"Behind the Counter Drugs"

You learn something new everyday. Today, I learned about "behind the counter" drugs (BTC). It seems that the FDA is contemplating a new class of drugs to be added to the traditional dichotomy of prescription vs. over the counter (OTC).

Learn more about them here.You learn something new everyday. Today, I learned about "behind the counter" drugs (BTC). It seems that the FDA is contemplating a new class of drugs to be added to the traditional dichotomy of prescription vs. over the counter (OTC).

BTC drugs will be halfway in between. They won't require a doctor's prescription but a patient can't simply purchase them on his own. A pharmacist can dispense them though, after questioning the patient and making a clinical judgment (presumably without performing a physical exam). I suppose that if this gives patients added access to health care, this may be a good thing.

But in all honesty, I have mixed feelings about it. Unfortunately it'll be difficult to voice them without giving the appearance of "protecting my turf". But here goes.

First of all, I can't believe that pharmacists will be willing to assume the role of clinician with its added liability without charging significantly for their services. Clearly, this marks them as direct competitors of physicians (particularly primary care physicians).

Will they then be objective about when a patient's problems are out of his range of expertise and be as willing to refer as previously?

Also, the pharmacist is in the same position that people often chide physicians about, namely having a vested interest in the treatment. When a pharmacist prescribes a BTC treatment, is he doing it out of purely clinical consideration or because in addition to collecting his counseling fee, he's also selling the drug as well?

Another obvious problem that would have to be worked out is the issue of malpractice. Will a pharmacist be held to the same standard as a physician? More to the point, will he be held to the same standard as a physician who diagnoses and treats without performing a physical exam?

Ultimately, I can't really think of a medication that I could imagine putting into this category. The dearth of potential candidates may in fact be the ultimate coup de grâce for such a policy. The article I linked failed to list a single example of such a drug.

On the other hand, perhaps there might be one exception.

Late one night, I was at a pharmacy picking up a prescription for my wife. I overheard the pharmacist talking to the customer next to me. The customer, a young woman, wanted to know which OTC could help her with the two days of terrible burning on urination she was suffering. The pharmacist told her that she'd have to see a doctor about that problem and that there wasn't anything she could recommend.

I came very close to ordering three days of Bactrim for her right then and there. Maybe a question about fevers and drug allergies...it would have been so easy.

I passed. Maybe the pharmacist had she been allowed to, wouldn't have.

Zyrtec-D Approved For OTC Use By the FDA

Medscape reports that he FDA has just approved Zyrtec-D for over-the-counter (OTC) use.

Anyone who knows me or my writing knows that I'm very much in favor of free markets. I strongly believe that most economic environments serve people better when government regulation is low or minimal.

In fact at Harbor-UCLA, situated as it is in southern California and having a largely poor and minority patient base, I'm surrounded by very idealistic housestaff and faculty who think I'm an apologist for big pharma, big corporations, and every other "big" thing with negative connotations.

But am I really? Am I a libertarian? No. And here's why.

I see classic libertarians as being almost completely averse to all government functions except for a few things such as minting money, protecting our borders, maintaining a military, and I believe maintaining a civil and criminal judicial system. My attitude is far too hands-on to support such a laissez-faire approach.

Call me hypocritical but there are many government intrusions I whole-heartedly embrace. I don't think, for example, that people should be allowed to lie or make unsubstantiated claims in advertising and I applaud laws preventing such transgressions. But truthfully, such a stance puts me at odds with many"true believers". Likewise, I'm perfectly content to have the government oversee things generally helpful to communities as a whole, such as street cleaning. Why should I pay for street cleaning like most of my neighbors but allow the occasional cheapskate on the block ride for free yet enjoy its benefits? Does that make me a hypocrite? I yam what I yam.

Likewise, I'm also in favor of government intervention when it comes to public safety. Rather than accept a purely libertarian position, I recognize the existence of circumstances in which the government has an overiding public interest.

So what does this all have to do with OTC Zyrtec-D?

I admit that I haven't done a complete review of the world literature on the subtleties of the different non-sedating antihistamines/decongestants on the market. However, no one has ever demonstrated to me (or even suggested) that cetirizine is any better than the others. So why do we need yet another "me too" drug to be approved for OTC use? Why should the FDA want to clog up the market with Zyrtec-D when there are other drugs already out there that do the exact same thing?

Now a true libertarian would welcome the added patient autonomy that OTC's provide (I've heard libertarians argue that there shouldn't be such a thing as the FDA in the first place). To me however, keeping the pharmacy lean and mean and not allowing medications that solve no new clinical problems is beneficial to society and falls under the category of the overiding public concern I mentioned above.

