Patients vs. Proof: Are Clinical Trials Ethical?

NYT had an interesting article last weekend about a promising new melanoma drug that was in clinical trials right now – profiling a pair of cousins in the trial, one who got the drug and one who didn’t get it. And couldn’t get it, despite the fact that it seemed to be helping. What an ethical pandora’s box we have here!The core dilemma:
In order to really know that a drug is both safe and effective, we have to do controlled clinical trials with a lot of patients – and to do these trials, we need a control group. Sick patients who aren’t getting the drug.

If we have a drug that shows great promise, it seems unethical to deny it to half of the patients. But at the same time, we can’t prove that it’s really a good drug without doing so, so ultimately, we get a great benefit as a population by making that “sacrifice” of some patients in the trial. It would be true if people were lab rats – but they’re not. Every patient is somebody’s kid, parent, sibling, etc.

So what can we do??

The regulatory pieces:
Besides just being good science/ arguably the best policy in terms of only spending healthcare dollars on treatments that actually work, companies do these trials because that’s what the FDA requires to approve the drug. And without FDA approval, the company can’t market the drug. If they can’t market it, they can’t make any money off it.

There is, however, an exception: a drug that shows great promise can be offered BY THE COMPANY that made it for “compassionate use,” or “treatment use,” that is, use, prior to approval. But this creates a problem: who would want to be in the study, where they might be in the control group and not get the drug, if it were available outside of the study context? Companies generally have little incentive to offer investigational drugs to non-trial patients, because they need approval to market the drug, and if they can’t market the drug, they can’t make any money, which pays for research and development, so. . . nobody would ever make new drugs.

How can we fix this:

Dad: I think a lot depends on the clinical trial design. Many have cross-over provisions if the patients don’t respond (i.e. if they get placebo). They can then get the “active” drug.   This is difficult in the case of cancer in which the time frames are long and the endpoints are generally  survival based.

Nurse: Although survival is certainly not the only benchmark for a drug’s success, especially in cancer. There’s a lot of discussion in evidence-based medicine about whether interventions increase survival, which is great, but it’s only one piece of the puzzle.

Lawyer: How does that work, though? Do they just put a check in the “didn’t work” box after the patient doesn’t respond in a fixed time-frame?

Why shouldn’t we just allow free access or marketing, as long as it’s clear that we don’t know for sure whether this works, once we’ve been through basic safety trials? In other words, if we think it’s safe, should the FDA, either directly or through the incentives they create, stand in the way of more sick patients being able to get the drug?

Nurse: Well, isn’t part of the FDA’s mandate to protect the public from totally bogus nonsense? I mean, think about supplements not regulated by the FDA and how much confusion that generates.

Dad: Safety has not been demonstrated for this drug. The Phase I trial was only 31 patients. Often, it takes thousands or more to identify serious safety concerns. This happened with Remicade [a drug Dad was instrumentally involved in. Or dare we say, invented.]

Nurse: That’s good to know/remember. This article, with its approach of profiling two specific patients, kind of mirrored (and encouraged) the public reaction to promising advances– as in, they have to have it and they have to have it now– when they may be jumping the gun. The article mentioned a promising breast cancer treatment from years ago that didn’t pan out. That happens, and I think that people may be a little misled and also may be unable to judge well if they are really starved for a crumb of hope.

Lawyer: What do they do with treatments for really rare diseases? Where the prospects of finding thousands of patients in a decent time frame isn’t so good?

Nurse: Also, as medical doctors, (even though they are researchers), shouldn’t they have some level of concern for patients as opposed to solely for data? At some point, shouldn’t we place patients’ well-being or relief of suffering above perfect data?

Dad: Then you would never find out if it really worked, and it would cost everyone a lot of money.

Nurse: Well but that’s where a crossover type design could be helpful. I think it’s inhuman to say to a patient, “we’re sorry, even though you are clearly deteriorating rapidly and your tumors are getting bigger, we refuse to try any other treatment because we might sully our results.”  And sure, it’s great if we prove that the drug increases survival, but if we have a fair amount of evidence (even if it’s not perfect evidence) that it has some beneficial effects, isn’t that good too? Why does death have to be the endpoint? That seems like a problematic element in the design.

Nurse: I wonder if there’s a way to do a retrospective study that would give us some insight– look at previous patients who received the chemo as a control. It’s not perfect, but perhaps it’s necessary from an ethical standpoint.

Lawyer: And don’t we already use lots of treatments that are FDA-approved, but really don’t work very well? They’re just the best we’ve got? I guess the question here is, are these better or worse than existing treatments? If we’re trying to improve, we need to know if we are — or not.

