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DBL%20Hendrix%20small.png College chemistry, 1983

Derek Lowe The 2002 Model

Dbl%20new%20portrait%20B%26W.png After 10 years of blogging. . .

Derek Lowe, an Arkansan by birth, got his BA from Hendrix College and his PhD in organic chemistry from Duke before spending time in Germany on a Humboldt Fellowship on his post-doc. He's worked for several major pharmaceutical companies since 1989 on drug discovery projects against schizophrenia, Alzheimer's, diabetes, osteoporosis and other diseases. To contact Derek email him directly: Twitter: Dereklowe

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December 2, 2011

Not Just FDA-Bashing?

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Posted by Derek

There have been a lot of complaints about the FDA over the years, from all sorts of people. Many of these complaints are, well, incompatible: there are those who feel that the agency is letting too many bad compounds through, and not keeping a close enough eye on drug companies and their marketing departments. Then there's another vocal contingent that think that the agency is stifling innovation with overbearing regulations. Those can't both be right.

I'm at neither end of this spectrum. I think that we need an FDA, and that its purview should be roughly what it is now. That is, I think that the agency should require proof of safety and efficacy for marketed drugs, and that this proof should include rigorous clinical trials. I think that it should, in fact, make sure that drug companies don't go too far in their efforts to market their compounds, with "too far" to be determined (as it is now) by continuous wrangling. But I don't mean to suggest that the agency is doing all of its jobs optimally, or that it couldn't think of new ways to fulfill its mission.

Here's an example, a column in Bio-IT World that (at first glance) comes across as just more FDA-hammering. But there are some interesting ideas, once you get past the boilerplate. Such as:

While wholesale FDA reform is needed, doing it right would entail a monumental effort that could take years. But there are modest steps we can take in the meantime. How about carving out one or more FDA-free Enterprise Zones where doctors, scientists, and volunteer patients can make their own decisions unfettered by the heavy hand of regulators? Imagine an experimental terminal-illness wing of the Cleveland Clinic where informed consent was the only law. How hard would it be to draft enabling legislation?

Defenders of the FDA’s prerogatives would fight such proposals tooth and nail. But what kind of nanny state arguments can be made against conducting such a policy experiment when anyone who objects doesn’t have to be treated? Breakthroughs that emerge would still have to pass through the FDA gantlet before they would be generally available. The difference is that researchers could continue making improvements while treating volunteers during this long process.

Now, it's fair to ask how heavy the hand of regulation is in the case of terminal illnesses. We already have an awful lot of unusual therapies being tried in such situations. But could we accomplish more under these proposed conditions? Should we? I invite debate in the comments.

Comments (23) + TrackBacks (0) | Category: Regulatory Affairs


1. Chemjobber on December 2, 2011 1:29 PM writes...

It will be important to come up with something better than "FDA-free Enterprise Zones" -- I suggest "Hamsterdam."

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2. Anonymous on December 2, 2011 1:34 PM writes...

The major problem with this approach is that for every true doctor/scientist collaboration you'd have about a thousand quacks selling magic crystals and water to terminal patients. All this would do is make the quacks even harder to get rid of.

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3. Josh on December 2, 2011 1:47 PM writes...

@anonymous I dont think there would be much selling going on.

Limited to volunteers right?

One issue I can see would be the terrible end result where the terminally ill patient ends up dying, and we have a de facto assisted suicide case on our hands.

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4. J.S. Boc on December 2, 2011 1:48 PM writes...


Seconded, provided that Herc and Carver monitor the border of said zone.

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5. Hap on December 2, 2011 2:01 PM writes...

It might work, but I'm not sure. 1)Informed consent has already been noted to be problematic - while it's what we have (if we can't take responsibility for ourselves, no one else can), informed consent for dataless therapies might attract the sketchy. 2) Small companies with less to lose in reputation for a failure (or rather less invested in their name) are most likely to take up the gauntlet - while they are where good things can start, they are also home to the pump-and-dump set. 3) Patient groups would have a much bigger hammer to get therapies out - it would be harder for them to use the FDA as an excuse for not expanding a trial if there is a way around the FDA.

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6. opsomath on December 2, 2011 2:07 PM writes...

Considering that this group would be so largely made up of people diagnosed with terminal illnesses, it's hard to make the case for a really big downside here.

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7. Biotechtranslated on December 2, 2011 2:14 PM writes...


I'm a little confused as to what the benefit of an "FDA-free Enterprise Zone" would be.

