How A Big Clinical Trial Made Little Difference
13 CommentsBy Ed Silverman // November 28th, 2008 // 8:36 am
In 2002, one of the biggest clinical trials ever organized by the USl government found that generic high-blood pressure pills, which had been in use since the 1950s and cost only pennies a day, worked better than newer drugs that were up to 20 times as expensive. The implication was that billions of dollars could be saved in treating tens of millions of people with hypertension.
Six years later, though, the use of the pills, called diuretics, is far smaller than some trial organizers had hoped. The percentage of hypertension patients receiving a diuretic rose to around 40 percent in the year after the Allhat results were announced, up from 30 to 35 percent beforehand, The New York Times writes. But usage has plateaued. And over all, use of newer hypertension drugs has grown faster than use of diuretics since 2002, according to Medco Health, a pharmacy benefits manager.
The Allhat experience is worth remembering, the Times points out, as some policy experts and government officials call for more such studies to directly compare drugs or other treatments, as a way to stem runaway medical costs and improve care. The aftereffects of the study show how hard it is to change medical practice, even after a government-sanctioned trial costing $130 million produced what appeared to be solid evidence.
A confluence of factors, the Times writes, blunted the trial’s impact. One was the simple difficulty of persuading docs to change their habits. Another was scientific disagreement, as many academic medical experts criticized the trial’s design and the government’s interpretation of the results. And pharma responded by heavily marketing expensive hypertension drugs - in some cases, paying speakers to publicly interpret the Allhat results in ways that made their products look better.
Usage “should have more than doubled,” Curt Furberg, a public health sciences professor at Wake Forest University who was the first chairman of the steering committee for the study, which was known by the acronym Allhat, tells the Times. “The impact was disappointing..the pharmaceutical industry ganged up and attacked, discredited the findings.” He eventually resigned in frustration as chairman of the study’s steering committee; one member received more than $200,000 from Pfizer, largely in speaking fees, the year after the Allhat results were released.
According to the Times, there was another factor: medicine moves on. Even before Allhat was finished, and since then, new drugs arrived. Others, meanwhile, became available as generics, reducing the cost advantage of the diuretics. And many docs shifted to using two or more drugs together, helped by drugmakers offering combination pills containing two meds.
So Allhat’s main query - which drug to use first became “an outdated question that doesn’t have huge relevance to the majority of people’s clinical practices,” John Flack, the chairman of medicine at Wayne State University, who was not involved in the study and has consulted for some drugmakers, tells the paper.
Sean Tunis, a former chief medical officer for Medicare, remains an advocate for comparative-effectiveness studies. But, as Allhat showed, “they are hard to do, expensive to do and provoke a lot of political pushback,” he tells the paper. He now runs the nonprofit Center for Medical Technology Policy, which tries to arrange such trials.
Nathan
This is really interesting - thanks for the perspective here. It certainly calls into question the value of lots of “comparative efficacy” trials that are being called for these days…
I wonder what the results would have been like in the absence of DTC ads? After drugs have gone generic, they don’t get any DTC ad $$. So even if they are proved to be equally efficatious, that message doesn’t reach the consumer. It would be interesting to see if this study differentially effected the sale of generic diuretics in countries without DTC ads vrs countries with DTC ads.
Dan A.
ALLHAT trial was released over a decade ago, and was the largest hypertension study ever performed, which was largely free of bias and interference that may potentially have altered the results of this trial. ALLHAT specifically showed that thiazide diuretics were superior especially to calcium channel blockers and beta blockers as the preferred class of medication to treat hypertesion, as illustrated by the ability of this class of diuretic to decrease cardiovascular disease.
Of course, and likely, this trial and its results concerned many who historically have profited off of the use of other inferior classes of medications for this particular treatment. So it seems the significance of the ALLHAT trial tacitly atrophied over time possibly to prevent recall of this trial by health care providers. In addition, copious amounts of samples of other classes of HTN medications given to health care providers by their makers assured the continued use of these classes by such providers, although they are clearly inferior based on this trial that potentially should have been more impactful than it was for obvious reasons.
Justice in MI
The article is worth reading in its entirety. One memorable line from Sean Tunis, the comes right after the part that Ed quotes, is:
“There’s a lot of magical thinking,” he said, “that it will all be science and won’t be politics.”
Tunis personally remains committed to Comp Eff Studies.
Generics are unions
In 1995 the JNC V was published, documenting why BBs and diuretics should be first line. I participated in the launch of Ziac, combining the best-selling BB in EU and 6.25mg of HCl. Highest dose has placebo-level side effects with 80% efficacy. Drug didn’t hit $100m in sales. The feedback from doc’s was v telling: I can’t Rx BB & diuretics because of side effects. ACE’s & CCB’s are well-tolerated. This is thee silent killer. Compliance is 1st priority.
Allhat may be all that. Would Rx’ing BB’s & diuretics to Americans decrease morbidity & mortality?! Doubt it. One side effect and Seniors wonder if the corrupt major pharma’s are trying to push one past them. Call their doc and get it switched!
Allhat experts must think US doc’s are stupid. Or, they just haven’t thought this one thru.
Now back the name I used:
If getting union workers to do less for more money is a losing proposition, where are we heading by increasing the share of generics? From Q1 to Q208, VC’s investment into life science dropped in half. Articles quoted VCs as saying their risk/return ratios suggest only the best ideas are investable.
