FDA's Internal Advisory Committee Meetings

Avandia. Vioxx. Ketek. Elidel. Palladone.

What do those drugs have in common? The obvious answer is that they are all associated with a major safety problem that resulted in a significant FDA regulatory action—either a “black box” warning in product labeling, or, in the case of Palladone and Vioxx, outright removal from the market.

But they have something else in common as well. In the months preceding those major regulatory steps, each product was the subject of a relatively unknown internal meeting at the Food & Drug Administration: a regulatory briefing.

Regulatory briefings can be described as “internal advisory committees” at FDA—a chance for review divisions to ask others in CDER for advice on how to handle a tricky regulatory or scientific decision. (For more on regulatory briefings, check out our coverage in The RPM Report. If you’re not a subscriber, you can sign up for a free trial to view the article.)

If you’ve never heard of a regulatory briefing, you’re not alone. Regulatory briefings have been kicking around FDA’s Center for Drug Evaluation & Research for more than a decade, but because they are closed to industry—and review divisions don’t always inform sponsors when one is held—many companies are unaware that they exist. But now FDA is holding more of them, as many as one per week. And they are quite popular with reviewers.

The good news for drug sponsors is that regulatory briefings are not intended to be decisional meetings; the final approvability decision remains with the review division after the meeting is over. But given the typical attendance list—John Jenkins, Janet Woodcock, Bob Temple, Doug Throckmorton and 50-100 other drug reviewers—it would be hard to ignore any advice.

A drug does not have to rise to the level of an Avandia or a Vioxx to be discussed during a regulatory briefing—given the frequency of such meetings, that could not possibly be the case. But, as the list above indicates, they do tend to skew toward the more problematic end of the continuum. The need for a regulatory briefings should not spell doom and gloom for a sponsor, but it could be an indication that something is wrong. That alone makes them worth watching.

image via FDA

Pharma Must "Continue to Take Chances" In Policy World: Merck VP's Parting Advice

We recently had the chance to talk at length with Merck VP-global public policy Ian Spatz (right, not actual size) about the challenges and opportunities facing industry amid the changes in Washington.

We've always found him to be a very thoughtful analyst of the policy climate, and a very forward thinking advocate for ways to improve that environment. (That's why, among other things, he is a regular on the program at FDC-Windhover's FDA-CMS Summit, and will be speaking there on Friday.)

Come January, Spatz will be leaving Merck after 15 years. He hasn't announced his future plans, but he expects to remain involved in health policy. We'll be publishing a full transcript of the interview in The RPM Report soon, but we wanted to share with you some of his thoughts about his time at Merck:

Q: You have been with Merck for 15 years. What are you proudest of, having been associated with Merck over that time? Is there something that stands out?

Ian Spatz: I've been very proud of all the time I've spent here. Merck's a great company, has great people, has done amazing things and will continue to do amazing things. And in terms of my own time here, I would pull out the about five years of work towards encouraging passage of the Medicare prescription drug benefit. It certainly was the most difficult challenge. I had enormous support from my colleagues and from everyone at Merck. It was a unique time when we had the opportunity to work with Medco and learn about pharmaceutical benefit management, and it was enormously gratifying to see legislation passed and be successful and to see so many seniors be able to get prescription drug coverage, including my own mother. So it was both professionally and personally very satisfying.

Q: You also were with Merck through the whole Vioxx period. What if any lessons are there from that experience for Merck or the industry as a whole?

Spatz: Vioxx was certainly the most difficult experience during my time at Merck. There's a little bit of distance between now and when that happened, but there's still more distance needed to fully reflect on it.

The lesson that we took away from that time was that we – at least, speaking personally – had overestimated the level of trust that existed out there in our science and in our company. The fact that people could believe the things that many of them did believe about Merck after that was very difficult for me to accept, given the people who I know at Merck who were involved in Vioxx, who made decisions related to it, knowing the kind of commitment that they've had and have to patient safety and patient care. That was the most difficult thing, to see that people could believe things about us that I know are not true.

Q: Knowing that you'll be leaving Merck in January, what things do you hope to see the company do in the future? What is your advice to your colleagues as you move on to bigger and better things?

Spatz: My area of expertise has not been science, marketing, manufacturing, or any of those areas. It's been public policy. So my advice– if it's valuable at all, it's valuable in that area. My advice is to continue to take chances, to continue to engage not only with our friends, but our critics, to continue to develop proposals and to study those proposals and to debate those proposals that are going to address the very real problems that exist out there for patients and for the pharmaceutical industry.

To the extent that there are challenges and controversies, my advice is to continue to work to address those. We've learned a long time ago, it's just not simply enough to try to explain them or tell people they're not true. When there are legitimate concerns out there, we need to do something about them, and that's been what I've tried to encourage here at Merck.

That's the advice I'll give, and I really believe that that will continue to be the company's philosophy.

Whose Life is it Anyway?

No one really wants to shout it from the rooftops, but for FDA and the drug industry, Monday's Supreme Court’s decision not to consider whether terminally ill patients have a legal right to access unapproved drugs is a little more sweet than bitter.

