Jeff Vance, 40, thinks he's probably still considered terminally ill. Colorectal cancer had spread by the time he discovered he had it. But no one's marking his time in months now. And he's feeling "really good."
Miles and a different diagnosis away, Judy Grant feels like she's in the happy part of the movie "Awakenings." She was, she said, "experiencing the world in a very ghostly way" because of chronic fatigue, an illness that left her so drained she had to force herself to get up and shower a couple of times a week, resting her head against the shower wall two or three times "just to get through it." Now the colors, the vibrancy, the zest have returned.
The difference, both say, was strict adherence to their treatment plan and participation in a clinical study just one of the steps an experimental drug must make on its way from being a notion that something might help to becoming a treatment you buy at the pharmacy or a better medical device or new surgical technique.
A surgeon may implant one patient with a new style of artificial hip and implant another with the standard hip to compare results. An oncologist may add a medication to chemotherapy for colon cancer, like the clinical study Vance participates in, or a hospital may give antibiotics to some patients and not others before certain surgeries. It's all done to learn what works, to improve treatment, to reduce suffering.
On any given day in the United States, experts estimate there are nearly 50,000 ongoing clinical studies. At Huntsman Cancer Institute alone, 86 different treatment variations are being examined. Type any medical condition into the search engine at www.clinicaltrials.gov, the National Institute of Health's database, and you're apt to find something hopeful that's being studied.
Patients can access many of those studies without leaving Utah, through hospitals, private physicians, research companies.The trials may be sponsored by organizations or individuals such as physicians, medical institutes, foundations, pharmaceutical companies, federal health agencies and others. Increasingly, large national groups dedicated to promoting research of a specific illness are helping fund studies of potential treatments.
"Clinical trials are the way we determine what works in treating patients," said Dr. Stephen Prescott, executive director of the Huntsman Cancer Institute. "The medications we have to treat diseases of all types all come from applying a scientific method of asking 'Does this treatment work?' "
www.clinicaltrials.gov summarizes why someone might want to be in a clinical trial and covers the risks.
Benefits to a "well-designed and well-executed" study include the ability to play a more active role in your own health care, to access new research treatments before they are widely available, to obtain expert care sometimes more extensive than you would normally receive and to contribute to medical knowledge.The flip side is potential "unpleasant, serious or even life-threatening side effects to treatment," treatment that may not help the participant, and protocols that may require more visits to the study site, more treatments, hospital stays, dosage requirements, need to log information, etc.
Clinical trials are divided into phases, each with a different goal. In Phase I, a new drug or treatment is tried in a very small group of people to find out if it's safe, what the safe dosage range would be and to identify side effects.
In Phase II, the participant pool grows to 100 to 300 people to assess if it works and to look more closely at safety.
Phase III tests it in thousands of people to confirm treatment works, to monitor side effects, to see how it stacks up against the standard care.
The medical motto "first do no harm" applies to trials. Participants receive solid standard treatment as well throughout the trial, Prescott said. No one's deprived of needed treatment already known to work.
The phases must be complete before the U.S. Food and Drug Administration will approve a new treatment, device or process. Even then, it's not over. Phase IV trials take place after that wonder drug is on the store shelves, providing additional information about risks, benefits, optimal use and more. A drug may even be pulled after it's been on the market.
Each clinical trial is designed to answer specific questions, so there are tight criteria of who can participate and who is excluded. Some clinical trials need healthy patients, others those with a specific medical condition. Some exclude a person based on previous treatment, others embrace someone because of it. The goal is simply to find out in a "careful, scientific way" whether a proposed treatment works, Prescott said.All trials are approved by institutional review boards, which view a proposed study from the ethics and safety angles. Some research facilities, like the University of Utah, have an in-house IRB. Others, like Radiant Research, contract IRB work out to a company that specializes in that line of work.
Eureka! I have an idea!
There's just a hint of melancholy when Dr. Guy Zimmerman, professor of internal medicine and director of the Program in Human Molecular Biology and Genetics at the U., tells the story of Pafase.
In the early '90s, he was part of a group of researchers who worked with a biotech company to clone an enzyme with anti-inflammatory properties. It had still has potential to interrupt key events that may influence the pathological process in various parts of the body.
