Off-Protocol: Getting New Treatments Outside a Clinical Trial

If you'd like to share your experience obtaining treatment off-protocol , please e-mail me at [email protected]

This article assumes you're in the US. If you're from another country, your options are likely to be similar though the details will differ.

There are a surprising number of ways to get treatments normally available only in a trial (or offered in one) outside of a trial, and frequently patients are simply not told that they may be able to obtain a treatment outside a trial (“off protocol” as its called). CancerGuide is about showing you how to research all your options. Therefore, this article covers ways to obtain treatments off-protocol without reservation.

While it isn’t true that you can always (or even usually) get trial treatments off-protocol, you should know this possibility is not limited to treatments which involve only FDA approved drugs (and which can legally be prescribed by any doctor), but also includes treatments involving promising new drugs which haven’t yet been approved.

Of course, even if you can get a treatment outside a trial, that doesn’t mean you should. Indeed most of the time you should not. If you can get into a trial, and participating is practical, that’s the usually best way for you to get the treatment. You will be in the hands of doctors with experience in giving it. You can also be assured you’ll be rigorously followed to make sure the treatment is safe and to determine if it’s working. You should be aware that for a variety of reasons, treatment in a trial will sometimes be covered by insurance when the same treatment outside the trial would not be. By participating in a trial you will also be helping future patients by contributing to medical knowledge.

There are some perfectly good reasons why you might want to obtain a trial treatment outside a trial:

  • There might not be an open trial even though the treatment is promising.
  • You might not qualify for a trial even though there is reason to believe the treatment might help you.
  • The trial is randomized and you have good reasons to prefer the treatment in one arm (Unless you prefer one arm, you should enroll in the trial as long as the trial treatments are otherwise your best options).
  • Travel to obtain the treatment in the trial would be exceptionally difficult for you (but note that traveling for treatment is often practical and many can and do).
  • Your insurance will cover treatment in their network, but not out of network in the trial (Just as sometimes treatments are covered only if given in a trial, unfortunately sometimes just the reverse is true).

Off-Label and Standard Uses of Approved Drugs

Off-Label Use

Many clinical trials involve “off-label” use of approved drugs. Off-label use of a drug simply means the drug is prescribed for a different specific purpose than the purpose for which it was approved by the FDA. Doctors can legally prescribe drugs for off-label uses and it’s very common in medicine, especially in cancer medicine.

Standard Use

If a standard treatment is in a clinical trial, it’s usually a randomized trial – either phase III or adjuvant – where it is being compared to either a new treatment or another standard treatment. In oncology many commonly used relatively standard treatments often haven’t been specifically FDA approved. In other words, standard uses are often also off-label uses.

Getting These Therapies Off-Protocol

If a treatment being tested in a clinical trial involves only approved drugs, you may be able to get it off-protocol whether or not the treatment is standard and whether or not it involves off-label use.

  • It still may not be easy to get the treatment off-protocol: Just because doctors could prescribe drugs off-protocol doesn’t mean they will. If the treatment is relatively standard it should be no problem. But other than that, it’s not likely a doctor offering you a trial will be willing to treat you off-protocol if you qualify for the trial. If you want the treatment off-protocol, you’ll probably have to find another doctor. The key is to find a doctor who is comfortable giving it. This means that the doctor believes there is evidence it would work and is comfortable administering it. Doctors can sometimes be convinced when you show them good evidence for a new treatment, but the best bet is probably to try to find a doctor who is already using it. If there really isn’t evidence to show that the treatment would be useful for your specific situation, you’re likely to have trouble. In the end, that might not be a bad thing.
  • You may not be told that the drugs in a proposed trial are FDA approved and it may not be obvious: Keep in mind that drugs which sound high tech or exotic may still be approved drugs. Monoclonal antibodies? Immune system proteins produced through genetic engineering methods? All bread and butter products these days


My Experience Trying to Get a Drug Off-Protocol

Back in 1989 after my surgery for a huge kidney tumor, I was offered an adjuvant trial of Interferon-alpha with the objective of preventing recurrence. The trial was randomized and the radiation therapy which had just been recommended would not be allowed even though there was no reason to think these treatments wouldn't play well together. I wasn't comfortable and made this clear, but the doctor who offered me the trial didn't tell me that Interferon was an FDA approved drug although not for this specific purpose. Prior to my diagnosis, I'd heard of Interferon in the media but assumed it was highly experimental - to me, it was like something out of a science fiction story. I had no clue it was an approved drug that could in theory be prescribed by any doctor outside of the trial until my uncle (who is a doctor) used the phrase "off-protocol" in passing and I caught on.