The decision by the high court ends a long, topsy-turvy, and often emotional legal fight by the Abigail Alliance to allow patients access to investigational drugs and biologics outside the clinical trial setting. (The alliance is named for Abigail Burroughs, who passed away in 2001 while trying to gain access to the then-investigational cancer drug cetuximab, now marketed by ImClone and Bristol-Myers Squibb as Erbitux.)

Along with the Washington Legal Foundation, the Abigail Alliance sued FDA in 2003 to allow access to unapproved drugs after the completion of Phase I studies. A Washington, DC district court initially dismissed the case, but the decision was overturned by a three-member panel of the US Court of Appeals. This August, an en banc appeals court reversed the decision, prompting WLF to ask the Supreme Court to consider the case.

Appealing to the Supreme Court is always a long-shot legal strategy, but the high court’s consideration of the Abigail Alliance lawsuit could have resulted in significant changes for FDA and industry. Check out full coverage of the Abigail Alliance lawsuit in The RPM Report here and here. If you don’t yet subscribe, you can sign up for a free trial at TheRPMReport.com.

For FDA, a win by Abigail Alliance would have meant changing its regulations to make it easier for patients to access investigational medicines. FDA has had mechanisms in place for patients to access unapproved drugs outside the clinical trial setting since the 1970s, including “treatment use” and “emergency use” INDs—mechanisms that the Abigail Alliance argued are insufficient and overly bureaucratic.

But FDA argued that it has a “compelling interest” to restrict some patients from getting investigational drugs—namely protecting them from what might be an unsafe product. And given the intense congressional scrutiny over drug safety since the Vioxx withdrawal, you can bet FDA doesn’t have warm and fuzzy feelings about giving really sick patients a drug that hasn’t yet passed the approval hurdle.

For manufacturers, expanding access would have presented a tricky dilemma: balancing the goodwill gesture of granting a patient a dying wish against the threat of litigation should something go wrong. That’s not a comfortable place to be: Amgen’s outside attorney Mark Gately (Hogan & Hartson) said he “dreaded the day” that FDA changed its regulations—or a court ordered it to do so.

But it doesn’t look like that day will come anytime soon. FDA obviously isn’t budging, and it’s unclear whether a new commissioner would change its legal interpretation of the issue. Congress could pass legislation to expand patient access to unapproved drugs, but the Abigail Alliance’s big advocate on Capitol Hill, Sen. Sam Brownback (R-Kansas), doesn’t seem to be making it a top priority this session.

The Washington Legal Foundation’s press release has an air of finality to it, but it isn’t conceding defeat: “We will continue our effort to persuade FDA that terminally ill patients deserve better access to drugs that FDA has deemed suitable for large-scale clinical trials.” But we’re not going out on a limb to say that’s a long-shot proposition.

Science Matters: A small personalized medicine bailout for Cox-2s?

There was little attention paid to last week's paper suggesting that PPAR delta agonists might be used to prevent the cardiovascular side effects of Cox-2 inhibitors (coxibs) such as Vioxx and Celebrex.

The study in the Journal of Experimental Medicine (JEM) showed that Cox-2 suppresses the expression of tissue factor (TF) -- the primary activator of blood clotting and a proximal cause of coxibs' CV problems -- via the activation of PPAR delta.

Of course, there are no approved PPAR delta drugs, although pharmas including GSK have tried developing them to treat cardiovascular disease. (One news outlet suggested GSK's drug could be an "unlikely savior" for Vioxx, but that's a far stretch.) And no one would think to couple a PPAR delta with a coxib for use as a combination analgesic--the risk/benefit ratio of that presumably is way off.

But there's another, intriguing aspect to this research result.

The problem with Vioxx is that it is associated with cardiovascular complications in a small number of patients. "We should look at these patients in terms of their TF levels and other clotting parameters," suggests Timothy Hla of the University of Connecticut Health Center and a principal author of the JEM paper. "Is the TF gene in these people somehow different? Is it regulated differently? Are they more sensitive or more resistant to the effects of the PPAR delta they produce? Instead of looking at the selectivity of Cox-2, let's look at patients' sensitivity."

Hla has a longstanding interest in Cox-2's role in normal blood vessel physiology and angiogenesis: he cloned the gene from human vascular cells in and named it Cox-2 in 1992, while at the American Red Cross Research Institute.

A first step would be to measure TF levels, which can be easily collected from plasma, in patients taking Celebrex and correlate them with treatment results. It's all well and good to talk about testing PPAR delta agonists for their therapeutic effects regulating the TF gene. (The most advanced may be GSK's GW 501516, which the Hla group used in its experiments. GSK in-licensed the compound from Ligand Pharmaceuticals, but its development has lagged at Phase II. Ligand's most recent 1o-K says the drug's development is 'on hold' pending the review of preclinical studies, and there is no mention of it on GSK's own clinical trials web site or in any recent publicity [clintrials.gov lists a 'completed' Phase II study], so for all we know it has been terminated.)

So that's a long way off. Most of the focus on the mechanism of Cox-2 has centered on its effect on platelets. A simple blood test might go a long way towards refining that effort.