FDA Becoming Conservative? Not So Fast

I have attended a number of meetings and panels of late and keep hearing the same thing over and over: FDA is more conservative. It seems that every speech starts: "With a more conservative FDA..."

I'm not so sure.

There are some developments that could lead one to say FDA is becoming more conservative, such as the recent creation of an Office of Drug Safety and the choice of a new director for that office.

http://www.fda.gov/bbs/topics/news/2005/new01245.html

But if you look more closely, the office will fall under the purview of the Center for Drug Evaluation & Research and the new director ultimately reports to CDER chief Steve Galson. Moreover, the new ODS Director - Gerald Dal Pan - is only a few years removed from the industry he helps to regulate now. Dal Pan formerly oversaw clinical research for Guilford Pharmaceuticals. He left that post in 2000 to join the agency.

And take a look at the new interim FDA Commissioner. Andrew von Eschenbach is most known for saying that his goal as the head of NCI is to have a cure for cancer by 2015.

So he has a meager 10 years left to accomplish that feat.

[If what FDA says and does matters to you, then make sure to attend the upcoming FDA/CMS Summit Nov. 29-Dec. 1 in Washington, D.C. A number of FDA topsiders and former FDA decision makers will be there to tell you their priorities in 2006 and help you find your way through the regulatory maze.]

Review times certainly haven't skyrocketed and the agency is looking for more ways to speed up reviews, such as rolling review under its Pilot 1 program, which could be made permanent under PDUFA IV.

Merck's Vioxx clearly has created the environment for people to say FDA is becoming more conservative, but that doesn't mean that they are. The agency's Endocrinologic & Metabolic Drugs Advisory Committee just voted in favor of approving Pfizer's inhaled insulin drug Exubera, a product that has a decade-old safety history. The Oncologic Drugs Advisory Committee just recommended accelerated approval for Celgene's Revlimid for a type of blood cancer known as MDS. Revlimid is a cousin of thalidomide, one of the more dangerous drugs out there and that has been used in over 130,000 Americans to date.

Even if you take a look at the COX-2s and NSAIDs, Pfizer's Celebrex remains on the market, although with a black box warning, as do all other prescription NSAIDs.

If you take a step back and look at the key personnel at FDA, the players are still the same: Janet Woodcock, Bob Temple, and Galson among others.

I think the real issue for discussion is Big Pharma's pipeline. It's not that FDA is becoming more conservative, it's the pipeline of drugs leading into the agency.

The Tysabri Conundrum: The Classic Risk Assessment Case

Sometimes I feel real sorry for FDA. And this is one of those times. They will be facing a grueling decision with Biogen Idec/Elan's multiple sclerosis drug natalizumab (Tysabri).

The companies announced Oct. 17 they had completed the safety evaluation of the pulled drug and found no new cases of the sometimes fatal disease, progressive multifocal leukoencephalopathy
(PML).

http://www.biogen.com/site/019_0.html

As you will recall, the drug was pulled in February after three reported cases of PML - two of which were fatal. It certainly was a doomsday scenario for the partnered firms since they - and The Street - were banking on blockbuster status for the breakthrough therapy. You see, Tysabri was shown to reduce the rate of clinical relapses by 66% in its pivotal trial study and most, including FDAers, thought that Tysabri could be a game-changer.

On a more personal note, a friend of mine, who has multiple sclerosis, was told by her doctor that a fantastic new drug had been approved for her condition and that she should consider it. Her physician also told her, in addition to his advice, to do some research on it for herself so that she could make as informed a decision as possible. She chose to hold off on Tysabri until more was known about the drug and its effects through clinical experience. It turned out to be a smart choice.

[If what FDA says and does matters to you, then make sure to attend the upcoming FDA/CMS Summit Nov. 29-Dec. 1 in Washington, D.C. A number of FDA topsiders and former FDA decision makers will be there to tell you their priorities in 2006 and help you find your way through the regulatory maze.]

Nevertheless, Biogen Idec and Elan did not give up because they had so much riding on the drug, including two separate indications already in the works. As I told you in July in my accelerated approval story, Biogen hired McKinsey & Co. to put together a very aggressive risk management program for Tysabri that would help get the drug back on the market.

The company now has data to give FDA on the drug's safety. Almost 90% of the 1,500 patients that have participated or are participating in a Tysabri study agreed to take part in a safety evaluation. Almost all of them - 98% - took a neurological exam and MRI. They found no new cases of PML.

So the question is: What will FDA do now? That's a tough one. But here's my guess: they will bring Tysabri back on the market with a black box, FDA's strongest warning. Re-entry will also come with as stringent a risk management plan as has ever been seen at the agency.

Still, I recall a conversation with one of FDA's top reviewer who had intimate knowledge of the Tysabri approval. He said that Tysabri represented the "classic" risk-benefit assessment dilemma. The PML cases shifted the argument way over to the "risk" side and the drug was withdrawn. Will the new safety data see-saw it back in the other direction? We'll have to wait and see.

