Reviewing these submissions in a timely way is a "great task," says DPME Director Eric Duffy. Although there are fewer supplements
for new drugs compared with generics, FDA must pay more attention to them because it has relatively little experience with
the new products, Duffy points out. The goal of his office is to develop a streamlined review process that encourages manufacturers
to be innovative and adopt continuous-improvement approaches. DPME uses a risk-based triage approach to identify supplements
that require more extensive scrutiny because of the impact a proposed change would likely have on pro-duct performance. The
approach also considers manufacturers' degree of understanding of product design, desired product performance, and the manufacturing
The importance of user-fee support for the drug-review program can be seen in the much slower pace for processing supplements
for generic drugs. A generic manufacturer often files 20–30 postapproval supplements during a product's life cycle, pointed
out Hospira vice-president Richard Stec, representing the Generic Pharmaceutical Association at the public meeting. This adds
up to thousands of supplements submitted each year to FDA's Office of Generic Drugs (OGD). It takes 9–18 months for OGD to
review a typical chemistry, manufacturing, and controls prior-approval supplement, says Stec. The whole process of developing
a new production system, filing the supplement, and obtaining FDA approval can take four years, Stec explained. OGD Division
Director Vilayat Sayeed says that the agency strives to review important supplements within a year but acknowledges that this
is a very long time for a company to wait.
To deal with its voluminous workload, OGD is implementing a triage approach to identify the risk associated with the type
of change being reporting and the importance of more immediate review. OGD also has launched a question-based review process
to accelerate the review of applications that provide information about how the sponsor's quality-control system can ensure
consistent product quality. This approach streamlines the application-review process for new generics and also facilitates
the evaluation of supplements.
Although there is broad agreement that the current supplement-review system is outmoded and overprescriptive, revising the
rules will not be easy. Some manufacturers propose eliminating CBE supplements altogether and providing needed information
in annual reports. One idea is to create a new reporting category of "changes that do not require notification to FDA," suggests
Clark of OPS.
A key need is to redefine "major" and "moderate" changes and other terms. Phrases such as "moderate potential to adversely
affect" a product are too vague. Almost any change has potential to affect a product, and the language encourages companies
to file supplements even for changes with limited adverse effects.
Manufacturers agree that many reporting categories described in current rules and guidances are not necessary. Leo Lucisano
of GlaxoSmithKline, representing the Pharmaceutical Quality Steering Committee of the Pharmaceutical Research and Manufacturers
of America, advocated reducing or eliminating CBE supplements for packaging and testing-site changes and adopting equivalent
or superior analytical methods, among other low-risk revisions.
Generics manufacturers similarly would like to use risk-based approaches to reduce supplements. FDA should establish more-specific
criteria for major changes that require prior approval, advised Stec, and should eliminate CBE-30 supplements for various
less-critical changes such as changes in and at raw material suppliers, as well as modifications to their own manufacturing
processes. Manufacturers are developing several lists of changes that can best be managed by a firm's internal quality systems,
instead of requiring FDA review and approval (see sidebar, "Opportunities to reduce supplements for generics manufacturers").
Opportunities to reduce supplements for generics manufacturers
While revising its own rules, industry wants FDA to pay attention to similar efforts in Europe to streamline oversight of
drug product "variations." These activities provide an opportunity for regulatory authorities to harmonize postapproval policies
globally. European manufacturers back a system with two variation categories: minor changes to be filed with the regulatory
authority and major changes requiring prior assessment. This structure could establish a model for revising US rules.