The FDA already has compassionate use exemptions available for promising therapies, so it's not like we need a new mechanism to get promising drugs to patients in desperate need of them.

Would it have a benefit in development? I suppose you could try and run a clinical trial on a small number of patients, but would you get any information out of it?

You'd still have to ensure the drugs are safe (pre-clinical), so I suppose you could skip Phase I (but maybe not, you do need the PK data!). Since you can already treat patients with disease in Phase II, you're not really speeding things up much.

I guess you could set lower hurdles for pre-clinical and Phase I data so that patients with disease could get therapies earlier on. But the problem there is that the patient population would be so small and only include those where the risk/benefit trade-off is worthwhile (terminal diseases with no effective treatments).

I'm all for finding ways to make the FDA more efficient, but I'm not sure this idea is all that great.


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8. opsomath on December 2, 2011 2:23 PM writes...

@ #7 - I'm guessing one thing that would happen in such zones is off-label use of existing drugs, so that safety data would be well established.

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9. Lu on December 2, 2011 2:27 PM writes...

FDA-free Enterprise Zones... experimental terminal-illness wing ...

Isn't it what Burzynski is doing?

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10. Polycom on December 2, 2011 2:28 PM writes...

@#8 - Why is an FDA-free zone needed for off-label use of approved drugs? Physicians are already free to use their judgement in this way (with patient consent).

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11. Polycom on December 2, 2011 2:30 PM writes...

@#8 - Why is an FDA-free zone needed for off-label use of approved drugs? Physicians are already free to use their judgement in this way (with patient consent).

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12. leftscienceawhileago on December 2, 2011 2:42 PM writes...

One area that isn't really clear to me is how much influence do politicians really have what should be objective decisions by the FDA?

Two examples spring to mind:

1)The FDA banning the use of stevia (a plant based low-cal sweetener) in 1991 in contradiction of its own guidelines for applying the GRAS label.

2)The 2006 FDA decision to age limit OTC sales of Plan B.

I've always wanted to hear a soundly worded opinion as to how much politics plays a role in FDA decisions, especially in the above cases. I believe there was a recent ruling on 2) that supported the idea that there was a an intentional delay imposed in extending access for political appeasement.

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13. RM on December 2, 2011 3:25 PM writes...

there are those who feel that the agency is letting too many bad compounds through, and not keeping a close enough eye on drug companies and their marketing departments. Then there's another vocal contingent that think that the agency is stifling innovation with overbearing regulations. Those can't both be right.

Actually, they can be (though I can't say if they actually are right).

For example, you can have a situation where the FDA regulations for vital treatment areas like antibiotics and cancer treatments, or for new classes of compounds are overbearing and stifling innovation, but where the regulations for lifestyle drugs and "me too"/patent extending knock-on drugs are too lax, letting a host of bad drugs through. (Think of an absolute ban on any drug with a 0.1% mortality rate from the drug itself. A great regulation when applied to arthritis medication, but devastating for chemotherapies, where reducing a 50% mortality to a 10% mortality from cancer far outweighs an extra 5% mortality from the drug itself.)

You can also have a situation where regulations to bring a drug to market are onerous and stifling, but once approved the tables flip, imposing overbearing and stifling regulations on those seeking to remove a dangerous drug from market or to stop deceptive advertising practices.

Again, I don't know if it is really the case, but we shouldn't make the mistake of thinking that regulation is some sort of linear continuum, where "too much" and "not enough" are the only ways to fail.

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14. Allison on December 2, 2011 4:50 PM writes...

Hm, it's an interesting idea. My one concern would be implementing it in the current health care climate in the US. Lots of people don't have access to the solutions that do exist (whatever you think the answer to that might be, and I know I differ from Derek in this regard). So, it would worry me that an "FDA-free zone" would become a situation where those without access to the current standard of care become experimental subjects. And, maybe good stuff comes out of it, and so people turn a blind eye to the ethical questions.

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15. LuWe on December 2, 2011 5:41 PM writes...

I like the idea of an aside wing for experimental treatments but do agree that this would open the door for more malpractice. I would propose multiple treatment wings (as opposed to the black and white FDA Approved vs. Non-Approved wings)where each wing might allow varrying levels of FDA approval. For example, treatments in each phase of clinical trials (I-IV) may be given their own 'wing' or voluntarily utalized by pateints who provide the nessecary consent. Maybe insurence companies could even be influenced to a portion of treatments comeing from the later stage trial categories...

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16. Dave on December 2, 2011 11:44 PM writes...

