D.C. District Court Invalidates TPSAC Menthol Report Because of Conflicts of Interest of Panel Members

A D.C. District Court judge has invalidated the FDA's Tobacco Products Scientific Advisory Committee (TPSAC) report on menthol because of severe financial conflicts of interest of several of its panel members.

The decision comes in response to a lawsuit brought by Lorillard on two grounds. First, the companies alleged that three TPSAC members (Drs. Benowitz, Henningfield, and Samet) were conflicted because "they have made tens of thousands of dollars as paid expert witnesses in litigation against tobacco products manufacturers." Second, the companies alleged that Drs. Benowitz, Henningfield, and Samet are conflicted because of "their continuing financial relationships with pharmaceutical companies that make smoking-cessation products."

As a result of the decision, the FDA will not be able to rely upon the findings and conclusions of the TPSAC menthol report. In addition, the Court instructed the agency to reconstruct TPSAC by replacing any members who have conflicts of interest. Dr. Samet is the only current TPSAC member who appears to be implicated by this instruction.

In October 2011, commenting on Lorillard's lawsuit, I wrote:

"I believe that the second grounds - the existence of severe financial conflicts of interest by virtue of these panelists financial connections to pharmaceutical companies that manufacture smoking cessation products - is entirely compelling. In fact, I revealed these conflicts of interest and called for the resignation of Drs. Henningfield, Benowitz, and Samet from the TPSAC panel in the first few days after the TPSAC members were announced by the FDA."

In fact, I went so far as to call for the removal of four FDA Tobacco Products Scientific Advisory Committee (TPSAC) panel members - Dr. Neal Benowitz, Dr. Jack Henningfield, Dr. Dorothy Hatsukami, and Dr. Jonathan Samet - because they had significant conflicts of interest with pharmaceutical companies that made it impossible for them to offer objective advice to the Agency on federal tobacco regulatory policy matters.

In September 2010, I pointed out specifically that:  

"The next major issue that TPSAC will consider (after menthol), in fact, is dissolvable tobacco products. Now that GlaxoSmithKline has come out in strong opposition to these products and directly petitioned the FDA to remove these products from the market, it is not possible for any TPSAC member who has a financial conflict of interest with Glaxo (or similar companies that manufacture smoking cessation products) to impartially participate in discussions on this matter."

The Rest of the Story

As I had suggested in my September 2010 column, Judge Richard Leon's decision was based in large part on his finding that Dr. Benowitz's ongoing conflict of interest with pharmaceutical companies rendered him unable to objectively consider the issue of dissolvable tobacco products (DTPs).

"The FDA erred in concluding that current, ongoing financial relationships with drug manufacturers did not constitute a conflict. Since manufacturers of smoking-cessation drugs compete with manufacturers of DTPs, ... and since Dr. Benowitz stood to profit from the sale of NRT drugs, he faced a conflict with regard to providing advice in the TPSAC's report on DTPs. ... the TPSAC was charged with studying the public health impact of a drug (i.e., DTPs), and Dr. Benowitz had an ongoing business relationship (i.e., consulting work) with companies developing "alternative" or competing drugs (i.e., smoking-cessation drugs). Accordingly, I find that the FDA's conclusion with regard to Dr. Benowitz was a 'clear error of judgment.'"

Judge Leon also found that a similar conflict existed on the menthol issue because a ban on menthol would increase the market for smoking cessation drugs by causing many smokers to want to quit. Thus, having a current financial interest in a pharmaceutical company was a clear conflict of interest.

While I still disagree with Leon's finding that serving as an expert witness is a relevant conflict because I do not see any relevant financial interest in the absence of the pertinence of a matter to a specific legal contract for hire of an expert, I do agree completely with his decision regarding the pharmaceutical conflicts of interest.

Perhaps the most discouraging aspect of the story is that the FDA failed to acknowledge these conflicts of interest. I explained in a previous post why the guidelines used by the FDA to determine eligibility for the TPSAC were inappropriate. Hopefully, this decision - having exposed the ridiculousness of those guidelines - will force the FDA to reformulate the guidelines so that they do actually screen out expert panelists with relevant conflicts of interest.

Will this decision have any impact on the regulation of menthol by the FDA? No. There are plenty of other sources that the agency could rely on for information if it wishes to regulate menthol. The bottom line is that the FDA is not going to ban menthol, with or without the TPSAC report.

The major implication of this decision is that it exposes the degree to which financial conflicts of interest are plaguing the current tobacco control movement. It should force anti-smoking groups and federal agencies to take conflicts of interest more seriously.

For years, the anti-smoking groups and public health agencies have taken tobacco industry conflicts of interest seriously. Now it is time to have some integrity and fairness and to consider all corporate conflicts of interest, whether they involve Big Tobacco or Big Pharma.

CDC is Intentionally Hiding Conflicts of Interest of Surgeon General's Report Authors

Earlier this week, I revealed that the 2014 Surgeon General's report fails to disclose the conflicts of interest of its authors, many of whom have received money from pharmaceutical companies which manufacture the very products about which the report opines. I also explained how this is particularly problematic, since the report itself complains about how historically, tobacco-funded scientists failed to disclose their conflicts of interest. I concluded that the 2014 Surgeon General's report is violating the very ethical principles that it attacks the tobacco company for violating in the past, and I note that while there has been substantial progress in the past 50 years in the area of disclosure of conflicts of interest, somehow that progress has evaded the producers of the Surgeon General's report itself.

Today, I reveal that the CDC's Office on Smoking and Health (OSH) - the lead agency that produces the report - is apparently intentionally hiding the conflicts of interest. In other words, OSH knows about these conflicts but has apparently decided not to share this information with the public. That is, OSH is intentionally hiding these conflicts from the public.

The Rest of the Story

Yesterday, I was informed by one of the contributing authors to the 2014 Surgeon General's report that each of the authors and reviewers of the report was required to complete conflict of interest disclosure forms. This makes the problem even more serious than it initially appeared. It now seems that this is not merely a matter of the CDC not knowing about, or failing to inquire about the conflicts of interest of report authors. Instead, this is now a matter of the CDC hiding, or covering up, these conflicts of interest, which are not revealed to the public anywhere in the report or on the report's web site.

There is no excuse for collecting this important information, but not revealing it to the public. The only legitimate justification for this would be if there were no reported conflicts of interest. In such a case, the report could have included a statement indicating that none of the report's authors reported a conflict of interest.

But we know this is not the case because in journal articles published by many of the report authors, they have acknowledged multiple conflicts of interest with Big Pharma.

Let's just take three of the Surgeon General's report authors alone (Dr. Neal Benowitz, Dr. Jack Henningfield, and Dr. Jonathan Samet). According to a D.C. District Court brief filed by R.J. Reynolds and Lorillard:

Dr. Benowitz: "Dr. Benowitz, as a paid consultant for pharmaceutical companies, has assisted them with the design, development, and marketing of smoking-cessation products. Among the companies for which he has consulted on such products are GlaxoSmithKline plc and its affiliates (collectively, “GSK”); Pfizer, Inc. and its affiliates (collectively, “Pfizer”); Novartis AG and its affiliates (collectively, “Novartis”); Sanofi-Aventis U.S. LLC and its affiliates (collectively, “Sanofi-Aventis”); and Aradigm Corp. and its affiliates (collectively, “Aradigm”). During the last ten years, he has received at least approximately $10,000 per year for such consulting. He has also received grant support for research and writing from GSK and/or Pfizer on at least five occasions. In 2010, he co-authored a study, funded by Pfizer, on the use of its drug, Chantix, for smoking cessation."

Dr. Henningfield: "Dr. Henningfield is a Principal at, and derives most of his income from, Pinney Associates, a firm that currently provides to GSK on an exclusive basis consulting services regarding smoking-cessation products. His formal title is: Vice President, Research & Health Policy. Through his association with Pinney Associates, Dr. Henningfield advises GSK specifically on the development of nicotine-replacement therapies and treatments for tobacco dependence. Pinney Associates has received on average more than $2 million per year in revenue from pharmaceutical companies, more than half of which relates to smoking-cessation products. In addition, during the last decade, Dr. Henningfield has received grant support for research and writing from GSK on at least eight occasions. Dr. Henningfield is also a partner in a company that holds patents for a nicotine replacement-therapy product. He has estimated that, if thess patents are successfully licensed, they could be worth more than $1 million to him as a partner in that company. Thus, Dr. Henningfield has a financial interest in bringing about regulatory policies that will drive current smokers to use nicotine-replacement-therapy products."

Dr. Samet: "During the last decade, Dr. Samet has received grant support for research and writing from GSK on at least six occasions, including in 2010. In addition, he formerly led the Institute for Global Tobacco Control, which is funded by GSK and Pfizer. Moreover, until 2009, Dr. Samet received regular honoraria from Pfizer for his service on the Pfizer Global Tobacco Advisory Board."

