respondents than the investigator’s finances. Patients’ willingness to participate in hypothetical trials varied slightly but significantly with disease, disease severity and the interaction between the two.
“We also found that some patients are savvy enough to distinguish between different types of financial relationships, and they have different reactions based on these distinctions,” Weinfurt, the lead investigator in the survey, adds.
In the online survey, funded by the National Heart, Lung and Blood Institute, 3,623 patients with diabetes and asthma of varying levels of severity were asked for their reactions to investigators’ disclosures of different kinds of financial interests in a hypothetical clinical trial.
Survey respondents had mixed reactions to the hypothetical disclosures in general. Some said they would trust investigators less as a result, and some said they would trust them more. The latter reaction is possibly a result of “viewing disclosure as an indication of a researcher’s honesty,” the article says. Two-thirds of respondents were not surprised to learn that some type of financial interest existed.
The survey presented five hypothetical disclosure statements concerning the researchers’ financial interests, along with a boilerplate statement that the institutional review board (IRB) and another committee at the research institution had reviewed those interests and concluded they were not likely to affect patient safety or the scientific quality of the study. The disclosures stated that the lead clinical investigator:
Trust, Surprise and Willingness to Participate
“We found that none of the disclosures significantly affected subjects’ willingness to participate with the exception of ownership of equity on the part of the researcher,” Weinfurt says. In that case, “it’s likely that patients felt ownership of equity could influence the researcher’s behavior in the trial, which might jeopardize the patients’ rights and welfare,” he adds.
Almost 30 percent of respondents presented with that disclosure said they would be unwilling to participate in the trial compared with 25 percent of respondents presented with a generic disclosure that an unspecified financial interest existed and 20 percent of those who were told the investigator received payments from the sponsor to cover the cost of running the study.
The respondents who were told that the researchers owned equity in the sponsor found that disclosure the most surprising, which suggests that “it would be inappropriate not to disclose such information when recruiting research participants,” the article says. “Surprise following enrollment could result in disappointment, anger or noncompliance among participants.”
Although one-third of all the potential trial participants said the financial disclosures damaged their trust in the investigator or the site, that fact “didn’t necessarily correlate with their willingness to participate,” Weinfurt says.
HHS and other organizations have called on scientists and medical practitioners to consider whether disclosing financial relationships between investigators and industry during the consent process would help protect the rights and welfare of patients.
The survey is one of several being conducted as part of the Conflict of Interest Notification Study, which is directed by Jeremy Sugarman, professor of bioethics and medicine at the Johns Hopkins Berman Institute of Bioethics. — Martin Gidron
The FDA’s drug centers intend to spend their user fees to hire more safety evaluators, epidemiologists, regulatory project managers and experts in risk management and medication errors to enhance their postmarket drug-safety activities.
In its draft, “Prescription Drug User Fee Act (PDUFA) IV Drug Safety Five-Year Plan,” the agency says it will focus on hiring the staff through this fiscal year 2009.
It will increase the number of risk-management experts responsible for reviewing proposed and implemented Risk Minimization Action Plans (RiskMAPs) or Risk Evaluation and Mitigation Strategies (REMS). It also will enhance its technological capabilities and communications as it improves its drug-safety system. According to the draft, “it takes at least two to three years of intense training to prepare new staff to be seasoned experts in drug regulation.”
Under the PDUFA IV program, the agency will get $29.29 million annually plus a yearly inflation factor to increase its drug-safety capabilities. It also is authorized to collect user fees to broaden the focus of drug safety. These fees are designated for implementing REMS, postmarket studies, safety labeling changes, active postmarket risk identification and other activities.
According to the draft, PDUFA fees from this fiscal year through fiscal year 2012 will be increased for the following:
CBER already has organized interdisciplinary product safety teams for tissues, blood product and vaccines. Jesse L. Goodman, its director, said Wednesday at a House Agriculture Subcommittee hearing. Premarket activities and deadlines are much better designed than postmarket activities, he added.
The FDA will use the PDUFA fees to access new data sources, “conduct population-based epidemiological studies” and take the following steps, according to the draft:
The agency will develop and issue draft guidance to address epidemiology best practices on carrying out scientifically sound observational studies using quality data sources. The FDA plans to publish the draft guidance by the end of FY 2010 and final guidance by the end of FY 2011.
Agency to Standardize Adverse Event Reporting
A crucial step toward automation of adverse event information is standardization of adverse event reporting, according to the draft. To link reported adverse event information with other clinical information and link pre- and postmarket adverse event information, it is necessary to standardize adverse event reporting.
The FDA also will work on its review of new drug trade names. The agency has formed a working group with representatives from CBER and CDER and is writing a guidance, “Complete Submission for the Evaluation of Proprietary Names.” It intends to publish a draft guidance on proprietary name evaluation best practices by the end of FY 2012.
