The FDA Gets Lost on its "Critical Path"

I have to admit it – even I am a little impressed with the continued good results from  Qnexa’s second year trial, Sequel. Subjects generally did not lose more weight, but they did an impressive job of sustaining the weight loss results of the one-year Equip trial. And apparently they did this without further complications of safety issues – but I do have to stress apparently, since we have only Vivus’ say-so to go by.

So Qnexa, whether it gets approved or not, is the harbinger of the future of weight loss drug development – what the FDA calls “combination products.” Qnexa is the first combination agent to be reviewed by the FDA. Contrave is up next, with a December Advisory Committee date.

There’s no need to belabor the urgency of the ever-growing rate of obesity in the American public. The U.S. is first among major nation is obesity rates, and it threatens to overwhelm the nation’s healthcare budget. Obesity has overtaken cigarette smoking as the number one health hazard & the leading cause of death. Healthcare costs related to obesity are already widely acknowledged to be 10% of all such costs – the most recent estimate is actually 17% – and growing. The Center for Disease Control just released an ominous study suggesting that one in three Americans could be diabetic by 2050.

The FDA’s Critical Path Initiative

Recognizing the developing urgency of the obesity epidemic, the FDA in 2003 and 2004 held Advisory Committee meetings on this topic. Both meetings reviewed the history of weight loss drugs, which highlighted the paucity of drugs, the checkered history of their approval & subsequent withdrawal, & their enduring lack of efficacy. In the face of this history, a prime motivation was to consider ways to encourage more drug development by the pharmaceutical industry.

In the 2003 meeting, Dr. Janet Woodcock, today’s current Director of the FDA’s Center for Drug Evaluation & Research, gave the meeting’s central presentation on the development of a Critical Path forward in obesity research and, in particular, to foster new product development.

There is this tremendous explosion of basic scientific knowledge. But

... we feel it hasn't been applied to actually the process of getting these

products developed.

This process, which is called the development process, is on the critical
path to getting these products to the patients. We think it is becoming
a serious bottleneck to delivery of new products as the basic science enables
more discovery and more candidates to be identified.

Dr. Woodcock stressed the importance of FDA guidance in achieving these ends:

FDA guidance documents . . . are known to foster innovation and
improve chances of success -- the existence of these guidance documents –
and they seem to. Where there is clarity in a development pathway, in
a critical path, it fosters attention and innovation and investment in
that product area. So, where developers see a clear path forward, they
will focus their innovation in that area.

FDA Assessment of the Current State of Obesity Agents

The 2004 meeting was convened specifically to discuss revisions to the original 1996 Guidance on weight loss products. Dr. David Orloff, then the Director of the DMEP, stressed, again, the importance of the FDA’s role in supporting industry in undertaking more obesity research & development:

Germane to our work here today, [former FDA Commissioner Mark McClellan]
charged the so-called therapeutic subgroup, which was led by our division,
to assess real or perceived barriers to obesity drug development and to
make recommendations on ways to encourage the development of new or
enhanced therapeutics for obesity.

Several reviews were presented at the 2004 meeting: of the regulatory history of weight loss agents (Dr. Eric Colman), an overview of the current situation (Dr. Frank Greenway), and a current & future perspective (Dr. Richard L. Atkinson). All of these reviews referenced the continuing modest efficacy achieved by virtually all obesity agents. Dr. Greenway concluded his overview of the current state of treatment:

In conclusion, all these drugs give between a 2 and 6.5 kg greater weight
lossmthan placebo in trials that last up to a year, and the amount of weight
loss appears to be medically significant. The weight loss between these
different drugs is not different statistically and the choice, therefore,
revolves around side effects.

In a slide presentation in 2003, Dr. Orloff had presented the following conclusion about the historical mean weight loss of obesity drugs: “Average placebo-subtracted weight loss of drugs evaluated to date [equals] 3-5% of baseline at year 1”

Dr. Orloff, in 2004, also speculated about the likely efficacy of future weight loss drugs:

Our experience … is with only modest efficacy of drugs that we have
approved and evaluated to date and ...[without the] anticipation,
frankly, that there is anything in the pipeline that is going to be
dramatically more effective than what we have seen already.

Given the accepted evidence of the continued modest efficacy of weight loss drugs, a prime consideration for the 2004 meeting was the development of guidance for the approval of “combination products” in the hope of increasing effectiveness. This “guidance” was incorporated into the 2007 revised Guidance on Weight Loss Products. As a first attempt at formulating standards of safety and efficacy for these products, perhaps I should not be overly critical. But this guidance is clearly inadequate, as I have detailed here.

The FDA gets lost on its Critical Path
However, it is not in its promotion of combination drugs that the FDA has gone astray. One aspect of the “wrong turn” the Agency has made is in forgetting what the “combination products” actually combine: individual single agents.