Thus, as revealed and described in this lawsuit brief and in an accompanying press release: "Drs. Neil Benowitz, Jack E. Henningfield and Jonathan M. Samet are conflicted ... due to their continuing financial relationships with pharmaceutical companies that make smoking-cessation products."

Incidentally, the Reynolds/Lorillard lawsuit seeks to have Drs. Benowitz, Henningfield, and Samet dismissed from the FDA's TPSAC (Tobacco Product Scientific Advisory Committee) panel because of these conflicts of interest. While these conflicts do not preclude the participation of these scientists as authors of the Surgeon General's report, they absolutely must be disclosed to the public.

To make matters worse, Dr. Samet is not just an author, but served as one of the two editors of the report.

The rest of the story is that not only is CDC failing to disclose the important conflicts of interest of the 2014 Surgeon General's report authors, but OSH is involved in a cover-up. Apparently, OSH has deliberately chosen to hide these conflicts of interest from the public.

It may take a Freedom of Interest Act (FOIA) request to obtain this information from OSH, or wherever this "secret" information resides, which is quite a shame given the fact that one of the major points made in the Surgeon General's report is its criticism of the unethical behavior of tobacco industry scientists who hid their financial relationships with the industry. It's sad that the federal government is condemning the past actions of scientists who hid financial connections with Big Tobacco, while it is engaging in the present action of hiding financial connections with Big Pharma.

Federal Government Wastes $10 Million on Nicotine Vaccine Studies; Money Would Have Been Better Spent Investigating Potential Role of Electronic Cigarettes

In 2009, the federal government awarded Nabi Pharmaceuticals a $10 million stimulus grant to conduct a clinical trial of NicVax, an injectable vaccination intended to help people quit smoking.

According to an NIH press release: "Successful completion of the study will bring the vaccine closer to final approval. Already given fast track designation by the U.S. Food and Drug Administration, NicVAX passed initial regulatory hurdles showing the basic idea is sound. Patients in the trial get six monthly shots in the arm. ... The award continues a public-private partnership between NIDA and NABI that started in 2001 with a grant to support the basic science that led to NicVAX. The effort continued in 2005 with a grant to help support early clinical trials to test the safety and efficacy of the vaccine."

At the time, the director of the National Institute on Drug Abuse (NIDA) predicted that the nicotine vaccine would be a powerful tool to promote smoking cessation: "A vaccine that limits the ability of nicotine to enter the brain, and that is effective for six to 12 months following vaccination will give smokers a fighting chance to end the addiction/relapse cycle that plagues the great majority of smokers trying to quit."

For several years, I have been arguing that the tobacco control movement's obsession with nicotine as the sole element involved in smoking addiction has been problematic and has hindered the search for a truly effective tool to promote smoking cessation. I have repeatedly pointed out that smoking addiction involves far more than just nicotine. There are many other aspects to the addiction, including physical stimuli, behavioral aspects, and even social aspects. The hand motions, blowing of smoke, holding of the cigarette, and many other physical, behavioral, and social stimuli serve as reinforcements of the overall smoking experience. A sole focus on just nicotine is not an effective strategy for finding a workable strategy.
 
I have also pointed out that for the first time, we now have a tool that does address the behavioral aspects of the addiction, not just the pharmacologic aspects. That tool is called the electronic cigarette. Because it looks like, feels like, and is used like a cigarette, in addition to supplying nicotine, the electronic cigarette addresses all aspects of the smoking addiction. It simulates the smoking experience. That is precisely why it has been helpful to so many smokers in quitting and why the product's use has been growing exponentially.

The Rest of the Story

As I predicted, the nicotine vaccine turned out to be a dismal failure. Yesterday, Nabi Pharmaceuticals reported the results of a phase II clinical trial in which the nicotine vaccine in combination with Chantix was found to be no more effective than Chantix alone: "Smokers who received both products quit smoking at the same rate as those treated with a placebo and varenicline, according to an initial evaluation of the study's data, Nabi reported. Those rates were similar to those involving smokers in other studies who had received only varenicline".

These results come on the heels of the revelation that the phase III clinical trial funded by the federal government was a complete failure: "the primary end point was not met and there was no statistical difference between the NicVAX and Placebo groups. As in previous trials, NicVAX was well-tolerated with a clinically acceptable safety and tolerability profile. These results are not different from the results of the first Phase III trial that were reported in July 2011, which had a similar design and protocol."

In  my opinion, the federal government put its eggs in the wrong basket. At the same time that the federal government was spending $10 million on the nicotine vaccine, it was engaging in a campaign to discourage smokers from using electronic cigarettes to quit - scaring them by grossly exaggerating information about trace levels of carcinogens detected in these products and trying to convince them that all electronic cigarettes may have anti-freeze in them.

So while the FDA gave "fast track" status to a drug that I believe was clearly doomed to failure, it essentially tried to pull off the market a new device which is perhaps the most promising innovation ever developed to treat not just nicotine addiction, but the smoking addiction as a whole.

To make matters worse, the anti-smoking researchers who had put their own eggs in the nicotine vaccine basket - showing poor judgment in their ability to evaluate the most promising strategies for smoking cessation because of their history of Big Pharma funding - were given prominent positions guiding federal smoking cessation strategy.

For example, the panel chair of the Joint Commission panel which established hospital standards for the treatment of smoking cessation was Dr. Michael Fiore. However, Dr. Fiore was receiving grant funding from Nabi Pharmaceuticals, whose nicotine vaccine had been given fast track status by the FDA "for use as a therapeutic for smoking cessation.'"

Clearly, it would have been to Nabi Pharmaceutical's great financial interest to have in place as it begins to market this drug a hospital standard requiring all smokers to be prescribed at discharge an FDA-approved smoking cessation drug. This is precisely the requirement that Dr. Fiore and his panel established.

In my opinion, it was inappropriate for Dr. Fiore to have accepted the position as chair of this panel, given his financial conflict of interest. The recommendations from the panel were clearly biased because of this financial conflict.

Another example is the appointment of not one, but two Nabi Pharmaceuticals-conflicted scientists as members of the Tobacco Products Scientific Advisory Board (TPSAC).  Dr. Neal Benowitz has consulted for Nabi Pharmaceuticals and Dr. Dorothy Hatsukami has received grant support from Nabi Pharmaceuticals for investigation of the effectiveness of NicVax.

Are these conflicted scientists really the ones we want on a panel that is supposed to be making objective, big picture recommendations on the best strategies to reduce smoking-related morbidity and mortality? NIH advisory panels are not supposed to have members with financial conflicts of interest in the first place. Why this special exception for the tobacco products advisory panel?

The rest of the story is that the detrimental effects of the financial relationships between Big Pharma and many of the leading scientists in the anti-smoking movement as well as with the federal government itself are now starting to show. The taxpayer money spent on the nicotine vaccine was a waste of money as I predicted before the trial had even begun. The bias towards a narrow "nicotine only" strategy for smoking cessation has inundated the FDA and the NIH, which has actually partnered with Big Pharma to waste taxpayer money on a strategy that was doomed to failure from the start. And now, a scientist who put her eggs in the wrong basket as well is serving as a member of a national advisory panel to the FDA on tobacco products. In the mean time, the FDA has done everything but place a formal ban on electronic cigarettes, the one product which shows promise because of its ability to address both the pharmacologic and behavioral aspects of smoking addiction.

Federal Court Rules that Lawsuit Against FDA for Conflicts of Interest on TPSAC Can Proceed

A federal district court judge has ruled that a lawsuit filed against the FDA by Lorillard and R.J. Reynolds, seeking an injunction against the use of the TPSAC's menthol report because of conflicts of interest on the panel, can proceed.

According to a CBS News article: "A federal judge has denied a Food and Drug Administration (FDA) motion to dismiss a suit filed by two of the nation's largest cigarette makers that claimed the advisory panel that reviewed tobacco products for the FDA had financial conflicts of interest. In an order posted Wednesday, U.S. District Court Judge Richard Leon in Washington said that the suit filed by Lorillard Inc. and R.J. Reynolds Tobacco Co. can move forward. The suit filed last year alleges financial conflicts of interest and bias by several members of the Tobacco Products Scientific Advisory Committee and asks the court to stop the federal agency from relying on the panel's recommendations." ...

"In a statement, Lorillard said: "The practice of appointing members to a government scientific advisory committee who have financial interests that violate conflict-of-interest laws and regulations should be subject to judicial review, as the court has now recognized." ... In the suit, the tobacco companies allege that the panel fails to meet the federal requirements that committee members should be fairly balanced and not inappropriately influenced by any special interest. The suit specifically alleges that some committee members have conflicts of interest because they were paid expert witnesses in anti-tobacco lawsuits and have financial ties to pharmaceutical companies that make smoking-cessation products." ...

