Below, a testimonial by Ana Cantu who was one of the healthy volunteers –"a human guinea pig" as she describes herself– in a month long study that tested the effects of Norvir, an HIV drug made by Abbott Laboratories, when coupled with the antidepressant Wellbutrin, made by GlaxoSmithKline."

Her first-hand experience provides insight about the immense "pressure for positive results in clinical trials," the level of discomfort a human subject is expected to endure from the adverse effects of the tested drug (or combination of drugs), and the dilemma for drug manufacturers whose drug causes adverse effects so severe, the test subjects in pre-marketing trials drop out in droves.  The FDA accepts study results–even if only 7 of 20 subjects complete the study. Companies are loathe to scrap a negative study: they hold on to the last 7 subjects despite severe adverse effects. The "volunteers" suffer for the payment which they would forfeit if they quit. 

Ana describes how and why corporate sponsors–in her case, GSK and Abbott Labs–conceal adverse event data that may damage a drug’s chances for approval.

Despite federal law requiring companies to fully disclose to the FDA all adverse events in pre-marketing clinical trials, drug companies have repeatedly violated the law with impunity: they have failed to include in their submission of data to the FDA, the worst adverse events suffered by subjects who, as a result, dropped out of the trials.

Her observations, published in The American Statesman (below) are disturbing and insightful:

"The study started out with 20 subjects, but 6 were eliminated during the in-patient stay by the drug company sponsoring the trial for various reasons (including drinking caffeine within 24 hours of check-in). For about a week, there were 14 subjects. Then they started dropping. The first one to go was a girl with a pronounced Texas twang named Denise, who had severe jaw and tooth pain. Then extreme nausea and emesis (the clinical term for vomiting, I discovered) claimed April. Jo Kay, Paula, Amy, Alyssa and Carrie went one after another. Now we’re down to 7."

Ana experienced severe black outs–clearly an adverse effect of the experimental drug–but she was kept in the trial against her best interest:

"The day got off to a bumpy start when I started to black out while reporting my side effects. Darkness closed in from my peripheral vision and then I saw nothing but big colored spots.
"That morning, we were standing around in the cafeteria waiting to dose. All of a sudden, I couldn’t see and lost the ability to balance. If I hadn’t been standing between two of my fellow subjects, who grabbed me and held me up, I would’ve slammed into the floor. I knew I hadn’t fainted; I could still hear just fine, but all I heard was chaos as everyone around me freaked out. I dropped into the nearest chair and put my head between my legs while the study coordinator called the on-site paramedics. While the coordinator frantically called the staff doctor, a paramedic checked and re-checked me. I did fine as long as I wasn’t on my feet for too long. The doctor cleared me to keep dosing."

Ana explains why her continued "participation" in the trial–disregarding the danger the black outs posed to her well-being–was to accommodate the sponsoring company’s need to maintain a minimum of 7 subjects in the trial:

"The drug company had a dilemma. To submit trial results to the FDA, the study couldn’t fall below seven participants. But, unfortunately, one showed signs of serious side effects and if those results were submitted, approval was highly unlikely. If my results were dropped, the FDA would never know about the problem and the drug company could start fresh with a third trial. However, the first clinical trial had to be scrapped because too many subjects dropped out as a result of their side effects, and it looked like the second study could soon follow the same path. To gather enough healthy volunteers who fit the protocol for a third trial would require a lot of time and money, and it wasn’t something the sponsor was willing to do. So, in the end, my results and I stayed in the study."

"Because the trial ended with the magic number of seven volunteers, the results could be submitted for review and the FDA had the opportunity to see the data. But what happens in the trials in which drug companies drop some of the subjects with the worst side effects?"

Ana Cantu’s first-hand experience confirms the finding reported by FDA’s safety officer, Dr. Thomas Marciniak, who analyzed the raw data from GSK’s  Avandia trial, and found that the company concealed from the FDA the worst adverse event data, resulting in its approval precipitating preventable heart attacks and deaths.

An editorial in today’s New York Times, calls upon the FDA to revoke its questionable approval of Avastin for breast cancer because it failed to extend patients’ lives while it caused serious side effects. The drug had gained "accelerated approval" without adequate testing.