It was an engineered version of a naturally occurring enzyme. In Phase I clinical trials, it was spectacular.
Here's the time line: For about 10 years, they worked on the biology, cloning it in the mid-'90s. By '97, the biotech company was several million dollars into it and ready for the small Phase 1 trial. Government estimates put the total cost of bringing a new drug to market at more than $300 million.
Which inflammatory disease would be the right target? They debated and finally zeroed in on sepsis (blood poisoning), a common, complicated condition that often kills.
Zimmerman had advised a number of companies against targeting sepsis because it is so complex. But there was a strong rationale, based on preclinical data. "If it worked, it would be a huge breakthrough."
In the Phase II clinical trial, participants were patients who had sepsis and a trauma with complications, such as acute respiratory failure. In such cases, half the patients normally die.
The evidence suggested that, introduced at the right time, Pafase could shut down the cascade of events.
The study took place in multiple centers, with 240 patients. Again, "spectacular" results.
"We were ecstatic about that," physician-researcher Zimmerman said.
The Phase III trial was multicountry, multicenter, mega-expensive. Then, a little over a year in, the regularly scheduled independent review of the 1,000 participants already enrolled found no significant improvement with Pafase. The study slammed to a stop.
The U. officials had no financial interest in the outcome, but they cared. And they wondered: Had the study simply chosen the wrong illness? The wrong timing? The wrong dose? Those questions are still on the table.
The biotech company was fortuitously involved in something else that paid off, so it survived. And moved on.
The U. has an agreement to do some animal model research into sepsis. "It could ride again. But once a drug has a first big mark against it . . .," Zimmerman said.
The hope that drives research is not easily killed.
"I am a physician, and I come at this as a physician. I am not doing investigational work because I don't like patients. It's that there's more we don't know than we do. It's the idea we can make a discovery that will help them."
For the U. and other research institutions, the dream is partly about money since scientific discoveries can be extremely lucrative. And it's partly the desire to be first and best. There's little payoff for being second, Zimmerman said. Besides that, "you need a track record" to attract federal research funds and other grants. And to bring in first-class scientists to continue the cycle, he said.The ultimate dream is to find a novel therapeutic agent with a dramatic impact on a common disease that's easy to take and inexpensive. "I think there may still be an aspirin out there," Zimmerman said.
The business of research
The first clinical trial Pharmacology Research Associates did, in 1976, was looking into the effectiveness of an antidepressant that eventually reached the market. The project involved "huge, huge amounts of money," recalled Dr. James Ferguson, the psychiatrist who founded the company, now called Radiant Research.
Currently, Radiant conducts studies ranging from Attention Deficit Hyperactivity Disorder to adolescent migraine, Alzheimer's disease, depression, diabetes, herpes, hypertension, insomnia, mild memory loss, psoriasis, sleep disorders, hives and more.
The caliber of the clinical trial at companies like his is equal to that of the academic and health institutions, he said. They're all carefully monitored, subject to on-site review and vast overview. Four times, the FDA has come in to go over records. Once, the Japanese government sent in a team. Study sponsors make more frequent quality-assurance visits.A specific treatment may be tested at many different sites, but each must conduct the research in precisely the same way. The ethical design is identical, as are the contracts. The protocol cannot vary from site to site. Participating sites sign a Document 1572, which has teeth including possible criminal prosecution. It's a highly regulated process, Ferguson said.
Privacy is a huge consideration, and names are closely protected in a clinical study. In genetic studies, for instance, the link between the patient and blood is severed.
There's a trade-off. That privacy means a participant doesn't get information about himself. If a blood test revealed a potentially life-threatening problem, there'd be no way to inform the participant. But such protections are the only way to make it work.Occasionally, in extraordinary circumstances, the seal can be broken. Ferguson arranged it once when a baby ate his mother's study medication. They had to know if it was dangerous.
Tales to tell
He tells a hilarious tale of a post-marketing study of a successful weight-loss remedy that had pounds almost pouring off patients.