"Vince Willmore, a spokesman for the Campaign for Tobacco-Free Kids, said the suit is an effort by the tobacco companies to 'obstruct effective policies to reduce tobacco use and to discredit anyone who advocates such policies.'"

The Rest of the Story

I don't agree with the Campaign for Tobacco-Free Kids that the suit is an effort to discredit anyone who advocates policies to reduce tobacco use. I think it is an effort to try to get rid of several specific individuals who have severe conflicts of interest by virtue of their financial ties to pharmaceutical companies or who have benefited financially from testifying against the tobacco companies in court and who could potentially use information gleaned during their work with TPSAC in future litigation testimony.

In other words, I agree that there is sufficient legal basis for the suit to move forward.

If this were a federal advisory committee providing guidance to the EPA on how to proceed with environmental regulation and four members of the advisory committee had financial ties to chemical companies, then by all means we would want the courts to review the appointments of those conflicted panelists. Just because the issue here is tobacco doesn't negate the need to ensure scientific objectivity in agency decision-making.

Now I do differ somewhat from Lorillard and R.J. Reynolds in my opinion on the basis for the lawsuit. I do not view the expert testimony as being a disqualifying conflict of interest. While it is true that panelists could potentially glean information from the proceedings which could subsequently be used in lawsuit testimony, I believe that needs to be handled at the judicial level at the time of their subsequent testimony. The companies would have legitimate grounds to contest the ability of those witnesses to testify. The potential use of confidential or proprietary information should be addressed at the level of the FDA panel itself. Those participants should be required to sign a statement attesting that they will not use any such information in litigation or otherwise share confidential or proprietary information with the public. And since the past litigation has already occurred, unless a scientist is currently a paid witness in an ongoing trial, I don't see the need to disqualify such a panelist, although I do believe that these other protections are warranted.

On the other hand, I completely agree that the financial conflicts of interest by virtue of four of the TPSAC members having financial relationships with Big Pharma companies that manufacture smoking cessation products should be disqualifying. The TPSAC is directly recommending policies that will have an impact on pharmaceutical companies that manufacture these drugs. Some of the recommendations could in fact have billion-dollar ramifications for various pharmaceutical companies, or for the industry as a whole. Therefore, it is inexcusable to allow these financially conflicted members to serve on the FDA advisory panel.

I have written extensively on this topic, opining that the four conflicted members of the TPSAC panel should resign because of their financial conflicts of interest.

I have also taken issue with the Campaign for Tobacco-Free Kids' argument that this lawsuit is baseless because the Campaign never provided a legal argument.

Here is what I wrote in March 2011:

In response to the lawsuit brought by R.J. Reynolds and Lorillard against the FDA to prevent it from relying on recommendations from an advisory panel which the tobacco company plaintiffs argue is impermissibly constituted due to the financial conflicts of interest of three panelists with pharmaceutical companies that manufacture smoking cessation drugs, the Campaign for Tobacco-Free Kids has attacked these companies, accusing them of acting the way they have for decades and asserting that the lawsuit is groundless.

The entirety of the Campaign for Tobacco-Free Kids' argument for why the financial conflicts of interest of three advisory committee members is permissible under the law is as follows: "Their lawsuit is groundless. The FDA's Tobacco Products Scientific Advisory Committee was constituted and is acting in accordance with the 2009 law granting the FDA authority over tobacco products, as well as other relevant federal laws."

The Rest of the Story

As usual, the Campaign for Tobacco-Free Kids is issuing propaganda devoid of any solid argumentation. There is a serious issue that needs to be addressed and rather than presenting an argument for why it is permissible to have conflicted panelists on an FDA advisory committee, the Campaign is falling back on its usual rhetoric.

Despite the Campaign for Tobacco-Free Kids' knee-jerk dismissal of the lawsuit, the complaint puts forward a very serious issue: Are we serious about ensuring that federal advisory panels make their recommendations based on an impartial review of the science, rather than under the influence of financial conflicts of interests of the panelists?

In this case, three of the TPSAC members - Drs. Henningfield, Samet, and Benowitz - have severe financial conflicts of interest with Big Pharma. They have served as consultants to, or received funding from, pharmaceutical companies that manufacture smoking cessation drugs. The financial interest of these companies is directly affected by the recommendations that TPSAC is going to put forward on a number of items already on its agenda, including menthol and dissolvable tobacco products.

For example, a menthol ban would be a financial boost for smoking cessation drug companies. As many people affected by the menthol ban would attempt to quit smoking, such a ban would yield a direct financial benefit to companies that manufacture smoking cessation drugs. Thus, it is unacceptable to have panelists who have financial interests in these companies.

Similarly, with dissolvable tobacco products, a ban on these products would be in the best financial interests of pharmaceutical companies that manufacture smoking cessation drugs. As dissolvable tobacco products could serve as a potential competitor (these products could be marketed to help smokers quit using cigarettes), they are a potential threat to smoking cessation drugs. Once again, it is unacceptable to have panelists who have financial interests in these companies.

Rather than directly address this critical issue and explain why it believes that these severe financial conflicts of interest are permissible under the Federal Advisory Committee Act, the Campaign for Tobacco-Free Kids has relied upon its usual propaganda and rhetoric. That rhetoric may have worked years ago, but we are now living in a new era, when (ironically, thanks to the Campaign for Tobacco-Free Kids), tobacco companies are now under federal regulation. And with federal regulation, the law must be obeyed. This is what the Campaign appears to fail to understand. Ironically, this is the Campaign's own doing, as it is the Campaign which promoted the Family Smoking Prevention and Tobacco Control Act in the first place, putting the tobacco companies under federal regulation and thus giving them the protection of the laws that govern federal regulation-making.

The magnitude of the problem is perhaps illustrated best by the fact that GlaxoSmithKline has intervened directly with the FDA, urging the Agency to take dissolvable tobacco products off the market. How then, can the FDA allow a GlaxoSmithKline consultant (Henningfield) to be a part of the decision-making process on whether dissolvable tobacco products will be banned? This is every bit as bad a conflict as having a drug company consultant on an FDA advisory panel that is making a recommendation on the approval of a drug made by that company.

Predictably Irrational: Campaign for Tobacco-Free Kids Blasts Reynolds/Lorillard for "Groundless" Lawsuit, But Fails to Defend Conflicts of Interest

In response to the lawsuit brought by R.J. Reynolds and Lorillard against the FDA to prevent it from relying on recommendations from an advisory panel which the tobacco company plaintiffs argue is impermissibly constituted due to the financial conflicts of interest of three panelists with pharmaceutical companies that manufacture smoking cessation drugs, the Campaign for Tobacco-Free Kids has attacked these companies, accusing them of acting the way they have for decades and asserting that the lawsuit is groundless.

The entirety of the Campaign for Tobacco-Free Kids' argument for why the financial conflicts of interest of three advisory committee members is permissible under the law is as follows: "Their lawsuit is groundless. The FDA's Tobacco Products Scientific Advisory Committee was constituted and is acting in accordance with the 2009 law granting the FDA authority over tobacco products, as well as other relevant federal laws."

The Rest of the Story

As usual, the Campaign for Tobacco-Free Kids is issuing propaganda devoid of any solid argumentation. There is a serious issue that needs to be addressed and rather than presenting an argument for why it is permissible to have conflicted panelists on an FDA advisory committee, the Campaign is falling back on its usual rhetoric.

Despite the Campaign for Tobacco-Free Kids' knee-jerk dismissal of the lawsuit, the complaint puts forward a very serious issue: Are we serious about ensuring that federal advisory panels make their recommendations based on an impartial review of the science, rather than under the influence of financial conflicts of interests of the panelists?

In this case, three of the TPSAC members - Drs. Henningfield, Samet, and Benowitz - have severe financial conflicts of interest with Big Pharma. They have served as consultants to, or received funding from, pharmaceutical companies that manufacture smoking cessation drugs. The financial interest of these companies is directly affected by the recommendations that TPSAC is going to put forward on a number of items already on its agenda, including menthol and dissolvable tobacco products.

For example, a menthol ban would be a financial boost for smoking cessation drug companies. As many people affected by the menthol ban would attempt to quit smoking, such a ban would yield a direct financial benefit to companies that manufacture smoking cessation drugs. Thus, it is unacceptable to have panelists who have financial interests in these companies.

Similarly, with dissolvable tobacco products, a ban on these products would be in the best financial interests of pharmaceutical companies that manufacture smoking cessation drugs. As dissolvable tobacco products could serve as a potential competitor (these products could be marketed to help smokers quit using cigarettes), they are a potential threat to smoking cessation drugs. Once again, it is unacceptable to have panelists who have financial interests in these companies.

