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Derek Lowe The 2002 Model

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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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May 3, 2006

Access to Phase I Drugs: A Constitutional Right?

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Posted by Derek

So, as mentioned, the DC Circuit Court of Appeals came down with an interesting ruling (PDF available here). Here's the background of the case, as summarized in the majority opinion:

The Abigail Alliance for Better Access to Developmental Drugs ("the Alliance") seeks to enjoin the Food and Drug Administration ("FDA") from continuing to enforce a policy barring the sale of new drugs that the FDA has determined, after Phase I trials on human beings, are sufficiently safe for expanded human testing (hereafter "post-Phase I investigational new drugs"). More specifically, the Alliance seeks access to potentially life-saving post-Phase I investigational new drugs on behalf of mentally competent, terminally ill adult patients who have no alternative to government approved treatment options . . .

The Alliance contends that the FDA's policy violates the substantive due process rights to privacy, liberty, and life of its terminally ill members. The complaint presents the question of whether the Due Process Clause protects the right of terminally ill patients to decide, without FDA interference, whether to assume the risks of using potentially life-saving investigational new drugs that the FDA has yet to approve for commercial marketing but that the FDA has determined, after Phase I clinical human trials, are safe enough for further testing on a substantial number of human beings. . .

As you may be able to tell from the direction that's taking, the majority opinion says that yes, the FDA does violate due process in these cases. They're reasoning from the Glucksberg case, in which the Supreme Court laid down some guidelines for such claims, but not being a con-law scholar, I'm not qualified to address this line of thinking. They also work from precedents which hold that patients have a due process right to refuse life-saving treatments, and hold that there's a similar right to access potentially life-saving ones. "In both cases", the majority opinion says, "the key is the patient's right to make her decision about her life free from government interference. . .the Alliance seeks for its members the same right of access enjoyed by those terminally ill patients lucky enough to secure a spot in Phase II trials. Accordingly, we hold that the district court erred in dismissing the Alliance's complaint . . ."

I'm torn by this line of reasoning. My libertarian streak likes the talk about being free from government interference, but my drug-industry experience keeps suggesting some practical difficulties. (For one thing, if we're telling the government to get lost, why mandate Phase I trials in the first place?) There's a pretty strong dissenting opinion from the recently-appointed Justice Griffith that goes into these problems. First off, he has a problem with the line of reasoning that the majority used:

. . .It does not help the majority's cause that the Supreme Court has rejected several similar challenges. . .To be sure, the Supreme Court has not addressed the constitutional argument raised by the Alliance. But contrary to the tradition asserted by the majority, there is a tradition of courts rejecting arguments that the Constitution provides an affirmative right of access to particular medical treatments reasonably prohibited by the Government.

It's the last paragraph of his dissent that I find rather persuasive, though:

The majority's new right to procure and use experimental drugs raises a number of vexing questions that are now constitutional issues, potentially insulated from the tug and pull of the political process. If a terminally ill patient has such a right, are patients with serious medical conditions entitled to the benefit of the same logic and corresponding access? If an indigent cannot afford potentially life-saving treatment, would the Constitution mandate access to such care under the right recognized by the majority? Can a patient access any drug . . .if she believes, in consultation with a physician, it is potentially life-saving? Would the majority's right guarantee access to federally-funded stem cell research and treatment? Perhaps most significantly, what potential must a treatment have in order for the Constitution to mandate access? Because the majority does not answer this last question, the District Court faces an impossible task on remand.

These are just the sort of problems that I think are glossed over by Justices Ginsberg and Roberts. Where do we draw the line? There are all sorts of things that make it through Phase I that wipe out in Phase II and beyond for lack of efficacy. It's all very well to talk about potentially life-saving therapies, but that potential is, in many cases, pretty damn well hidden. What sort of Phase I study is enough to trigger this right to treatment? (And who pays for it, for that matter, and how is that figure arrived at?) And it's important to realize that Phase I only studies acute safety, for the most part. Keep in mind that compounds drop out in Phases II and III for safety problems that only showed up in larger samples and longer trials. The threat of lawsuits is bad enough already, with drugs that have made it through a lot more than Phase I. How are we going to fare with even earlier compounds?

