"Priority" Review Slow Down: The Prasugrel Delay

FDA is looking at a February advisory committee for the Lilly/Daiichi anti-clotting drug. That would put the review of the "priority" application at 14 months and counting. What does prasugrel mean for the priority review process?

By Ramsey Baghdadi

The most highly anticipated drug of 2008 is now the most highly anticipated drug of 2009. So it goes in the new world of drug safety.

An FDA approval of Eli Lilly & Co.’s anti-platelet drug prasugrel looked like a safe bet after the agency deemed the application as justifying a "priority" review in February. The only clear debate that appeared to loom over the drug was the level of postmarket controls FDA would mandate to monitor safe use in broad populations.

During an earnings call in July, Lilly hinted that the discussions over the post-approval controls were going well. The Risk Evaluation and Mitigation Strategies (REMS) for the drug were likely to be "much simpler and much less difficult to comply with" than what was generally being speculated. ("The Pink Sheet" July 28, 2008.) (Also see "Prasugrel Could Avoid More Restrictive REMS Options, Lilly Hints" - Pink Sheet, 28 Jul, 2008.)

Now, however, the very approval of the drug appears less certain.

Prasugrel is an important guidepost on the regulatory landscape for drug developers for three major reasons:

●Prasugrel demonstrated superiority over the gold standard, Plavix, in a head-to-head trial. The pivotal Phase III TRITON study is the kind of trialFDA says it would like to see more of in classes of drugs with multiple therapeutic options.

●The anti-clotting drug represents an advance in primary care practice, an area in which companies have been finding it more and more difficult to bring out major new products. Even Pfizer Inc., which built its fortunes over the last decade around Lipitor, is exiting cardiovascular drug development to focus on seemingly less crowded and less treacherous disease areas. (Also see "The FDA Roundtable Part I: The Regulators' View of Drug Development" - Pink Sheet, 1 Sep, 2008.)

FDA’s official description of what constitutes a priority review is straightforward: "A priority review designation is given to drugs that offer major advances in treatment, or provide a treatment where no adequate therapy exists....The distinction between priority and standard review times is that additional FDA attention and resources will be directed to drugs that have the potential to provide significant advances in treatment."

The agency notes the designation does not change the scientific standard or quality of evidence needed for approval. There a number of ways the agency uses to define "advances":

1) evidence of increased effectiveness in treatment, prevention, or diagnosis of disease;

2) elimination or substantial reduction of a treatment-limiting drug reaction;

3) documented enhancement of patient willingness or ability to take the drug according to the required schedule and dose; or

4) evidence of safety and effectiveness in a new subpopulation, such as children. Prasugrel, it would seem, fits under the first bullet. And according to the experience from 2007, the drug looked like a sure thing with an approval coming no later than the September deadline.

After all, most priority review drugs are approved within the six-month timeframe. In 2007, the average approval time for priority reviews was 6.5 months compared to almost 17 months for standard review NDAs, according to FDA’s most recent data. In other words, about a half year compared to a year and a half.

But there are indications that 2008 could see a marked increase in priority review times. CDER is already taking longer on review decisions, and has had the option of taking an extra two months on priority reviews since the beginning of the year. (Also see "The New User Fee Rules: FDA Sacrifices Timeliness, Tries to Save Predictability" - Pink Sheet, 1 Mar, 2008.) A review of recently approved and pending priority products seems to bare that out. (See Exhibit 1.)

So does prasugrel serve as a sign of things to come for priority reviews?

It may. One former senior FDA official says an estimate of 10 months for priority reviews going forward is "reasonable." However, for more complicated applications, drug sponsors should be thinking 13 months when taking into account a REMS plan and other circumstances, including a "complete response" letter and a review of a resubmission.

"I would predict the perturbations to ease by middle and end of 2009 and you’ll begin to see benefit instead of drain from new reviewers."

However, some say prasugrel is a unique case, and not indicative of a larger slowdown. "I don’t think prasugrel is a compelling precedent," says former senior CDER official and Wyeth executive Bruce Burlington. "Most priority drugs don’t have the safety and the ‘did they get the dose right?’ questions it has."

Despite examples of other delays, including GlaxoSmithKline’s drug eltrombopag (Promacta) and Lundbeck Inc.’s GABA-transaminase inhibitor vigabatrin (Sabril), Burlington is somewhat optimistic.

"I expect that most priority applications with clean profiles and modest sized number of trials and number of patients, for example, most orphan and many oncology products will continue to go through in six months, plus or minus."

A Race Ahead of 2011

Still, timing is everything when it comes to prasugrel. In addition to trying to blunt the blow of the introduction of generic olanzapine, Lilly’s marketing plan is rooted in getting prasugrel on the market as quickly as possible before it has to compete with generic clopidogrel on drug coverage formularies.

Lilly is cleaning up its financial statements to prepare for a new blockbuster period. The company’s recent $1.4 billion charge to third quarter earnings from charges of off-label marketing of Zyprexa is the kind of move that cleans away a lingering blemish on future results and sets a framework for positive reports in the prasugrel period. The payments on Zyprexa marketing will settle charges brought by the federal government, 32 states and the District of Columbia.

Bristol-Myers Squibb says it has been watching the prasugrel review closely in order to develop its own strategy going forward.

"As you can imagine, we are following with interest all of the news we read about prasugrel and we are readjusting our forecasts depending on the interpretation of that news," Bristol EVP and chief operating officer Lamberto Andreotti said during the company’s third quarter earnings call. "We have been ready for a launch of prasugrel for quite some time now."

Bristol has bolstered its hospital sales force and implemented "additional efforts" to "remind" prescribing physicians of the breadth of data supporting use of clopidogrel, Andreotti maintained. "Again, we are ready if they launch."

Still, given the twists and turns, it’s hard to predict what lies ahead for prasugrel. But the anti-clotting drug reinforces three assumptions in the new world of drug safety and an under-resourced FDA. First, it’s more difficult than ever to get a primary care drug through FDA, plain and simple. Second, user fee deadlines have slipped in importance and relevance. And third, the premium value of a priority review is waning.

Prasugrel may eventually get approved. For Lilly though, the product is already months late.