After I found out, I tried to get the drug combined with radiation off-protocol. Two different doctors refused me and in truth the only evidence for it was very, very modest activity in metastatic kidney cancer. I hadn't given up, but my search became moot when I was diagnosed with widespread metastatic disease only a month after surgery. In the end the data showed that adjuvant interferon for kidney cancer didn't work anyway.

Finding Out If Drugs are Approved

  • Your oncologist should be able to tell whether a drug is approved but it’s not too hard to research this yourself.
  • See the drug information links in my Research Tools article for how to find information on most drugs. Newly approved drugs may not appear in these databases immediately.
  • If you know the name of the drug maker (which may be on an informed consent or database listing for the trial), check their website. Check the products, research pipeline, and news release sections.
  • Do a Google search for the drug and look for information indicating it has already been approved – but beware that articles which imply it isn’t approved yet may be old. Often the Google search will lead you to the manufacturer’s name – then check their website to find out the status.

Substances Which Aren’t Legally Drugs

You should be aware that rarely substances used in clinical trials aren’t legally drugs at all. Instead, they may be classified as “nutritional supplements” or they may even be industrial chemicals. It is possible to obtain these substances without a prescription, though obviously you should be careful about self-treating your cancer.

As with drugs, it may be far from obvious when something is freely available. For instance, you might never guess that hormones like melatonin or DHEA are freely available without a prescription. Other substances with complex chemical names may also turn out to be available as nutritional supplements. N- Acetyl-Cysteine, Inositol Hexaphosphate, and L-Arginine are all names of easily obtained nutritional supplements (I am not suggesting these are effective cancer treatments). While it can be hard to guess that something is available as a nutritional supplement, such substances are likely to be taken orally, non-toxic or less toxic, and derived from natural substances.

If a trial tests something from a natural source, such as a plant, don’t make the mistake of assuming you can get the same thing just by taking a crude supplement made from the plant. You need to carefully compare dose and purity to what’s being used in the trial. The material used in trials is often so highly concentrated and purified you’d have to take a unreasonable amount of a raw plant or crude extract to get the same amount. Absorption from a raw herb or crude extract can be different than from a pharmaceutical grade material. Even if you really can obtain the same thing being used in a trial over the counter, you should be aware that nutritional supplements used medically may not always be non-toxic. Sometimes, they are used in much higher than normal doses where there is risk of side-effects.

Industrial chemicals such as hydrazine sulfate and tetrathiomolybdate have been used in cancer clinical trials. In theory, you could probably obtain such chemicals off protocol – but, unlike nutritional supplements, these chemicals are not normally intended for human consumption and such chemicals purchased from a chemical or scientific supply house may have dangerous and even lethally toxic impurities. This can be so even if the chemicals are quite pure as a whole if the impurities which are present are toxic even in small amounts. In addition, the chemical itself may be dangerous. Be careful out there!

Formal Compassionate Use Programs

A formal compassionate use program is a mechanism for getting an unapproved but promising new treatment to patients who would otherwise be unable to receive it. Compassionate use programs are for people who have a life threatening with “no comparable or satisfactory alternative drug or other therapy available to treat that stage of the disease in the intended patient population” (in the words of the FDA regulations).

Formal compassionate use is a bit like a clinical trial in that you will still have to meet specific requirements such as the type and stage of disease, and usually you must be treated by doctors who participated in the clinical trials for the drug, but compared to trials, the requirements are somewhat relaxed. If you qualify for an open clinical trial of the treatment, obtaining it through compassionate use is not an option.

