So far, it has been up to each company to decide whether it will adopt QbD approaches and develop continuous quality-control
operations. Proposals that mandate such activities will surely generate opposition on many fronts. FDA's challenge is to devise
a strategy that offers regulatory relief to companies that adopt modern manufacturing practices without penalizing those that
In addition, a regulatory change that even remotely appears to compromise drug safety will raise a red flag. In the current
political climate, critics of industry and FDA could regard modified reporting rules for manufacturers as allowing production-system
changes without appropriate oversight of safety effects.
A recent FDA proposal to clarify when manufacturers can file CBEs for labeling changes that reflect new safety information
was blasted on Capitol Hill. Congressional leaders objected that the proposed rule would encourage pharmaceutical companies
to hide drug-safety information and protect marketers of unsafe products from legal action. Though the point of reducing supplements
is to help FDA handle its expanding workload and to encourage modern manufacturing practices, even the best intentions face
intense scrutiny these days.
Streamlining adverse events
Skepticism about FDA regulatory actions may affect efforts to streamline the agency's complex and costly process for adverse
event (AE) reporting. Current rules require manufacturers to submit reports that involve serious and unexpected events within
15 days. Less serious problems may be filed in quarterly reports. After a product has been marketed for three years, minor
problems may be filed annually.
In the US, most AE data are fed into FDA's Adverse Event Reporting System (AERS). AERS holds about 4 million case reports,
and this number is growing by about 300,000 reports each year. This spontaneous reporting system relies on patients and healthcare
professionals to detect and inform manufacturers and regulatory authorities of problems related to medical products.
AERS is considered effective at detecting signals of rare, unexpected drug-safety problems such as new drug interactions and
confusion about product names and labeling. But reports are often incomplete. In addition, the system does not address safety
issues that involve heavy background noise (e.g., cardiac problems related to COX-2 inhibitors or diabetes drugs).
In reauthorizing the Prescription Drug User Fee program under the FDA Amendments Act of 2007, Congress approved additional
funds to expand and improve the AERS system. The legislation also supports developing an active AE detection system linked
to health-system and government healthcare databases.
As part of this effort to modernize drug-safety oversight, legislators instructed FDA to engage outside experts to assess
the value of AERS. Experts will determine how long the current system takes to identify safety problems and the extent that
passive or spontaneous reports from patients and health professionals lead to regulatory action.
FDA held a public workshop in January to gain input on how to assess the current AE reporting system, as well as its capabilities
and shortcomings. Solomon Iyasu, of CDER's Office of Safety and Epidemiology (OSE), explained that AERS is valuable because
it covers all FDA-regulated products. Moreover, the system reaches a large real-world patient population, including those
who take drugs for off-label uses.
At the same time, many safety problems go undetected, and reports filed with AERS are often uninformative.
Despite these and other weaknesses, the healthcare community believes that spontaneous AE reporting should be retained and
strengthened. Practitioners and patients say a new, active safety detection system should complement what already exists.
OSE researchers found that safety issues occur throughout a drug's life cycle and that many serious issues emerge after drugs
are on the market for more than 13 years.
How can regulators make AERS more effective and efficient? At the AE workshop, Ralph Edwards of the World Health Organization
commented that the massive volume of reports in AERS "varies from utter nonsense to real gold." The challenge is to identify
those "utterly ridiculous" reports and avoid using them to make regulatory decisions.
Jill Wechsler is Pharmaceutical Technology's Washington editor, 7715 Rocton Ave., Chevy Chase, MD 20815, tel. 301.656.4634, firstname.lastname@example.org