When the market for a particular clinical purpose is fractionated among several different drugs, there is an unfortunate consequence. Adverse reactions and serious side-effects become much harder to monitor. It will be harder to detect truly harmful drugs and remove them from the market. This is so because when smaller numbers of patients are taking them, bad outcomes are more likely to make it under the radar than with more commonly used drugs.

For this reason, I would vote for a more active FDA that demands improved efficacy before approving (or in the case of Zyrtec-D, simply expanding its market to OTC).

I do understand that when more companies are allowed to compete, prices inevitably come down and obviously, this benefits the consumer. But in an era where there are tremendous pressures on the FDA to act on drug applications faster and faster, after-market monitoring becomes increasingly important for safety. To me this concern should take precedent and me-too drugs shouldn't be allowed to expand their markets without real demonstrated advantages over what's already out there.

The one caveat to this would be if a company would formally agree to market a new drug at a substantial discount compared to existing drugs performing the same function. Again, this would result in a substantial benefit to the consumer.

I realize that my positioning of the dividing line that separates the public interest from unfettered free trade is arbitrary and derives from my own personal opinion. I'm willing to live with a certain degree of inconsistency.

And if I were emperor of the world, you would have to as well.

The FDA, Puffer Fish , and Homer Simpson

This may not be important to anyone that's not a sushi lover such as myself. The FDA is worried about establishing a safe source for the lowly puffer fish. Why? Properly prepared puffer fish, or fugu, is a delicacy among sushi aficionados. I myself do not eat it because of its unfortunate association with a very funny Simpson's episode.

In it, Homer is cajoled by Lisa to take the family to a sushi restaurant in an attempt to get out of the "meatloaf rut". Homer discovers that he loves it and even becomes adventurous enough to try fugu.

Because the master chef was otherwise romantically "involved" with Miss Crabapple, his inexperienced protege had to prepare the potentially poisonous dish. Hilarity ensues as Homer is rushed to Dr. Hibbert's office.

There, he is told he has 24 hours to live (actually 22 hours because Dr. Hibbert kept him waiting two hours).

It's nice to know that the FDA is overseeing my gastronomic needs. Who knows? The next time I'm eating sushi, I may, like Homer, demand the waitress to "Fugu me!"

The FDA and Advisory Committee Member "Conflicts of Interest"

My essay on some new legislation making its way through Congress is up at techcentralstation.com. A bill that has passed in the House would prevent the FDA from empaneling scientists and clinicians on advisory committees who have potential financial conflicts of interest.

My view on such legislation might surprise you.

Psychiatry and the surgical treatment of depression, Part II

Yesterday I posted on a NY Times article about an implantable vagus nerve stimulator being used to treat severe depression. This device is surgically implanted in the chest and electrical leads are threaded up into the neck in contact with the vagus nerve. It was developed by Cyberonics originally for the purpose of treating intractible epilepsy and the company is seeking FDA approval to expand its indications.

The previous post expressed my "squeamishness" with this kind of surgical solution for modifying mood and behavior. In the end however, I recognized both the paralyzing impact of severe depression and the need to accept any therapy that is proven to work where other less invasive therapies have not.

I closed with an admonition that "when we're dealing with those aspects of our being that cut at the very heart of our humanity, we need to be especially careful."

Unfortunately, regarding this device, it appears that such has not been the case.

In June 2004, an FDA advisory committee recommended such approval. However, the following August the FDA denied approval pending further data from the company. (Advisory committee recommendations are not binding and can be overruled by the agency.) Recently, the FDA announced that it is reconsidering approval for the marketing of this device for the treatment of intractable depression.

In a randomized trial, the vagus nerve stimulator was implanted in 235 severely depressed patients. In only half of them, was it turned on. 17 of 111 such patients reported significant improvement. 11 of 110 in the control group did. (No mention was made of the remaining 24 patients.) The difference was not statistically significant which means that it could have been attributed to mere chance. In other words, efficacy was not demonstrated by this study.

In addition, this device is not without side-effects. Patients have complained of hoarseness and "odd" inflections in the voice. At least one patient cited a constricting pain in the back of her throat which at times left her unable to speak. In addition, removal is technically difficult should this ever be necessary and the wire leads must generally be left in place. It should also be noted that there are only two years of safety data thus far which is not much for a device that presumably will be left in for life.

So why did the advisory committee approve this device? With no phase III trials demonstrating efficacy and no long term safety data on depressed patients, their decision amazes me. This hardly seems the appropriate background for a "reasonable assurance" of safety and efficacy as mandated by the FDA. As it turns out, this recommendation appears to have arisen largely out of emotion.

The committee's chairperson, neurologist Kyra Becker MD made the extraordinary statement that if she had voted her conscience, soley on the basis of the evidence, she would have voted not to approve.

