Experimental Treatments

Unapproved But Not Always Unavailable

The scalpel has failed. The IV tubing stands abandoned on the side of the room. Friends and nurses visit less often. The doctors say the limits of medical knowledge have been reached and there is nothing left for you to do but go home and put your affairs in order.

This is a crushing moment. It's even more frightening than the day the doctors announced that you had a serious and life-threatening disease, such as AIDS, cancer or Alzheimer's disease. For many people, however, the limitations of medical knowledge do not define the limits of human hope. As long as life lingers, many patients will fight on, refusing to give up even when biology is against them. So, they set out on a search for treatment options.

And many alternatives exist. In today's medical bazaar, options range from alternative and complementary therapies like acupuncture and homeopathic and naturopathic medicine to nutritional supplements and macrobiotic diets, home-brewed remedies, and even outright frauds like laetrile. But greater promise resides in the drug development pipeline where tomorrow's therapeutics await proof that they work. Unlike alternative therapies, billions of dollars and decades of scientific study often have been invested in the research that leads to promising new therapies. Might there be, somewhere in that high-priced gauntlet, just the right molecule that cures a patient who is running out of time?

The answer is possibly, but finding it isn't easy. Short of randomly hearing about a promising study through the media, most people know relatively little about what drugs are in development. Even if experimental drugs existed in a database, "it is hard to know which drugs are truly promising," says David Banks of the Food and Drug Administration's Office of Special Health Issues. But on average, about 80 percent of the drugs in testing will ultimately be approved.

Getting your hands on a novel medicine can be even more difficult. Usually, only the company has any supply of the new medicine, which is extremely limited to begin with, and most of what is made will be used in clinical studies.

As if these hurdles are not enough, there is the long-held, but incorrect, public perception that FDA erects regulatory barriers that block patients from getting investigational new drugs (INDs). These are drugs that pharmaceutical companies have in clinical trials to demonstrate their safety and effectiveness, but which have yet to be approved by FDA for marketing. For those with a serious illness, the agency rarely blocks access to unproven medications. But FDA does strive to protect all patients, even those who may be dying, from undue risks associated with investigational new drugs. At the same time, FDA believes that the best way to benefit all patients is to speed promising new therapies through the development and approval process so safety, effectiveness and proper use can be established.

"FDA has worked diligently to balance two compelling, and sometimes competing, factors," says FDA Commissioner Jane E. Henney, M.D. "On one hand, there is the need for the disciplined, systematic, scientifically controlled studies necessary to identify treatments that may improve patient health and that lead to the approval of new drugs. At the same time, there is the desire of seriously ill persons, with no effective options available, to have the earliest access to unapproved products that could be the best therapy for them."

Over the last decade, FDA's institutional philosophy has evolved to be more supportive of thoughtful risk-taking by patients who have run out of options. As a result, the agency has put in place a number of regulatory mechanisms and worked with manufacturers to ensure that seriously ill patients can get access to promising, but not fully evaluated, products. At the same time, FDA has protected the critical scientific studies that must be carried out so that patients, physicians and the agency can determine which drugs are truly safe and effective, and how they can best be used.

"We believe that the best means of providing access to useful medical treatments for all Americans is to continue to shorten the review times," Henney says, "and to continue to work with the industry to shorten development times for drugs, biologics and medical devices."

The Intervention of AIDS

Before the 1980s, a more paternalistic medical community argued that it was the government's job to protect patients from possible harm by withholding experimental drugs until there is proof that they work and are safe.

AIDS helped alter that view. Not only did that lethal disease spread with terrifying speed, but it struck a patient population capable of mounting a political response that grabbed the nation's attention and galvanized public health policymakers to reconsider long-held beliefs.

Experimental treatments should be available, the Washington Post quoted one activist at the time, "so people would be able to choose for themselves, working with their doctors, whether they want to risk taking a drug because of the possible benefits."

