Cobert's Manual Of Drug Safety And Pharmacovigilance (Third Edition). William Gregory
There are several, but the key one for safety is MAUDE (Manufacturer and User Facility Device Experience). This database contains AE reports involving medical devices. It contains data submitted by mandatory reporters (manufacturers, importers, and device user facilities) and voluntary reporters (healthcare professional, patients, and consumers). Data goes back to 1991 for device user facilities, to 1993 for distributor reports, and to 1996 for manufacturer reports. It is online and searchable by product problem, product, class, manufacturer, event type (death, injury, malfunction, other), brand name, registration number, and time frame. The focus is on medical devices which may have malfunctioned or caused a death or serious injury.
Some of the MAUDE data are downloadable. These files consist of voluntary reports since mid-1993, user facility reports since 1991, distributor reports since 1993, and manufacturer reports since mid-1996. The searchable portion of the data contains records for the most recent 10 years and is refreshed weekly. Note that MAUDE may not include reports made under waivers, exemptions, variances, or alternative reporting requirements. There also is a separate database for pre-1996 reports from manufacturers. A detailed review of medical device safety or drug-device combination products is not in the scope of this manual.
Over-the-Counter Products
OTC products are regulated by CDER’s Office of Non-prescription Drugs and are drug products that can be sold in the United States without a prescription and, thus, without any medical professional intervention. That is, they are sold without a clear medical diagnosis being made by a medical professional and, thus, are purchased largely for symptoms as self-diagnosed by the lay public. Some products are not truly over the counter and are held by the pharmacist “behind the counter” such that the consumer must speak with the pharmacist, who will/should assess the need and appropriateness of the patient and product. OTC products have benefits that outweigh their risks, have low potential for misuse and abuse, can be adequately labeled, and do not require a health practitioner for their safe and effective use.
Drugs can enter the OTC market in several ways. A drug may be approved via the usual NDA process and then may be moved to OTC status through various routes. One is the “Rx to OTC switch”. Other drugs that are “generally recognized as safe and effective (GRAS/E)” are listed in the FDA’ s “OTC monograph(s)” that specify which drugs may be marketed without further studies, FDA review, or approval. There are also so-called negative monographs that limit specific indications for certain drug ingredients. The monographs are very detailed specifications in the Code of Federal Regulations that specify ingredients, doses, formulations, indications, and labeling.
The FDA can act quickly to restrict marketing or remove a product from sale if there is significant risk or lack of evidence for effectiveness, or if the FDA finds that the usual notice and public procedure method are impracticable, unnecessary, or contrary to the public interest. The FDA can, thus, issue a rule requiring immediate label changes and marketing restrictions. In non-urgent situations, the FDA can use the notice and comment rulemaking mechanism to change marketing status.
Regarding safety reporting, OTC reporting by industry was not required until December 2007 for OTCs that did not have NDAs. That is, there was no requirement for AEs to be collected, analyzed, or submitted by manufacturers. This changed in 2007 when FDA issued a guidance that required reporting of serious AEs for OTC products found to be “associated with the drug”. These were to be reported via MedWatch by manufacturers, packers, and distributors, using the 3500A-form. This essentially required that all serious AEs (whether in the label or not) must be reported to FDA within 15 calendar days. Requirements for minimal validity criteria are essentially the same as for drugs. Manufacturers are now required to submit reports electronically, but others are not yet required to use electronic means to make OTC case reports.
Drug Safety Oversight Board
The FDA created an internal Drug Safety Oversight Board (DSB) in 2005. The DSB was subsequently mandated by the FDA Amendments Act of 2007 and advises CDER Center Director on handling and communicating important and emerging drug safety issues, especially regarding how such issues impact federal healthcare delivery and payment systems. The DSB is composed of representatives from two FDA Centers and eight other federal government agencies, the Agency for Healthcare Research and Quality (AHRQ), Centers for Disease Control and Prevention (CDC), Centers for Medicare and Medicaid Services (CMS), Department of Defense (DOD), Health Resources and Services Administration (HRSA), Indian Health Service (IHS), National Institutes of Health (NIH), and Department of Veterans Affairs (VA). An important role of the DSB is to help FDA assess the impact of their safety decisions on the healthcare systems of its Federal Partners. The Board, with its broad representation from federal healthcare organizations, can provide valuable input and allows FDA to hear varied perspectives on drug safety issues.
Monthly meeting minutes and outcome reports are available online.
Prescription Drug User Fee Act
In 1992, the Prescription Drug User Fee Act (PUFA) was passed and then renewed 5 years later in 1997 (PDUFA II), and again in 2002 (PDUFA III), 2007 (PDUFA IV), 2012 (PDUFA V), and 2017 (PDUFA VI). This Act allows the FDA to collect a fee from an applicant whenever the applicant submits an NDA or BLA. In addition, companies pay annual fees for each manufacturing establishment and for each prescription drug product approved for marketing. Previously, taxpayers alone paid for product reviews for regulatory action by the FDA, through congressional appropriations.
In the program authorized under PDUFA, industry provides the funding in exchange for FDA agreement to meet drug-review performance goals, which emphasize timeliness without a loss of scientific quality of the review. As examples, the PDUFA fee rate for FY 2018 was $2,421,495 for an application requiring review of clinical data and was $1,210,748 for an application not requiring review of clinical data. The fees are adjusted on an annual basis. The typical allowed review time for an NDA under PDUFA is 10-months (or 6-months for priority reviews). Questions have been raised about the appropriateness of what is, in effect, industry funding of the government process for approving a medical product for entry into the commercial marketplace. In reality, user fees are for application review, not approval. Approval is not guaranteed.
Prescription Drug User Fee Act: Five-Year Plan
The FDA created multiple action plans to address the requirements of the law. In particular, FDA issued a “Prescription Drug User Fee Act Five-Year Plan” with each sequential renewal of PDUFA. Each plan includes steps to address the requirements in the legislation. Details and milestones are posted on the FDA website.
Other FDA initiatives under way are briefly mentioned below. The landscape changes frequently and FDA’ s website should be checked periodically for updates and new initiatives.
Food and Drug Administration Act (FDAAA) of 2007
In 2007, PDUFA was actually a part of major new legislation known as the Food and Drug Administration Amendments Act (FDAAA) of 2007.
The FDAAA has multiple parts. The ones that deal with post-marketing safety are known as Title IX and give enhanced authority to the FDA regarding safety. In particular, it created the concept of Risk Evaluation and Mitigation Strategies (REMS), which are briefly outlined in this chapter and described in more detail elsewhere.
Another section strengthened the FDA’ s authority to unilaterally modify product labeling. Before 2007, the FDA did not clearly have the power to force labeling changes and most changes were done on a “voluntary” basis, though the FDA, in practice, could force most changes they desired. FDAAA formally empowered FDA to “notify” the applicant of new safety information that the agency “believes should be included in the labeling”. The applicant then has 30 days to submit an amendment proposing new labeling that reflects FDA’s communication or to notify the FDA that it disagrees and why. FDA may