  Vera Hassner Sharav

~~~~~~~~~~~~~~~~~

AMERICAN-STATESMAN
Cantú: Anatomy of a drug trial
By Ana Cantú
Friday, July 23, 2010

Exactly five years ago, in exchange for the most miserable month of my life, I got paid $4,800 to test the effects of a drug made by GlaxoSmithKline.

You know where you’ve heard the name GlaxoSmithKline recently, right? That’s the company on the verge of losing the approval of the Food and Drug Administration for the diabetes medication Avandia after regulators discovered omissions in a key clinical trial report. On Wednesday, the FDA ordered Glaxo to stop enrolling people in another Avandia trial.

According to a review reassessing the drug’s safety by the FDA’s Dr. Thomas Marciniak, a number of patients taking Avandia appeared to have serious heart problems that were not counted in the study’s tally of adverse events, otherwise known as side effects.

Such repeated mistakes "should not be found even as single occurrences" and "suggest serious flaws with trial conduct," he wrote.

It can cost hundreds of millions of dollars — in some cases, close to a billion — in research and development for a drug company to secure FDA approval.

By the time a drug gets to point where it can be tested in humans, the pressure for positive results in clinical trials is immense. And I found that out first-hand when as one of the healthy volunteers — a human guinea pig — in a study that tested the effects of Norvir, an HIV drug made by Abbott Laboratories, when coupled with the antidepressant Wellbutrin, made by GlaxoSmithKline.

In exchange for that $4,800 paycheck, I spent about a month going in and out of a blocky silver building in an office park not far from Austin-Bergstrom International Airport, the site of a contract research lab that conducts medical studies.

During the lab’s second clinical trial of the Norvir-Wellbutrin combination, which I chronicled in a personal blog, I was known only subject No. 40.

July 12: I check in tomorrow for 4 days. I’ll be taking an antidepressant and an AIDS drug in combination for about a month.

July 13: The facility is freezing. We’re still waiting on blankets. I should’ve brought a hat and gloves. You can tell the people who do studies regularly by their baggage — they bring extra pillows and blankets and huge rolling suitcases. The building is pretty new and it’s painted in all kinds of "modern" colors like bile, which complement the black-and-white tiled floors nicely. Subjects sleep 8 to a room in bunk beds, though there are only 3 people in my room. …

My first dose of Wellbutrin is tomorrow. I hear it gives you crazy dreams.

July 14: I’ve been stuck so many times today I feel like a junkie. I had to be up by 6:12 a.m. to check vital signs and get a pre-dose blood draw. Then I had breakfast, which I had to finish: two potato, egg and cheese tacos with pico de gallo and a carton of 2% milk, which I don’t like. I took the Wellbutrin at 7:27, so precisely every hour after that I’ve been having blood drawn. For the rest of the day, it’s blood draws only every 2 hours. I carry around a clipboard that has all my procedures and meals scheduled — everything has to be done exactly as it says on the sheet or they can dock pay off your study-completion bonus.

Amusing sign near the toilets: Please do NOT use cellphones in urine monitoring stations.

July 15: Dinner was decent — teriyaki chicken, rice, salad with Italian dressing, a hunk of zucchini bread and a sugar cookie. I tried the cookie and didn’t like the aftertaste so I hid it in a spare napkin and arranged everything else on the tray to conceal it. The cafeteria workers check how much of our food we eat — we’re supposed to finish at least 50% of everything. Sometimes it’s hard, like with yesterday’s trail mix. I hope we get a good snack, which I will take my first bite of at precisely 9:32 p.m.

About half of the subjects have done trials before and say that ours isn’t so bad, even with all the blood draws. Apparently, there are some where you have them every 15 minutes. …The people who usually play Monopoly switched to Uno.

July 18: Yesterday I had my first bad blood draw.

July 20: Tomorrow I start my doses of Norvir, the AIDS drug. Fun, fun.

July 23: I started on the AIDS drug on Thursday — 300 mg twice a day. The dosage gets upped to 400 mg tomorrow. I don’t feel bad yet, though I’m sleeping less than normal. And today my stomach objected to the egg facsimile we had to eat.

July 25: I was pretty excited that I didn’t get sick after my dosings. … I think the secret is to not drink the milk. And not to eat more than 50% of the food. I’m becoming an expert in artfully rearranging things on my plate so it looks like I’ve eaten. They (try to) make us eat after taking the giant AIDS pills, but since we get the same few meals over and over, it’s gotten really hard to do. Plus, there’s a chance you’ll get sick after so you really don’t want to see nasty food twice, if you get my meaning.

July 28: I discovered that I feel better if I don’t eat after taking the horse pills. This morning, I refused to eat the breakfast tacos and felt fine. So I followed the same strategy at dinner — I did eat the peas and carrots and drank some caffeine-free root beer, but most of the meal was untouched.

Over the course of the trial, as a result of a near-constant state of nausea, I lost about 10 percent of my body weight.

To keep up my strength, for lunch, I’d go to a fast-food restaurant and order the heaviest combo on the menu (double bacon cheeseburger, fries and a huge non-caffeinated beverage) and eat as much as I could before I started to feel sick again.

Every night, insomnia cut my sleep to three hours.

Aug. 1: The study started out with 20 subjects, but 6 were eliminated during the in-patient stay by the drug company sponsoring the trial for various reasons (including drinking caffeine within 24 hours of check-in). For about a week, there were 14 subjects. Then they started dropping. The first one to go was a girl with a pronounced Texas twang named Denise, who had severe jaw and tooth pain. Then extreme nausea and emesis (the clinical term for vomiting, I discovered) claimed April. Jo Kay, Paula, Amy, Alyssa and Carrie went one after another. Now we’re down to 7. In what I view as biological injustice, none of the males have shown noticeable symptoms.

Aug. 2: I had to go see an opthamologist today, just for my safety, since I reported a migraine with aura a few days ago. Unfortunately, I’m fine. Curses. I was hoping I could get medically excused from the study — that way I’d still get paid. But it looks like I’m going to have to finish it. Only 10 more days of dosing to go. My current side effects include oral numbness and tingling in my extremities.

Aug. 6: It’s another day in lockup: cloudy skies (I think) and cold air conditioning. The day got off to a bumpy start when I started to black out while reporting my side effects. Darkness closed in from my peripheral vision and then I saw nothing but big colored spots.

That morning, we were standing around in the cafeteria waiting to dose. All of a sudden, I couldn’t see and lost the ability to balance. If I hadn’t been standing between two of my fellow subjects, who grabbed me and held me up, I would’ve slammed into the floor. I knew I hadn’t fainted; I could still hear just fine, but all I heard was chaos as everyone around me freaked out. I dropped into the nearest chair and put my head between my legs while the study coordinator called the on-site paramedics. While the coordinator frantically called the staff doctor, a paramedic checked and re-checked me. I did fine as long as I wasn’t on my feet for too long. The doctor cleared me to keep dosing.

A few days after my first blackout episode, during a scheduled outpatient visit, one of the study coordinators said I had to be examined by the on-staff doctor. "Why?" "The sponsor is concerned about your side effects," she said.

The drug company had a dilemma. To submit trial results to the FDA, the study couldn’t fall below seven participants. But, unfortunately, one showed signs of serious side effects and if those results were submitted, approval was highly unlikely. If my results were dropped, the FDA would never know about the problem and the drug company could start fresh with a third trial. However, the first clinical trial had to be scrapped because too many subjects dropped out as a result of their side effects, and it looked like the second study could soon follow the same path. To gather enough healthy volunteers who fit the protocol for a third trial would require a lot of time and money, and it wasn’t something the sponsor was willing to do. So, in the end, my results and I stayed in the study.

Aug. 21: So yesterday I had the exit screening/physical for my drug study. I had to have my blood pressure checked 3 times because it was low, even for me. The paramedic checked me, but I was asymptomatic. She asked how I was feeling. "Fine, especially now that I’m off the drugs." She said, "Well, it was for the good of mankind." "I guess … and the money."

Because the trial ended with the magic number of seven volunteers, the results could be submitted for review and the FDA had the opportunity to see the data. But what happens in the trials in which drug companies drop some of the subjects with the worst side effects?

Actually, we’ve seen what happens — with Avandia.