Critics accused FDA of denying dying patients access to possibly lifesaving drugs. To drive home the point, in October 1988, more than 1,000 gay activists staged a protest outside FDA's Rockville, Md., headquarters, trapping the agency's staff inside.

"FDA is the nexus between the government, the private sector and the consumer," the spokeswoman for one of the protest organizers told the Post. "That's why we're targeting [the agency]."

The protest had an effect. The agency, already focused on the issue by the urgency of AIDS, accelerated its reexamination of the way people with serious and life-threatening diseases could gain access to unproven remedies. Although the treatment IND regulations were finalized in 1987, FDA put in place additional mechanisms to make experimental drugs available to seriously ill patients earlier in the drug development process.

With the activism around AIDS and the demands of people with other serious illnesses for access to unproven treatments, the medical community, including FDA, began to appreciate that the traditional risk/benefit models may have been inappropriate for people with serious and life-threatening diseases. Dying patients were willing to take bigger risks for even the slenderest hope of benefit.

"The hope part of it is that it might work and keep them alive a little longer," says Theresa Toigo, associate commissioner for the Office of Special Health Issues. "Even if it is only two months, by then there might be a cure. It is a wonderful survival instinct."

Getting Access

For patients in search of a cutting edge treatment, the possibilities have improved dramatically. First of all, there are more clinical studies under way than ever before. FDA has on file more than 13,000 active drug and biologic studies. These range from a few dozen patients to as many as 50,000 participating in a single investigational new drug trial. More than 100,000 patients are enrolled each year in National Institutes of Health-sponsored studies conducted all over the United States.

Studies with investigational new drugs can be conducted by the federal government, primarily through the National Institutes of Health; by research universities, usually with federal funding, though also through private foundations or drug companies; and by private, for-profit companies on behalf of pharmaceutical manufacturers.

Clinical trials are essential to the development and approval of new drugs. In these studies, a group of human volunteers receiving the investigational therapy are compared with another group that receives either the standard treatment or a placebo. Placebos, sometimes called sugar pills, are any fake treatment that has no therapeutic benefit. This allows the researchers to compare the effect of the treatment to no treatment in otherwise similar patients. When the control group is given the standard treatment, researchers are able to determine whether the experimental treatment provides a better outcome than what is already available.

The clinical trial setting helps ensure that risks are minimized because the research protocol, the set of rules by which the clinical trial is conducted, have been scrutinized by FDA and a local ethics committee called an institutional review board.

"We want to encourage people to participate in the clinical trial process because that is where information is best developed about the drug product," says David Lepay, M.D., director of the division of scientific investigation in FDA's Center for Drug Evaluation and Research.

The downside of being in a clinical trial, indeed the downside of using any unproved medication, is that the new drug may not work. It may even be dangerous and, sometimes, deadly.

Not everyone who wants to participate in a clinical trial can do so. Limits on the number of participants and specific eligibility criteria keep some people out. In addition, it is often inconvenient for the patient to travel to the research center.

When individuals are unable to participate in a clinical study, FDA provides alternative mechanisms for patients and their doctors to get their hands on a promising new drug.

Beyond Clinical Trials

In 1987, FDA created a regulatory mechanism (first proposed in 1982) to permit expanded access to investigational drugs outside of controlled clinical trials. The "treatment IND" allows people with serious and life-threatening illnesses to take investigational drugs while the products are being tested in a clinical trial. Typically, however, drugs allowed under treatment INDs already have shown promise and proven safety. In addition to the benefit to individual patients, treatment INDs generate useful information about how the drug affects larger segments of the patient population than might otherwise receive it in a clinical study.

For example, the AIDS drug Videx (ddI) was made available to people with AIDS outside the clinical trial at a time when the choices for AIDS therapy were few and many people had already exhausted the then available options. Although patients seeking treatment with ddI were told that it was still under study and that there were risks, more than 20,000 decided to take ddI anyway. This not only gave them a better chance to survive but also gave researchers more information about the drug's safety than would have been possible from the some 4,000 patients involved in the clinical studies.