Rather than directly address this critical issue and explain why it believes that these severe financial conflicts of interest are permissible under the Federal Advisory Committee Act, the Campaign for Tobacco-Free Kids has relied upon its usual propaganda and rhetoric. That rhetoric may have worked years ago, but we are now living in a new era, when (ironically, thanks to the Campaign for Tobacco-Free Kids), tobacco companies are now under federal regulation. And with federal regulation, the law must be obeyed. This is what the Campaign appears to fail to understand. Ironically, this is the Campaign's own doing, as it is the Campaign which promoted the Family Smoking Prevention and Tobacco Control Act in the first place, putting the tobacco companies under federal regulation and thus giving them the protection of the laws that govern federal regulation-making.

The magnitude of the problem is perhaps illustrated best by the fact that GlaxoSmithKline has intervened directly with the FDA, urging the Agency to take dissolvable tobacco products off the market. How then, can the FDA allow a GlaxoSmithKline consultant (Henningfield) to be a part of the decision-making process on whether dissolvable tobacco products will be banned? This is every bit as bad a conflict as having a drug company consultant on an FDA advisory panel that is making a recommendation on the approval of a drug made by that company.

Lorillard and R.J. Reynolds File Suit Against FDA to Prevent it from Relying Upon TPSAC Recommendations; Alleges Conflicts of Interest Among Panelists

Last Friday, two tobacco companies - Lorillard and R.J. Reynolds - filed a lawsuit against the Food and Drug Administration (FDA) to enjoin the agency from relying upon any recommendations that come out of the Tobacco Products Scientific Advisory Committee (TPSAC). The suit alleges that the composition of the TPSAC is unlawful because three of the panelists have severe conflicts of interest which violate federal law, including the Federal Advisory Committee Act (FACA) regarding the presence of conflicts of interest among members of federal advisory bodies.

The tobacco companies argue that three members of the advisory panel - Dr. Neal Benowitz, Dr. Jack Henningfield, and Dr. Jon Samet - have severe conflicts of interest which preclude the panel from conducting a balanced and objective review of the scientific and policy issues it is charged with addressing.

The Federal Advisory Committee Act holds that all federal advisory panels (including TPSAC) must be "fairly balanced in terms of the points of view represented and the functions to be performed," and its members cannot have severe financial conflicts of interest such that the committee's assessments, reports, or recommendations and decisions will be "inappropriately influenced . . . by any special interest."

The plaintiff tobacco companies argue that Drs. Benowitz, Henningfield, and Samet have two severe conflicts of interest which put the committee's composition in violation of the Federal Advisory Committee Act:

First, the companies allege that these three members are conflicted because "they have made tens of thousands of dollars as paid expert witnesses in litigation against tobacco products manufacturers."

Second, the companies allege that Drs. Benowitz, Henningfield, and Samet are conflicted because of "their continuing financial relationships with pharmaceutical companies that make smoking-cessation products."

Regarding the financial conflicts of interests of these committee members with pharmaceutical companies that manufacture smoking cessation drugs, the plaintiffs allege as follows:

Dr. Benowitz: "Dr. Benowitz, as a paid consultant for pharmaceutical companies, has assisted them with the design, development, and marketing of smoking-cessation products. Among the companies for which he has consulted on such products are GlaxoSmithKline plc and its affiliates (collectively, “GSK”); Pfizer, Inc. and its affiliates (collectively, “Pfizer”); Novartis AG and its affiliates (collectively, “Novartis”); Sanofi-Aventis U.S. LLC and its affiliates (collectively, “Sanofi-Aventis”); and Aradigm Corp. and its affiliates (collectively, “Aradigm”). During the last ten years, he has received at least approximately $10,000 per year for such consulting. He has also received grant support for research and writing from GSK and/or Pfizer on at least five occasions. In 2010, he co-authored a study, funded by Pfizer, on the use of its drug, Chantix, for smoking cessation."

Dr. Henningfield: "Dr. Henningfield is a Principal at, and derives most of his income from, Pinney Associates, a firm that currently provides to GSK on an exclusive basis consulting services regarding smoking-cessation products. His formal title is: Vice President, Research & Health Policy. Through his association with Pinney Associates, Dr. Henningfield advises GSK specifically on the development of nicotine-replacement therapies and treatments for tobacco dependence. Pinney Associates has received on average more than $2 million per year in revenue from pharmaceutical companies, more than half of which relates to smoking-cessation products. In addition, during the last decade, Dr. Henningfield has received grant support for research and writing from GSK on at least eight occasions. Dr. Henningfield is also a partner in a company that holds patents for a nicotine replacement-therapy product. He has estimated that, if thess patents are successfully licensed, they could be worth more than $1 million to him as a partner in that company. Thus, Dr. Henningfield has a financial interest in bringing about regulatory policies that will drive current smokers to use nicotine-replacement-therapy products."

Dr. Samet: "During the last decade, Dr. Samet has received grant support for research and writing from GSK on at least six occasions, including in 2010. In addition, he formerly led the Institute for Global Tobacco Control, which is funded by GSK and Pfizer. Moreover, until 2009, Dr. Samet received regular honoraria from Pfizer for his service on the Pfizer Global Tobacco Advisory Board."

The plaintiffs then argue that "the continuing roles of Drs. Benowitz, Henningfield, and Samet as consultants to manufacturers of nicotine-replacement-therapy products and other smoking cessation products constitute circumstances that demonstrate their lack of impartiality, or at least raise questions regarding their impartiality, in particular matters that have been, are, and/or will be presented to them as voting members of the TPSAC, or as members of the Constituents Subcommittee. As to those expressed views, a reasonable person with knowledge of the relevant facts would perceive the appearance of a conflict of interest."

The reasons why these financial conflicts of interest would be expected to affect these panelists' consideration of, and opinions on, specific business before the advisory committee, is stated as follows:

"Manufacturers of nicotine-replacement-therapy products and other smoking cessation products, including the pharmaceutical companies, GSK, Pfizer, Novartis, Sanofi-Aventis, and Aradigm, are in direct competition with tobacco-product manufacturers for the purchasing choices of adult smokers. This competitive dynamic is reflected in the discussion at the March 31, 2010 meeting of the Committee of whether banning menthol from cigarettes would result in smokers trying to quit smoking, rather than switching to a non-menthol brand (Tr. 92 (public comment), 199-200 (committee discussion)). A ban or restriction on the sale of menthol cigarettes might increase the sales of nicotine-replacement-therapy products and other smoking-cessation products. Similarly, FDA regulations banning or further restricting the availability of dissolvable or other smokeless tobacco products might increase the sales of such products. The opportunities for Drs. Benowitz, Henningfield, and Samet to continue to obtain income from consulting with pharmaceutical companies with respect to nicotine replacement-therapy products and/or other smoking-cessation products depend on the continuing sales and profitability of such products. Therefore, these individuals have an interest in protecting and enhancing the sales and profitability of such products, and may consciously or unconsciously influence the other members of the TPSAC inappropriately to recommend bans on, or unduly strict regulation of, the smokeless tobacco products with which they compete. Even if these individuals did not influence the TPSAC in such a manner, their mere presence on the committee poses (and appears to pose) severe financial conflicts of interest because their remunerative relationships with pharmaceutical companies will prevent them from being (and from being perceived as) open-minded and from considering impartially the submissions and presentations to the TPSAC or Constituents Subcommittee by tobacco-product manufacturers and others."

The Rest of the Story

While I do not believe that the first grounds for the court declaring an impermissible conflict of interest among these three panelists is compelling because all scientists have existing opinions on issues and are entitled to serve as expert witnesses without precluding their participation in national scientific and policy issues, I believe that the second grounds - the existence of severe financial conflicts of interest by virtue of these panelists financial connections to pharmaceutical companies that manufacture smoking cessation products - is entirely compelling.

In fact, I revealed these conflicts of interest and called for the resignation of Drs. Henningfield, Benowitz, and Samet from the TPSAC panel in the first few days after the TPSAC members were announced by the FDA.

On March 1 of last year (the day the panel members were announced), I wrote a commentary entitled "GlaxoSmithKline Given a Seat on FDA Tobacco Products Scientific Advisory Committee" in which I argued that the presence of Dr. Henningfield on the committee rendered it impossible of conducting an objective review of any issue relating to harm reduction.

Specifically, I wrote: "The last individual in the world who you would want to serve on such a panel would be a Big Pharma consultant, especially one who consults specifically in the area of smoking cessation medications. The fact that this individual also has a personal financial interest in such medication and who also has testified in court on behalf of Big Pharma simply adds insult to the public's injury."

I argued that the appointment of Dr. Henningfield to TPSAC undermines the "entire point of the panel and turns the whole thing into a joke, rather than a serious scientific and policy undertaking for the benefit of the public's health."