Huh?

Then on what basis did she vote? I've heard some poorly thought out statements to the media before, but this one redefines the term malapropism. She also relates that "the whole meeting was uncomfortable, and everyone wanted to see another trial done, no question about it." So why vote for approval before such a trial was done?

Dissenting committee member Dr. Richard Malone said "I walked out of there thinking I was nuts. It was stunning..."

Since there are so few options remaining for patients with intractable depression, grasping at straws can seem the compassionate thing to do. Unfortunately, such decisions can have unintended consequences.

First, severe depression almost always has other treatments that are efficacious, usually in the form of multi-drug regimens. This being the case, treatments with unproven efficacy might very well direct a patient away from other potentially beneficial therapies. In fact, with FDA approval, there is nothing to stop physicians enamored by high tech solutions from utilizing this device in patients with even moderate depression (or severe depression for which established therapies haven't been exhausted.)

Second, any treatment such as this device that may be capable of making depression better, may in fact make it worse. What would we think if down the line, we found higher rates of social dysfunction or suicide among those who opted for this product? Every intervention has potential downsides.

Third, should a device with essentially no established benefit be allowed to be aggressively marketed by the company? This is exactly the right that FDA approval would grant. Should insurance companies and other third-party payers be required to foot the bill for this $15,000 treatment (not including the costs of implantation and maintenance)?

For these reasons, the FDA needs to make a well thought out, rational decision, not one based on emotion as has apparently been done by members of this committee (especially the chairperson).

I agree that there are many bureaucratic obstacles to FDA approval of medical technology, many of which are manifestly unnecessary. Demanding proof of safety and efficacy is not one of them.

As an aside, I will mention that there are some questions about the propriety of the FDA's reconsidering approval in this case:

"Cummins (Cyberonics Chief Executive Robert Cummins), who personally owns 1.15 million Cyberonics shares, acknowledged the company appealed to a number of Republican and Democratic Senators and Congressmen, as well as the Senate Finance Committee for help after the negative decision from the FDA."

I'll leave it up to the reader to ponder the morality of doing an "end run" around the FDA.

Psychiatry and the surgical treatment of depression, Part I

Thanks to Kidney Notes for linking this article in the NY Times. It was only a matter of time: Michael Crichton's 1972 book The Terminal Man becomes reality.

I have enough strong thoughts about this that I've chosen to post on it in two parts.

Cyberonics, a biotech company, manufactures an implantable vagus nerve stimulator used to treat seizures. This company has been trying to get FDA approval to market the device for the treatment of intractable depression as well.

In June 2004, an FDA advisory committee recommended such approval. However, the following August the FDA denied approval pending further data from the company. (Advisory committee recommendations are not binding and can be overruled by the agency.) Recently, the FDA announced that it is reconsidering approval for the marketing of this device for the treatment of intractable depression.

Are we about to enter a brave new world where psychiatry becomes a surgical subspecialty? While I like to think of myself as "forward-thinking", this development has left me with deep feelings of ambiguity. What are we as a society to think about the prospect of altering human behavior and mood through computers and integrated circuits?

Don't get me wrong, I'm all in favor of treating severe depression that's unresponsive to conventional therapies. Certainly, this is one of the most horrendous maladies to befall a human being. Depression cuts at the heart of all aspects of one's being, one's psyche.

I lecture on the treatment of depression to our residency program's interns during their ambulatory medicine rotation. I describe the following in an effort to get them to appreciate the impact of major depression on a patient's life: All of us have experienced a severe depressive mood at some point in our lives. For most of us, such episodes have been situational that is to say triggered by some cataclysmic event in our lives. Such events might be the loss of a job, the failure of a relationship, severe medical illness or even the death of a loved one.

That gnawing, unremitting pain is something all of us can relate to. At times it can be searing and can leave us with the sense that things will always be like this, that we'll never get over it. And yet...most of us do. We move on. Perspectives change. What was once an insurmountable gloom eventually lifts. We start to feel normal again. In fact, for many of us, we even begin to wonder how it was that we ever felt so bad, so down, so filled with hopelessness.

Almost all of us have gone through this, but we get over it. Imagine now that this depth of feeling, this personal torment persisted. Imagine this overpowering gloom following us forever. How paralyzed would we be? How empty would our lives be? How hopeless? And yet that is exactly what major, severe depression is like, an almost unimaginable pall over the very fabric of life.

So no, I never underestimate the psychic pain of my truly depressed patients. I have wholeheartedly embraced the use of psychotherapy, of antidepressants and yes, even electroconvulsive (shock) therapy, in short, whatever works. If planting a pacemaker into the chest and threading leads up into the neck to the vagus nerve will help, then I guess I'll come to grips with it.

