The House Energy and Commerce Health Subcommittee has scheduled a hearing for March 10 on "Drug Safety: An Update from the FDA." At the hearing, the FDA will detail its current challenges and successes in the area of drug safety. Joshua M. Sharfstein, M.D., FDA Principal Deputy Commissioner, is slated to testify.
This post was written by Paul Sheives.
On February 18, 2010, the FDA posted updated listings of specific drugs that are being evaluated for potential safety issues based on a review of reports in FDA's Adverse Event Reporting System. The postings, which are mandated by the Food and Drug Administration Amendments Act of 2007, reflect safety information through September 2009. The FDA cautions that the appearance of a drug on this list does not mean that FDA has concluded that the drug has or causes the listed risk, nor does it suggest that healthcare providers should not prescribe or patients should not take the drug. If the FDA determines after further evaluation that the drug is associated with the risk, FDA could require labeling changes, require development of a Risk Evaluation and Mitigation Strategy (REMS), or gather additional data to better characterize the risk.
This post was written by Paul Sheives.
FDA published a guidance document aimed at sponsors that are developing drug products with the potential for abuse that may need to be scheduled by the Drug Enforcement Agency (DEA) under the Controlled Substances Act. Within the draft guidance document, FDA addresses both the definition of abuse potential and information on submitting an adequate abuse potential assessment and scheduling request – covering such topics as study design and administrative recommendations. Comments should be submitted by March 29, 2010 to be considered when the FDA drafts its final guidance.
This post was written by Paul Sheives.
FDA recently issued a revision of an International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) guidance document, M3(R2), that was published in 1997 and is intended to harmonize and recommend international standards for non-clinical safety studies conducted to support human clinical trials of a given scope and duration, and/or to be relied upon for marketing authorization for pharmaceuticals. In this revised guidance document, FDA includes a new discussion relating to exploratory clinical studies. Also included are recommendations to help sponsors determine when certain nonclinical studies should be performed, such as phototoxicity studies, immunotoxicity studies, juvenile animal toxicity studies, and abuse potential studies.
This post was written by Paul Sheives.
To maximize the agency’s efforts to process submissions for the evaluation of proprietary names within the deadlines under the Prescription Drug User Fee Act (PDUFA), FDA issued a guidance document to assist manufacturers in making a complete submission, which is required for the PDUFA review clock to begin. FDA discusses the collection of information that the agency requires to assess: (1) the safety aspects of a proposed proprietary name in order to reduce medication errors, and (2) the promotional implications of a proposed proprietary name, to ensure compliance with other requirements for labeling and promotion using traditional FDA review methods.
This post was written by Paul Sheives.
A recent GAO report points to improvement in FDA’s postmarket drug safety oversight, but the agency expresses concern over continued gaps in particular areas. The GAO recommended that FDA develop a plan and timeline for transferring additional regulatory authorities from the Office of New Drugs to the Office of Surveillance and Epidemiology. FDA comments regarding the report were generally supportive, but the agency is hesitant to commit to any timelines.
This post was written by Paul Sheives.
The Food and Drug Administration (FDA) has announced the Safe Use Initiative, a program aimed at reducing the likelihood of preventable harm from medication use. The program is summarized in an FDA report entitled “FDA’s Safe Use Initiative – Collaborating to Reduce Preventable Harm from Medicines.” The report outlines FDA’s intention to identify safety issues linked to preventable harm via collaboration with health care professionals and other stakeholders. The report also provides examples of several risk-reduction areas in which Safe Use collaborations may prove useful, including evaluating consumer medication information, communicating about the risk of inadvertent overexposure to acetaminophen, implementing safeguards against surgery fires caused by alcohol-based surgical preps, and avoiding contamination of multiple use medication vials.
This post was written by Paul Sheives.
On November 19, 2009, FDA completed a coordinated and collaborative international effort intended to curb illegal actions involving medical products sold via the internet. The agency issued 22 warning letters to the operators of these web sites and notified internet service providers and domain name registrars that the web sites were selling products in violation of U.S. law. FDA noted that, in many cases, because of these violations, internet service providers and domain name registrars may have grounds to terminate the websites and suspend the use of domain names.