I concluded: "These type of panels should consist of individual scientists who are impartial and do not have personal financial conflicts of interest with industry, especially if that industry is to be directly regulated by the FDA and if the use and profitability of its products will be directly affected by the national policy decisions that the Agency makes. For example, one issue that the FDA is going to have to deal with immediately is the regulation of electronic cigarettes. As these products are a tremendous threat to GlaxoSmithKline profits ... there is no way that the Scientific Advisory Committee can have an objective discussion about this issue. Unfortunately, the FDA has chosen to invite Big Pharma to the table. So much for an objective scientific panel."

On September 29, I called for the resignation of Drs. Henningfield, Benowitz, and Samet from the TPSAC panel because of their financial conflicts of interest with pharmaceutical companies that manufacture smoking cessation drugs, arguing that "it is inexcusable to have individuals on the Tobacco Products Scientific Advisory Committee (TPSAC) who have financial conflicts of interest with Big Pharma."

I pointed out that "the next major issue that TPSAC will consider (after menthol), in fact, is dissolvable tobacco products. Now that GlaxoSmithKline has come out in strong opposition to these products and directly petitioned the FDA to remove these products from the market, it is not possible for any TPSAC member who has a financial conflict of interest with Glaxo (or similar companies that manufacture smoking cessation products) to impartially participate in discussions on this matter. Due to the FDA's ignoring financial conflicts of interest in appointing the TPSAC panel, however, it turns out that Glaxo essentially has a seat on the panel." ...

"To make matters worse still, the chair of the Committee - Dr. Jonathan Samet - has received grant support from GlaxoSmithKline. In addition, the organization that he directed - the Institute for Global Tobacco Control - is funded by GlaxoSmithKline and Pfizer.

And to make matters even more unacceptable, a third member of the panel - Dr. Neal Benowitz - has consulted for GlaxoSmithKline. Dr. Benowitz also co-authored a study on the use of Chantix in smoking cessation which was funded by Pfizer and has served as a Pfizer consultant. In particular, Dr. Benowitz served as a Pfizer consultant on how to develop a scientific base to support the use of Chantix in smoking cessation. In addition to consulting for Glaxo, Benowitz has also consulted for Nabi Pharmaceuticals." ...

"Given GlaxoSmithKline's direct request to the FDA and given these ... panel members' significant conflicts of interest with Big Pharma, I call on these panel members to withdraw from the Tobacco Products Scientific Advisory Committee. Short of that, I call on the FDA to remove these members from the Committee and to replace them with unconflicted scientists who can make unbiased decisions about federal regulatory policy."

I think that Lorillard and R.J. Reynolds have put forward a very compelling argument that the TPSAC panel is not balanced and fair and that it cannot conduct an objective review of multiple specific areas before it because of severe, impermissible, financial conflicts of interest of Drs. Henningfield, Samet, and Benowitz.

Thus, although I am not swayed by the argument that Henningfield, Samet, and Benowitz should have been disqualified from the panel because they have served and continue to serve as expert witnesses in litigation against tobacco companies, I believe that the conflicts of interest with respect to pharmaceutical company funding are sufficient to render all three individuals ineligible for participation on the panel under federal law.

I therefore agree with the following major declarations that the plaintiffs are seeking from the Court:

"1. That the presence of Drs. Benowitz, Henningfield, and Samet as voting members of the TPSAC creates financial conflicts of interest that violate 18 U.S.C. §§ 202(a), 208; FDCA § 712, 21 U.S.C. § 379d-1; and 5 C.F.R. pts. 2635, 2640 (2010) because these individuals have financial interests that are disqualifying under these provisions of law."

2. "That the financial conflicts of interest of Drs. Benowitz, Henningfield, and Samet incapacitate the TPSAC from preparing a report on menthol in cigarettes that is unbiased and untainted by financial conflicts of interest."

3. "That the current voting membership of the TPSAC prevents the TPSAC from properly performing its broad statutory function of advising the Defendants with respect to issues relating to dissolvable tobacco products and other smokeless tobacco products because it does not represent the view of those members of the public-health and tobacco-control communities who have no financial or other ties to tobacco-product manufacturers (and so are not industry representatives of tobacco-product manufacturers), but who believe that current scientific knowledge about smokeless tobacco products shows that, now and in the future, at least some smokeless tobacco products can play a beneficial role in reducing the harm from tobacco in the United States."

4. "That, therefore, the current voting membership of the TPSAC violates 5 U.S.C. app. 2 § 5."

While I called for the resignation or dismissal of these panelists because of their conflicts of interest immediately after the TPSAC panel was announced, the FDA failed to pay heed to these concerns. Now, I'm afraid that the situation is exactly as Lorillard and R.J. Reynolds allege: the TPSAC is impermissibly constituted under federal law, it is not balanced and cannot make an objective recommendation regarding several specific issues before it, and it is unduly influenced by severe financial conflicts of interest among these three panelists.


ADDENDUM:

For my complete commentaries on this issue, please see the following:

1. GlaxoSmithKline Given a Seat on FDA Tobacco Products Scientific Advisory Committee

2. Washington Ethics Group Calls for Investigation into Conflicts of Interest of Two FDA Tobacco Panelists, Citing Their Financial Ties to Big Pharma

3. GlaxoSmithKline Urges FDA to Take Dissolvable Tobacco Products Off the Market; Rest of the Story Calls on Four TPSAC Panel Members to Resign

4. FDA Guidelines for Determining Eligibility for Advisory Committees are Ridiculous and Ensure that Conflicts of Interest Will Continue to Plague Agency

FDA Guidelines for Determining Eligibility for Advisory Committees are Ridiculous and Ensure that Conflicts of Interest Will Continue to Plague Agency

Yesterday, I called for the removal of four FDA Tobacco Products Scientific Advisory Committee (TPSAC) panel members - Dr. Neal Benowitz, Dr. Jack Henningfield, Dr. Dorothy Hatsukami, and Dr. Jonathan Samet - because they have significant conflicts of interest with pharmaceutical companies that make it impossible for them to offer objective advice to the Agency on federal tobacco regulatory policy.

A major issue that the panel will soon consider is regulation of dissolvable tobacco products. These are a direct threat to the profits of pharmaceutical companies because they may be used as an alternative for smoking cessation. The threat is so significant that GlaxoSmithKline petitioned the FDA to remove these products from the market.

As I revealed, the rest of the story is that Dr. Henningfield is a GlaxoSmithKline consultant. Clearly, it is unacceptable for Dr. Henningfield to remain on the panel. Similarly, Dr. Benowitz and Dr. Samet should be removed from the panel because they have either consulted for or received grant support from GlaxoSmithKline. Dr. Hatsukami did not receive Glaxo support but did receive funding from another pharmaceutical company to research a nicotine vaccine.

Today, I reveal that the procedure used by the FDA to determine eligibility for participation on advisory panels is severely flawed and essentially guarantees that the Agency will continue to be plagued by conflicts of interest.

Research has shown that FDA advisory committee panelists' conflicts of interest affect their voting behavior. Based on this research, Public Citizen had threatened to sue the FDA to force elimination or remediation of these conflicts (a threat which should be renewed based on the analysis I am about to report).

The Rest of the Story

While the FDA made it look like it was addressing these concerns by adopting new guidelines regarding conflicts of interest in August 2008, an examination of these guidelines reveals that they are woefully inadequate and inappropriate and demonstrate a profound misunderstanding of the problem of conflicts of interest.

A conflict of interest policy should be designed to ensure that decisions regarding federal policy are not influenced by financial conflicts of interest of panel members. The way to do this is to determine what constitutes a disqualifying conflict of interest and then not to allow any scientist with such a conflict to serve on an advisory panel.

Instead of adopting such an approach, the FDA completely copped out by making it look like the Agency was going to disqualify scientists with conflicts of interest, but then giving the Agency the opportunity to nevertheless allow such scientists to serve on the panels.

The FDA guidelines accomplish this in three ways:

1. Waivers

First, the FDA has allotted itself a certain number of waivers. These waivers are essentially free passes, where a conflicted scientist can still be appointed to a panel as long as the the FDA hasn't used up its waiver quota.

While federal law allows the FDA to grant these waivers, the FDA is under no requirement to do so. The FDA has admitted it has created a problem by granting these waivers, but instead of agreeing to eliminate the waivers the FDA has simply agreed to reduce the number of the waivers.

What the FDA apparently fails to understand is that there is no waiver of an otherwise disqualifying conflict of interest. Either an individual has a disqualifying conflict of interest or she does not. If you start making waivers, you are essentially gutting the conflict of interest policy and destroying its entire purpose. You are ensuring that conflicts of interest will continue to plague the Agency's decision-making.

2. Exceptions for Scientific Expertise

The conflict of interest policy goes out the window if the FDA declares that a scientist's potential contribution to an advisory panel outweighs the potential for a conflict of interest. This is obviously an arbitrary or subjective judgment which allows the Agency complete reign to continue allowing conflicted scientists to serve on these advisory panels.

