User:MichaelFurrow

From Cyberlaw

Thoughts on class 4.17: Given some of the general consternation surrounding so-called “off-label” uses, I’d just like to talk about certain aspects of the FDA’s drug approval process – and from the perspective of a medicinal chemist (as, in a not too distant former life I was a practicing medicinal chemist at a pharmaceutical company). A cartoonish, birds-eye view: we want to cure a disease (or mitigate some of the adverse symptoms). biologists work to identify proteins (or genes) that are involved and as much of the relevant biological pathway as possible. The chemists then try to identify small molecules that can modulate the state of this pathway [maybe we’ll want to have a drug that can turn a biological process on, maybe we’ll want one that can turn a process off]. However, it is almost a rule that these biological pathways interweave in complex ways, such that modulating one step in the process can have numerous downstream effects. Ok, so say we find a few small molecules that seem to be very effective at modulating this process in in vitro cell models and then in animal models. What we may (and frequently do) learn is that these drug candidates hold promise for a number of disorders/diseases. So, the next question is (assuming we think they’ll be safe and effective – derived from in vitro and animal studies) what indication do we want to seek FDA approval for. This question takes into account the various markets (both size and perceived acceptable pricing) and the expected expenses and durations of the drug approval process for each indication (different clinical endpoints might be easier or harder to reach). It shouldn’t come as any surprise that one very important factor involves making a determination as to which indication will give us the quickest statistical endpoint such that we can get the product to market as quickly as possible. Why do I mention all this? to point out that the vast expense and time commitment of the FDA approval process makes it unrealistic to require approval for each indication. There appeared to be much consternation in class today about “off-label” uses, but the reality is that these off-label uses are essential to medical practice. The FDA has long recognized that many small molecule drug candidates may be effective for multiple indications, and the view seems to be that further efficacy testing is best performed in the clinic. The risk of strong adverse effects is much smaller at that point since the drug has already been through efficacy and safety testing for one indication (although, it’s still possible that a particularly susceptible population will not be identified in the approval process). Also in support of this is the fact that, as implied above, many indications can be supported by the same scientific theory (e.g., modulation of X will have multiple downstream outcomes that may correlate with the indications) [for example, hard though it may be to believe, the underlying science behind the original indication sought for approval of Viagra as a treatment for certain heart conditions also supports it’s use for treating erectile dysfunction]. And the learned intermediaries (Drs) and payors do critically evaluate these theories because they bear much of the risk for pursuing any innovative measures. To a large extent, the hodgepodge of controls that have arisen are simply a random product of the changing landscapes in the areas of medicinal chemistry, medicine, liability, and regulation. To look at the “off-label” uses as different in kind from approved uses is inaccurate and hopefully the above discussion will shed light on why we are willing to allow this regulation window.

Another area that I had a thought on: current high R&D costs for the development of drugs. What are these some of these R&D costs? well, there’re too many to mention, and it’s too complex for a journal comment, but allow me to point out a couple of ones that bear on the cost of research in synthetic organic chemistry (the area of chemistry that the medicinal chemist practices). First, the much increased knowledge about environmental impact and human safety has led to changes to what solvents we use, leading to the use of higher cost, but safer or more environmentally-benign solvents (in some cases) or slowing the rate at which we are able to achieve success in a particular chemical reaction (for lack of ability to use a chemically ideal, but hazardous solvent) what safety equipment is used (running hundreds of fume hoods and exhaust furnaces constantly costs a lot of money) the depth of the in vitro, in vivo and clinical studies Perhaps most important is the fact that we’re tacking more chemically difficult challenges. Synthetic organic chemistry really only reached a level of useful predictability and efficiency about 30 years ago (give or take), and progress has been continuing since. Perhaps another way to put it is that we’ve only been able to justify tackling complex synthetic targets recently because the technology has only become accessible recently. But, making these difficult targets is expensive. some drugs today require in excess of 50 chemical steps to prepare, and each individual step requires extensive experimentation and optimization to arrive at a reproducible and useful result. The labor and material costs are much higher than they were when we were tackling simpler targets. But, the benefit is new medicines and better medicines.

