FDA Advisory Panels: Elephants in the Room

The New York Times recently reported that "Ten of the 32 government drug advisers who last week endorsed continued marketing of the huge-selling pain pills Celebrex, Bextra and Vioxx have consulted in recent years for the drugs' makers..." (10 Voters on Panel Backing Pain Pills Had Industry Ties, NYT, 2/25/2005).

If these 10 panelists were taken out of the voting, which would be expected if FDA policies on conflict of interest were adhered to (they weren't -- more on that below), then the committee would have voted to take both Bextra and Vioxx off the market (12 to 8 against Bextra and 14 to 8 against Vioxx).

Ninety-three percent (93%) of the time these 10 panelists voted in favor of the drugs, whereas the 22 other panelists favored the drugs in their votes only 56% of the time.

"Of the 30 votes cast by the 10 panel members on whether Celebrex, Bextra and Vioxx should continue to be marketed, 28 favored the drugs. Among the 66 votes cast by the remaining 22 members of the panel, just 37 favored the drugs." -- NYT

It should be noted that the voting preferences of these 10 panelists did not influence the decision to keep Celebrex, marketed by Pfizer, on the market. That is, the vote would have been in favor of Celebrex even if these panelists were excluded from voting.

Financial ties to industry of FDA advisory committee members is not a new issue. A USA TODAY analysis of financial conflicts at 159 FDA advisory committee meetings from Jan. 1, 1998, through June 30, 2000 found:

• At 92% of the meetings, at least one member had a financial conflict of interest.


• At 55% of meetings, half or more of the FDA advisers had conflicts of interest.


• Conflicts were most frequent at the 57 meetings when broader issues were discussed: 92% of members had conflicts.


• At the 102 meetings dealing with the fate of a specific drug, 33% of the experts had a financial conflict.

Elephants in the Room
If you have ever attended one of these Advisory Committee meetings, you would find that the majority of attendees are representatives of drug companies with perhaps a smattering of public interest groups and a large contingent of press people.

So you can expect that every vote by each panelist is noted and reported back to drug companies with an interest in the matter. This has got to put a lot of pressure on the panel members, many of whom have accepted money from the industry in the past or perhaps would like to accept money from them in the future!

This goes with the territory of open, public meetings. It certainly would not be in the public interest to have secret ballots. So there's not much we can do about that.

But, can't the FDA find panelists without any ties to the pharmaceutical industry? Apparently not. A Washington lawyer "who was until last year the agency's general counsel, said that finding knowledgeable experts without financial conflicts was difficult." (NYT)

The reason is that the industry creates these "knowledgeable experts," which has as much to say about physician education in this country as it does about pharma industry influence over physicians. In short, physicians absolutely depend upon the industry to learn about new products and even the conditions they treat. At least a couple of the "gang of 10" advisors stated as much:

Dr. Steven Abramson, a rheumatologist at New York University School of Medicine who was on the panel, has consulted for Pfizer and Novartis. "The F.D.A. is looking for people who understand the science behind these medicines," and such an understanding often results from working with drug makers, he said.

Dr. John Farrar, a neurologist at the University of Pennsylvania who has received research support from Pfizer and is a panel member, agreed. "I think F.D.A. would have a hard time finding people who are good at what they do who never spoke to a pharmaceutical company," he said.

Pharma companies "educate" physicians directly and indirectly in many ways:

• Sales Representatives -- these "detail" men (and women) are supposed to provide physicians with much needed details about products, but more often than not sales reps are merely there for the hard sell and to drop off samples (see, for example,"A Crisis in Professional Detailing")


• Support of Continuing Medical Education -- pharma companies often support accredited continuing medical education for physicians, which means that physicians need not spend their own money to obtain CME credits that are required to maintain their licenses to practice medicine. There is some debate on how unbiased industry-supported CME is and there have been abuses (e.g., paying for junkets for physicians to attend "educational" activities at resorts along with their spouses). See, for example,"Provider/Pharmaceutical Partnerships - Are They Possible Without Conflict of Interest?" and "When Is Commercial Support Appropriate for CME Activities?"