Such a policy is completely ignorant of the purpose of conflict of interest guidelines: to eliminate the formulation of federal policy by conflicted scientists. Every scientist that will be considered for a panel has special scientific expertise and one could always make an argument that his expertise outweighs the potential for a conflict of interest. You see, conflicts of interest are only severe when they actually occur. Looking in advance at a situation, one will never see the tremendous damage that could be done. It is a flawed premise from the start that one can make a judgment, in advance, about how a conflict is going to play out in the future.

Either a conflict of interest is disqualifying or it is not. Either the FDA is committed to ensuring that federal regulatory policy decisions are made by unconflicted scientists or it is not. Putting waivers and subjective judgments of scientific expertise into the procedure has the effect of completely gutting the policy and destroying the very purpose for which the policy exists in the first place.

3. High Threshold for Level of Disqualifying Conflicts of Interest

While some universities set a threshold of $10,000 per year for the amount below which a conflict of interest is not disqualifying, the FDA has set that level at a whopping $50,000. Even a lower threshold has little validity, because there is no evidence that conflicts of interest no longer bias decision-making when the conflict is below a certain amount. But it should be clear to all readers that a conflict at the level of tens of thousands of dollars, even if it does not exceed $50,000 a year, is a huge financial interest.

Let's face it - $49,999 per year is more than most U.S. households make. To be exact, 53% of U.S. households bring in less than $50,000 in income in total. To declare that only above $50,000 a year does a financial interest become disqualifying is insane. It's also insulting, frankly. Are we really to believe that someone who makes $40,000 per year from GlaxoSmithKline consulting is going to nevertheless be completely objective in making a decision that could devastate the company's profits? There is no rational basis for this income threshold and once again, it undermines the entire purpose of the conflict of interest policy.

The End Result? No Effective Conflict of Interest Protection

As we are observing with the Tobacco Products Scientific Advisory Committee - which is a virtual boardroom full of pharmaceutical company (smoking cessation drug) consultants, the FDA's conflict of interest policy is not working. It is essentially no policy at all.

The ineffectiveness of the policy is perhaps best seen by the recent revelation that one of the FDA advisory panel members who voted to keep Avandia on the market without any additional warnings or restrictions was a paid speaker for GlaxoSmithKline, the manufacturer of Avandia. On the same panel, another scientist - this one who voted to remove Avandia from the market - had been a paid speaker for a rival pharmaceutical company which manufactures a competing drug.

It should be noted that these conflicts were on the order of just a few thousands of dollars per year, making the $50,000 limit for disqualifying conflicts of interest a complete joke.

Frankly, the entire policy is a complete joke. It does nothing to prevent the formulation of federal regulatory policy by scientists who have significant financial conflicts of interest.

Seeing how the FDA is not going to remove the conflicted TPSAC panelists, I hope Dr. Benowitz, Dr. Samet, Dr. Hatsukami, and Dr. Henningfield will voluntarily withdraw from the advisory panel due to their clearly disqualifying conflicts of interest. The FDA may be willing to grant them waivers, but these scientists should play no part in promoting the continuing plague of industry influence on federal public health decision-making.

GlaxoSmithKline Urges FDA to Take Dissolvable Tobacco Products Off the Market; Rest of the Story Calls on Four TPSAC Panel Members to Resign

According to an article in yesterday's Wall Street Journal, the pharmaceutical company GlaxoSmithKline urged the FDA to remove dissolvable tobacco products from the market.

According to the article: "GlaxoSmithKline PLC called for the U.S. government to remove so-called dissolvable smokeless-tobacco products from the market, a move that shows emerging battle lines between pharmaceutical and tobacco companies aiming to sell alternatives to cigarettes. GlaxoSmithKline, which markets quit-smoking aids such as Nicorette gum, said Monday that it urged the Food and Drug Administration to take oral dissolvable tobacco products from store shelves until companies that make such products, including tobacco giant Reynolds American Inc., 'can demonstrate to the FDA that their marketing is appropriate for the protection of public health.'"

The Rest of the Story

This story demonstrates that Big Pharma views alternative tobacco products - such as dissolvable smokeless tobacco - as a threat to its profits because such products may be used as an alternative to nicotine replacement therapy among smokers who want to quit or cut down on their smoking and reduce their health risks.

But a more important implication of the story, and one which is not generally being reported elsewhere, is that it demonstrates why it is inexcusable to have individuals on the Tobacco Products Scientific Advisory Committee (TPSAC) who have financial conflicts of interest with Big Pharma.

The next major issue that TPSAC will consider (after menthol), in fact, is dissolvable tobacco products. Now that GlaxoSmithKline has come out in strong opposition to these products and directly petitioned the FDA to remove these products from the market, it is not possible for any TPSAC member who has a financial conflict of interest with Glaxo (or similar companies that manufacture smoking cessation products) to impartially participate in discussions on this matter.

Due to the FDA's ignoring financial conflicts of interest in appointing the TPSAC panel, however, it turns out that Glaxo essentially has a seat on the panel.

A GlaxoSmithKline consultant - Dr. Jack Henningfield of Pinney Associates - was appointed to the Tobacco Products Scientific Advisory Committee. Pinney Associates is a pharmaceutical consulting firm that provides consulting support to GlaxoSmithKline on an exclusive basis regarding tobacco dependence treatment. GlaxoSmithKline is the manufacturer of Zyban and NiQuitin.

In addition to his serving as an exclusive consultant to GlaxoSmithKline specifically on the issue of tobacco dependence treatment, Dr. Henningfield also has a personal financial interest in smoking cessation treatment, as he has a financial interest in a potential new oral nicotine replacement therapy product.

To make matters even worse, Dr. Henningfield has testified in court as an expert witness on behalf of GlaxoSmithKline.

To make matters worse still, the chair of the Committee - Dr. Jonathan Samet - has received grant support from GlaxoSmithKline. In addition, the organization that he directed - the Institute for Global Tobacco Control - is funded by GlaxoSmithKline and Pfizer.

And to make matters even more unacceptable, a third member of the panel - Dr. Neal Benowitz - has consulted for GlaxoSmithKline.

Dr. Benowitz also co-authored a study on the use of Chantix in smoking cessation which was funded by Pfizer and has served as a Pfizer consultant. In particular, Dr. Benowitz served as a Pfizer consultant on how to develop a scientific base to support the use of Chantix in smoking cessation. In addition to consulting for Glaxo, Benowitz has also consulted for Nabi Pharmaceuticals.

To make matters downright ugly, a fourth member of the panel - Dr. Dorothy Hatsukami - has received grant support from a pharmaceutical company to study the nicotine vaccine for use in smoking cessation.

Given GlaxoSmithKline's direct request to the FDA and given these four panel members' significant conflicts of interest with Big Pharma, I call on these panel members to withdraw from the Tobacco Products Scientific Advisory Committee.

Short of that, I call on the FDA to remove these members from the Committee and to replace them with unconflicted scientists who can make unbiased decisions about federal regulatory policy.

Members of TPSAC Acknowledge There is No Science Base to Support Redution of Nicotine as Measure to Have Profound Effect on Tobacco-Related Disease

Three members of the FDA Tobacco Products Scientific Advisory Committee (TPSAC), in an article published in the current issue of Tobacco Control, acknowledge the lack of a scientific basis for mandating reduced nicotine levels as a means to achieve a profound reduction of tobacco-related morbidity and mortality (see: Hatsukami DK, Perkins KA, LeSage MG, Ashley DL, Henningfield JE, Benowitz NL, Backinger CL, Zeller M. Nicotine reduction revisited: science and future directions. Tobacco Control 2010;19:e1-e10).

The paper reviews the scientific basis for the idea of requiring reductions in nicotine levels in cigarettes. The FDA Tobacco Act allows the Agency to reduce, but not to eliminate nicotine in cigarettes. Anti-smoking groups, such as the Campaign for Tobacco-Free Kids and the American Cancer Society, have boasted that this is going to result in millions of lives being saved. The paper, however, reviews the actual research and demonstrates that there is presently little scientific evidence to support the contention that reducing nicotine levels will save any lives, much less millions of lives.

First of all, the article points out that there is no known threshold below which nicotine is not addictive and below which cigarettes would not be addictive:

"Although studies of the threshold for nicotine discrimination have been conducted, to date no systematic human study has examined the threshold dose for the development or maintenance of nicotine addiction nor directly examined the best approach for reducing levels of nicotine in cigarettes to maximise public health benefits."