Comment on “me-too” drugs: These seem to be an easy target. One drug company brings a product to market for a new indication. They make money. Other drug companies look at the science: what are the biological targets of the drug, how does the drug interact with these targets, how can use this information to bring an effective competitor drug to market for this indication [of course without violating the IP rights]? The popular view is that just by looking at the competitor’s drugs, we can make little modifications and get similar results (although a good patent attorney will ensure that little modifications are not legally accessible). But, the investment in the synthesis of the drug by the first company does not translate to savings by the next. This is because the reality is that the body treats every different compound, well, differently. A subtle modification can make all the difference (and many of our neurotransmittors are perfect examples of this: they differ in very slight ways, but are treated completely differently by the body, and have completely different effects upon the body). So, to a large extent, the chemist starts from square one again. [In this case, the savings come from bypassing the role of the biologists in identifying targets and pathways.] So, the chemists start making compounds. Lots of compounds. Initially they may start with a structure that bears a resemblance to that of the approved drug (and thus there will be many patent filings on similar structures, and the patent landscape will get crowded quickly), but as the results of in vivo and in vitro studies come in, further modifications are made that may take the structure further from that of the “parent.” Now, I recognize that for some people, there are still problems here. one is that we already have an effective drug on the market, where’s the benefit to bringing more drugs in? Well, the one that I’m sure everyone sees is that of competition and it’s effect on the marketplace in terms of reducing cost. Perhaps that bothers some people because of the perceived piggy-backing upon the R&D of the earlier drugmaker. without postulating as to relative costs of investment, I’ll just offer other reasons why we might not want to discourage this. First, in the process we make many many new compounds. true, most won’t be effective for this pathway, but that doesn’t mean that we won’t find uses for them later (this has happened numerous times). When the biologists are testing compounds for efficacy in a new pathways, they often will screen much or all of the companies library of compounds. [with this in mind, it shouldn’t make some of the class cringe so much when thinking about the fact that all of these compounds are being patented and arguably not being used]. so, new compounds could mean new drugs for other indications. Furthermore, remember the earlier discussion about subtle differences in structure being treated as completely new compounds by the body? well, even when talking about the same indication, we may be able to make huge advances in terms of efficacy or safety (or tolerability). Although generalizing has be overdone today, I would suggest that seeking to improve upon existing technology is merited in many instances where patient quality of life would be implicated. uh, that’s it.

Thoughts on class 4.24: A point about the “compelling” nature/degree of ethical v. legal arguments: it’s certainly understandable given the limitation to 5 minutes, that the legal arguments were limited to interpretation and application of existing law. however, legal arguments can be very emotive, and tend to be when the underlying substantive principles upon which such precedent (including the Constitution) were founded are described. At the substantive level, legal arguments do seem to draw from ethical considerations. For example, Lochner-era constitutional legal imagery had a tendency to frame the individual as small, weak, and in need of protection against the tyranny of an unregulated legislature. This is an expression of the value of individual autonomy, which seemed central to the bioethics debate. This image, of course, is in tension with the view that we have a functioning popular democracy and that the majority, or at least the plurality, view should not be brushed aside without reason (imagery of a judiciary run wild). [Along the lines of what was suggested in class, Gov Bush appears to have perceived that the majority of his constituency held a view on this public politicized case, and he sought to ensure that that voice was given adequate access to our legal system. Although, I do wonder just how the support within his state actually was distributed on this issue.] Of course, our judicial system is not inclined to allow populism to proceed unchecked, affording close review of situations in which the political process might not have functioned properly, including cases where a minority voice lacks appropriate access to the system. This raises an interesting question when one considers the “voice” of a group of people that obviously can only speak through a proxy. The legal imagery in the realm of privacy law is often emotive as well: the pictures that have been painted include Gestapo-like soldiers breaking in your door and charging into the comfort of your bedroom (Griswold gives some sense of this). [just providing further support for the suggestion that legal and ethical arguments can play to emotions with equal effect.]

To generalize about legal, the emotive arguments and imagery that, well, at least I, find most compelling are those that invoke innate fears about our position within this society. Where ethical arguments seem to diverge is this yuck factor. But, what justifications can made for making normative legislative arguments based on the yuck factor? Reinforcing majoritarian values? This again implicates problems with access that was mentioned above. I would love to hear some thoughts on this one.

Epistemological questions that we didn’t really get to: and how can we know what we’d want in Schiavo’s situation, when we’ve never been in that situation? what constitutes brain death? are the external measurable features of such a thing even meaningful, or are we relying more on our imagination of such a thing, as filtered through our, possibly adopted, value system? Check out: http://www.eurekalert.org/pub_releases/2006-04/jaaj-etp042106.php which provides a summary of a study that shows how patients are not good at predicting how they will feel about certain treatments when they are in end-of-life situations -- cutting against the value of advance directives.