This post was written by Paul Sheives.
FDA released a number of final and draft guidance documents in November, including the following:
The OIG has issued a report entitled “Renal Dialysis Facilities’ Dosage Protocols for Administering Erythropoiesis-Stimulating Agents.” The report, which was requested by members of Congress, found that 93% of Medicare-certified dialysis facilities had established protocols in place for administering erythropoiesis-stimulating agents (ESA). While only 56% of these protocols explicitly state a target hemoglobin range, 94% of those that did were consistent with the boxed warning on FDA-approved labeling and the Medicare benefit policy for ESAs. The OIG pointed out that since almost half of the dialysis facilities either did not have protocols or did not specify a target hemoglobin range in their protocols, the OIG cannot determine whether these facilities’ policies target the hemoglobin range consistent with FDA labeling.
This post was written by Paul Sheives.
FDA is authorized to approve applications based on clinical trials that demonstrate a new drug’s impact on a “surrogate endpoint,” or laboratory measure or physical sign used as a substitute for a clinical endpoint. When FDA approves a drug based on a surrogate endpoint under an accelerated approval process, a sponsor must, as a condition of approval, conduct postmarketing confirmatory studies to validate that a drug’s impact on a surrogate endpoint also leads to clinical benefits. Responding to concerns raised about FDA’s reliance on surrogate endpoints and its oversight of postmarketing studies, the GAO issued a report that (1) identified drugs approved based on surrogate endpoints; (2) obtained the status of related postmarketing studies; and (3) reviewed FDA’s oversight of a sample of 35 studies it required under its accelerated approval process, selected to include studies at varying levels of completion. According to the GAO, although FDA has authority to expedite the withdrawal of a drug from the market if a sponsor does not complete a required confirmatory study with due diligence, or if a study fails to confirm a drug’s clinical benefit, it has not specified the conditions that would prompt it to do so. The GAO notes that this authority has never been exercised by the agency, even when such study requirements have gone unfulfilled for nearly 13 years. The GAO report recommends that FDA clarify the conditions under which it would utilize its authority to expedite the withdrawal of drugs under its accelerated approval process, but FDA disagreed with the need to develop such clarifying guidance.
The Agency for Healthcare Research and Quality (AHRQ) has released for public comment its draft Technology Assessment, "Report on the Evidence Regarding Off-Label Indications for Targeted Therapies used in Cancer Treatment." The document reviews the medical literature regarding 19 different drug/diseases indications that, at the time of their selection, were all off-label. The report concludes that for "some diseases, despite limited and/or ambiguous data, the use of an off-label indication may be a reasonable clinical decision." The report suggests additional research in this area. Comments will be accepted until November 16, 2009 (extended from initial November 9 deadline).
On October 1, 2009, the Food and Drug Administration (FDA) published a proposed rule clarifying postmarketing safety reporting requirements that apply when regulated products (drugs, devices, and biological products) are combined to create a combination product. The FDA is accepting comments on the proposal until December 30, 2009.
The FDA has issued its “Strategic Plan for Risk Communication,” which outlines how the agency intends to communicate information about the risks and benefits of FDA-regulated products with various public audiences, including health professionals, patients, and consumers. The plan includes more than 70 actions the FDA plans to take over the next five years to: strengthen the science that supports effective risk communication; expand FDA’s capacity to generate, disseminate, and oversee effective risk communication; and optimize FDA policies on communicating risks and benefits.
