Compassionate Drug Use

A "60 Minutes" episode reported on the controversial topic of "compassionate drug use." Some people with late-stage cancer are hopeful about this practice, which allows them to receive new but unapproved drugs after traditional treatments have failed. Could one of these drugs be their miracle pill? What is "compassionate drug use," who can receive it, and how effective is it?

What Is Compassionate Drug Use?

Compassionate drug use describes the use of investigational drugs by seriously ill people not enrolled in clinical trials. Investigational drugs are those that are being studied but have not yet been approved as safe and effective by the Food and Drug Administration (FDA).

Normally, investigational drugs go through strict testing through many stages of clinical trials before they are sold to the public. They are tested for safety, side effects, how well they work and at what doses, and with what conditions or diseases they are to be used. The process may take up to many years.

Compassionate drug use is a fairly new practice. The FDA first approved investigational drugs to be used in this way for critically ill patients in 1987.

Who Is Eligible to Use These Drugs?

The most common means for people to access unapproved drugs is to enroll in a clinical trial. This is the safest route, as the FDA closely regulates clinical trials, and people taking new drugs are carefully watched. However, not everyone will qualify for a clinical trial. Because the use of new, unapproved drugs is risky, only certain people who are not enrolled in clinical trials can receive them. According to guidelines from the National Cancer Institute, eligible patients:

• Have used standard treatments and found them unsuccessful

• Are ineligible for any ongoing clinical trials

• Have a cancer diagnosis for which an investigational drug has shown some benefit and is currently being studied in clinical trials

Who Is Regulating Compassionate Drug Use?

The FDA regulates this practice, but the decision to offer the drugs to the public is entirely up to pharmaceutical companies. Grant Williams, MD, Medical Team Leader for the FDA's Division of Oncology Drug Products, explains, "The FDA has one main role, and that is to make sure that patients are protected and offered appropriate treatments, and that the investigational drug is used properly.

"But the drug companies create the rules about their own compassionate use, and rightly so. They are basically offering a drug out of the goodness of their heart. They have no need to do it and are always under close watch of the FDA. It is very expensive for them to produce these drugs, which are usually given out free of charge," he says.

Williams says that compassionate drug use is not tightly regulated. "We've put different labels on it, but there are no formal laws or procedures yet. So there aren't any numbers or statistics of who is doing this and how successful it is."

However, the FDA announced this past May of plans to formalize compassionate use programs that take place but are not clearly outlined. The intent of the FDA initiative is to clarify the programs that already exist. It will not create new situations in which compassionate use will be allowed.

Future conferences are planned to explore unanswered questions and better define when it is appropriate to use these drugs.

These questions include:

• When is it appropriate to allow compassionate drug use?

• When is it appropriate to expand it to a larger group of people instead of on a case-by-case basis?

• What if the drug company has more patient applicants for an investigational drug than they have supply for or feel is right to treat? How can these patients be selected in a fair manner?

Accessing Unapproved Drugs

As one way to help people access compassionate-use drugs, the National Cancer Institute (NCI) and the FDA have set up a class of investigational drugs called "Group C" drugs. These are drugs not approved for sale by the FDA but have shown some benefit in clinical trials. A patient's doctor may use a treatment investigational new drug application (Treatment IND)   to apply for Group C drugs or another investigational drug. It includes information on the patient's condition and past treatments. The NCI and FDA collect safety information about the drugs from doctors who give them to their patients.

The most common practices for getting investigational drugs to patients outside of clinical trials are through expanded access or special exception or single-patient exception.

• Expanded access uses drugs that have been well tested and are nearing FDA approval. The drug must show in studies that it is effective in treating a specific cancer. The program is offered by a drug company and the drug is given out to a group of people.

• Special exceptions are individual requests (usually by a doctor) made to drug companies or to whomever is overseeing a program or clinical trial. The decision to give out the drug is weighed on a case-by-case basis. There must be some proof that the drug would either improve the patient's quality of life or lengthen his or her life.

Alan Goldhammer, Associate Vice President for Regulatory Affairs at the Pharmaceutical Research and Manufacturers of America (PhRMA), says, "Expanded access programs use a drug in clinical trials where a certain level of safety and effectiveness has been found. It's up to the drug company if they want to have the program, because they are supplying the drug. How much of these unapproved drugs are available outside clinical trials is limited. A lottery system may decide who gets them."