If one day, we're treating major depression with IC chips implanted in the brain and that works, well I'll get used to that too. But I think all of us are at least a little bit squeamish about such developments. And I think that some healthy skepticism is definitely in order. Before embarking on such heroic measures to alter mood and behavior, we need to be sure that the science is good, that the procedure is indicated and that safety and efficacy is established.

When we're dealing with those aspects of our being that cut at the very heart of our humanity, we need to be especially careful.

I've posted Part II on this topic here.

Plan B and the FDA

Things don't look good for Lester M. Crawford's final senate confirmation as FDA commissioner. There have been several unfortunate turns of events under his interim watch. One of the most significant is just now starting to unfold.

In December 2003, an FDA advisory committee ruled 23 to 4 in favor of converting Plan B, a "morning after" pill requiring a prescription to over-the-counter (OTC) status. Despite this lopsided majority, in May 2004 the FDA overruled the recommendation and failed to grant approval. Rulings counter to committee recommendations occur but are extremely rare.

Clearly, without direct physician involvement, this would dramatically expand the availability of this form of contraceptive. According to its package insert, Plan B (levonorgestrel) works by a number of different mechanisms one of which may be the prevention of uterine implantation of a fertilized egg. In the eyes of some, this is tantamount to the termination of an incipient life. Because of this, the question of whether this decision was influenced by politics has been raised on multiple occasions including here.

The reason the FDA initially gave for overruling the committee had to do with the safety of this product in young teenage girls who presumably would be using it and with whom only limited safety data was available. I must admit that I was impressed with this argument when this ruling was initially reported. The safety margin has to be extremely wide when dealing with medications that will be administered without the input of a physician such as OTC products.

It now turns out that Dr David Hager, one of the committee members and an openly conservative Christian, recently delivered a speech to a college chapel in which he stated that he was asked to submit a "minority" opinion to the FDA. The FDA denies soliciting such opinions. Hager has apparently given different versions of who invited him to do so. Regardless, his arguments happened to be the same ones cited by the FDA in justifying its ruling.

In his speech, he used the following language:

"I argued it from a scientific perspective, and God took that information, and he used it through this minority report to influence the decision...Once again, what Satan meant for evil, God turned into good."

I have no problem with devoutly religious experts serving on FDA committees, even committees making recommendations regarding politically charged issues such as a morning after pill. To exclude them from participation strictly on the basis of their religious orthodoxy seems manifestly unfair. However, they need to understand quite clearly that it is their clinical expertise that is being sought, not their theology.

When it appears that one's objectivity is compromised by his or her personal agenda, that becomes a problem in the same way that members' financial ties to drug companies constitute a problem when they make recommendations on drugs manufactured by those companies.

I have no proof that Hager was less than objective in his minority opinion. His arguments against approval of Plan B for OTC use may in fact prove prescient. His language during the above quoted speech clearly does not constitute a smoking gun. Without getting into his scientific qualifications or lack thereof, it is disquieting and makes one wonder if his clinical judgement was clouded by his ideology.

The possibility that the FDA approval process may have been corrupted by the political agendas of high ranking FDA officials (or higher) is very disturbing. The FDA's decision-making apparatus must never be driven by mere political expediency. For this reason, the public should demand to know exactly who asked Hager to submit his opinion which happens to be a position ideologically aligned with the Bush administration. This, despite being counter to the committee's overall opinion. If this information is not made available, we'll never know if the process is truly as objective as the public deserves it to be.

I am certainly not qualified to speak authoritatively on constitutional issues but I do know this: The president and the various elements of his administration are charged with the enforcement of federal laws. One set of those laws constitutes the charter of the FDA.

The mandate of the FDA in its current iteration is to ensure that the medications and medical devices used by the American public are both safe and efficacious. Nowhere buried within its charter is there a provision designating the FDA an agent for furthering the political agendas of the executive branch of government's administration du jour.

Comments regarding my post on FDA and nutritional supplement regulations

In response to my post yesterday on the FDA and nutritional supplements, Fred refers us to a column by republican congressman Dr. Ron Paul. Congressman Paul is properly concerned with the impact of government intervention on consumer choice and presumably was cited because Fred feels the same way.

Perhaps we can reach some common ground. Would you be willing to accept that government has an overriding interest in insuring that:

• Any nutritional supplements on the market are at least be proven to be safe for consumption and are at least not deleterious.
  
  
• Such supplements are marketed only with claims that have been validated on the basis of medical data i.e. that the packaging reflects supportable claims.
  
  
• Such supplements meet standards with regards to claims of purity, strength, etc.

Government regulations such as these would allow companies to market any supplement they can prove is safe as long as the label accurately reflects what's in it and that no unproven claims are made with regards to efficacy.