Since the final treatment IND rule was published more than a decade ago, FDA has made more than 40 drug or biologic investigational products available to patients early and has approved 36. Of these, nearly a dozen were for cancer and another dozen for AIDS or AIDS-related conditions.

Single-Patient INDs

As with a clinical trial, there may not be an appropriate treatment IND for an individual patient's condition, but there may be a new drug still working its way through development. If enough is known about the drug's safety, and there is some clinical evidence of effectiveness, FDA may allow a patient to become his or her own study. This so-called single-patient IND, or compassionate use IND, virtually ensures that any patient can get access to any investigational new drug.

Although FDA's requirements for a single-patient IND are relatively simple, setting up this kind of access for an individual patient is not. First of all, the company must be willing to provide the new drug to the patient. This can be expensive and time consuming for the company since, in addition to providing the drug, the company needs to track shipments of the drug, create special instructions for its use, and create a way of collecting safety data and a mechanism for tracking outcomes for each patient. Second, the patient must give informed consent, understanding that the drug is not approved and may cause side effects from mild to fatal. Third, the patient's physician must be willing to take responsibility for treating the patient and agree to collect information about the effects of the drug.

Companies sometimes say that they cannot make the drug available to a patient because FDA won't allow it, but that is rarely true. FDA only denies access when there is evidence that the risk of using the experimental drug clearly outweighs any potential benefit to the patient.

If a drug is frequently used in single-patient INDs, FDA streamlines the process for obtaining permission. One example is thalidomide, a drug initially associated with birth defects in the 1950s but now being used experimentally to treat cancer. (FDA approved thalidomide in 1998 to treat leprosy.)

FDA has similar rules that give patients access to investigational new medical devices.

A Difficult Decision

All things being equal, is it worth it for a patient to get access to an experimental medication?

For society the additional safety information about the new drug may prove useful. And sometimes it does make a difference for individual patients. For example, people with AIDS who participated in the clinical trials for a category of drugs called protease inhibitors probably benefited because this class of drugs proved so dramatically effective. But for many other INDs, the success rates are much less impressive, such as tacrine (Cognex) for the treatment of Alzheimer's disease.

Even if access does not change long-term survival, it may provide for the patient and the family a sense that they are doing something and are not simply victims of some serious disease. Biomedical research advances rapidly and breakthroughs come from unexpected places, all feeding the hope that the next experimental drug will be the one that cures our ills.

Larry Thompson is a member of FDA's public affairs staff.

Finding Information About Investigational New Drugs

While finding and getting into an appropriate clinical trial for your individual disease is something like a scavenger hunt, the Internet has made it much easier to track down these studies. The following is a listing of major Internet sites where you can search for a clinical trial that may benefit you.

Information Program on Clinical Trials, (www.lhncbc.nlm.nih.gov/clin/) mandated by the FDA Modernization Act of 1997, is a joint FDA/National Institutes of Health resource. While initially containing only NIH studies, it will eventually include all federally and privately financed clinical studies.

CancerNet (http://cancernet.nci.nih.gov) is run by NIH's National Cancer Institute (NCI). It provides information on clinical trials. Information is also available through NCI's Cancer Information Service at 1-800-4-CANCER.

ACTIS (www.actis.org), the AIDS Clinical Trials Information Service, provides a wide range of information on current AIDS research, including drug trials, vaccine trials, and other educational material. Sponsored by the U.S. Public Health Service, including FDA, NIAID, Centers for Disease Control and Prevention, and the National Library of Medicine, ACTIS also can be reached at 1-800-TRIALS-A.

Information regarding clinical trials for rare disease can be found at http://rarediseases.info.nih.gov/ord/research-ct.html, a database compiled by NIH's Office of Rare Diseases.