It seems to have forgotten that without novel drugs, based on new research, combination drugs will just keep combining old anergenic, stimulatory drugs like phentermine with haphazard, already-approved drugs that happen to demonstrate some weight loss properties. That field is pretty narrow – & the low-hanging fruit has already been picked. The FDA needs to encourage the development of new agents – that’s what its 2003 and 2004 meetings were designed to do.

In the 2003 advisory meeting, new developments in obesity research were hailed as promising innovative new treatments to come. Dr. Orloff’s slide presentation detailed the following new avenues for research, any of which could result in the development of effective new medications:

* Serotonin
* Leptin/CNTF
* Neuropeptide Y
* Peptide YY
* Ghrelin
* MC 3, MC 4
* MSH
* MCH
* CRH
* Urocortin
* Galanin
* H3
* CART
* Amylin
* Orexin
* CCK-A
* GLP-1
* Bombesin
* Beta 3 adrenergic system
* GH
* Cannabinoid receptor
* Topiramate
* Thyroid modulators

The research avenues were many & promising – but the very abundance of them augured something less positive. Apparently, weight is regulated by the human body in many different ways. The body’s weight was maintained by an evolutionary-designed abundance of feedback & homeostasis mechanisms. All of these avenues might provide just one small piece of the overall obesity puzzle. Given the multiplicity of mechanisms, however, even an effective intervention with one aspect would likely be overcome by the combination of all the other mechanisms.

So the “many avenues” of new research was a double-edged sword. Yes, it augured new drugs to come. But it also suggested that the weight loss from any one such agent was likely to continue to be modest, and likely to be short-term. Its effect would be swamped by the other biological mechanisms mandating a return to the body’s state of “normalcy.” It was this discouraging realization – that even future anti-obesity agents would be likely to provide only “modest” results, which stimulated the current interest in developing combination products.

The FDA’s mission was obvious: how could they encourage development of new obesity agents, so they can be utilized in creating safer and more effective combination agents?

Lorcaserin – the only novel obesity product under review

The only product of the new wave of obesity research is Arena Pharmaceuticals’ lorcaserin (brand name Lorqess).  It is the result of innovative research on 5HT2c receptors, and as such it is the only novel weight loss agent under FDA review.

Incredibly, the FDA seems intent on discrediting Lorqess based on what it has termed “marginal” efficacy, despite its clear achievement of the FDA’s categorical standard for efficacy. 

(Let me acknowledge here that lorcaserin may have unresolved safety issues. That is an entirely separate issue, & not the subject of this particular essay.)

Lorcaserin’s mean placebo-adjusted weight loss is 3.3% – clearly in line with the 3% – 5% historical average cited by Dr. Orloff.  True, the 3.3% mean efficacy does not satisfy the FDA’s first criterion for effectiveness. However, it clearly meets the FDA’s second, alternative criterion: the categorical guideline, requiring at least 35% of a trial’s drug arm to achieve the 5% weight loss standard; and that the proportion of the drug arm meeting this standard be “approximately double” the placebo arm.

A few more words about the 2004 meeting are in order here, because that meeting also discussed the categorical standard in some detail. One doctor at this meeting was extremely critical about using it as an acceptable standard for judging a drug’s efficacy.  Dr. Jules Hirsch argued:

I think the categorical thing, I would worry about that. I think
that is a snare and a delusion and any statistician knows that post
hoc you can always find a category that you can make significant.
You can pick between 8-11 percent, 3 percent, whatever it is. So,
if you do categorical things, they must be stated ante hoc and you
must examine the distribution, that is, the mathematical distribution
of the weight loss. . . one must be statistically extremely careful
about categorical things.

The critical thing to realize about Dr. Hirsch’s assessment is that he is criticizing the 1996 Guidance. In the 1996 Guidance, the categorical standard was very different than the current standard detailed above. It simply required that the proportion of drug arm subjects who achieved 5% weight loss be GREATER than the proportion of placebo arm subjects who did likewise; and that the difference be statistically significant. So by this guidance, a drug that had only, say, 10% of responders could be declared approvable, as long as still fewer placebo subjects achieved 5% weight loss. It was also not required that a Sponsor pre-specify the categorical standard as the trial’s endpoint. They could specify a mean weight loss of 5% as their endpoint; and then, if they failed to achieve it, they could “fall back” on the categorical standard to justify their agent’s efficacy.

Important in retrospect,at the 2004 meeting Dr. Eric Colman, Deputy Director of DMEP, not only endorsed the categorical criterion, but actually stipulated that it was not even necessary to pre-specify the categorical standard in a clinical trial:

Dr. Eric Colman (2004):

"I have seen companies choose one or the other [Mean Difference Criterion or Categorical Criterion] as the primary efficacy outcome. In some cases, if a company prespecifies that they will only use the mean difference between groups of 5 percent and they don't make it on that

but they have, as a secondary outcome, the categorical, and that does make it, then we would be inclined to consider that drug efficacious."