It seems to me that this kind of legislation might strike a happy medium of government's overriding interest in public safety and the consumer's right to choose what goes into their bodies. Or do you believe that no government intervention is warranted as far as nutritional supplements are concerned?

Yes? No?

Banning Ephedrine-Containing Products

Here's an article about the recent federal court decision to overrule an FDA ban on an ephedrine containing product. Herbal supplements are categorized as foods by federal guidelines and are therefore not regulated in the same way as medications.

Accordingly, they are not subject to FDA safety, purity or efficacy standards. About the only control the FDA has with such supplements is when they are contaminated with other forbidden toxins. Essentially what this means is that companies manufacturing herbal supplements and vitamins don't have to establish that their products are safe let alone efficacious. In addition, the companies can make many claims about their benefits without any proof whatsoever. In fact, companies aren't even required to establish the exact amount or quality of the substances in the supplements.

Obviously, medications are held to much higher standards and claims in package inserts are much more tightly regulated.

What this district court ruling basically did was re-establish that the FDA has no jurisdiction under current law.

I think the vast majority of physicians are opposed to this and feel that herbal and nutritional supplements should be held to the same standards when it comes to safety and efficacy (and at least purity) as medications. Unfortunately, the supplement lobby argues that since there is little academic and industrial motivation to actually study these substances, it's unfair that they should be held to the same standards.

To me this is preposterous. If the supplement manufacturers want to market their products, why shouldn't they have to spend the money to demonstrate safety and efficacy? If the product isn't patentable (as is the case with most supplements), companies obviously will be reluctant to spend such money. So what? If the price of these substances go up, so be it. The claims made should be no less sustainable than with medications. At the very least safety must be established. To me this is just common sense.

Such a change will be incredibly unpopular politically and I doubt that congress and any sitting president will have any desire to confront the vast numbers of constituents who believe in and use such supplements. Many people swear by their properties despite a lack of evidence and despite the well-established existence of a placebo effect.

Of course, just because the benefit of some of these ingredients hasn't been established, that doesn't prove that something doesn't work as labeled. But as a scientifically-minded person who also believes in the first precept of the Hippocratic oath, I subscribe to the rule of first do no harm. Some of these supplements (with data suggesting so) may in fact do just that.

Personally, I feel the federal district court made the only ruling it could make given the existing law and was only acting within its proper purview. The true solution is to simply change the law.

The FDA approves the Mentor Silicone Breast Implant

Somewhat surprisingly (at least to me), an FDA advisory panel voted to allow the Mentor silicone breast implant to be marketed in the U.S. under limited conditions. Yesterday the same panel rejected a similar application for the Inamed implant.

Apparently the panel's concerns about implant rupture in the Inamed product did not extend to Mentor's. Mentor's reliability data appears to have been more compelling to the Panel than Inamed's.

Contrary to the headline of this (and numerous other headlines on the same story) the panel's action did not constitute a "flip-flop" or reversal. They simply ruled against one product and in favor of a completely different product.

For Mentor to sell their implant, the panel's recommendation requires that they

• Require patients to sign an informed consent stating that they understand that the implants can rupture.
• Maintain an accurate registry to track patient outcomes.
• Perform continuing ongoing long-term safety studies.
• Require surgeons using the implants to have taken a special course in their use.

Each of these requirements appear quite reasonable although I'm sure that had the requirements not been made, any surgeon using this or any such problem would have required the informed consent anyway.

There was one other requirement I found rather puzzling: The surgeon would have to be board certified in plastic surgery. I'd have to look into it but I'm not aware of any medical products where the federal government requires board certification in order to use them.

The issue of requiring board certification for various medical procedures is generally left up to individual hospitals and facilities. If I wanted to perform brain surgery at my institution, there's no law that I'm aware of to prevent me from doing so. On the other hand, Harbor-UCLA Medical Center (or any other hospital in the U.S.) would have a problem with it considering that I'm an internist!

The panel's recommendations are suggestions and the FDA can still decide one way or the other. Personally, I'd be surprised if they mandated board certification per the panel's recommendation. But that's a another topic.

As an aside, look at the article I've linked. Three column inches are spent on the completely unsubstantiated claims of one self-reported "victim" including allegations of "Incident after incident of quality control problems, contamination issues, documents being destroyed," on the part of Mentor. No opportunity for rebuttal from the company was offered.

Is this quality journalism?

FDA committee's rejection of silicone breast implant product

An FDA advisory panel came down against one of two manufacturers seeking to market silicone breast implants today. The panel rejected Inamed's application. Mentor will be presenting data in support of its product for the next day or so.