The FDA has issued a final guidance document for industry on “Implementation of Medical Device Establishment Registration and Device Listing Requirements Established by the Food and Drug Administration Amendments Act of 2007.” The FDA also is soliciting comments on a number of draft guidance documents, including the following:
A number of Congressional committees have held hearings recently on health policy issues, including the following:
On August 21, 2009, the FDA published two proposed rules that would require manufacturers and other covered entities to report adverse drug, biological, and device events electronically. The FDA expects that the proposed changes would help it “more rapidly review postmarketing safety reports, identify emerging safety problems, and disseminate safety information in support of FDA's public health mission.” In the first rule, the FDA is proposing to amend its postmarketing safety reporting regulations for human drug and biological products to require that persons subject to mandatory reporting requirements submit safety reports in an electronic format that FDA can process, review, and archive. Likewise, with regard to devices, the FDA is proposing to amend its postmarket medical device reporting regulation to require that manufacturers, importers, and user facilities use an electronic format to submit mandatory reports of individual medical device adverse events. Comments on both rules will be accepted until November 19, 2009, and comments on related information collection issues are due September 21, 2009. Separately, the FDA released a draft guidance document that provides recommendations on how to prepare and submit electronic medical device reports to FDA in a manner that satisfies the proposed rule; comments on the draft are requested by November 19, 2009.
On September 24-25, 2009, the FDA is holding a public workshop entitled “Providing Effective Information to Consumers About Prescription Drug Risks and Benefits.” Comments on workshop documents (including a series of prototypes on different written approaches to conveying prescription drug information to consumers) will be accepted until November 25, 2009.
The AHRQ Effective Healthcare Program has released a final research report on "Developing Evidence-Based Research Priorities for Off-Label Drug Use." The report finds that more than 20% of outpatient prescriptions are for off-label use and identifies 14 top-priority drugs that are commonly used for off-label indications with inadequate supporting evidence. The report recommends that future research into off-label drug use focus on drugs used frequently without such evidence, particularly if further concerns are raised by known safety issues, high drug cost, recent market entry, and extensive marketing. Additional research is especially needed in the area of antipsychotic and antidepressant medication. Top priority drugs were quetiapine, warfarin, escitalopram, risperidone, montelukast, bupropion, sertraline, venlafaxine, celecoxib, lisinopril, duloxetine, trazodone, olanzapine, and epoetin alfa.
The FDA has released guidance on “Medication Guides: Adding a Toll-Free Number for Reporting Adverse Events.” Beginning July 1, 2009, manufacturers of prescription drug products approved under the Federal Food, Drug, and Cosmetic Act that are required to have a Medication Guide must add a verbatim statement to their Medication Guides containing FDA's toll-free number for reporting side effects. These manufacturers also must report to FDA that they have complied with this requirement. This guidance explains what statement to add to Medication Guides, where to add it, and how to notify the agency that such a statement has been added.
The Government Accountability Office (GAO) has issued a report entitled “Privacy and Security: Food and Drug Administration Faces Challenges in Establishing Protections for Its Postmarket Risk Analysis System.” The report focuses on the FDA’s Sentinel Initiative, a postmarket risk identification and analysis system based on electronic health data. Although the Sentinel system is still in the early planning stages, the GAO believes that the system will pose significant privacy and security challenges, including among other things: ensuring that appropriate legal mechanisms are established to protect privacy and implement security consistently across the Sentinel system; effectively informing the public of the program’s planned uses of their personal health information; ensuring that de-identified information is not re-identified; establishing adequate security controls to protect the personal health information associated with Sentinel; and establishing sufficient oversight and enforcement mechanisms to ensure that privacy and security requirements are consistently implemented. In the report, the GAO recommends that the Commissioner of FDA develop a plan, including milestones, for developing the Sentinel system and for addressing these privacy and security challenges.
The FDA has issued draft guidance on “Label Comprehension Studies for Nonprescription Drug Products.” The draft guidance provides recommendations on the design of label comprehension studies, which can be used to assess the extent to which consumers understand information conveyed by proposed nonprescription drug product labeling and then apply that information when making hypothetical drug use decisions. Comments on the draft are due July 30, 2009.
The Food and Drug Administration (FDA) has released draft guidance for industry entitled “Submission of Summary Bioequivalence Data for ANDAs.” The draft guidance is intended to assist ANDA applicants in complying with new requirements in a January 2009 final rule that requires ANDA applicants to submit data from all bioequivalence studies (BE studies) the applicant conducts on a drug product formulation submitted for approval. The guidance is applicable to BE studies conducted during both preapproval and postapproval periods. FDA is accepting comments on the draft guidance until July 16, 2009.
