Healthy Skepticism Library item: 13510

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Publication type: news

Tartakoff J.
Generic drugs' quick, simple route to market has many roadblocks
SeattlePI.com 2008 Apr 13
http://seattlepi.nwsource.com/business/358888_calcitonin14.html?source=rss

Full text:

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.