Dr. Susan Yanovski was the first of several doctors to express disagreement with Dr. Hirsch regarding the usefulness and appropriateness of the categorical criterion:

Regarding magnitude of effect, I am going to disagree with Dr. Hirsch,
my esteemed colleague, on not having categorical definitions. First

of all, I don't think any of the drugs we have today--I am not sure

any of them would meet the 5 percent across the board difference from

placebo. We are going to find responders and non-responders and I think
that having the categorical variables and allowing a drug to be approved
that may have a standard number of responders is important. Now,

the magnitude of responders versus non-responders in the studies that

I have seen is often pretty substantial. It might be 35 percent versus

17 percent in the placebo group. There is often a doubling of the

responders. I think it would be a good idea to actually quantify the
difference between placebo and active treatment groups in the percentage
of responders and non-responders, not just make it statistical significance.

As it turned out, Dr. Yanovski’s references were the standards actually incorporated into the revised 2007 Guidance: a minimum of 35% responders, which is “approximately double” the placebo group (“35 percent versus 17 percent in the placebo group”).Note that a 35% responder rate is considered "pretty substantial," in and of itself. The new 2007 categorical standard represented a much higher hurdle to overcome in establishing a drug's efficacy.

So how did Lorqess stack up against this guidance? Solidly – a full 47% of the drug arm achieved the 5% standard, versus only 22% of the placebo arm.

Yet how does the FDA view lorcaserin’s efficacy? Not a single FDA official appears to be able to get five simple words out of his mouth: “Lorcaserin meets the categorical standard.” He must insert “just” or “by a slim margin.” Dr. Colman summed up his opinion on lorcaserin’s efficacy, in the introductory Memorandum in the FDA briefing document, this way:

Therefore lorcaserin did not satisfy the guidance’s mean efficacy  criterion. However,
the lorcaserin 10 mg BID dose did, by a slim margin, satisfy the categorical efficacy
criterion.

Dr. Colman is denying basic arithmetic truth – 47% of responders is substantially higher than the required 35%. It is also plainly, mathematically, more than “double” 22%. What will he deny next: gravity?

This point cannot be made too often or too emphatically – lorcaserin met the categorical standard.  It met the standard solidly. It met the new, revised, much harder to achieve 2007 criterion. It met the criterion that Arena pre-specified in both its Phase III trials.

No one in the FDA has publicly challenged Dr. Colman in this false conclusion. He persisted in minimizing lorcaserin’s efficacy throughout the advisory panel, & his attitude was reinforced by Dr. Golden’s short, biased presentation on the subject. Their attitude was picked up & echoed by several panel members.

So extreme was Dr. Colman’s attitude that he all but said he would not consider lorcaserin approvable even if it had no safety issues. Is it any wonder, in the face of such intransigent casuistry, that many spectators are questioning the impartiality & integrity of the FDA in general, and Dr. Colman in particular?

The FDA appears to have “forgotten” the rationale for the categorical criterion. By taking lorcaserin, almost half the obese/overweight population would lose 5% or more of their excess weight – this is undeniably clinically significant.  

In addition, Dr. Frank Greenway, at the 2004 meeting, argued for the greater relevancy of the “completer” data:

The traditional way of analyzing these studies, as Susan suggested, has been the last observation carried forward [ITT-LOCF], and what that does is it dilutes the effect of the
drug because it assumes that the reason the people dropped out is because they didn't lose weight. Actually, what the physician treating a patient is interested in is ... what happens to the patient ... who stays in treatment, rather than the more public health perspective of this last observation carried forward, which looks at the entire group. If you treat everybody, what does the total group gain from this experience? So, from the way in which these medications are used, it is much more informative to me, as a clinician, to have the analysis of completers rather than the last observation carried forward.

Using the clinically relevant “completer” statistics, you can start to get an idea of how truly impressive lorcaserin’s weight loss can be. The average weight loss among all subjects who completed a year on lorcaserin was 17 pounds. Sixty-four percent (64%) of the subjects who completed a year on lorcaserin lost > 5% of their weight – the average weight loss for this 64% was 26 pounds. Over one-third of completers lost > 10% of their weight. For the top 25%, the average weight loss was 35 pounds.

This health-changing and life-changing degree of weight loss, which could be obtained by large subsets of the obese population, will be denied by a deranged or deeply biased FDA who insist on focusing on the 3.3% mean weight loss criterion, and who deny, contrary to rudimentary arithmetic, lorcaserin’s achievement of the categorical standard.

FDA Guidance is Central to the Critical Path

The purpose of FDA guidance bears reiteration. I think it’s appropriate to let Dr. Colman help out here. He concluded his address to the 2004 meeting on FDA regulation thus:

Dr. Eric Colman (2004):
Since the topic of today's discussion is the obesity guidance document,
I thought I would just provide a visual reminder of the goal ...of all [FDA] guidance
documents, and that is obviously, on the one hand, to facilitate industry's 
development of safe and effective drugs but, just as importantly, to provide
regulators with the best available evidence upon which to judge a new drug's
risk/benefit profile before the drug is approved.

It follows that,  when the new Guidance was crafted in 2007, the categorical standard was considered to be "best available evidence" upon which to judge efficacy. What changed by 2010?