Justice Griffith is correct in seeing this as a practice that can only expand. The demand is certainly there. I'm more willing than I was a few years ago to see what a safety-trial-only system for pharmaceuticals would look like, but this isn't, to my mind, the way to get there. We're not running Phase I trials in a such a way that they can stand on their own for drugs to go right into patients - perhaps not even patients that are dying. If we want to change that, let's change it - but from the ground up, not by going through a hybrid regime that might give us the worst of both approaches.

Comments (18) + TrackBacks (0) | Category: Clinical Trials


1. Gyan on May 3, 2006 9:07 PM writes...

For one thing, if we're telling the government to get lost, why mandate Phase I trials in the first place?

For advisory purposes. Companies can be mandated to reveal whether their product has been sent through testing, and what those results were. But the regulatory aspect of controlling access is loosened or removed.

If we want to change that, let's change it - but from the ground up

Come on, that's not happening. Almost all changes are incremental. I wonder what kind of tipping point will be necessary for this proposed foundational change to occur.

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2. qetzal on May 3, 2006 10:09 PM writes...

Interesting to consider how FDA might react to this. Might they become much more reluctant to determine that a drug is "sufficiently safe for expanded human testing" if they know that will make it immediately available? Phase I trials might suddently get much larger and more involved.

And, what about payment? Does this ruling imply that pharma could actually sell the drug to (some) patients post Phase I? Would pharma be willing to do that? Maybe not, given liability considerations.

I see a lot of problematic issues here. Not necessarily insurmountable, but very problematic.

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3. schinderhannes on May 4, 2006 2:00 AM writes...

Has anybody ever thought of what this would mean for the (all evil) drug industry?

Are they supposed to give out those drug for free, or should they sell them to everybody who has not made it into the phase 2 trial groups?

What would they do with clinical data coming from those outside patients? Ignore it? I bet some lawyers would love this, find side efffects in this subgroup that were "ignored" and sue those companies for big time money. Or the company could closely monitor these patients which would be equivalent to including them into their phase 2.

Basically this would mean public demand rather than scientific reasons would determine the size of clinical trials.

I cannot see this happening.

BTW: Do US-citizens have the constitutional right to make pharma companies give them investigational drug? I hope not.....

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4. LNT on May 4, 2006 7:28 AM writes...

One "easier" way to implement the ruling would be to make it easier for patients to "self-enroll" into phase-II/III trials. If the patient wants access to a new experimental drug, fine. Give them the name and number of the coordinator of the clinical trial and they are free to enroll.

(the problem, of course, is that clinical trials are designed to be on a very controled population set -- if people are free to enroll in any clinical trial they want, then we loose control over "defining" the population set that we need to test)

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5. Felix on May 4, 2006 7:35 AM writes...

"A right of control over one’s body has deep roots in the common law. The venerable commentator on the common law William Blackstone wrote that the right to “personal security” includes “a person’s legal and uninterrupted enjoyment of his life, his limbs, his body, [and] his health,”."

Gee, I wish the REST of our Govt. could figure this out and start PROTECTING a woman's right to choose instead of using the issue as a perpetual "whipping boy" for demagogs.

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6. RKN on May 4, 2006 7:35 AM writes...

I agree with Gyan: phased drug trials don't benefit the FDA, ostensibly they benefit doctors and the patients who rely on their advice. Trials make sense regardless of the FDA.

The systemic changes required here have to do with absolving drug makers from devastating lawsuits when things don't go well for people who were desperate to try a drug before safety and efficacy trials were complete. Unfortunately, I doubt very many people are willing to accept this amount of personal responsibility when making decisions for themselves, so I'm not holding my breath.

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7. Paul Parry on May 4, 2006 8:01 AM writes...

(Full disclosure: I'm with the Abigail Alliance, which brought this suit.)

Yes, the dissent raised a lot of interesting and anxiety-ridden questions, but the majorty opinion addressed them fully in the footnotes. The right here is limited to "self-preservation" -- that the government can't deny access to potentially life-saving drugs for patients who face certain death without them, especially if those drugs are already undergoing widespread testing in other patients. There's no slippery slope to unapproved cosmetic drugs or medical marijuana, because there's no allegation that those products could save lives.

In some Phase 1 trials such as Gleevec, the potential to save lives is as clear as day, yet it was three years before CML patients could get Gleevec outside of trials. Many other Phase 1 trials do not explore and/or do not show the potential to save lives -- we don't expect those drugs to meet this threshold, and that's a line that either the lower court (or hopefully the FDA sooner) will need to draw.