Moreover, the article points out that existing evidence indicates that cigarettes with very low nicotine levels are still effective in reducing nicotine craving and still produce pharmacologic effects associated with nicotine. Apparently, the article concludes, even very low doses of nicotine are capable of binding to receptors and causing pharmacologic effects:

"Laboratory studies show that denicotinised cigarettes produce acute subjective effects similar to those of nicotine cigarettes. For example, denicotinised cigarettes have been shown to reduce craving and negative affect due to withdrawal during short-term abstinence periods from usual brand cigarettes. The acute withdrawal relieving effects are found not to be due to expectancies for nicotine or the simple motor aspects of smoking (eg, handling), highlighting the importance of smoke inhalation per se. Denicotinised cigarettes and standard nicotine cigarettes can produce similar self-reported liking and satisfaction in smokers although another study found results to the contrary, and can produce similar delays in the latency to smoke (ie, the time to smoke a cigarette) or reductions in the amount of subsequent smoking of nicotine cigarettes. Denicotinised cigarettes may also be as acutely reinforcing as nicotine cigarettes in dependent smokers, suggesting that denicotinised cigarettes may serve as an effective short-term substitute for nicotine-containing cigarettes when the latter are unavailable." ...

"The responses observed with denicotinised cigarettes may be because non-nicotine sensory aspects have acquired reinforcing effects, non-nicotine constituents other than nicotine are reinforcing, or that low levels of nicotine are sufficient to maintain smoking behaviour because these levels can produce effects of physiological significance, at least acutely. For example, recent brain imaging studies show that smoking a single very low nicotine cigarette results in significant (23%) occupancy of α4β2 nicotinic receptors, which are considered the primary receptor subtype mediating nicotine's reinforcing and other behavioural effects. Thus, the reinforcing and mood effects of very low nicotine cigarettes may be attributable, in part, to nicotine's pharmacological effects. Other evidence also suggests that very low level nicotine exposure may have important pharmacological effects. This includes in vitro studies showing that significant nicotinic receptor desensitisation, a potential contributor to nicotine addiction, can occur with nicotine doses below a threshold for activating receptors, which mediates nicotine's acute reinforcing effects. In summary, abrupt switching to denicotinised cigarettes does not appear to result in significant withdrawal symptoms and may maintain similar levels of smoking reward and reinforcement in the short term."

The article also points out that animal studies indicate that extremely low doses of nicotine in animals are still capable of producing nicotine dependence:

"While NSA in animals typically decreases at unit doses below 0.01 mg/kg, unit doses as low as 0.003 mg/kg have been shown to maintain NSA in rats above saline extinction levels when substituted for a higher training dose (eg, 0.03 mg/kg), though variability between subjects is apparent (see also De Noble and Mele and Donny et al). No animal studies have specifically characterised the reinforcement threshold dose of nicotine during acquisition of NSA in adolescents or in the context of progressively reducing the unit nicotine dose during maintenance of NSA in adults."

The paper also points out that it is unknown whether reducing nicotine levels would have any effect on decreasing youth smoking:

"The dose of nicotine that will lead to extinction of smoking may not be the dose that is associated with the onset of dependence symptoms or nicotine addiction. Studies conducted with adolescent smokers suggest that the potential threshold for onset of nicotine addiction is likely to be substantially lower than the five standard nicotine cigarettes per day suggested by earlier research. Several cross-sectional and longitudinal studies have shown that youth smoking on a less than daily basis nevertheless report onset of dependence symptoms. About half the youth smokers who reported 1 or more symptoms reflective of a loss of autonomy over smoking had smoked on average 2 cigarettes 1 day per week, and half of those who met WHO International Classification of Diseases, 10th edition (ICD-10)-defined dependence reported smoking cigarettes a month, or 1–2 cigarettes per day. That symptoms of dependence can develop with low rates of smoking is consistent with results from a small study of adults demonstrating about 50% occupancy of α4β2 nicotinic acetylcholine receptors (nAChRs) for 3 h after just 1–2 puffs on a 1.2–1.4 mg nicotine yield cigarette. Similarly, other prolonged brain effects (long-term potentiation of the excitatory transmission to the brain reward centres) have been observed after brief application of low concentrations of nicotine (0.5–1.0 μM). Human and animal studies have shown that the adolescent brain is more vulnerable and sensitive to nicotine's effects. For example, adult smokers who initiated smoking during adolescence exhibit greater cigarette consumption, lower likelihood of trying to quit and increased risk of relapse compared to those who started smoking later in life. Adolescent rats and mice might also be more sensitive than adults to the rewarding and reinforcing effects of nicotine, as indexed by greater conditioned place preference, faster acquisition of nicotine self-administration (NSA) and higher baseline NSA rates compared to adults (see also Shram et al). What remains unknown are the effects of low dose nicotine cigarettes in adolescents and whether there is a dose that reduces the probability of sustained cigarette use."

Importantly, the article points out that there could be adverse consequences of reducing nicotine levels in cigarettes:

"In the literature concerning human and animal trials, there is a scarcity of data on the effects of reduced nicotine doses on smoking or nicotine intake and on other responses. Even if a threshold reinforcing nicotine dose is identified and a non-addictive cigarette can be produced, it will be important to determine whether there are other adverse effects from the nicotine exposure that occurs in adolescents who nonetheless experiment with such cigarettes. The threshold for nicotine's reinforcing effects may be higher than the threshold for nicotine's other potentially adverse effects, including enhancing vulnerability to other drug use. ... Therefore, low level nicotine exposure in adolescents experimenting with cigarettes designed to prevent nicotine addiction could potentially produce risk of addiction to other drugs of abuse." ...

"Among potential concerns are: (1) a switch to other drugs of abuse, particularly among populations smoking for social reinforcement, self-identity, or self-medication purposes; (2) dual use of tobacco products, such as reduced nicotine cigarettes with oral tobacco or small cigars, which may lead to greater exposure to toxicants, especially if these other tobacco products continue to contain higher nicotine levels; (3) use of reduced nicotine cigarettes as starter products. Just as low freebase nicotine smokeless tobacco products served as starter products for higher nicotine and more toxic smokeless tobacco products, these reduced nicotine cigarettes may lead to the use of other tobacco products with higher levels of nicotine, unless these other products also contain low nicotine levels; (4) illicit cigarette marketing and smuggling including through the internet and through territories that do not require reduced nicotine content of cigarettes; (5) product tampering or manipulation (such as adding nicotine to the product); and (6) industry manipulations (eg, nicotine analogues, companion products to increase nicotinic effects)."

Ultimately, the article concludes that reducing nicotine levels would not necessarily result in an improvement in the public's health, and that surveillance would be necessary to determine the effects of such a policy:

"If nicotine reduction is enacted, then large-scale surveillance is needed in order to understand the population-level impact of such changes. Marketplace monitoring and assessing unintended consequences (smuggling, nicotine spiking, new product introductions, etc) will also involve broad surveys."

The Rest of the Story

Once again, the anti-smoking groups have been tricked by Philip Morris into supporting federal legislation that does more for Philip Morris than for the public's health. The Campaign for Tobacco-Free Kids, in negotiating the legislation with Philip Morris, agreed to the clause that prohibited the FDA from eliminating the nicotine in cigarettes, and only allowed the agency to reduce nicotine levels. As a result, the agency is powerless to mandate changes in cigarettes which would actually result in a dramatic reduction in their addictive potential. As is clear from the article, even with low levels of nicotine, cigarettes retain strong addictive potential as only a minute amount of nicotine is necessary to occupy enough nicotine receptors to produce a pharmacologic effect.

Even more troubling than the fact that the Campaign for Tobacco-Free Kids was duped by Philip Morris in the negotiations over the tobacco legislation is the fact that the Campaign is boasting about how this provision in the law is going to save millions of lives. The Campaign is apparently unaware of the science which demonstrates, quite convincingly, that even low levels of nicotine are capable of producing reinforcing pharmacologic effects.

But the most troubling aspect of the story is the conclusion of the paper: "Reduction of nicotine in tobacco products could potentially have profound impact on reducing tobacco-related morbidity and mortality. ... an organised and multidisciplinary effort should be established to set priorities and goals..., engage appropriate scientific, research and government communities/organizations, shape the direction of research, and ensure that efforts stay focused on the ultimate goal of understanding how nicotine reduction could impact the morbidity and mortality of tobacco use."

After a comprehensive review of the literature in which the authors convincingly demonstrate that the science base does not support the idea that reducing nicotine levels will substantially reduce the addictive potential of cigarettes and that such a policy could have severe negative public health consequences, they still conclude that reducing nicotine levels is a desired public health policy which should be vigorously pursued, and that millions of dollars of taxpayer money should be funneled into research to study a policy which quite likely might be doomed to failure from the get-go.

There is a strange disconnect between the scientific evidence presented in the review and the conclusions and recommendations of the article.

For example, while the authors state that: "switching to denicotinised cigarettes does not appear to result in significant withdrawal symptoms and may maintain similar levels of smoking reward and reinforcement," they nevertheless conclude that reduction of nicotine levels could have a profound impact on tobacco-related mortality. If the levels of smoking reward and reinforcement are not substantially reduced in very low-nicotine cigarettes, then how would such a reduction have a profound impact on tobacco-related mortality? The conclusion just doesn't follow from the scientific evidence.