The FDA is announcing the availability of final guidance for industry entitled “Integrated Summaries of Effectiveness and Safety: Location Within the Common Technical Document.” The guidance clarifies where within the new drug application (NDA) and biologics license application (BLA) common technical document (CTD) format to include an integrated summary of effectiveness (ISE) and integrated summary of safety (ISS), and it addresses other related FDA requirements.
On May 1, 2009, the FDA is holding a public meeting regarding economically motivated adulteration (EMA), which FDA defines as the fraudulent, intentional substitution or addition of a substance in a product for the purpose of increasing the apparent value of the product or reducing the cost of its production (i.e., for economic gain). EMA includes dilution of products with increased quantities of an already-present substance (e.g., increasing inactive ingredients of a drug with a resulting reduction in strength of the finished product) to the extent that such dilution poses a known or possible health risk to consumers, as well as the addition or substitution of substances in order to mask dilution. Several recent incidents involving FDA-regulated products (heparin, glycerin, infant formula, and pet food), are suspected to be examples of EMA. The purpose of the meeting is to stimulate discussion about ways in which the food (including dietary supplements and animal food), drug, medical device, and cosmetic industries, regulatory agencies, and other parties can better predict and prevent EMA, with a focus on situations that pose the greatest public health risk. The agency also invites written comments on this issue; the comment deadline is August 1, 2009.
On February 4, 2009, the FDA posted updated listings of specific drugs that are being evaluated for potential safety issues based on a review of reports in FDA's Adverse Event Reporting System. The postings, which are mandated by the Food and Drug Administration Amendments Act of 2007, reflect safety information through September 2008. The FDA cautions that the appearance of a drug on this list does not mean that FDA has concluded that the drug has or causes the listed risk, nor does it suggest that healthcare providers should not prescribe or patients should not take the drug. If the FDA determines after further evaluation that the drug is associated with the risk, FDA could require labeling changes, require development of a Risk Evaluation and Mitigation Strategy (REMS), or gather additional data to better characterize the risk.
The Government Accountability Office (GAO) has issued a report entitled “High-Risk Series: An Update,” which identifies areas where federal programs are at risk of fraud, waste, abuse, and mismanagement. This biennial report highlights areas of continuing concern, including Medicare and Medicaid program management. While the GAO points to certain improvements in Medicare program operations, it recommends further actions, such as monitoring beneficiary grievances; eliminating inappropriate payment incentives; safeguarding the program from payment errors; and addressing deficiencies in oversight of care quality in nursing homes and hospitals. The GAO also identified continued weaknesses in oversight of state Medicaid claims and supplemental payments, review of the budget neutrality of Medicaid demonstrations prior to approval, and the overall level of improper Medicaid payments. The GAO also adds a new high risk area this year focusing on the FDA’s ability to ensure the safety and efficacy of drugs, biologics, and medical devices. The GAO recommendations in this area address, among other things, foreign drug inspections, review of promotional materials, and presentation of clinical trial results by drug sponsors.
The FDA published a notice on January 13, 2009 announcing a final guidance document entitled “Good Reprint Practices for the Distribution of Medical Journal Articles and Medical or Scientific Reference Publications on Unapproved New Uses of Approved Drugs and Approved or Cleared Medical Devices.” The guidance, which finalizes a February 20, 2008 draft policy, is intended to provide manufacturers with the agency's views on permissible distribution by a company's sales representatives of medical journal articles and scientific or medical reference publications that discuss unapproved new uses for FDA-approved drugs or biologics or FDA-approved or cleared medical devices to healthcare professionals. As with the 2008 draft guidance, the final version notes the need to balance the law’s prohibition on distributing or promoting “unapproved uses of approved drugs and approved or cleared medical devices” with the “important public policy” of providing information that “may even constitute a medically recognized standard of care.” The FDA concludes that the touchstone for lawful dissemination of literature about unapproved uses is that the publications “are truthful and non-misleading.” To meet this standard, the FDA final guidance lists “principles of Good Reprint Practices” that include criteria for determining the type of publication and the manner in which the publication can be distributed. Although the final guidance closely tracks the draft guidance, it has some important clarifications, including revisions to the Good Reprint Practices and a specific reference encouraging manufacturers to seek approvals and clearance for new indications and intended uses for medical products. A Reed Smith analysis of the final guidance is available here.