Recall also the words of Dr. Janet Woodcock, in the central presentation of the 2003 advisory meeting:

FDA guidance documents … are known to foster innovation and improve
chances of success. Where there is clarity in a development pathway,
in a critical path, it fosters attention and innovation and investment
in that product area. So, where developers see a clear path forward,
they will focus their innovation in that area.

Dr. Woodcock specifically endorsed the importance of FDA guidance documents in providing this clarity -- clarity upon which industry could rely as they developed a new weight loss agent:.clarity that would prevent a biopharm from wasting hundreds of millions of dollars developing a product that would not meet the FDA's standards.

Eventually, if we have recommended a scientific approach, as we take these 
to our advisory committees or we publish guidance, we have a public process for 
discussion and then that becomes a public standard that developers can use. 

So they can pick up that standard, if they have a product, and they can just 

apply it. They don't have to develop it.They don't have to agonize over it. 

That is the standard they can use.We find that this really facilitates development.

Dr. Janet Woodcock is the Director of the Center for Drug Evaluation & Research, and the agency’s foremost proponent of the Critical Path. Where is Dr. Woodcock on this issue? Will she allow her subordinates to undermine the entire basis for industry trust in FDA Guidance, as well as her Critical Path initiative?

What chilling effect does she think this will have on industry as a whole? Dr. Woodcock cited the “bottleneck” in the obesity development cycle -- tremendous strides in obesity research are not being utilized to develop into usable products. What biopharm company will undertake novel product development in such treacherous waters -- which one will feel it can rely upon the Division of Metabolic/Endocrinology Products to apply its own Guidance fairly?

I would remind the FDA of Dr. Orloff's own assessment -- that future products, developed on the basis of new scientific advances, are likely to be as modest in efficacy as anything produced to date. I would remind them again of the wrong-headedness of comparing a single agent like lorcaserin to a double agent like Qnexa.

Given their own acknowledgment that virtually all obesity agents have produced mean weight loss of 3% – 5%; given their understanding that this modest efficacy is likely to characterize future as well as past drugs; given their stated commitment to standing by the standards they have themselves imposed – how can they reasonably deny lorcaserin’s acceptable efficacy?

This is an appraisal that the FDA needs to re-think and recant.

FDA Bias on Lorcaserin

The FDA presented, unexpectedly & at the last minute, a hugely exaggerated supposed cancer risk based on a fatally flawed analysis of tumors occurring in rats. Despite their intention to make cancer risk the centerpiece of their presentation, they inexcusably failed to appoint a toxologist or oncologist to the panel. Panel members expressed over & over their complete inability to assess the relevance of these rat tumors to humans. Normally these panels have the appropriate medical expertise to assess the specific issues that will be under discussion. Lorcaserin's biggest safety concern was expected to be valvular heart disease, and accordingly there were 3 cardiologist on the panel. The omission of a clinical cancer expert guaranteed that this cancer risk would not be addressed adequately during the meeting. This left a huge, scary cloud of question marks in the minds of all the panelists, which hung over the entire meeting.

Most of the panelists clearly stated, in giving the reasons for their vote, that the unresolved cancer risk was primary or predominant in their decision. It's all on tape, & it's in the transcript. If they are backing off on the cancer risk now, that's good-- several physicians sent them a detailed critique of the errors in their analysis, so they should back off. But apparently, to save face, they plan to fall back on the supposed "modest efficacy" of lorcaserin as their reason for voting no.

Unacceptably low efficacy is another canard promoted by the FDA throughout their presentation. Lorq's efficacy is in line with all other such agents approved or reviewed or studied for weight loss properties in the past 20 years. This list includes sibutramine, orlistat, and rimonabant; anit-depressants fluoxetine and bupropion; and anti-epileptics topiramate and zonisamide. Lorq did not meet the first of the two alternative criteria that FDA Guidelines provide to indicate evidence of sufficient efficacy. Neither did any of these other agents! Lorq met the second of the FDA's two alternative criteria-- and it achieved it quite solidly, despite Dr.Eric Colman's denigrating remarks at the hearing.

Dr. Colman headed the FDA panel & clearly indicated he opposed lorq's approval -- even if there were zero safety concerns -- because of low efficacy. This is in complete contradiction to his own recorded statements when the Guidelines were being drafted-- that meeting the second criterion of categorical efficacy would establish an agent as effective. We are asking the FDA-- why is Lorqess being held to a higher standard than previous weight loss agents?

Is the answer to that question Qnexa, with its highest efficacy ever achieved? If it is, then their thinking is inexplicably muddled. Lorcaserin is a single agent- with the characteristic modest efficacy of almost all single agents. Qnexa is a double, combination agent --with two drug constituents that contribute to its efficacy. It is wrong-headed to expect a single agent to have comparable efficacy. The new norm for bariatric physicians trying to help their patients is the acknowledgment that effective help will probably require a "cocktail" of drugs. Lorcaserin is a highly selective drug that targets one specific piece of the obesity puzzle. It can be combined with other anti-obesity agents to increase efficacy, just like Qnexa. It has a much better safety profile than either phentermine or topiramate, the two components of Qnexa.