In trying to understand why the science is so divorced from the recommended policies and the strategic agenda, I can only point to two possibilities.

First, as researchers in the area of nicotine science, the authors have a vested interest in promoting research funding into their area of expertise. This is a financial conflict of interest that appears to be influencing the conclusions and recommendations of the article.

Second, all three of the TPSAC authors and two additional authors of the paper have a vested financial interest in maintaining the paradigm that nicotine is the agent responsible for smoking addiction because they have financial ties to pharmaceutical companies which manufacture nicotine replacement or smoking cessation pharmaceutical products:

"DKH has received grant funding from Nabi Biopharmaceuticals to conduct nicotine vaccine clinical trials. JEH provides consulting support for GlaxoSmithKline Consumer Health through Pinney Associates on an exclusive basis on issues related to tobacco dependence treatment, has financial interest in a potential new oral nicotine replacement product and serves as an expert witness in litigation against tobacco companies. NLB serves as a consultant for Pfizer and as an expert witness in litigation against tobacco companies. MZ provides consulting support to GlaxoSmithKline Consumer Health through Pinney Associates on an exclusive basis on issues related to tobacco dependence treatment. KAP has served as a consultant to Cypress Bioscience."

That pretty much says it all. With this magnitude of conflict among the study authors, there is no way we could expect an objective set of recommendations and conclusions. And, by the way, this is exactly the reason why I have argued that scientists with financial conflicts of interest should not be making national policy recommendations.

The rest of the story is that there is a complete disconnect between the scientific base and the policy agenda in tobacco control today. Financial and political influences have wrested the policy agenda in tobacco control firmly away from the science base.

Washington Ethics Group Calls for Investigation into Conflicts of Interest of Two FDA Tobacco Panelists, Citing Their Financial Ties to Big Pharma

On Monday, the group Citizens for Responsibility and Ethics in Washington (CREW) - which focuses on government ethics and accountability - wrote to the Inspector General of the Department of Health and Human Services, urging him to investigate the participation of Dr. Jack Henningfield and Dr. Neal Benowitz on the FDA Tobacco Products Scientific Advisory Committee. The letter cites the financial conflicts of interest of Drs. Henningfield and Benowitz, who have both received money from pharmaceutical companies that make smoking cessation products.

According to the letter, Henningfield and Benowitz have "received millions of dollars in grants from pharmaceutical companies that stand to profit from decisions made by the committee. Specifically, Drs. Neal Benowitz and Jack Henningfield have received money from companies that actively market products designed to help people quit smoking."

According to CREW: "the business interests of two members of the panel, Dr. Neal L. Benowitz and Dr. Jack L. Henningfield create significant conflicts of interest. As a result, CREW requests that the Office of the Inspector General investigate to determine whether these conflicts should disqualify them from serving on the TPSAC [Tobacco Products Scientific Advisory Committee]."

Specifically, CREW notes that "Dr. Benowitz has served as a paid consultant for pharmaceutical companies, including Pfizer, GlaxoSmithKline, Novartis and Aradigm, assisting with the design, development, and marketing of smoking cessation products. ... Dr. Henningfield serves as a paid consultant for pharmaceutical companies seeking approval of smoking cessation products. The firm [Pinney Associates] has received over $2 million a year from pharmaceutical companies, over half of which is directly attributable to its work on smoking cessation products. Finally, Dr. Henningfield is a partner in a company that holds at least one patent for a nicotine replacement product -- a potential nicotine-gum delivery system -- and he has estimated that if he is successful in licensing this patent, it may be worth over a million dollars to him as a partner in that company."

The letter notes that the FDA has been widely criticized for allowing scientific panelists with conflicts of interests, but that the Agency responded by issuing new policies. However, CREW says, the appointments of Dr. Benowitz and Dr. Henningfield do not follow these policies. CREW writes: "In the wake of these systemic problems, the FDA issued new transparency and public disclosure policies for advisory committees in August 2008. ... Beyond these policies, the Federal Advisory Committee Act (FACA), under which the TPSAC was formed, mandates that any advisory committee put in place 'appropriate provisions to assure that the advice and recommendations of the advisory committee will not be inappropriately influenced by the appointing authority or any special interest...' ... The FDA's selection of membership in the TPSAC does not follow these legal mandates and the FDA's implementing guidance."

While CREW is only asking for an investigation, it makes it very clear that it believes the Inspector General should disqualify Drs. Benowitz and Henningfield from participation on the TPSAC: "Drs. Benowitz and Henningfield have clear financial conflicts of interest as defined by statute and FDA guidance. As outlined above, both stand to receive direct financial benefits from teh TPSAC's recommendations on smoking cessation products. ... Their outside financial interests will be directly and predictably affected by the recommendations from TPSAC on particular matters within its assigned jurisdiction. These conflicts unquestionably disqualify Drs. Benowitz and Henningfield from serving as members of the TPSAC."

The CREW letter follows a similar request to the FDA from Philip Morris to reconsider the appointment of Drs. Benowitz and Henningfield to the TPSAC because of their Big Pharma financial ties. In its response denying that request, the FDA fails to even acknowledge the financial conflicts of interest with Big Pharma and fails to explain whether it had determined that the conflicts of interest with pharmaceutical companies were non-disqualifying.

According to an article in the New York Times, Dr. Benowitz fails to even see any conflict of interest. He is quoted as stating: "I really don’t see any conflict. My involvement with pharmaceutical companies is aimed at reducing the risk of smoking, quitting smoking. The aim of the committee is also to reduce the adverse health consequences of tobacco use."

CREW was disappointed that FDA failed to directly address the pharmaceutical conflict of interest issue, stating: "We just thought the financial conflicts were clear. The FDA has not explained how these are unavoidable conflicts."

The Rest of the Story

The financial conflicts of interest that are the subject of Monday's letter from CREW were first highlighted here at The Rest of the Story on March 1 and March 2, as soon as the TPSAC membership was announced. I argued that these conflicts were substantial because the TPSAC will be making decisions that directly affect the profitability of pharmaceutical smoking cessation products.

I argued: "Given that the FDA has already been under siege for complaints about the undue influence of politics over science, due to the influence of industry, it is unclear why the Agency would want to compound the problem by crafting a highly conflicted panel to advise it on tobacco issues. There is enough bias in this field to begin with; we don't need to add to it by appointing a panel with numerous members who have severe, personal financial conflicts of interest."

"The rest of the story is that by virtue of its appointment of numerous members with financial conflicts of interest with Big Pharma, the FDA Tobacco Products Scientific Advisory Committee has now become a literal extension of pharmaceutical company financial interests. These companies have been given the gift of a seat at the table (actually, four seats). The ... pharmaceutical industr[y] must be laughing all the way to the bank. There's nothing like sitting on the panel of the Agency that regulates your products or makes decisions about the regulation of the products of your chief competitors."

It seems to me that two things are indisputable in this case. First, there is no question that there is a financial conflict of interest. Both Dr. Benowitz and Dr. Henningfield have significant financial interests in pharmaceutical companies that manufacture smoking cessation products whose profitability will be directly impacted by the decisions of the TPSAC about how to regulate the potential competitors to these products.

Second, there is no question that the products the TPSAC will be advising the FDA about how to regulate include direct competitors to the smoking cessation products made by these pharmaceutical companies. For example, products like electronic cigarettes (which could well fall under the jurisdiction of the FDA tobacco law, and therefore, the TPSAC), are potentially fierce competitors of pharmaceutical smoking cessation products. If electronic cigarettes prove to be effective, they could put a huge dent in the market share of pharmaceutical products and could irreversibly alter the profitability of those products.

Thus, I fail to see how one can credibly argue that there is no financial conflict of interest here or that the conflict is not relevant to the subject matter that will be considered by the Advisory Committee.

At best, the FDA could argue that there is a relevant conflict of interest, but that the Agency has carefully considered it and decided that it need not disqualify the pharmaceutical consultants from participation on the panel. Obviously, I wouldn't agree with such reasoning; however, it is imperative that the FDA directly address the issue.

I agree with CREW that the FDA's response so far has been inadequate. It can't simply ignore the conflict and pretend that it doesn't exist. It must directly answer the question: "Given this clear conflict of interest, how can the continued participation of these two pharmaceutical consultants on the advisory committee be justified?"

Perhaps most troublesome is the response of Dr. Benowitz that he fails to see any conflict of interest. If that is the case, then the conflict is even more worrisome. Conflicts of interest that are out in the open can at least be managed. But when the consultant doesn't even acknowledge that there is a conflict, then that signals trouble. You can't manage something when you're not even aware of it, and don't even acknowledge that it exists.

In light of the rest of the story, I believe that Drs. Benowitz and Henningfield should voluntarily step down from their seats on the TPSAC panel and allow the FDA to appoint two unconflicted scientists to serve.