The decision says that government can't stand in the way of life-saving aid willingly given from one party to another. That would indicate that companies can't be compelled to do anything, but doesn't address whether they can charge for the drugs or require strict informed consent and liability waivers. That, too, will need to be addressed either by the court or the FDA.

This does not throw out the three-phase system by any means. The FDA could honor this right by tweaking existing "compassionate use" mechanisms (as ASCO and NCCS proposed last month), or they could mandate a new level of limited conditional approval for these drugs (which we proposed to the FDA in 2003, and because they didn't respond within 180 days, we were allowed to bring this suit).

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8. Patri Friedman on May 4, 2006 1:04 PM writes...

The whole argument of your last two paragraphs assumes that a patient and doctor together cannot reasonably assess the cost benefit. Pointing out that Phase I does not ensure safety is very different from saying that allowing access to Phase I drugs is unsafe. The latter only follows from the former if patient+doctor are believed to be incompetent to assess the best course of action.

Of course, this is pretty much the attitude our government usually shows, so it's no surprise. But to those of us whose libertarian streaks are a bit more pronounced, the argument is not exactly convincing.

More information leads to better decisions. But that is very, very different from saying that decisions made with little information are net negatives. Given that "do nothing" is always an option, as long as you have a reasonable feel for the distribution and likelihood of outcomes, you can decide to take a drug only if you and your doctor feel it is a positive-expected-value gamble.

So a prohibition on medecines only does net good if the average decision made by a doctor+patient is a net negative, ie if the average EV is negative. I have an awfully tough time believing that, when someone's health is at stake, their average decision would be that bad.

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9. Jim Hu on May 4, 2006 1:38 PM writes...

IANAL, but my sense is that (as Paul Parry notes above) the decision is a lot narrower than how it's being covered. When I looked at the pdf last night, it seemed like the appeals court is only telling the lower court that they can't dismiss the case without examining the circumstances just on the principle that "we're the FDA, we can do anything to regulate drugs". The decision leaves the door open for FDA to assert a compelling government interest for restricting access, even to these terminal patients. It just has to explain what that interest is.

The majority also took care to address the slippery slope arguments. They're arguing that this ONLY applies to life-saving situations...not even to quality of end-of-life. They specifically said that this would not address medical pot, for example.

The requirement for life-or-death situations means that this particular decision only addresses abortion law insofar as a) life of the mother is at stake and b) compelling government interest fails. If anything, the life-or-death exemptions to normal rules of law might be argued as supporting a pro-life position (imposition on the rights of the mother is justified on behalf of the fetus), IFF one accepts that the fetus has that right to life (regardless of the personal beliefs of prolifers, I don't think that argument flies with current law - again IANAL)...which brings us back to where the abortion debate always goes: when are fetuses people?

For terminal patients, on the other hand, it's hard for me to see the compelling interest to keep people from being able to do voluntary transactions with long as this doesn't transmogrify into a right to have insurance or government pay for it, or a right to sue if the efficacy isn't there after all. Perhaps the FDA will make an actual argument and change my mind.

BTW, am I the only one who can't get corante to write a cookie for me at pipeline?

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10. Andrea Gallagher on May 4, 2006 2:45 PM writes...

I think the messiness this adds to clinical trial data is an interesting problem.

Could pharmas look to other statistical / methodology techniques to make good use of the data they get back from these patients? My lay-persons understanding is that bayesian statistics could allow you to have an additional result value that includes these data points, adjusted based on the patient's closeness to the core trial selection criteria.

The liability issue, of course, then lies in trying to get a jury to grasp advanced statistics...

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11. Kir Zila on May 4, 2006 4:16 PM writes...

Pharmaceutical pipeline is one of the most attractive titles in the industry. Everybody is looking for a complete and cheap source of data. The trick is you can get the whole pipeline for Glaxo or Pfizer but you cannot get the whole data for let's say diabetes. First you must search which companies do something in the area and then look for their drugs in development.

is a database with over 3 000 records of drugs in development of more than 600 companies. And guess what - you can have a subscription for half an hour that costs only 20 USD and 30 minutes is more than enough to find what you are looking for. So there is no necessity to pay lets say 500 USD for monthly subscription.


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12. Clark on May 4, 2006 4:53 PM writes...

**This does not throw out the three-phase system by any means.**

Maybe not - but it definitely de-incentivizes the company from working expeditiously through the FDA trials. If you can sell the drug anyway ... .