Unlike Qnexa, lorcaserin is a totally new, novel weapon in the fight against the diabesity epidemic. Qnexa, in contrast, brings NOTHING NEW to the table-- it is simply a combination of two drugs, phentermine and topiramate, that are freely available, inexpensive, and already being used in combination in clinical practice. Approving Qnexa will only increase the cost of these drugs to patients who can't afford it, considering that health insurance generally doesn't cover weight loss meds.

Why would the FDA be biased against one tiny little biotech? We don't know for sure.We know that obesity is the largest unmet need in the pharmaceutical industry, with huge potential profitability for "Big Pharma." We know that Dr. Colman favors the approval of Qnexa--he as much as said so immediately after the Qnexa advisory conference back in July-- when he held an unusual, impromptu press conference to reassure Vivus investors that he was "surprised" that the panel voted against approval (since, he said, both drugs are already approved) & suggested that they were merely "hesitant," and  "not strongly opposed," and had only "lingering concerns."  These statements were immediately telegraphed throughout the biopharm universe, & just happened to stop the free-fall of the VVUS stock price.

We know that Dr. David Orloff, former Director of the Metabolic/Endocrinology Division that reviews weight loss drugs, left the FDA in 2005 under a cloud of suspicion: for "coaching" (read "biasing") another advisory committee- to approve a diabetes drug with unacceptable cardiovascular safety concerns -- on a panel where there just happened to be no cardiologist -- which led to a major FDA embarrassment when Cleveland Clinic doctors published a scathing critique -- of the biased & inadequate FDA analysis. Sounding familiar? So guess where Dr. Orloff went after he left the FDA. Go ahead, just guess. He went to be Medical Director of Medpace, the Clinical Research Organization that ran all of Vivus' clinical trials. Oh, and he "crafted" the NDA (New Drug Application) for Qnex--that's a quote from Vivus itself -- to be reviewed by his former close associates & subordinates. I would not have believed this was legal.

And we know that Harry Markopolos, the whistle-blower who brought down Bernie Madoff, testified before Congress that the FDA (as well as the SEC) was a "captured" agency -- meaning that these agencies are no longer serving the public interest, but rather are "captured" by powerful financial & corporate interests and now serve THEIR interests.

So we don't know if the bias comes from Big Pharma, or Small Pharma, or just some shady quid pro quo. We just know there's bias.

Through a glass, Darkly – The FDA Perspective on Obesity Agents

It remains to be seen how this race will turn out. The FDA, in the final two weeks of October, issued a Complete Response Letter (CRL) to both Arena and Vivus Pharmaceuticals. The letters to both companies requested clarification on a number of safety issues, with the threat of more clinical trials if they could not satisfy the FDA.  The CRL issued to Arena additionally cited its "marginal efficacy" as being problematic in its approval.

Lorcaserin’s "marginal efficacy" was a canard continually promoted by the FDA in the lorcaserin briefing documents & in the lorcaserin advisory meeting.  Yet the FDA has written guidance that establishes the criteria by which a drug's efficacy should be judged – and lorcaserin clearly meets this guidance. This guidance also provides additional criteria that should be met by “combination products” such as Qnexa. The FDA, however, seems unable to correctly apply the clear language of its own guidance.  As a result, their views of both lorcaserin & Qnexa are seriously skewed.

I have taken the time to go back & review the FDA's purported views on efficacy.  I have reviewed not just the current 2007 Guidance for weight loss products, but the original 1996 Guidance and the transcripts from two Advisory Committees that the FDA held specifically on obesity drug development: one, their 2003 Advisory Committee on  the obesity epidemic & the Critical Path forward to develop new products ; and two, their 2004 Advisory Committee, which considered specific revisions to the 1996 guidance  The FDA appears to have selective memory of these events, and appears to apply their precepts haphazardly.

The current guidance offers two main alternative criteria to establish a drug's efficacy. The first is the mean weight loss standard, which requires mean placebo-subtracted weight loss of at least 5%. The second is the so-called "categorical standard," which requires demonstrating that the proportion of subjects who lose > 5% of their baseline weight is greater in the drug arm versus the placebo arm.

Frequently overlooked, however, is the additional guidance that is provided, for the first time, for combination products. The advisory committees just referred to, held in 2003 and 2004 to consider a "path forward" in obesity drug development, endorsed the necessity of trying combination products, combining two or more agents, in an attempt to procure greater efficay. To that end, the revised 2007 guidance made a first attempt at establishing efficacy and safety guidelines for such combination products.

Qnexa, as the preponderance of evidence will show, does not meet this guidance, and it should not be approved.  Its multiple serious risks outweigh the modest 3% benefit it provides in comparison to its constituent elements. This is the standard by which it should be judged. Lorcaserin, on the other hand, fully meets the FDA's guidance, & deserves approval once the FDA's illegitimate cancer concerns have been allayed.