The FDA’s user fee rates for fiscal 2008 under PDUFA became effective Oct. 1, 2007, and will remain through Sept. 30. Revenues from each of the three fee categories — application, establishment and product — provide one-third of the total fee revenue collected each year, according to the FDA (DID, Oct. 11, 2007).
The draft plan is available at www.fda.gov/cder/pdufa/PDUFA_IV_5yr_plan_draft.pdf. — Yuliya Melnyk
After conducting a review of biosimilar products, a member of the British Parliament proposed a number of safety measures this week during a debate in the House of Commons.
Brian Iddon, a Labor Party member, led a panel of parliamentarians last year in reviewing information on biosimilars, which resulted in several recommendations for protecting patient safety. The European Medicines Agency had approved eight biosimilars as of last October when the review was conducted.
“At present, biological drugs are mainly used in a hospital setting, but it is expected that they will be prescribed in the future by general practitioners and dispensed by community pharmacists,” Iddon said.
As biosimilars become more common, automatic substitution for innovator products should be prohibited, and all biologics need to be prescribed by their brand names to avoid accidental substitution, Iddon said at the Wednesday’s debate. Furthermore, biosimilar product labeling should contain information on the potential dangers of substitution, he said.
Dawn Primarolo, also a Labor member of the House of Commons and minister of state for Public Health, pointed out that current UK law does not allow substitution without first asking the prescriber. She noted that a recent safety announcement from the Medicines and Healthcare products Regulatory Agency (MHRA) cautioned against generic prescribing of biologics even though prescribing drugs by their generic names is generally promoted as a cost-saving measure (DID, Feb. 5).
Iddon recommended that all biosimilar products bear a black triangle symbol, which denotes drugs that are new to the market and require robust safety monitoring. Additionally, pharmacovigilance and the yellow-card system of reporting adverse drug reactions need to be strengthened, and a database is necessary to track adverse reactions to biosimilars across all of Europe, he said. The yellow-card system is run by the MHRA and is used to collect information from health professionals and patients on suspected adverse drug reactions.
Primarolo confirmed that the MHRA has launched initiatives to increase the use of the voluntary yellow-card reporting system. Regulators are working to ensure that physicians who report adverse reactions to biosimilars provide the brand and batch number of the product, she said.
Iddon also proposed an awareness campaign to inform the public about biosimilars and associated safety issues.
In response to the debate, the British Generic Manufacturers Association (BGMA) urged members of Parliament to take into account the significant cost savings that competition in the biologics market produces.
“Without this competition, the prices of the originator products would remain artificially high,” BGMA Director Warwick Smith said. “Similarly, this competition stimulates research into new originator medicines.” — Breda Lund
Amgen’s experimental osteoporosis treatment denosumab increased bone density at multiple skeletal sites in early and later stage postmenopausal women, the company said in citing the results of a pivotal Phase III clinical trial.
The trial enrolled 332 patients with early and late-stage postmenopausal osteoporosis. Results appeared in the Journal of Clinical Endocrinology and Metabolism.
Patients received twice-yearly subcutaneous injections of denosumab for two years. They had increased bone mineral density (BMD) at all sites measured, including highly cortical areas of the skeleton, which account for 75 percent of skeletal mass and are key to the overall strength of vertebral and nonvertebral sites.
Denosumab treatment significantly increased lumbar spine BMD compared with a placebo after 24 months and produced significant increases in BMD in the hips, wrists and total body. Time since menopause did not influence the BMD response to denosumab, an investigational, fully human monoclonal antibody.
Serious adverse events (SAEs) were reported for 18 subjects (11 percent) in the denosumab group and nine subjects (5.5 percent) in the placebo group. The higher incidence of SAEs in the denosumab group was primarily caused by eight subjects who had infections that required inpatient treatment, while just one patient on placebo had to receive such treatment.
However, the overall incidence of infections reported as adverse events was approximately equal between the two groups, and the clinical investigators did not consider any of the infections to be related to denosumab treatment. The incidence of other adverse events was similar between the two arms of the trial. The most common of these events were arthralgia, nasopharyngitis and back pain.
Amgen is running a separate pivotal Phase III registrational study examining the impact of denosumab on fracture risk reduction in women with postmenopausal osteoporosis. The results of this large study are expected in the second half of this year.
Last September, Amgen reported that denosumab increased patients’ lumbar spine BMD by 10.6 percent (DID, Sept. 21, 2007). — Martin Gidron
Sandoz has announced the launch of a generic version of Antizol, an injectable drug for treating ethylene glycol or methanol poisoning.
The company said this week that it would market generic Antizol (fomepizole) in 1.5-gm/1.5-mL single-dose vials.
Jazz Pharmaceuticals’ Antizol is indicated as an antidote for poisoning from ethylene glycol, such as antifreeze, or methanol, either alone or in combination with hemodialysis.
The drug had sales of approximately $14 million last year, according to Jazz’s full-year 2007 earnings announcement. — Breda Lund
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