CenterWatch Clinical Trials Listing Service (www.centerwatch.com) is published on the Internet by CenterWatch Inc., a multimedia publishing company in Boston, Mass. It provides information on more than 5,000 active clinical trials as well as other information.

When a clinical trial is not an option, FDA facilitates access to an investigational new drug or an investigational medical device through other programs. For information on programs for, or access to, an unapproved investigational new drug, call FDA's Office of Special Health Initiatives at 301-827-4460.

-- L.T.

Is The Risk Worth It?

No matter how promising a clinical trial or investigational new drug seems, there is no way to know about all the risks before the study begins. While the hope is that the study will produce a cure, it's important to recognize that risks can prove significant. For example, in 1992, tests for a promising hepatitis B drug severely damaged the liver in 10 patients. Some died and others required liver transplants.

Because of these inherent uncertainties the health-care professionals conducting the study must ensure that the patient understands the risks as well as the benefits beforehand and is willing to proceed.

Here are some questions patients might want to ask to make sure they understand the consequences of entering a study or using an investigational new drug:

  • What are the potential benefits from the treatment being studied? What have the animal or other human studies shown about the effectiveness of the drug?

  • What are the potential dangers from using this drug? Again, what do other animal and human studies show about the side effects?

  • In what phase is this clinical trial?

    Clinical trials are generally performed in three phases. A phase 1 trial is primarily designed to assess the safety profile in a small number of patients. Phase 2 tests the effectiveness of the treatment in a relatively small number of patients. Many drugs never progress beyond phase 2 because they are not effective. In phase 3, a large number of patients receive the drug to substantiate that the effectiveness seen in phase 2 is real and to work out the details of its use. Individual patients are most likely to benefit from drugs in the later phases of development.

  • Will there be a control group?

    For a clinical trial to produce useful information, the group of patients receiving the new treatment needs to be compared with patients who receive something -- or nothing -- else. Often, patients in the control group receive whatever is the current standard therapy for the disease. Sometimes, the control group patients will receive a placebo -- so-called sugar pills that produce no therapeutic benefit. In a clinical study, patients are randomly assigned to either the group treated with the experimental drug or to a group receiving the standard therapy or placebo.

  • How do I know if I am eligible to be in the study?

    Every trial has a set of criteria to select the people that will be included in the study. These criteria generally relate to general health, stage of disease, and prior treatments and are designed to produce useful scientific information.

  • Do I have to pay to be in a clinical study?

    Generally, studies funded by the federal government are free for the patient. Many studies funded by drug companies also do not cost anything. Some costs, however, may be paid by a patient's health insurance or managed-care plan.

  • So I'm just a guinea pig, right?

    By the time most studies reach the stage where the new drug is being tested in people, a great deal is known about how it affects the body. While there is always the chance that something could go wrong, the safety of most drugs being studied is well understood. It is true, however, that researchers do not know if a treatment being studied works better than current therapies or not.

-- L.T.

What FDA Does Not Do

Although FDA is responsible for overseeing the field of drug development, there are a number of services the agency cannot provide to individual patients. For one thing, it cannot give out the name of drugs in development, a common request from patients who call the agency. Unless the company publicly releases information about the experimental treatment, FDA is currently forbidden to even acknowledge that it knows about the drug.

Along the same lines, FDA cannot make the drug available to individual patients or physicians. The agency simply does not have the product; only the company that is developing the drug has a supply. And FDA has no authority to require that the company make its drug available outside of the clinical trial.

FDA, itself, does not conduct any clinical trials or drug studies. The agency carries out its drug review and approval responsibilities by examining clinical and other data generated by the drug company.

And lastly, FDA does not give advice. While staff from the Office of Special Health Issues and the Center for Drug Evaluation and Research's drug information branch will often provide detailed information and explain the process for getting access to an experimental medication, the agency does not steer patients in one direction or the other. Information is provided so patients, in consultation with their physicians, can make their own informed decisions.

-- L.T.