Accelerated Approval: FDA Meeting Could Be A Sign Of Things To Come

Pharmaceutical companies and biotechs, beware. FDA will be holding a meeting of its Oncologic Drugs Advisory Committee on Nov. 8 to discuss post-approval study commitments by sponsors for drugs granted accelerated approval.

For those of you who don't already know, the agency can grant AA to certain cutting edge drugs that point to a clinical benefit based on accepted surrogate endpoints. In exchange for conditional approval, drug companies must conduct a Phase IV postmarket study to confirm the earlier results.

This meeting is a must for drug developers and as close as you'll get to must-see TV at FDA.

Right now, there are essentially two camps at FDA. One group feels you should get drugs out to patients for serious and life-threatening illnesses as quickly as possible, despite sometimes questionable efficacy, and let the docs decide. The second camp believes drugs must show "reasonable" efficacy before you can put novel treatments out on the market.

In other words, one believes physicians should be the gatekeepers, while the other group believes FDA is the one and only gatekeeper. All of this is occuring under the perception that FDA is getting more conservative in general due to Vioxx, COX-2s, antipsychotics etc. There are flaws with both philosophies, but we won't go there today. The bottom line is accelerated approval is being increasingly used - with decreasing reliability - by the pharmaceutical and biotech industries to keep development costs down and get products to the market faster.

The single biggest problem right now with AA is that drug companies have not been doing the promised post-approval study. ODAC will discuss the best ways for sponsors to keep their word and follow through with study follow-ups. Postmarket trials for Johnson & Johnson's Doxil, MedImmune's Ethyol, SkyePharma's DepoCyt and Pfizer's Celebrex, among others, will be discussed by the panel.

More importantly, though, this meeting could be a marker for where FDA is headed with accelerated approval. Will there be a crackdown on Phase IV? How does ODAC feel about AA? Which individual panel members appear to be the most disheartened by the lack of postmarket follow-up commitments?

The answers to these questions will be critical for current and future accelerated approvals. With ODAC recommending approval for GlaxoSmithKline's leukemia drug Arranon and Celgene's MDS therapy Revlimid, it looked like a big win for AA. However, there has already been a serious setback for one of those decisions (more on that in my next post).

The November meeting is not the end-all, be-all. But it will serve as an important reference point for accelerated approvals. So mark your calendar, because this is one meeting you won't want to miss.

Speaking of meetings, for more insight into AA, FDA's priorities and where the Medicare drug benefit is headed in 2006, you should make sure and attend the Windhover FDA/CMS Summit Nov. 29-Dec. 1 in Washington, D.C. The speaker lineup is exceptional and the topics for discussion are sure to provide solutions and opportunities for a wide range of health care stakeholders. For more on the meeting, go to http://www.windhover.com/fda-cms.

FDA Commissioner: The Job Everybody and Nobody Wants

The twists and turns the FDA has experienced in the commissioner's office have been pretty remarkable over the last several years. After the resignation of Jane Henney in 2000, the agency has been on a rollercoaster ride.

First, there was a long search, which included a number of people that had been employed by pharmaceutical and biotech companies. Former HHS Secretary Tommy Thompson finally found his man: Lester Crawford. But the White House put the kibosh on Thompson's choice and instead went with someone close to home in Mark McClellan. McClellan was one of those rare political appointments that appeared to make everyone happy. But the Bush Administration needed someone to sell the Medicare benefit so McClellan, a health economist at heart, was moved over to CMS. Re-enter Lester Crawford. It is painfully obvious that Crawford has wanted all along to be FDA Commissioner. He suffered through a number of crises, and to be quite frank, indignities, to get permanently appointed. And Crawford finally did it.

I can tell you from talking to Crawford on several occassions, he is as good a person as you'll ever meet, and old McClellanites would say the same. So it's a shame that after such a long journey to that plush Rockville office, Crawford was forced to resign last Friday after just a few months with the title.

Now, former NCI Director Andrew von Eschenbach has been named "acting" FDA Commissioner. Aren't we all getting a little tired of this? It looks like the von Eschenbach Era won't last long, either. Comments made by Senate HELP Committee Chairman Michael Enzi (R-Wyo) clearly indicate that von Eschenbach's tenure at FDA will be very temporary.

http://help.senate.gov/vonesc.htm

It's obvious that the old NCI chief went up the road and didn't like the new digs. There is some watercooler talk that von Eschenbach is still the guy and he could be put in place permanently in February. But I wouldn't bet on it. Now the question is: who's next in line for the commissioner carousel?

Career staff and old agency hands are clearly - and rightfully - demoralized. But with FDA in its current situation, it's becoming quite clear: nobody wants this job.