The Double Standard, Part I
The FDA considered Qnexa's efficacy to be so solidly established that the FDA deputy director of the Division of Metabolic & Endocrinology Products (DMEP),  Dr. Eric Colman, opened the Qnexa Advisory Committee in July by taking it off the table as an issue for consideration:

In general, the FDA is in agreement with the company with respect to the

weight loss effects of the drug that's been proposed, trade name of Qnexa.

So you will see during the FDA presentation that the focus is primarily on

safety.

This "pass" which Dr. Colman gave Qnexa on efficacy was important, because Qnexa's efficacy, if examined, does not hold up to scrutiny.

In 2004, the FDA Advisory Committee met to discuss revisions to the 1996 Guidance. At this meeting, Dr. Colman provided an overview of the history of obesity agents, which emphasized the modest efficacy achieved by virtually all such agents.

In the face of this record, the advisory panel considered the future of obesity drug development, the obstacles the pharmaceutical industry faced in developing new & more effective agents, and how the FDA could encourage this development. The many new advances in obesity research foretold two developments in drug development: (1) since obesity seemed to involve so many biological processes & feedback loops, new research highlighted the near impossibility of finding any one simple solution; and (2) this research yet held out hope for many new avenues to exploit in drug development. The problem was, each individual “solution” to any specific piece of the “obesity puzzle” would likely be counterbalanced by some other biochemical process. This augured continued modest efficacy, and short-term weight loss that would tend to revert to “normal” by the body's homeostatic mechanisms.

Given these issues, the panel discussed how to encourage more research on combination products – whether by universities, the National Institute of Health (NIH), or the pharmaceutical industry. Given the size – and cost – of the trials necessary to provide sufficient evidence of efficacy and safety, it appeared industry must be encouraged to develop combination agents, with the opportunity to exploit these agents financially with new patents on the combinations themselves.

In a discussion of how to provide guidelines by which to assess the efficacy & safety of these new combination products, it soon became evident that many variables impinged on this issue. Should a combination be required to offer twice the efficacy of either of its constituents? Perhaps – but what if the combination offered a superior safety profile in addition to better efficacy? In that case, should not a lower efficacy be acceptable, as tradeoff for the better safety? And what if a combination agent attained similar efficacy, but at lower dosages than usually prescribed? And so on – to the point that Dr. David Orloff, Director of DMEP in 2004, decided it was too complicated to come to any resolutions at the panel meeting.

Given, perhaps, this complexity, the 2007 Guidance that eventually emerged did not provide very clear guidelines for combination products. On efficacy, the Guidance states:

   
            We have not defined a minimum difference in weight loss between a fixed-
            dose combination and its individual component products that should be
            achieved for the combination to be considered more efficacious than either
           of its components when used alone. However, a fixed-dose combination 
           that is associated with at least twice the weight loss observed with that of 
           each of the individual components will be viewed more favorably than
           combinations that do not achieve this degree of relative weight loss.

With regard to safety, the guideline is spelled out in the FDA Qnexa Advisory Committee briefing documents:
             Although not a requirement for approval of a fixed-dose combination
             product, the Division looks more favorably on combination products
             that exhibit a potentially meaningful improvement in the safety profile
             compared to the individual components.

So the guidance the FDA provides is not terribly clear, and is therefore amenable to interpretation.  Certainly, it did not meet either of these "preferred" guidelines, neither in efficacy nor in safety.

 “But they don’t have to,” says Vivus and the FDA. The Guidance just says it will be viewed more favorably.  That is true. However, if the weight loss was worse than the individual components, then that would obviously be viewed extremely unfavorably. It would not be approvable – it would negate the whole point of combining agents. 

Likewise, if the safety profile of the combination agent was worse than its constituent components, then that would also be viewed extremely unfavorably.  That may also negate the approvability of a combination product – unless, possibly, the efficacy was truly stellar.

The 2007 Guidance requests that a study trial be done which compares a combination product with both of its constituent components separately, as well as with placebo:

We recommend that the efficacy and safety of fixed-dose combinations be compared with the individual product components of the combination and placebo in phase 2 trials of sufficient duration to capture the maximal or near-maximal weight-management effects of the products

Vivus performed this comparison in its first Phase III clinical trial, OB-301. This trial showed that Qnexa High-Dose produced mean weight loss of 9.0 kg, compared to 6.1 kg  for its toparimate component and 5.8 kg for its phentermine component.

	PLACEBO	PHEN 7.5 MG	TPM 46 MG	QNEXA MID-DOSE	PHEN 15 MG	TPM 92 MG	QNEXA HIGH-DOSE
Mean % Weight Loss	-1.5%	-5.2%	-4.9%	-8.2	-5.8%	-6.1%	-9.0%
Placebo-adjusted Weight Loss	-----	-3.7%	-3.4%	-6.7%	-4.3%	-4.6%	-7.6%
Individual Component-Adjusted Weight Loss	-----	-----	-----	-3.0%*	-----	-----	-2.9%**

  *Qnexa at Mid-dose (Phen7.5/Tpm46) mean weight loss minus Phen 7.5 mean weight loss.