Interestingly, the panel's rejection (which is not binding to the FDA) seemed more concerned about the risk of rupture of the product then of concerns specifically related to the silicone inside. Their position was that Inamed only presented data that went out three to four years.

I wonder how long a follow-up period the panel wants. These implants presumably will have to last a lifetime. No product requires that length of testing before acceptance. If the problem is merely one of structural engineering, there are provocative tests that simulate a lifetime of use. Remember that commercial for a bed mattress that showed a machine pounding it over and over again to demonstrate its durability?

If the reason for rejection was as stated, then I see little chance of Mentor's data being any more compelling than Inamed's.

This is a shame because as one who has examined patients with both the saline and the silicone products (post-mastectomy and purely cosmetic implants) I can state with some certainty that the silicone ones have a much more realistic feel.

At any rate, it appears that the final decision will ultimately be based on the mechanics of the implants rather than a concern for imagined disease associations that have never truly been proven. Purely mechanical concerns are obstacles that will eventually be overcome. Imagined, speculative disease associations might not be. See my previous post on this.

Silicone Breast Implants and the FDA

FDA hearings are beginning today on the subject of silicone breast implants. This has been an incredibly contentious controversy ever since the lawyers got involved in this issue in the 1990's. Currently, silicone can only be used in the setting of an ongoing research protocol.

It is noteworthy that this is one of the very few cases where the FDA set aside the recommendations of an independent advisory committee and refused to allow such implants to be generally marketed. One has to think that this was because of the tremendous amount of press coverage of a very vocal minority of patients and lawyers who succeeded in creating the perception of a risk when no real risk has ever been clinically demonstrated.

Emotions will be high because strong women's advocacy groups on both sides of the issue will be pitted against each other. On the one hand, women who claim to have been injured by the implants will present personal, but anecdotal stories about their own poor experiences. They will face women who rightly demand access to a product that leads to significantly improved cosmetic results. This especially in light of the limited data available pointing to actual risk.

If you're interested in a good review of the world literature regarding silicone implants and rheumatologic disorders, two good references are here and here. You'll need a subscription to Arthritis & Rheumatism and the New England Journal of Medicine to access the complete articles.

A very complete, but technical, review compiled for the European Parliment is here. This last citation not only reviews the scientific literature but also reviews the results of questionaires sent to special interest groups such as women's self-help groups, surgeons and implant manufacturers. This review also addresses numerous other issues such as the impact of silicone implants on mammography and breast cancer screening, risk to breast-feeding infants, local complications and even psychological morbidity.

What is known about silicone breast implants?

• There is no data to support an association of silicone breast implants with any specific rheumatological disease (this includes women with MRI-documented implant rupture).
  
  
• There is no data to support an association with any known neurological disorders.
  
  
• One study demonstrated an association of silicone breast implant and respiratory cancers but such differences disappeared when tobacco use was controlled. Apparently patients opting for breast implants smoke more. Another study showed similar findings but did not have the ability to control for smoking.
  
  
• There was one study that showed an a barely statistically significant association with implant rupture and fibromyalgia (a poorly charactorized disorder of unknown etiology). There were some significant methodological problems in this study, most notably that the diagnosis of fibromyalgia was self-reported.
  
  
• A slight increase in congenital malformations were noted in pregnant women with implants. Further analysis, however, showed no such association when malformations among children born prior to implant surgery were compared with malformations in their siblings born after surgery.
  
  
• There was great variability from study to study but the risk of local complications (deflation, scarring, poor cosmetic result, pain, etc.) of silicone breast implants is real. Unfortunately, no good comparisons of the silicone versus saline-filled implants have been done.
  
  
• The quality of mammography is impeded with implants but no studies are currently available on late diagnosis of breast cancer or mortality differences.

Given the politically-charged nature of this debate, it will be very interesting to see what the FDA's final decision will be.

A new FDA-approved product

This may be of interest to some of my readers.

FDA's move against Bextra (despite advisory committee's recommendations)

I was very surprised to read that the FDA, against their own advisory committee's recommendations, rejected the approval of Pfizer Pharmaceutical's Bextra for marketing. The FDA's decision to overule their committee in this manner seems to be extremely rare.

The only other time I know of this happening was in 2004 when against committee recommendations, the FDA failed to grant approval to Plan B, a morning after pill. I'm trying to determine the overall frequency of such occurrences.

The press has yet to report on just what the FDA's reasons for the rejection were. Of course I'm wondering if it has to do anything with the statistically obvious bias manifested by the committee members with financial ties to Pfizer and Merck.

For my more cynical readers, I will say this: although the FDA can never be realistically thought of as "apolitical", to make such a decidedly anti-big-pharma decision is quite striking. It will be very interesting to find out more information regarding the FDA's reasoning as the press reports it.