Having been in the extreme stress of a major health crisis the idea that "informed consent" is possible is at best partially true and in many cases not possible. I believe my IQ probably dropped 30 points and I had virtually no short term memory. "Ms Jones your baby has a 30% chance of survival but with my magic jelly beans (at $12,000 a pop), I believe we can improve that to 80%. Ms Jones, do you love your baby?"
Picture a high school drop out age 63 who doesn't know the difference between a kidney and a liver. Knows nothing about type I and II errors, clinical trials, placebo effect, confirmation bias. We, as a society, think that she is able to exercise informed consent? With no constraints? Really? I don't think so. But then many if not most of us here are able to understand the issues and perhaps even (somewhat doubtful) better deal with the emotional baggage and expectations involved. Such a Free Enterprise zone is bound to attract massive abuse. So how do you insure informed consent and how do you prevent abuse at the same time making the environment useful for (non-randomized) trials and protecting the pharmaceutical companies and the doctor from the inevitable lawsuits?
How do you prevent "Used at Cleveland Clinic to save Joey's life" claims? Sick people are desperate. Many are not rational. Caveat Emptor?
I'm generally against the nanny state. But this is clearly an area where society needs to ensure that the vulnerable are not taken advantage of. Government needs to be involved. Perhaps just local boards to review protocols? But then how will it differ from the status quo? And who will watch the watchers? The State Medical Board, maybe? LOL

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17. Wile E. Coyote, Genius on December 3, 2011 10:29 AM writes...

@16 Dave: You scare me when you say "the government must be involved". I agree that informed consent is not optimal, and that many cannot understand it. Instead of the government being out protectorate and deciding what is best for us, why not this. Go to your physician for treatment. Have him explain the informed consent. If you do not understand it, get a second opinion or further advice from a second physician. How about have the one treat you and the second physician act as your advocate? Sounds much better to me than to have the government make the decisions. We know how well government does at making decisions (just looks at the Fast and Furious brainchild - now there's some true genius - dripping with sarcasm).

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18. Fred on December 3, 2011 1:31 PM writes...

#12 has the best post-- the FDA is not always unfettered by politics.

Beyond that, I think MOST would agree they are too strict. Vioxx and, also, how they have essentially brutalized the obesity market by setting the safety bar ridiculously high are ample evidence.

Points to consider:

1) The FDA has other important roles. Plant inspection. You can hardly be "too" strict there.
2) The FDA only approves for disease states. If you invent a magic pill for Ray Kurzweil that will stop the human aging process cold-- the FDA has no mechanism to review it, I believe.
3) The FDA does a POOR job with biologicals. Lack of clear standards on bioequivalents has been BAD for those of us who see the clear benefits of small moelcules vs high side-effect, expensive, injectable-only biologicals.

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19. Doglotion on December 3, 2011 3:55 PM writes...

I don’t think this idea has a lot of merit. As noted above, terminally ill patients already have access to many experimental therapies through compassionate use programs. But CUP data is almost always viewed as anecdotal and is not given much weight – the population is too heterogeneous, too sick in most cases, and dosing is open-label with no placebo control.

Perhaps more importantly, decision-makers in pharma these days are itching to find reasons to kill programs. Most everyone realizes this, and takes great care to structure exploratory/POC trials so they have the greatest possible chance of success - that is, use the patient population most likely to respond. No project team in their right mind would want to run a Ph Ib/IIa trial in terminally ill patients, the most likely outcome would be no signal and the project gets canned. So I don’t think anyone would use this option even if it existed.

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20. cliffintokyo on December 5, 2011 4:19 AM writes...

Great discussion.
Numerous examples, (most recent, overprescribing of ADHD drugs to children, including OMG babies under 12 months of age) have shown that altruism is dead in the medical community in the US, and probably a lot of other places too.
Therefore have to conclude that FDA strict policy on trying out unusual therapies is about right.
Uninformed, uneducated, ESL, and potential subjects located overseas need to be protected.

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21. passionlessDrone on December 5, 2011 9:47 AM writes...

#1 Chemjobber for the win!.

- pD

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22. Ella on December 5, 2011 12:06 PM writes...

I've been reading you for quite some time now. Informative, intellectual, entertaining, and sometimes funny as hell -- just what I enjoy! Cheers!

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23. Vader on December 6, 2011 1:47 PM writes...

The biggest reform FDA needs is to have its authority restored to regulate homeopathic, naturopathic, and other "alternative" medicines.

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