**Qnexa at High-dose (Phen15/Tpm92) mean weight loss minus Tpm 92 mean weight loss.

This table clearly shows how Qnexa compares to placebo versus how it compares to its individual components. Just as any weight loss agent must show that it provides a substantial increase in effectiveness as compared to placebo, a combination agent should additionally demonstrate substantial increase in effectiveness as compared with either of its individual components. As the FDA repeatedly emphasized in regard to lorcaserin, a 3% differential in efficacy is modest.  In the CRL, the FDA characterizes this difference as "minimal."

Why is lorcaserin being held to a higher standard than Qnexa?

The FDA reviewer concluded: “Treatment with PHEN/TPM [Qnexa] resulted in an additional 3% weight loss compared to the individual components alone.”   This degree of improvement in efficacy does not meet the FDA's preferred guidance of "at least twice the weight loss observed with that of each of the individual components."  More importantly, it also fails to meet the reasonable difference of 5% over each individual component – this 5% difference over components would be the natural corollary of the basic efficacy requirement which requires a 5% difference over placebo.

So although the  FDA has not yet set clear guidelines for the degree by which a combination agent should exceed the efficacy of either of its constituent elements,  nevertheless the cue should reasonably be taken from its efficacy guidance for weight loss drugs in general: a difference of 5% or greater compared to placebo. Since they require that the "efficacy and safety of fixed-dose combinations be compared with the individual product components of the combination and placebo,” it seems reasonable that the same 5% difference that applies to placebo should also apply with regard to the individual components.  That is a standard that Qnexa clearly fails.

But it’s the safety profile that really does not bear scrutiny.

Moving to the safety side of the equation, the FDA prefaces its safety review of the OB-301 data with its own statement of a desirable safety profile, then with two interesting hypotheses made by Vivus:

Although not a requirement for approval of a fixed-dose combination product, 
the Division looks more favorably on combination products that exhibit a 
potentially meaningful improvement in the safety profile compared to the 
individual components.

 In addition, the applicant has theorized that some of the expected side effects 
of the two drugs alone may be “mitigated by oppositional pharmacodynamic 
effects associated with the other component.” In particular, the cognitive slowing observed with topiramate treatment may be lessened with co-administration of phentermine.

This is followed by ten pages of complicated tables and lovely, colored charts -- and several bland statements of damning import.  These results might be best illustrated with a few simple charts, pulled from the chaotic detail of the data tables.

The safety issues most closely associated with phentermine and toparimate include psychiatric-related issues, cognitive-related issues, & cardiovascular issues. (These are three of the five explicitly labeled by the FDA as the relevant safety concerns – the other two are teratogenicity and metabolic acidosis.)

Percentage of  Adverse Events in OB-301, by treatment category.

Nervous System disorders

PLACEBO             24.8%

PHEN 7.5               22.0%

TOP 46                   38.7%

Qnexa MID-dose          40.6%

PHEN 15                20.4%

TOP 92                   36.4%

Qnexa HIGH-dose                   49.1%

Psychiatric disorders

PLACEBO             13.8%

PHEN 7.5               10.1%

TOP 46                   17.0%

Qnexa MID-dose      17.0%

PHEN 15                15.7%

TOP 92                   17.8%

Qnexa HIGH-dose                  25.0

Cardiac disorders

PLACEBO             0.9%

PHEN 7.5               1.8%

TOP 46                   1.9%

Qnexa MID-dose            2.8%

PHEN 15                0.0%

TOP 92                   0.9%

Qnexa HIGH-dose                                                             6.5%

These simple tables clearly illustrate that, for the safety issues most closely associated with phentermine and toparimate, the combination of these drugs in Qnexa creates a synergistically much worse result – especially in the Qnexa high-dose..

Vivus may argue that, although the differences look stark as set out in these tables, nevertheless many of these side effects are mild and frequently don't result in discontinuation on Qnexa. Though there may be some truth in that anticipated assertion, this table shows nevertheless that the safety profile of Qnexa does cause many more discontinuations than either placebo or phentermine or topiramate alone.

Adverse Events as Main Reason for Discontinuation of Study Drug:

PLACEBO       7.3%

                                                           

PHEN 7.5        9.2%   

TOP 46            7.4%

Q MID                        15%

PHEN 15         10.2%

TOP 92            16.8%

Q HIGH                      21.3%

The bottom line is this -- if an obese person was treated with phentermine or topiramate alone, even at the reduced dosages used in the Qnexa trials, they would achieve significant weight loss.  The modest incremental weight loss achieved by the combination of these agents in Qnexa is not justified by the additional safety concerns.