How do we spur development of new antibiotics?

At my hospital (Harbor-UCLA Medical Center) Dr. John Edwards, an infectious disease specialist, spoke at our grand rounds this morning.

He gave a rather chilling review of a problem many people aren't aware of. There is much more of a profit to be made on drugs people will be taking for a lifetime (anti-inflammatories, antihypertensive meds, anti-cholesterol meds, etc.) Because of this, there is very little incentive for drug companies to develop new antibiotics which will only be taken for a short time.

Given the extraordinary cost of bringing a drug to market, there are very few new antibiotics in the pipeline at this time. Unfortunately, the microbes are developing multi-drug resistance very rapidly and in time, will evolve to a state where they're resistant to just about anything now available.

Without new classes of antibiotics being developed to treat these evolving organisms, we could be facing a biologic disaster of literally biblical proportions.

Some ideas proposed to resolve this problem:

• Establishment of a governmental body to determine drug classes with major public health implications who's development should be somehow encouraged.
• Give drug companies financial incentives to pursue "less profitable" drug classes (eg. tax cuts on expenses directed at antibiotic development).
• Cut some of the "red tape" currently in place to streamline the FDA approval process for such drugs.
• Enhance intellectual property protections for such drugs (eg. extend patent protections, or give companies "vouchers" to extend patent protections to other drugs that the company produces in return for developing novel antibiotics.
• Granting companies the ability to recover patent time lost during the development process.
• Granting some sort of liability protections for drugs deemed of unique public health importance.

Personally, I would be in favor of some of the above proposals as long as they didn't interfere with patient safety and only conferred financial advantages to drug companies. Granting tax incentives and extending patent protections fall into that category.

I don't think that I'd be in favor "streamlining" the approval process or limiting liability for certain drug classes at this point. To me, that can only encourage a lack of conscientiousness and would not promote patient safety.

One general question I have for the drug companies is this. Why aren't antibiotics profitable? In a free market, wouldn't it be reasonable for drug companies to recoup their development costs by simply charging more for those medications? If a course of antibiotics was as expensive as a brief course of some chemotherapeutic agents ($1,000+++) wouldn't the market pay it if there was no other option? Isn't this the essense of supply and demand?

One would think that providers would then conform to established guidelines suggesting when antibiotics are actually indicated. They would then be expected to prescribe the standard first line regimens when indicated reserving these new "big guns" for specific situations.

At any rate, a good review of these issues was presented in this Infectious Diseases Society of America (IDSA) white paper called Bad Bugs, No Drugs.

Update On My Last Entry

Read this article in Medical News Today:

"ViroLogic, utilizing its proprietary eTag(TM) assays will test tumor samples from lung cancer patients treated with Iressa to evaluate the utility of these assays in targeting patients who would most likely benefit from Iressa."

So obviously the people of AstraZeneca read my blog today. They then immediately brokered this deal with ViroLogic to do a cancer biomarker study. Presumably this will facilitate the development of a commercial assay for one or more of the mutations that would be expected to predict a good response to Iressa.

But seriously, two questions:

1) Why didn’t they plan for this in the first place? They knew that these mutations in the epidermal growth factor receptor protein were the likely mediators of the drug’s response. (There must be involvement of other factors as well because the drug does have activity in tumors without the mutation.)

2) More importantly, why are we only now finding that Iressa doesn't do what it's supposed to do (extend life in patients with advanced lung cancer) after it’s already been on the market for almost two years?

Public Citizen vs. FDA and Iressa

Reuters reports on an interesting story that raises a number of issues.

In December of last year, AstraZeneca announced that its drug for treating advanced non-small cell lung cancer, Iressa (gefitinib) failed to increase life expectancy. This is despite the fact that Iressa was demonstrated to actually shrink tumor size. A similar drug, Tarceva (erlotinib) has been shown to prolong life (6.7 months vs. 4.7 months).

Iressa has been marketed in the U.S. under the FDA's "fast track program". It hasn't yet been granted full approval (as Tarceva, also initially fast tracked has). The Public Citizen, a nonprofit consumer advocacy organization, has asked the FDA to ban the drug last week. Their position is that since Tarceva already has a documented benefit, then the availability of Iressa, which does not, will only serve to divert patients from an efficacious therapy.

People with serious life-threatening illnesses (eg. late stage lung cancer) constitute an important lobby and a lot of emotionality surrounds policy regarding their care. One of the reasons for creating a fast track approval system was to increase the armamentarium for such diseases. Many AIDS drugs were initially evaluated on this basis.

