[Ip-health] News story on use of citizen petitions to FDA to delay generic entry

[Mike Palmedo]

Generic drugs' quick, simple route to market has many roadblocks -
Nastech's case shows why medicine, despite law, is slow to reach consumers

By JOSEPH TARTAKOFF
Seattle Post-Intelligence
April 13, 2008

For almost three years now, a mystery company has foiled Nastech
Pharmaceutical's hopes of bringing its first product to market.

The product -- Calcitonin -- would provide patients who have
postmenopausal osteoporosis with a generic alternative to Miacalcin, a
nasal spray treatment with nearly $145 million in sales last year.

It could also produce a much-needed boost for Nastech, which has been
forced to cut its budget and lay off more than half its staff in the
months since Procter & Gamble withdrew from a lucrative partnership with
the company.

The Food and Drug Administration agreed to review Nastech's Calcitonin
for approval in February 2004, three months after Nastech submitted its
application.

But, in a bizarre twist, an unnamed pharmaceutical company, represented
by an attorney who once worked for the FDA, challenged the application.

The resulting standstill is a case study in how difficult it can be to
bring generic drugs to market, even though that process is designed to
be relatively quick, according to the FDA. (Legislation signed into law
last September is supposed to speed up the process even more.)

To bring a new drug to market, manufacturers must prove in animal and
human studies that the drug is both safe and effective. But to apply to
sell a generic drug, manufacturers do not need to repeat those tests;
they only need to show that the drug performs in the same manner as the
drug it seeks to copy.

Companies hoping to sell new drugs pay the FDA fees of up to $1.2
million and receive a review usually within 10 months. Generic
applicants do not pay fees and there are no timelines for review. On
average, it took about 16 months to get a generic product approved in
2005, according to the FDA.

Nastech has now been waiting almost 50 months.

Letter wars

In September 2005, more than a year after Nastech submitted its product
for review, David Rosen, an attorney at Foley & Lardner in Washington,
D.C., filed a so-called citizen's petition on behalf of a client,
challenging Nastech's application.

In the letter, Rosen argued that there was a possibility that the active
ingredient in Miacalcin and Nastech's product -- a hormone derived from
salmon -- would not necessarily be the "same" because there could be
contaminants in the production process.

To ensure that these contaminants would not result in an immune response
to the Nastech product, Rosen argued, Nastech needed to conduct testing
in humans. He also said there could be safety issues with the
preservative used in Nastech's formulation.

Adding to the complexity: By claiming that there could be immune
responses to the Nastech product, Rosen seemed to imply that the product
should be classified as a biologic -- produced from living cell cultures
-- since immune responses are usually associated with those and not
drugs produced by chemical synthesis.

In fact, generic versions of biologics are not allowed, and some
pharmaceutical companies argue that they should not be because of the
greater possibility of immune reactions.

A month after Rosen wrote his letter, Nastech responded that the company
did not need to provide additional data on immune responses to the drug
in order to prove "sameness."

"Nastech wishes to emphasize that FDA is under no legal obligation to
withhold approval of an otherwise ready-to-go ANDA (abbreviated new drug
application) to allow time to deal with petitions such as this. Thus,
Nastech's ANDA should be approved as soon as it is ready, whether or not
FDA is prepared to respond to this meritless petition," wrote Gordon
Brandt, who is now Nastech's president.

Nevertheless, the FDA delayed.

In a March 2006 letter to Rosen, the agency said, "the FDA has been
unable to reach a decision on your petition because it raises complex
issues requiring extensive review and analysis by Agency officials."

Roughly a week later Rosen fired back a letter to the FDA, responding to
Nastech's previous response.

Then, on July 10, 2006, the FDA finally replied to Nastech, saying the
spray was not approvable because of a "concern relating to the potential
for immunogenicity that might result from a possible interaction between
calcitonin-salmon and chlorobutanol, the preservative in the formulation."

Since then, Nastech has provided additional information to the FDA. Late
last year, the FDA notified Nastech that its review was complete and
that "the citizen's petition is actively being addressed by the FDA,"
according to a Nastech filing with the Securities and Exchange Commission.

"As far as we are aware the last piece of the process is the resolution
of the citizen's petition," Brandt said in a recent interview.

The secret client

The identity of Rosen's client, who wrote the citizen's petition, hasn't
been made public.

Rosen said the client is a pharmaceutical company.

But the company with the most at stake, Miacalcin maker Novartis, denies
it is involved.

"The manner in which the above-referenced Citizen Petition has been
written suggests that it was filed on behalf of Novartis. It was not,"
wrote Roxanne Tavakkol, Novartis' associate director of drug regulatory
affairs, in a September 2005 letter to the FDA. "Furthermore, Novartis
does not know on whose behalf Foley Lardner submitted this petition."

In an interview Friday, Rosen said, "When people ask me to write things
I believe in, I write them."

"At the time when I wrote that citizen's petition you didn't have to
disclose who was the client," he said. "They would rather keep that
confidential."

Legislation passed in September 2007 has changed much of the process.

Previously, "there was no predetermined time for the review of the
citizen's petition," said Andrea Hofelich, a spokeswoman at the Generic
Pharmaceutical Association.

"What was happening was there were some brand companies routinely filing
citizen's petitions on the eve of a generics application approval, which
would then delay the generic from coming to market because the FDA would
have to stop, review the petition, and then allow the generic to
continue to move forward," she said.

Under the FDA Amendments Act, the FDA now has to rule on a citizen's
petition within six months of its filing. Writers of citizen's petitions
also need to identify who is paying them.

Still, there are doubts about whether those rules are being followed.

In a letter addressed to the FDA commissioner dated Wednesday, seven
senators wrote:

"Although the citizen petition provision has been in law for more than
six months, it is unclear to us whether or to what extent FDA has taken
steps to implement this provision. At a time when healthcare costs
continue to increase exponentially, we cannot afford the added delay in
the approval of lower-cost generic pharmaceuticals."

If the FDA resolves the questions around the Calcitonin citizen's
petition -- a decision that could come any day, Brandt said -- Nastech
could immediately begin manufacturing the generic drug, which will be
sold by partner Par Pharmaceutical under an October 2004 agreement.

But there is another twist in the story of Nastech's Calcitonin.

It turns out that another company, Apotex, submitted an application to
the FDA to produce a generic version of Miacalcin before Nastech did.

"We are second in line," Brandt said.

That means if both products are approved at the same time, Apotex will
be able to sell its version exclusively for six months.

To make matters more complicated, though, Apotex is being sued by
Novartis for patent infringement. Because of the pending litigation, it
is unclear whether Apotex will want to go ahead and sell its product,
even if it is approved.

"Maybe we could work together and get one of them on the market," Brandt
said.

---
P-I reporter Joseph Tartakoff can be reached at 206-448-8293 or
joetartakoff@seattlepi.com. For more information on life sciences, read
blog.seattlepi.com/lifesciences.

--
Mike Palmedo
Research Coordinator
Program on Information Justice and Intellectual Property
American University, Washington College of Law
4910 Massachutsetts Ave., NW Washington, DC 20016
T - 202-274-4442 | F 202-274-0659
mpalmedo@wcl.american.edu