• Key Opinion Leaders -- Key Opinion Leaders are physicians who influence their peers' medical practice, including but not limited to prescribing behavior. Pharmaceutical companies generally engage key opinion leaders early in the drug development process to provide advocacy activity and key marketing feedback. See "Developing Win-Win Key Opinion Leader Relationships" for insights on how pharma companies leverage key opinion leaders. It is probably from this pool of physicians that most FDA advisory boards solicit members.

Anyway, physicians are beholding to the industry for much of their education, a point that was well-documented by Marcia Angell in her book "The Truth About Drug Companies. How They Deceive Us and What to Do About It" (see "The Truth About the Drug Companies: What To Do About It" for a review). As long as that is the case, it will be impossible to find a group of experts without some past ties to the pharmaceutical industry to serve on advisory committees.

Is this necessarily bad? I mean, can advisory committees still make credible decisions given these conflicts?

The FDA, in 2003, did a study of "public attitudes and opinions" regarding conflicts of interest and FDA advisory committee meetings (see "Conflicts of Interest and FDA Advisory Committee Meetings"). They surveyed a sampling of people who attended FDA advisory committee meetings in the spring of 2003 and advisory committee members who participated in those meetings. The study's intent was to examine the perceived fairness and credibility of FDA advisory committee meetings related to FDA's management of real or potential conflicts of interest among advisory committee members.

An overwhelming majority of respondents (67%) disagreed with the statement "When committee members have conflicts of interest, they will always decide in favor of their interest." Maybe they don't "always" do so, but the COX-2 gang of 10 did so 93% of the time (see above). Eighty-seven percent of respondents disagreed with the statement "You cannot trust an advisory committee's decision if any of its members have conflicts of interest." What about if 10 out of 32 have conflicts?

This study was really a survey of the "elephants" in the room -- i.e., representatives of pharma companies. 82% of respondents were "paid by an employer or organization to attend the meeting." Guess what organizations pay employees to attend such meetings?

FDA "Openness" Is At Issue Here
The law requires that FDA advisory committee members disclose financial interests in the subject of the meeting. Financial interest is defined in FDA regulations "as the potential for gain or loss as a result of government action on a particular matter."

But the FDA chose not to reveal the financial ties to the pharma industry of the COX-2 committee members. As reported in the NYT:

Before each of three meetings of the advisory board last week, an agency secretary read a statement absolving panel members of conflicts of interest because the committee's agenda involved "issues of broad applicability and there are no products being approved."

The secretary also said, "The Food and Drug Administration acknowledges that there may be potential conflicts of interest, but because of the general nature of the discussions before the committee, these potential conflicts are mitigated."

On February 15, HHS Secretary Leavitt said "The public has spoken and they want more oversight and openness" (see "Reforms Will Improve Oversight and Openness at FDA" FDA Press Release). Unfortunately, during the COX-2 meetings the FDA chose not to take this path, chose to ignore the public and was far from "open" and transparent.

Febraury Issue of Pharma Marketing News Is Here

Pharma Marketing News
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CURRENT ISSUE: Vol. 4, No. 2: February 2005

Links to summaries of individual articles below.

Articles

• You May Walk Like a Duck and Quack Like a Duck, But You're No Duck!


• Relationship Marketing Program Management for Pharmaceutical Marketers


• DTC in 2005: Can You Teach Old Dogs New Tricks?


• Numbers, Math and Communicating Risk


• Does the FDA Need to be Overhauled?

This Month's Survey

• Pharma Cost Cutting
  Is the "arms race" over? Is it time to cut back on sales and marketing spending? How deep will cuts be? Will cuts be industry wide?
  

  What do you think? Click here to take this survey. You will be able to see a summary of the de-identified results immediately after completing the survey.