That said, the Iressa experience is instructive. Patients and physicians alike (myself included) often don't understand how a drug that causes a clinical response (eg. tumor regression) doesn't prolong life. Unfortunately, this is a common pattern. I remember when Proscar (finasteride) came out for treating benign prostatic hypertrophy (enlarged prostate). The drug was shown to shrink the prostate and promote faster urinary flow rates. Unfortunately, when studied, patients were unable to perceive the improvement and essentially felt that their ability to urinate was unchanged.

It may be that in addition to its tumor shrinking effects, it may have other side-effects that shorten life expectancy. Interstitial lung disease is one possibility and a number of deaths have been attributed to ILD. AstraZeneca states that the incidence of ILD is low (they cite .22% in the U.S.) and that even those cases can't be proven to be due to Iressa. They also note that ILD occasionally can occur with lung cancer anyway.

If Iressa shrinks tumors but doesn't lengthen life (or can't be demonstrated to improve quality of life), then it should be taken off the market. On the other hand, it may be that the study failed to detect a true improvement because it either wasn't powerful enough (didn't have a large enough sample size) or that it was powerful enough but was the victim of an anomaly the statisticians call a type 2 error (another name for bad luck).

A more significant possibility was raised in this article published by the Journal of the National Cancer Institute. Iressa's efficacy appears to be dependent on a mutation in a protein found on some lung cancers. It may be that through statistical chance, the number of tumors studied in their trial didn't have enough of the mutations. If this were so, the Iressa arm wouldn't be expected to show much difference in life expectancy compared with the placebo arm.

An analogous situation would be to do a study testing an antibiotic for say pneumonia against a placebo and finding no benefit because instead of having pneumonia, most of the patients had emphysema instead (for which any antibiotic wouldn't be effective).

I don't have the original data so I can't say for sure. If this is so, then a very good argument can be made for testing tumors for one of the 20 some mutations that may respond to Iressa (assuming that such an assay is commercially available) and limiting treatment to only those that have it. It may be that Iressa is effective against mutations that are unresponsive to Tarceva and vice-versa. If this can be demonstrated then it is reasonable to make both drugs available.

To me the goal of the FDA shouldn't be to complicate the treatment of illness but to increase the availability of proven, efficacious therapies. We don't just need more and more drugs (and more "me too" drugs). We need confidence that the drugs we do have will work and that their benefits outweigh their downsides. We shouldn't simply rubber stamp drugs because they may work. At best this can be a waste of money and at worst, catastrophic.

This is why I believe that even drugs for "hot button" diseases such as breast cancer or any other life-threatening diseases should go through the same methodical, careful evaluation as other drugs. Patients in desperate situations need to be able to enroll in clinical trials designed to evaluate. Drugs without proven efficacy should not be on the market.

As an aside, I should say one thing about Public Citizen. This organization was formed in the 70's by Ralph Nader and is almost reactionary in their zeal to get drugs off the market. I don't know how much of this is true patient advocacy and how much is a general mistrust and dislike of the pharmaceutical industry. See their companion website worstpills.org. They list 182 DO NOT USE drugs. Some of their indications for being on the list are "questionable" to say the least.

Impact of financial remuneration on FDA Advisory Committee voting

I'm not sure how the PDUFA's provisions for mandatory fees paid by drug companies to the FDA constitute a conflict of interest as suggested by GW in a comment. These fees are required to get their drugs into the FDA approval process whether the drug is approved or not.

However, for an FDA advisory committee member evaluating the COX-2 inhibitors, affiliation with Pfizer or Merck appears to constitute a clear conflict of interest. Consider these numbers I extracted from the vote breakdown in one report. If you were one of 10 committee members taking money from Pfizer or Merck,

• You had a 100% probability of supporting Bextra compared with a 35% if you had no such tie.
• You had a 90% probability of supporting Vioxx compared to 36% if you had no such tie.
• If these 10 committee members had abstained from the vote, neither drug would have been approved for marketing.

To suggest that this breakdown occurred by mere chance and had nothing to do with drug company affiliation strains credulity to say the least!

(Celebrex was approved 31 to 1 so the votes of those 10 would have made no difference.)

Conflict of interest in the FDA

So it looks like I was right. There were some previously undisclosed potential conflicts of interest relating to the FDA "endorsement" of the COX-2 inhibitors (Yahoo). Very problematic. If the government and academia doesn't get its act together, the public will have NO reason to trust research results.

Not ambitious enough!

The "Center for Science in the Public Interest" is suing the FDA. They want them to classify salt as a food additive thus giving the feds the ability to control its amounts in food (FOX). Currently salt is considered to be "generally safe" by the FDA and is therefore not subject to such oversight.

Personally, I think this watchdog group is under-reaching. If they had any real strength of conviction, they'd aim to have it classified as a medication so it would only be available by prescription.