Lastly -- with regard to Vivus’ proposal that the safety issues would actually be “mitigated by oppositional pharmacodynamic effects associated with the other component”? The FDA reviewer provides no explicit conclusion – perhaps he hopes we’ll have forgotten Vivus’ awkward hypothesis by that time.  And Vivus’ even more hopeful conjecture – that the cognitive slowing associated with toparimate will be mitigated by phentermine?  Nope. Cognitive function was specifically demonstrated to be worse on Qnexa, at both dose levels, compared to phentermine or toparimate alone.

The Double Standard, Part II

The FDA recently rejected Arena Pharmaceuticals drug candidate lorcaserin, partly due to what they termed 'marginal efficacy."  This conclusion is truly puzzling, since lorcaserin easily met the required criterion. In the same 2004 Advisory Committee that debated the approvability of combination products,  other proposed revisions to the 1996 Guidance on weight loss products were considered & discussed. One such provision was the “categorical efficacy” guideline. Following discussion, the categorical efficacy criterion was judged to be relevant & important.

Importantly, however, the 2007 revision made this goal much harder to achieve.  In 1996, the standard only required that there be a difference in the proportion of subjects who achieved at least 5% weight loss, drug arm versus placebo arm, and that the difference is statistically significant. The new categorical criterion set much higher hurdles: at least 35% of the drug arm must achieve the goal; in addition, the percent of the drug arm achieving 5% must be “appoximately double” the percent of the placebo arm; and the difference must be statistically significant.

 Lorcaserin met this goal solidly -- 47% of the lorcaserin arm achieved the 5% weight loss goal.  Only 22% of the placebo arm met this goal.

Yet the FDA, primarily in the person of Dr. Eric Colman, has repeatedly characterized this achievement as minimal – Dr. Colman has all but said that lorcaserin should not be approved even with no safety concerns whatsoever. This is in direct contradiction to statements he made at the 2004 Advisory Committee, where he explicitly stated that the categorical standard would be considered evidence of efficacy – even if the sponsor did not pre-specify the categorical standard as the trial endpoint. Additionally, he made this statement before the categorical hurdle was raised.

Arena explicitly specified the categorical criterion as the endpoint of both of its clinical trials. Lorcaserin met the higher revised standard easily. And yet Dr. Colman persisted in characterizing its efficacy as “marginal.” It is hard to exaggerate the blatant bias displayed by his attitude.
 

It is also important to understand the context of lorcaserin in relation to all other weight loss agents that have been approved or under review in the past 20 years. Whether you look at drugs specifically designed for weight loss, like sibutramine, rimonabant, or orlistat; or antidepressants with anorectic properties like bupropion or fluoxetine; or anti-epileptics with the same properties, like toparimate or zonisamide – the result is the same in all cases.  All demonstrated similarly modest but clinically significant weight loss. Only amphetamines and amphetamine-like agents, such as phentermine, achieved better than 5% placebo-adjusted efficacy. (The weight loss indication has nevertheless been withdrawn from most such amphetamine agents, due to safety and abuse concerns, and the ones that retain it are restricted to short-term usage.)

In a review of all these drugs at the 2004 advisory meeting by Dr. Frank Greenway, he concluded that these drugs demonstrated:

 "between a 2 and 6.5 kg greater weight loss than placebo in trials

that last up to a year,and the amount of weight loss appears to be 

medically significant.  The weight loss between these different drugs 

is not different statistically and the choice, therefore,revolves around 

side effects."

Lorcaserin’s efficacy is right in line with that of all other such agents in the past 20 years.  It clearly meets the categorical efficacy standard. So why, all of a sudden, is this not sufficient?

Once again -- Why is lorcaserin being held to a higher standard?

Conclusions

The answer to that question can only be Qnexa -- misguided though that opinion has been shown to be. For the average obese person looking desperately for help, or for any average individual looking for any easy way to lose 10-20 pounds, it is not hard to understand the irresistible appeal of a drug that holds out the possibility of 37 pounds weight loss. What is very hard to understand, however, is why a supposedly independent, impartial agency like the FDA is being blinded by these numbers to the exclusion of safety concerns & common sense. The safety issues associated with phentermine & toparimate are exacerbated by their combination in Qnexa – this one point should determine the compound’s unapprovable status.

For any common sense approach,  comparing Qnexa and lorcaserin is like comparing apples to oranges. Qnexa is a combination product. Lorcaserin is a (novel) single agent. It is so completely inappropriate to compare a single agent to a double agent -- and hold the single agent “marginally” effective because its efficacy is less – that it staggers the mind that the FDA insists on doing it.

By the FDA's own guidelines, & by historical standards, lorcaserin is an eminently approvable drug, based on its efficacy.The safety issues for lorcaserin -- "drummed up" by a hostile FDA -- can be and will be resolved. At that point, lorcaserin should be approved without further demurral.

Qnexa, on the other hand, should be held to the same standards by which lorcaserin is approvable. It should be held to the additional, common-sense standard which is the primary efficacy standard for weight loss agents: Is the mean weight loss, individual component-subtracted, greater than 5%?   It is not -- it is only 3%. In addition, the safety profile for the combination of its components is clearly worse than either component individually.  This is a drug that completely deserves rejection by the FDA.