Vioxx Redux

Just when you thought it was safe to go back into the water, Merck suggests that it may put Vioxx back on the market, according to an article in today's Wall Street Journal ("Merck May Return Vioxx to Market").

A reversal of the Vioxx withdrawal would be "a shocking turn of events." So, why is Merck considering doing it?

The article lists several reasons, but none really have to do with serving the interests of their customers (patients and physicians). It's really a matter of "strategy": Merck could benefit in its court battles by arguing that Vioxx is a benefit to some patients; the additional revenue could help boost its finances (e.g., pay for court awarded damages); it would also help its case in getting a similar drug, Arcoxia, approved for sale in the U.S.

As more and more evidence piles up that all cox-2 inhibitors, including Vioxx and Celebrex, may cause increased cardiovascular events, isn't an odd time to suggest the return of Vioxx? Apparently not. That's just the risk side of the issue. You have to look at the benefit side.

"If the advisory committee and the FDA conclude that the benefits of this class outweigh the risks in some patient populations," said Merck research head Peter S. Kim, "then we would have to consider the implications of these new data given the unique benefits Vioxx offers."

In other words, if Celebrex is allowed to stay on the market -- because its benefits outweigh the risks to some patients -- then Vioxx should be allowed to come back. OK, I'll buy that argument. It's a valid point from Merck's perspective.

If Vioxx does come back on the market, Merck should consider renaming it Reduxx.

But does returning Vioxx -- or whatever it's called -- to market make sense from a patient perspective?

Mothra AND Godzilla?
It's like the citizens of Tokyo dealing with Godzilla and Mothra in their midst. Many citizens always argued that one monster was enough, why do we need two of them? They began focusing on Mothra and listing all her bad traits that were harmful to citizens. Mothra, always seeing herself as the friend and savior of Tokyo, decided to leave town and vowed never to return for the good of the citizens. She also felt a bit guilty, recalling many instances in which she inadvertently crushed a few citizens with her wings while fighting Godzilla. .

Meanwhile, Godzilla absolutely refused to leave town. He was powerful and he claimed that there was not enough evidence that his bad traits harmed anyone. At least no one wanted to be first and come forward with accusations.

Eventually, however, the citizens of Tokyo accumulated enough evidence that all monsters, including Godzilla, were bad for some people - especially those that invited them to dinner or hung around with them long enough. Realizing her opportunity, Mothra argued that given this new evidence, she should be allowed back in town if Godzilla was allowed to stay. Is it in the best interest of the citizens of Tokyo to allow Mothra to return?

Tune in next week.

Meanwhile, how are painkillers remaining on the market doing? The following chart, from my friends at ImpactRx, shows the share of New Treatment Starts (NWRx + New Sample Only), which includes prescriptions and sample only for newly diagnosed patients and previously diagnosed patients with a change in medication.



The period covers from the end of October, 2004 to the first week in February, 2005. Note that Celebrex and Bextra have a very low share of NRx. Of course, Vioxx is not shown because it is off the market during this period.

It appears that doctors are voting with their prescription pads and prescribing non-Cox-2 painkillers like Mobic, ibuprofen, and naprozen. Note in particular the success of Mobic because its glory days may be over.

As reported in today's Washington Post ("Vioxx Alternative Potentially as Risky, Official Says"):

"David J. Graham, a veteran Food and Drug Administration safety officer and recent whistle-blower, told a conference reviewing the risks of arthritis painkillers yesterday that Mobic, the medication that hundreds of thousands turned to after Vioxx and other COX-2 inhibitors came under a cloud, is potentially just as dangerous.

"Graham said a large new study he and a colleague had just completed, which FDA officials initially did not want him to present because it was preliminary, indicates that the anti-inflammatory drug is a 'bad actor.' His agency, he added, needs to 'weed the garden of bad actors.' "

Or, as the good citizens of Tokyo might say, All Monsters Must Die!

