The legislation also encourages manufacturers to conduct additional testing to demonstrate that a drug is interchangeable
with the reference product, instead of just being comparable. Interchangeable products would produce the "same clinical result(s)"
as reference products, a claim that would require clinical testing because there is no simple bioequivalence study for biologics
as there is for conventional drugs. Because interchangeable products would be "significantly more costly and difficult to
produce than comparable products," the bill offers manufacturers tax credits to cover the extra studies, plus six months exclusivity
for the first applicant that establishes interchangeability. The policy becomes a little murky, though, because it permits
FDA to approve a subsequent comparable biotechnology product while the initial exclusivity period is in effect for the interchangeable
The bill also aims to prevent innovator firms from maneuvering to extend patents and block new follow-on products from market.
It prohibits brand-name firms from producing authorized generics during the exclusivity period and imposes curbs on "frivolous"
citizens' petitions. And, the measure seeks to resolve patent disputes early on by establishing a new patent listing and notification
procedure that requires the manufacturer of a reference product to disclose all valid related patents so that generics firms
know which patents to challenge.
A call for user fees
Because follow-on biologics would be more difficult and time-consuming for FDA to assess and approve, the bill establishes
user fees for follow-on biologics applications to boost agency resources. This move may set a precedent for the generic-drug
industry, which is the only drug-industry segment that does not ante up to file applications or support FDA oversight of marketed
products. The issue has been discussed for years, and the current squeeze on FDA resources has put generic drug user fees
on the table as part of the debate on the renewal of the Prescription Drug User Fee program in the coming year.
Officials at the Generics Pharmaceutical Association (GPhA) point out that long delays in bringing new generics to market
sometimes occur even after FDA approves an application, making it unfair to require generics makers to pay a fee and wait
months to resolve patent disputes before being able to sell their products. But, FDA has been pushing for more fees unofficially
and emphasizes that its Office of Generic Drugs (OGD) in the Center for Drug Evaluation and Research (CDER) needs more staff
to deal with its mounting workload in a timely manner.
In fact, the number of ANDAs has been growing steadily as important blockbuster drugs lose patent protection. In fiscal year
2006, which ended on Sept. 30, OGD approved a record 510 ANDAs, passing the 500 mark for the first time. The list includes
several first-generic products such as pravastatin ("Pravachol"), sertraline ("Zoloft"), simvastatin ("Zocor"), clopidogrel
("Plavix"), and fluticasone ("Flonase" nasal spray).
Despite the boost in approvals, OGD's backlog swelled to more than 1500 pending applications because the total number of submissions
rose to almost 800 this past year. "If you approve 500 applications but get 800 submissions, the backlog number is going to
go up," lamented OGD Director Gary Buehler at the GPhA fall meeting in October. OGD's 200 staffers are struggling to reduce
application review times. About 70% of ANDAs were assessed in less than 14 months, but difficult submissions boosted the median
approval time to 16.6 months.
In addition to dealing with applications, OGD had to process more than 1700 letters last year (up from about 500 in 2000)
that sought information on generic-drug testing, development, and regulatory issues. Citizens' petitions, lawsuits, and queries
from manufacturers all add to OGD's workload.
In response, FDA is trying to make OGD processes more efficient and productive. A new policy will permit the agency to modify
its "first-in, first-reviewed" rule to quickly approve certain applications for products that address public-health needs.
CDER Director Steven Galson announced at the GPhA conference that FDA would expedite the approval of applications for a first
generic version of a drug, provided no patent or exclusivity issues arise. The six-month review policy also applies to certain
AIDS therapies and to products that meet public-health emergencies and drug shortages. The program is expected to affect only
a handful of drugs each year, but represents a visible effort to make the OGD approval system more flexible.
Buehler already has instituted joint reviews for multiple applications for the same drug, instead of repeating the process
for each ANDA separately. Another key initiative is to encourage electronic submissions of ANDAs based on the format of the
Common Technical Document (CTD). The office received 26 electronic CTD submissions through the end of August 2006 and is encouraging
more. OGD also seeks to improve operations with several new measures.
One plan suggests implementing the Question-Based Review (QbR) program. FDA approved the first QbR application in September
after an eight-month, one-cycle review. OGD's call for all ANDAs to follow the CTD format as of Jan. 1, 2007 should help expand
the QbR approach.
Another tactic entails finalizing the Individual Product Bioequivalence Guidance. This long-anticipated listing of bioequivalence
data for more than 300 drugs promises to reduce queries from manufacturers. Last year, OGD established a public Dissolution
Methods Database with recommended dissolution methods to help streamline product development and review.
In addition, OGD hopes to reduce the application queues. To speed up reviews of clear and complete applications, OGD's Division
of Bioequivalence is using an abbreviated review process for assessing bioequivalence data for uncomplicated, immediate-release
products. Separately, chemistry review teams are shifting around applications to prevent any one group from being overloaded.
And, noticeable delays in microbiology reviews are prompting efforts to develop a more efficient review template.
Finally, OGD hopes to achieve more first-cycle reviews. Increased use of telephone communications late in the review process
can inform an applicant of minor problems that can be remedied easily. This year, OGD approved 63 applications in one cycle,
compared with only three in 2004.
Jill Wechsler is Pharmaceutical Technology's Washington editor, 7715 Rocton Ave., Chevy Chase, MD 20815, tel. 301.656.4634,