The drug company applies to the FDA to make the drug available for an expanded access program. A patient's doctor is involved as an "investigator" in the program to oversee the effects of the drug on the patient. With the special or single-patient exception, a patient's doctor can fill out a Treatment IND and contact the drug company or trial sponsor. The FDA oversees both of these situations.

Why Not to Use an Unapproved Drug?

There are drawbacks to compassionate drug use -- for the patient and to the drug approval process. One is that they may interfere with clinical trials if more people seek this route rather than participating in trials. Goldhammer says, "Although the NCI gathers some safety information on compassionate-use drugs, it is not as helpful to the approval of these drugs. Patients are not watched as closely as in clinical trials."

Williams adds, "The benefit is small. We are talking about the use of drugs in which the likelihood that they will help someone is extremely low. The likelihood of cure is almost zero and the chance of toxicity is fairly high.

"Consider results of early clinical trials on new cancer drugs. Well under five percent of these drugs show any anti-tumor benefit in the participants. Based on these low response rates, there's no reason that compassionate use drugs should be more popular," he says.

Other problems include the chances of receiving no lasting benefit from the drug, undiscovered harmful side effects, and extra costs not covered by health insurance associated with using the drug.

For More Information

"There needs to be a balance in people's minds between the belief that ‘because the drug is new and hasn't been approved, there's hope,' and the reality that there is only a low chance that the drug will work," says Williams.

Both Williams and Goldhammer recommend people first seek out clinical trials with a drug that has shown early positive results.

To learn more about investigational drugs and clinical trials, talk with your doctor about your options. Call NCI's Cancer Information Service at 1-800-4-CANCER (1-800-422-6237) or visit www.Acurian.com to search for clinical trials for your condition.

If you do not qualify for a clinical trial, your doctor can ask the trial's sponsor about requesting a single-patient exception. He or she may also contact the NCI or a company making the drug to find out if expanded access programs exist.

Physician Request for a Single Patient IND for Compassionate or Emergency Use

Source: Food and Drug Administration (FDA)

When a physician would like to request an Investigational New Drug (IND) application to use an unapproved drug or other product for a single patient, the first step is to obtain permission from the manufacturer. Without the consent of the manufacturer, the unapproved product will not be available to the patient. After the manufacturer agrees to provide the product, the recommended procedure is to submit the following information to the appropriate review division. The request may be made by facsimile with a letter to follow.

1. Request for a single patient IND  for Compassionate or Emergency Use should be stated at the top of the correspondence.

2. Brief Clinical History of the patient including the diagnosis, the disease status, prior therapy, response to prior therapy and the rationale for requesting the proposed treatment.

3. Proposed Treatment Plan including the dose, route, planned duration, monitoring procedures and modifications (e.g. dose reduction or treatment delay) for toxicity. Reference a published protocol or journal article if appropriate.

4. Drug Supply Reference Statement which would name the supplier or manufacturer and a statement that a Letter of Authorization to cross reference an appropriate IND of the supplier or Drug Master File (DMF) of the manufacturer is included. The treating physician must contact the supplier or manufacturer for such a statement.

5. Informed Consent Statement that states that informed consent and approval of an appropriate Institutional Review Board (IRB) will be obtained prior to initiating treatment. There are some IRBs that have specific procedures for approving emergency requests.

6.   Investigator Qualification Statement that specifies the training, experience, and licensure of the treating physician. The first two pages of a Curriculum Vitae typically contain this information and are usually sufficient.

7. FDA Form 1571 completed with the treating physician listed as the sponsor. Form 1571 and other forms can be downloaded from the Internet.

8. Contact telephone number and facsimile number. If the request is approved, an IND number will be issued by the FDA and the treating physician will be contacted by phone or fax with a letter to follow. The IND is considered active upon issuance of the number. The IND sponsor (treating physician) will then contact the drug supplier and provide the IND number. The supplier may then ship the drug directly to the treating physician.

For further information, please contact the appropriate Review Division:

	Phone	Fax
CDER Oncology Drug Products (most drugs)	301-594-2473	301-594-0499
CBER Oncology Branch (for biologicals)	301-827-5093	301-827-5394
CDER Urologic and Reproductive Drug Products (for prostate cancer hormones)	301-827-4260	301-827-4267
CDER Radiopharmaceuticals and Medical Imaging	301-827-7510	301-443-9281