Drug Safety: A Matter of Trust!

Those Canadians are at it again! Quick they are at being contrary to the U.S. This even extends to drug safety issues.

As reported in the WSJ on 9 February 2005, the U.S. and Canada differ on whether or not the attention-deficit drug ADDERALL is safe ("Why U.S., Canada Differ on Safety Of Attention-Deficit Drug").

Health Canada -- the equivalent to the FDA in Canada -- instructed Shire BioChem Inc., the manufacturer of ADDERALL XR to withdraw the drug from the Canadian market (see "Health Canada suspends the market authorization of ADDERALL XR , a drug prescribed for Attention Deficit Hyperactivity Disorder (ADHD) in children").

The FDA has not followed suite in the U.S. In an advisory it said: "FDA does not feel that any immediate changes are warranted in the FDA labeling or approved use of this drug based upon its preliminary understanding of Health Canada's analyses of adverse event reports and FDA's own knowledge and assessment of the reports received by the agency."

These days, anything the FDA has to say about drug safety -- especially if it is contrary to what its Canadian and UK regulatory counterparts have to say -- may understandably be taken with a grain of salt. Critics of the FDA have questioned not only its ability to fairly evaluate drug safety issues but also its criteria for safety:

"[FDA believes] a drug is safe until you can show with 95% or greater certainty that it is not safe," said FDA whistleblower David Graham before a Senate committee. "This is an incredibly high, almost insurmountable barrier to overcome. It's the equivalent of "beyond a shadow of a doubt." And here's an added kicker. In order to demonstrate a safety problem with 95% certainty, extremely large studies are often needed. And guess what. Those large studies can't be done." (see the upcoming February Issue of Pharma Marketing News).

It appears that Canada and the US (and the UK and the US, maybe even the whole world outside the US and the US) have different paradigms by which they view drug safety. Maybe Canada and the rest of the world outside the US are too quick to pull drugs from the market without adequate scientific evidence?

But, what is "adequate scientific evidence"?

If two renowned organizations with access to the same data and with staffs of medical experts can't agree on when a drug is safe or not, how can an ordinary, non-scientifically-trained patient do so? Even some physicians are confused: "From the doctor's point of view, I find it very confusing and worrisome when two different agencies using the same databases reach very different conclusions," said Murali Doraiswamy, psychiatrist at Duke University Medical Center (WSJ article).

Some FDA regulators are also confused - "We found [the reported cases of death] difficult to interpret and ambiguous," said Dr. Temple, director of the office of medical policy in the FDA's drug center. Is this a case of the FDA's 95% certainty "rule" or honest scientific appraisal of benefit vs. risk?

I wouldn't attempt to answer that question. My only point is that as long as the FDA's ability to fairly judge drug risk is under a cloud of suspicion for reasons that I point out in the article "Does the FDA Need to be Overhauled?" in the upcoming February Issue of Pharma Marketing News, then we -- and I include physicians as part of "we" -- have no way of knowing who to trust.

To improve public trust, the FDA needs to be overhauled so that its drug safety function is separated from its drug approval function. In his Senate critique of the FDA, Dr. Graham said: "The same group that approved the drug is also responsible for taking regulatory action against it post-marketing. This is an inherent conflict of interest."

A large majority (84%) of respondents to a Pharma Marketing News survey agreed or strongly agreed that the job of monitoring safety approval should be separated from that of approving drugs.

The FDA, on February 15, announced a new independent Drug Safety Oversight Board to oversee the management of drug safety issues (see "FDA Improvements in Drug Safety Monitoring"). The plan, however, has already come under attack. The board will have no powers other than to advise the FDA and publish findings on a public web site (the rules for doing so have not been revealed). The board is also internal and will be comprised of FDA staffers and other government employees.