Maybe insurance reimbursement will provide the incentive? Maybe we should put legal incentives in place (e.g. patent extension of some sort?)? But regardless there is reason to be concerned.

Other issues (some related):

a) Will the drug companies change the way they do Ph I trials so as to allow themselves to get compassionate use, but in the process damage the normal use of ph 1 trials (dose ranging, patient population)

b) Will drug companies focus more on lethal diseases and less on non-lethal?

c) What is 'lethal'? Heart disease? Diabetes? Lupus? PAD? Asthma? ED?

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13. Dave Meleney on May 4, 2006 7:08 PM writes...

What, the darn plaintiff wants dying folk (who have run out of options) to be able to use drugs that are only proven somewhat safe....and they want to do this without us first having cleaned up the mess of nasty folk who often sue pharma wrongly and the judges who enable it? ! !

With all the billions pharma spends on television and magazine advertising...when will they get together some funds to plead their case for legal sanity here...?

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14. srp on May 4, 2006 7:21 PM writes...

This ruling is interesting because the principle behind it, despite the majority's assurances, may be extended in future cases with different fact patterns. For example, if you are subject to excruciating pain or the onset of permanent paralysis rather than death, would it be reasonable to block access to an experimental drug that might help?

Obviously, it would be preferable to reform our system of drug regulation in a methodical way. Well-informed and trustworthy people would develop a new regulatory regime including various options, we would experiment with those options, gather data, and then home in on a final setup. But you might as well wish for the tooth fairy, or to live in an alternate reality, because American politics never works that way, for obvious reasons.

I continue to think that the best system would involve certification rather than licensing of drugs, with the government being one of any number of competing certifiers (there should be free entry). That way, competition would work to improve the scientific assessment process as well as the pharmaceuticals themselves. Short of that, we ought to be allowed to get access to any drug approved in the U.K. (and maybe Germany), so as to get some kind of competitive reality check on our technocrats.

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15. PandaFan on May 5, 2006 10:23 AM writes...

Given the last comment, it is worth pointing out that the current FDA regulations are largely driven by reaction to serious pharmaceutical disasters -- and the most famous of these involved a drug approved for use in Europe...

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16. Paul Parry on May 5, 2006 10:48 AM writes...

Maybe not - but it definitely de-incentivizes the company from working expeditiously through the FDA trials. If you can sell the drug anyway ...

That's still in the air. The lower court will have to decide if this right extends to sales or only to Pharma charity. But even if it does allow sales, it would only be to refractory patients who've already tried everything else and can't get into a clinical trial. Not much of a market there... they'll still have a huge incentive to go for full approval as a first line therapy.

It will certainly lead to changes in how randomized trials are designed. I'd guess that there would be more use of advanced Bayesian statistics on self-selected populations, and fewer "reject the prior-stated null hypothesis" studies that have limited enrollment because of the need for strict eligibility criteria. And if all willing patients are studied and the data sorted out based on known characteristics, it means they'll collect more data faster, and know sooner about efficacy and safety in truly life-saving drugs.
However, in cases where a drug's effectiveness is so marginal that it could only be seen in p-values against a placebo and not in clinical practice, that drug will have a harder time getting approved than it would today. Probably not a bad thing form the perspective of medical progress.

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17. Jonathan Robinson on May 5, 2006 8:15 PM writes...

Probably not a bad thing either that it could guide to more work on lethal diseases and less on DTC product candidates.


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18. srp on May 6, 2006 4:30 AM writes...

Pandafan: There is a myth that the thalidomide case was rationally related to efficacy testing. There was a political linkage, because the pro-regulation side used the case to create an unjustified panic, but the problems with thalidomide had everything to do with safety and nothing to do with efficacy.

Furthermore, there is a huge bias among legislators, regulators, and apparently folks such as yourself to overweight highly publicized cases of bad drugs approved and underweight unpublicized cases of good drugs kept off the market (both directly and through deterrence due to costs).

There is no systematic evidence that regulation improves our overall health. Alex Tabarrok has shown that off-label uses of drugs are no worse than on-label uses in terms of safety and efficacy, even though these off-label uses are non-regulated. Derek has pointed out that aspirin couldn't make it even to a trial today, yet it is one of the best and most versatile drugs we have. (My doctor just recommended that I take it every day, and not at baby-aspirin doses, because they just figured out that it reduces heart disease by reducing inflamation as well as by anticoagulation.)

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