How many years before the Big 3 major pharma’s come to Congress looking for a loan?
Signed,
Wall St Hedge Fd Analyst
(1st priority is to understand macro events & profit from them… not a bias here, just watching Rome smolder and selling fire extinguishers)
Justice in MI
Generics - I don’t follow this part of your post:
“The feedback from doc’s was v telling: I can’t Rx BB & diuretics because of side effects. ACE’s & CCB’s are well-tolerated. This is thee silent killer. Compliance is 1st priority.”
What are/is the “silent killer”? Whose compliance is at issue, docs or pts?
Meg
Dr. Fuhrburg - one of my heroes from an FDA Hearing on placing black box warnings on all the dangerous ADHD drugs. He and Dr. Nissen got their committee to vote yes, much to the shock of the FDA. FDA and Pharma were “saved” however when the Pediatric Advisory Committee voted no, no black box warnings.
Every now and then a reputable doc sticks his/her neck out on one of advisory committees, even if nothing happens in the end.
ol cranky
In truth, I think a lot of GPs routinely prescribe newer, more expensive, drugs so they feel like they’re on the cutting edge and treating their patients in the ‘most up to date” fashion. A lot of this comes from within the docs themselves and not from being detailed by sales reps - the docs, like the average consumer, just automatically think new = better regardless of the truth of the matter. While the pharma companies do their share of bad, too many docs are just plain lazy.
Doc
Ol Cranky,
ALLHAT was a solid study, at release many docs were impressed and started to re-prescribe those standbys, which were dirt cheap. But with no regular push, the BBs and diuretics were doomed.
It wasn’t side effects that killed these drugs, it was thousands of well spoken, well dressed, honorarium toting, meal providing, marketing financed, pharma sales reps using the “Emporer’s new clothes” approach. If you couldn’t see the multitude of benefits from ACEIs, CCBs, ARBs - then you were not fit for your job.
Generics can’t really compete in that environment, and it’s costing us taxpayers mucho dinero.
Justice in MI
Ol Cranky and Doc - Good to “see” you here again; I think it’s been a while (at least for Ol Cranky).
What has struck me about the original article (definitely recommended) is a kind of disconnect between its themes and its substance. The Cardura and Norvasc sagas, the relative suppression of increased relative risk of heart failure and stroke with these newer drugs, is generally overwritten by a narrative of mulitple factors and “life and medicine are complex.” But if you read the article for facts, and ignore the narrative superimposed upon them, I don’t think that’s where you come out.
Just A Thought
Reading this article instantly brought Aggrenox to mind. A couple of compounds combined into a very pricey pill. Someone convinced doctors that it was worthy of replacing aspirin and dipyridamole (which I believe was available in generic form at the time). It’s creation was not exactly the height of R&D.
The industry shouldn’t be taking effective products and making them more costly than they have to be, calling them cutting edge, and pricing them high as if they are something new.
Maybe a diuretic is sufficient for one man- but in prescribing a combo-drug, how can a doctor know? All he can know for sure is that the risks are increased by the addition of another compound.
Still, it looks good on paper. Doctors are getting the hard sell. The FDA approves them. How much research should the family doctor be required to do between patients?
Am I misinformed?
Pharma Newbie
Just a thought– the dosing combination for the aspirin and the dipryidamole was 6 times a day for the same efficacy. Hence the reason for Aggrenox effectiveness is the extend release component. Not an apples to apples comparison, secondly most physicians worth a salt due prescribe a Diuretic first then an ACE and lastly an Arb.
Just A Thought
Pharma Newbie,
It is apples and apples. You can eat a couple of big pricey apples or 4 smaller ones bought at a discount in a 5 pound bag. Ounce for ounce the nutritional value is the same.
Dosing combination = 6 times a day? That’s a reach. If low dose aspirin can be taken in conjunction with dipyridamole (thus Aggrenox) are you dosing the aspirin separately? Come on. The huge cost is not justified for that small level of convenience.
Pharma observer
I too was working on a hypertension launch when ALLHAT was in the field, similar to Generics is Union. Let me clarify what I think GIU is saying (and that I learned when working in this field)
Hypertension is a silent disease, that people don’t know they have until they go to the doctor. I have heard patients talk about that as long as they stay away from “the pressure” (stressful situations) they believe they don’t need medication. A big group of people never pick up their second prescription and another group stop taking their medication before 12 months are up. But meanwhile, their hypertension is still as bad as ever, but they don’t know it. If you add potential side effects - impotence from Beta Blockers and having to go the bathroom all the time (diuretics) - then patients are even more likely to stop taking medication that they don’t believe they need and don’t want to pay for/think they can’t afford to pay for.
Doctors know this and they try to avoid giving medication that patients won’t tolerate well. And now that ACE Inhibitors generics are available, they don’t have to make that trade off - except if their patient is an ACE I cougher (20% approx) …..then they are stuck with the ARBs - the cleanest drug class for treating High Blood Pressure.
So, yes, medicine has moved on. I also do agree that promoting the results would have had a bigger effect. The state of Pennsylvania is experimenting with counter detailing with a program designed by Jerry Avorn - I wonder what their result have been in hypertensio. I do see one article that says they have saved over half a billion dollars in Nexium prescriptions.
http://bulletin.aarp.org/yourhealth/medications/articles/drug_rep_ties_that_bind_1.html