As reported in WSJ Online ("FDA Offers Placebo"):

Merrill Goozner, director of the Integrity in Science Project at the Center for Science in the Public Interest, suggested that the new board would be toothless without greater independence, funding and authority. He added that it should be peopled with full-time staff, rather than pulling government employees from other jobs. "This is a full-time job," he said. Independent monitors "should be the cop on the beat -- not somebody called in once a month to ruminate on the question of whether there's crime."

Also, there needs to be a better program for drug safety surveillance AFTER a drug is put on the market. As the author of the cited WSJ article stated: "The disagreement between the two national health regulators .... is an extreme example of the problems of limited data available on the safety of marketed medicines."

"There's no right or wrong because there's no science." -- Brian Strom, a professor at the University of Pennsylvania.

Left without adequate science to make decisions, the public and medical community can only put their trust in their regulatory agencies. "I'm going to follow the FDA. They're our agency," said a physician quoted in the WSJ article. Unfortunately, under the current drug safety regime at the FDA, such trust may not be warranted.

Time for Pharma to Revamp Its Physician Marketing Strategy

Should pharma companies revamp their physician marketing strategies? Some idea of pharma's thinking on this topic is revealed in the emerging story of Pfizer's plans for its own sales force.

Today in the WSJ, for example, appears an article about Pfizer's plans to change it's method of detailing -- marketing and selling to -- physicians. Essentially, the article says that Pfizer plans to "reverse a decadelong infatuation with multiple sales forces pitching the same products to the same doctors." (See "Pfizer Plans $2 Billion in Cost Cuts," WSJ, 2/11/2005). This refers to the use of sales rep "pods" in which several reps coordinate visits to the same physician to detail the same product (see the article "A Crisis in Professional Detailing" in which two physicians criticize this and other physician sales and marketing tactics - also see http://www.pharma-mkting.com/news/PMNsfeReprints.htm for other Pharma Marketing News reprints on the subject of sales force effectiveness).

Familiarity Breeds Contempt?
The article goes on to state: "In the recent past, it hasn't been unusual for six or more different Pfizer representatives to pitch the same doctor on heavily marketed products such as Celebrex. The industry theory behind these multiple sales forces is that familiarity breeds contempt. [my emphasis] Different faces have better odds, the dogma goes, of getting into the doctor's office than the same representative calling more frequently."

If you read the above cited Pharma Marketing News article, you will see this comment from a physician: "It is much better to have one rep who is valuable, who has a relationship with the office staff, and knows when it’s a good day or not a good day to see me, than to have ‘storm trooper’ representatives coming to the door."

Relationship Marketing
It's not clear to me whether the familiarity breeds contempt "dogma" cited in the WSJ article is something Pfizer or other pharma companies actually believe or if it was made up by the author of the article. Regardless, there is an emerging marketing technique called relationship marketing that relies on the exact opposite dogma, namely that familiarity breeds increased loyalty and sales, certainly NOT contempt.

I think the idea of sales "pods" and multiple reps calling on docs about the same product has more to do with an older notion of marketing: reach and frequency. With sales rep pods, you can reach more physicians more often. It's equivalent to bringing mass market advertising to physician marketing. However, just as this technique has cluttered the consumer marketing landscape with messages that are ignored and have little impact, when applied to phyicians, it has lead to "lack of physician access" bemoaned by the industry.

Relationship marketing also embraces the idea that you have to build upon previous contacts with the customer and modify your message according to unique customer behavior. Docs would like to see a progression in the information that reps deliver. A lot of times reps come in and start at the beginning with the same message. It would be much better if they built upon what they covered a few weeks ago.

Perhaps pharma companies should consider how to better employ relationship marketing techniques in order to improve efficiencies. There is a question, however, whether pharma with its silos of information can effectively employ relationship marketing (see "Out-of-the-Box Marketing: Will It Work for Pharma?").

Also important is sales rep preparedness and ability to teach. Unfortunately not every representative has the ability to teach and some just push the sales aid. It's not just a matter, therefore, of implementing a new technique in marketing, it also involves changes in sales rep management and training.