The FDA published a notice January 15, 2009 announcing the launch of a voluntary Secure Supply Chain pilot program to help promote the safety of imported drugs and active pharmaceutical ingredients (APIs). According to the FDA, the program would enable the FDA to focus its resources on imported drugs that fall outside the program and that pose a risk of being adulterated, misbranded, or unapproved, while increasing the likelihood of expedited entry for specific finished drug products and APIs into the U.S. that meet the pilot’s criteria. The FDA plans to select 100 applicants to participate in the program, and each applicant may designate up to five drugs for selection in the pilot program. To qualify, applicants will need to meet the pilot's criteria, including a requirement that they maintain control over the drugs from the time of manufacture through entry into the U.S. The FDA will accept comments on the program through March 16, 2009.
On January 13, 2009, the FDA announced on behalf of the Interagency Working Group on Import Safety the availability of draft guidance on “Good Importer Practices.” The draft guidance document provides general recommendations to importers on possible practices and procedures they may follow to increase the likelihood the products they import (including drugs) comply with applicable U.S. safety and security requirements. Comments will be accepted through April 13, 2009.
The FDA has released draft guidance on “Standards for Securing the Drug Supply Chain – Standardized Numerical Identification for Prescription Drug Packages,” which recommends standards industry should use for the identification of individual packages containing prescription drugs under the FDAAA. The standards are designed to facilitate adoption of a uniform electronic track and trace system for prescription drugs to further improve their safety and security. The FDA is soliciting comments on certain aspects of the guidance, as detailed in a January 16, 2009 notice. Comments will be accepted until April 16, 2009.
On January 16, 2009, the FDA published a notice announcing “Draft Guidance for Industry on Submission of Laboratory Packages by Accredited Laboratories,” which is intended to enhance the quality and reliability of test results submitted by importers to demonstrate that their products meet the FDA's requirements. The guidance advises importers how to use accredited laboratories and makes recommendations about the quality and type of test data that these laboratories should produce to support test results submitted to the FDA. According to an FDA press release, the guidance also is intended to reduce the likelihood that an importer will submit only favorable test results to the FDA. Comments on the draft will be accepted through April 16, 2009.
The Agency for Healthcare Research and Quality's Centers for Education and Research on Therapeutics (CERTs) has launched a new educational web site offering clinicians and consumers expert information on drugs, biological products, and medical devices from a federally-sponsored network of leading research centers. The Clinician-Consumer Health Advisory Information Network (CHAIN) also provides access to informational resources developed from research conducted by CERTS and intended for use in improving health care quality, safety, and effectiveness.
On January 2, 2009, the National Vaccine Program Office (NVPO) announced that it is seeking public comment on the Centers for Disease Control and Prevention’s Immunization Safety Office draft Scientific Agenda related to scientific research questions in vaccine safety. Comments will be accepted through February 2, 2009.
The FDA has released draft guidance on “Genotoxic and Carcinogenic Impurities in Drug Substances and Products: Recommended Approaches.” The document reflects the agency's views on genotoxic and carcinogenic impurities in drug substances and drug products, including biologic products regulated by the Center for Drug Evaluation and Research. It also provides recommendations on how to evaluate the safety of these impurities during clinical development and for marketing applications, including additional testing and exposure threshold recommendations when genotoxic or carcinogenic impurities are present. The draft guidance addresses synthetic impurities and degradants in drug substances, but not the genotoxicity or carcinogenicity of actual drug substances or intended drug product ingredients. This draft guidance also applies to known starting materials or anticipated reaction products. The FDA will accept comments on the guidance through February 17, 2009.