Further study called in question the drug's mechanism. It seems a side effect was severe gastric distress and raging diarrhea. Further study showed people who had experienced the side effect, even once, simply chose to avoid food at all costs whenever possible.In a mid-'70s trial of a cholesterol-lowering drug, the NIH sponsors found that participant side effects varied from one study site to another. It turned out it depended on the order the side effects were listed on the consent form. "If constipation was listed first, that's what you got," Ferguson said.
To the finish line
Avastin has become a frontline treatment for colorectal cancer patients, according to its Web site. Even the earliest study data suggested those who received it lived about four months longer than patients on chemotherapy alone. The drug blocks new vessels and thus tumor growth, said Dr. Graydon Harker, president of Utah Cancer Specialists. The trial looked at whether it, combined with chemotherapy, works better than either one alone.
Physicians say they think they can sometimes tell who's getting what, based on the results. That's true of the pills that Vance is testing in a different clinical trial, as well. Vance said he doubts he's getting the placebo. "I have the side effects, including high blood pressure. And the improvement."
Harker said he's seen some very dramatic results during clinical trials. "Probably better than I had hoped for."
Like all clinical study medications, there are potential problems. Avastin was no exception. Since tumors need new blood vessels to grow, shutting down their development would likely hurt the cancer. But the body needs new blood vessels for tissues that are regenerating, including bone marrow and muscle. There's a risk that needed vessel development could be thwarted. And the list of potential, unknown complications during the trial included concerns about stroke, kidney problems and even contradictory complications, bleeding and clotting.There were questions besides simple effectiveness, too. Is the drug or the combination more toxic? Does it cause more mouth problems, sores, nausea, vomiting, diarrhea?
Downside with an upside
One downside to clinical trials is patients may not get new medication that could help them. Some receive a placebo.
Still, that's a powerful tool. Doctors know all about the "placebo effect," amazing responses by those receiving nothing more potent than sugar, based on the belief they're getting the study drug.
"It's clear that the placebo effect is powerful," said Harker, who noted that patients on placebo may experience the known side effects of a drug. They also experience some of the positives. "They have more energy, feel better, more upbeat, hopeful. They're more positive about the treatment, whether or not the drug is helping them."
And there's another good-bad aspect to clinical trials. Patients in clinical trials tend to be more closely monitored. But they often also are subjected to more tests, more restrictions, more time requirements. Some clinical trials pay participants for their time or cover travel expenses, while others don't. In Phase I, where there's no benefit to the participant at all, payment is likely to be higher.
Vance has wrestled with the extra time commitment. But he won't argue with this result: After the fourth treatment, whether placebo or medication, his tumor was half the size. And a lesion on his lung found when he started chemo disappeared after eight weeks. Liver tumors are shrinking.
He battles fatigue but continues to work as a computer specialist with the Utah Valley Emergency Communication Center."Things have gone pretty well. I have convinced myself I am getting the drug in the study and I have a positive outlook. But I'm not where I thought I would be this time in my life or ever. It's changed a lot of my perspective on things."
What about after?
After the clinical trial, but before final FDA approval, some investigational drugs may be available to patients through "expanded access" protocols, which may also make the substance available to patients who don't actually qualify for a particular study. It only happens with serious or life-threatening illnesses that have no good alternative treatment. It can also be done to get more information about the drug, especially safety. But clinical investigators must monitor the new treatment in a well-controlled study or the completed study must have shown clear positive results.
What happens after is a concern for Grant, who believes she's received the real drug Ampligen for chronic fatigue. She had the side effects for a day or so after every infusion of the powerful drug, which has antiviral and immunomodulator properties. After about six weeks, those faded. After 10 weeks, "my brain came on," she said.
Participants who were convinced they were getting the medication felt sorry for anyone receiving placebo. But the "carrot" for the study was that at the end, everyone would receive the real drug, which is expensive, for a period of time, after which they could pay for it. Five of the 12 participants Grant knew have continued on, though not everyone can afford it.
Ampligen is on the "fast track" because it's the only drug to demonstrate improvement for those with chronic fatigue. Predictions are it will win the FDA nod quickly.Still, not all participants will have access to study medication in the time between completion of a study and approval if approval ever comes.
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