Supreme Court Score Card

Well, the good people of SCOTUS just wrapped up their term and now get a nice long summer vacation. (Or a long rest-of-life vacation, if you’re Justice Souter.) But nurse & lawyer are still hard at work! Of the 83 cases decided by the Supreme Court this term, these lucky 7 addressed health care-type issues. For the next week, Lawyer will review one case each day with a brief summary and an even briefer opinion!

Wyeth v. Levine: Oooh, remember this one from the early days of Nurse & Lawyer? The question was whether a drug company could be sued for damage caused by the on-label use of an approved drug. (In other words, for insufficient warnings on the label.) The drug company says that being FDA-approved should give them protection. But the patient – who lost an arm, by the way, to a gnarly infection — prevailed! The FDA requirements represent a MINIMUM – and are not sufficient to get the manufacturer off the hook.

Lawyer says: Patient Protection Win!

The Vermont Crackdown

Vermont has been busy passing a law that restricts gifts to doctors (and nurses and pharmacists and hospitals) from drug and medical device companies, and requires them to report all gifts they receive that ARE still allowed. A few other states have laws to this effect, but this one seems to be the toughest.

Lawyer says: bravo Vermont! One of the best ways to work on big problems is to expose them to the sunlight — if this business has to be conducted out in the open, it will have to be conducted more cleanly.

The New York Times reports that the Pharmaceutical Research and Manufacturers of America  (PhRMA) has a code that companies can voluntarily sign that prohibits gifts that aren’t educational and places some restriction on meals.  Apparently PhRMA objects to Vermont’s law because… it’s redundant? And will waste doctors’ and companies’ time?

Well, PhRMA, I’m glad you have a code. That’s a good step. But come on!The code limits some types of gifts, and the law limits others. It also does something the code does not: requires reporting of things that continue to be allowed. Reporting requirements are, if you ask me, the best way to fix this problem. It encourages both good behavior on the part of doctors and pharma companies, AND  it can create public investment in and awareness of the process – very important where healthcare is concerned.  In addition, unlike the code, the law applies to everyone in the state  – not all pharama companies have signed the code.

Side note: previous regulations (and those that still stand in many places) allow large gifts to slip through, protected as trade secrets. Last time I checked, shady business practices (i.e. bribery) were not legitimate trade secrets that would allow other companies access to proprietary information about a company’s inventions.  Close the loophole!

Patients have a right to unbiased care. Vermont is helping them get that. Way to go, Vermont.

Advertising Woes

Lawyer says:

You may have seen them: the TV ads for birth control pill Yaz that explicitly state that the FDA has asked the company that makes it, Bayer, to correct their previous advertising. Or, like me, you may have missed all that until the New York Times ran this aritcle about the campaign. But either way, it’s a rare occurrence, and an interesting one. The FDA has stepped in and said no, you can’t run these ads, they are too misleading, overstating benefits and understating risks. And though I don’t know that Yaz was especially worse than any other drug, the intervention was overdue.

While there is a part of me that wants to defend Yaz to the end because it shares a name with one of the great heroes of the best baseball team ever, the rest of me says, good. While requiring a corrective ad campaign is far from ideal, paying more attention to direct-to-consumer marketing of drugs is a big step forward.

Since when were drugs — prescription medications with complex risks and benefits — like cars, products from which people could just choose the particular features they found most appealing and then pull out their checkbooks? I’m all for information being made available to consumers. After all, we’ve all seen those pens, calenders, notepads, luxury travel, and hefty speaking fees that doctors get from pharmaceutical companies hoping to put their brand names on the tips of professional tongues, and no patient wants it to be swag that causes their doctor to recommend one drug over another. (Did I hear a rumor about that coming to an end?) But advertising isn’t the way to do it. The information is out there — the NIH and the National Library of Medicine sponsor a website called Medline plus that provides information about just about every prescription and over-the-counter medication that’s out there — but it isn’t put in friendly terms with cute, smiling girls and couples frolicking on the beach. It isn’t interrupting American Idol or whatever else is on these days. (That’s right. I don’t have cable. The TV hasn’t actually been turned on in… I don’t know. A while.)

The point is, direct-to-consumer marketing of pharmaceuticals needs more oversight — BEFORE the ads reach millions of viewers who don’t have the time or expertise to sift through all the technical information themselves. And drug companies should no longer be allowed to woo doctors with the sorts of perks that raise eyebrows all over Washington when they involve lawmakers, which will allow drugs to speak for themselves.

Thoughts? Information about limitations on the wooing of physicians?