On December 3, 2008, the FDA announced it is teaming with WebMD to expand consumer access to FDA safety alerts and other public health information. Among other things, the partnership includes a new online consumer health information resource on WebMD.com where consumers can access information on the safety of FDA-regulated products.
On October 28, 2008, the Food and Drug Administration (FDA) published a final rule requiring a statement to be included on certain human drug product labeling that provides a toll-free number for reporting side effects and specifies that the number is not intended to be used for medical advice. The rule, which confirms a January 3, 2008 interim final rule on this issue, implements provisions of the Best Pharmaceuticals for Children Act and the Food and Drug Administration Amendments Act of 2007. The compliance date for the final rule is July 1, 2009 (rather than the January 1, 2009 compliance date anticipated under the interim final rule).
HHS announced it is preparing to open FDA offices in China, India, Europe, and Latin America before the end of 2008 to beef up efforts to ensure the safety of imported food and medical products. FDA personnel overseas will be tasked with providing technical advice to local authorities and industries, conducting additional inspections, and working with government agencies and private sector entities interested in developing certification programs. This initiative is part of the federal government’s Import Safety Action Plan.
On October 22, 2008, the Government Accountability Office (GAO) issued a report entitled "Drug Safety: Better Data Management and More Inspections Are Needed to Strengthen FDA's Foreign Drug Inspection Program." Among other things, the GAO found that: FDA databases contain inaccurate information on foreign establishments subject to inspection; FDA inspects relatively few foreign establishments each year to assess the manufacturing of drugs currently marketed in the United States; and FDA’s identification of serious deficiencies has led foreign establishments to take corrective actions, but inspections to determine continued compliance are not always timely. The GAO recommends that FDA improve the data that it uses to manage its foreign inspection program, conduct more inspections of foreign establishments, and ensure more timely inspection of foreign establishments where FDA has identified serious deficiencies. HHS agreed that FDA should conduct more foreign inspections, and discussed other FDA oversight initiatives, such as database improvements.
On September 5, 2008, the FDA posted its first quarterly report listing 20 specific drugs that are being evaluated for potential safety issues based on a review of reports in FDA's Adverse Event Reporting System, as mandated by the Food and Drug Administration Amendments Act of 2007. The FDA cautions that the appearance of a drug on this list does not mean that FDA has concluded that the drug has or causes the listed risk, nor does it suggest that healthcare providers should not prescribe or patients should not take the drug. If the FDA determines after further evaluation that the drug is associated with the risk, FDA could require labeling changes, require development of a Risk Evaluation and Mitigation Strategy (REMS), or gather additional data to better characterize the risk.
On August 22, 2008, the FDA published a final rule amending its regulations regarding changes to an approved new drug application, biologics license application, or medical device premarket approval application. Specifically, the rule provides that a labeling change to an approved product to reflect "newly-acquired information" that adds or strengthens a contraindication, warning, precaution, or adverse reaction, may be made prior to FDA approval upon the submission of a "Changes Being Effected" or "CBE" supplemental only if there is sufficient (reasonable) evidence of a causal association with the use of the drug, biologic, or device. In a change from the January 16, 2008 proposed rule, CMS is revising the definition of “newly acquired information” to clarify that data, whether derived from reports of adverse events or from new clinical studies or new analyses of previously submitted data (e.g., meta-analyses) needs to be of a “different type or greater severity or frequency than previously included in submissions to FDA.” This standard could limit the circumstances under which a company can make changes without prior FDA approval. The rule is viewed by many as FDA's attempt to address preemption questions raised in state product liability lawsuits against holders of marketing applications for their failure to amend labeling before or without FDA's approval. The rule is effective September 22, 2008.
On May 22, 2008, the Food and Drug Administration (“FDA”) announced plans for what it is calling the “Sentinel System” -- a new, national electronic health information surveillance system to track the performance and safety of medical products once they are on the market. According to the FDA, the Sentinel System will be created through public-private partnerships and will capitalize on existing large electronic claims and medical records data sources maintained by private and government entities that agree to participate in this nationwide effort. A Reed Smith bulletin discussing this initiative in greater detail is posted here.
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