~~~~~~~~~~~~~~~~~~

THE NEW YORK TIMES
July 25, 2010
When a Drug Fails

The flameout of an enormously expensive drug to treat advanced breast cancer will pose a critical test for the Food and Drug Administration. Will the agency have the courage to reverse course when a medical treatment that it approved based on preliminary evidence flops badly in follow-up studies?

Two years ago, the F.D.A. gave Avastin, which is made by the Genentech unit of Roche, “accelerated approval” as a treatment for breast cancers that have spread to other parts of the body. Such cancers are essentially incurable so the best that current treatments can do is extend a patient’s life.

The hurry-up mechanism allows approval of a drug that has not yet been proved safe and effective in thorough clinical trials but has shown promise that it might benefit patients with life-threatening diseases. Rather than make such patients wait, they are treated with the drug while the manufacturer completes additional tests.

When Avastin was granted “accelerated approval” to treat advanced breast cancer, the primary evidence was a single clinical trial. It found that Avastin, when used with another drug, slowed progression of the disease but did not significantly extend patients’ lives.

Now two follow-up trials by the manufacturer have failed to confirm even those meager gains. In the initial trial, Avastin held tumor progression at bay for five and a half months. In the two new trials, pairing Avastin with different chemotherapy drugs, the delay in tumor worsening was much shorter: up to three months in one trial and less than a month in the other. The Avastin combinations also caused serious side effects.

Britain’s National Institute for Health and Clinical Excellence, a pace-setter in evaluating medical advances, issued draft guidance this month against using Avastin for advanced breast cancer patients in the National Health Service. It called the clinical trial data “disappointing” and the cost “too high for the limited and uncertain benefit it may offer patients.”

By a 12-to-1 vote last week, an F.D.A. advisory committee quite sensibly urged the agency to revoke Avastin’s approval for breast cancer. That would not affect its other approvals, gained through the standard regulatory process, for treating colon, lung, kidney and brain cancers. Avastin would remain available to doctors for off-label use against breast cancer. Many insurers, however, might refuse to cover an unapproved use.

The cost of Avastin has always seemed outrageously high for the medical benefits it confers. The wholesale price for a typical breast cancer patient is about $88,000 a year. Genentech has been capping annual spending at $57,000 for patients with incomes below $100,000.

The F.D.A. has rarely removed drugs that were given accelerated approval and sometimes has failed even to compel completion of follow-up studies. But there are signs it may get tougher. In June, the agency finally forced a leukemia drug off the market that had been given accelerated approval a decade ago, after a long- delayed follow-up study showed no clinical benefit and an increased risk of death. With Avastin, the follow-up studies were completed in a timely manner — with such meager results that withdrawal seems the right response.