According to the FDA regulations, compassionate use programs are normally for drugs which are in phase III or have completed accrual to their trials (it takes significant time to allow the data to mature, compile it, and get it reviewed by FDA – often several years), but the regulations do say compassionate use might be possible for some drugs which are only in phase II testing. I presume there would still have to be applicable promising results – such as spectacular results from an ongoing phase II trial. You won’t find compassionate use programs for drugs which are in the very early stages of testing. If you just heard about the latest cancer cure for mice on the nightly news, you can be sure there will not be a compassionate use program. There have to be results in people with your type of cancer.

Although the FDA has to approve compassionate use programs, they normally do so without fuss. Whether there is a compassionate use program largely depends on whether the drug company has decided to have one. The decision depends on many factors including the cost which can easily run into the millions and whether there is an adequate supply of the drug (which is often an issue). In the past, agitation by organized patients has sometimes made the difference. For instance, Genetech granted expanded access to the breast cancer drug, Herceptin, only after breast cancer activists conducted an intensive campaign. (“Demand Grows for Early Access to Promising Cancer Drugs”,Journal of the National Cancer Institute, November 20, 2002)

Finding Compassionate Use Programs

  • If you’re interested in a particular drug you can find out if there’s a compassionate use program by contacting the company. The first step is to find their web site.
  • There is no definitive database of open compassionate use programs but CancerActionNow maintains a small list of programs they’re aware of.


Single Patient IND

First you need to know I am not well versed in this area. I find it somewhat mysterious and I’ve only learned enough to give you an outline. Basically a single patient IND is permission to treat an individual patient with an unapproved drug off-protocol.

An IND is a permit from the FDA to treat patients with an unapproved drug, normally in a clinical trial. A Single Patient IND is permission from the FDA to treat a single patient with an unapproved drug outside of a trial. This applies in similar circumstances as for a formal compassionate use program. You must not qualify for a trial of the same drug, and you must have advanced disease for which there’s no other good treatment and there must be evidence it could be of benefit. Given these requirements are met, my impression is that the FDA is unlikely to stand in your way.

But, and this is absolutely critical, like the compassionate use program, the drug maker must agree to it, only here you have to personally convince them. There is no law or requirement that the drug maker has to agree and no standard process for getting them to.

A major difference is that the doctor has to file a complete IND which is a major piece of work. My intuition is that this will be far easier if the doctor is already an investigator conducting trials with this drug and difficult otherwise. My impression is that single patient INDs are quite rare in practice. The exception is the National Cancer Institute’s Special Exception program which is quite active – see below.


  • CancerActionNow has good advice on how to pursue a Single Patient IND.

Special Topic: National Cancer Institute Compassionate Use Programs

The National Cancer Institute (NCI) has three different programs to make promising drugs they’re developing available on a compassionate basis before FDA approval. In all cases, to qualify for these programs, you must not qualify for trials involving the same drug, or have other good treatment options. In all cases there must be evidence the treatment is promising for people in your particular situation. If a drug is promising in a different type of cancer, that’s probably not enough.

  • Special Exception
    • Program Overview
      • This program releases drugs being developed at NCI for specific individuals and amounts to the NCI’s implementation of Treatment IND. It’s exciting because the program is active and because NCI is involved with so much of the best cancer research. Generally, drugs released under special exception have promising Phase II data.
      • The program is quite active and released at least ten different promising drugs to a total of over 500 patients in 2002. I suspect even more would take advantage of this program if it were more widely known. I believe that if you find promising evidence in the literature for a drug being developed at NCI for your type of cancer then if you don’t qualify to get it in a clinical trial, you stand a real chance of being able to get it off-protocol through this program.
    • Finding Special Exception Drugs
      • There is no predefined list of drugs available for release under special exception. If your research uncovers promising data for your situation for a drug being tested under NCI sponsorship and you don’t qualify for a trial, you can investigate by calling the contact number on the NCI Compassionate Use Page , or preferably by having your doctor call.
  • Treatment Referral Center (TRC) Protocols
    • Program Overview
      • TRC protocols are the NCI’s version of a formal compassionate use program. These are special clinical trials which have expanded access as a major purpose. Like other clinical trials, TRC protocols have specific eligibility criteria for each different trial but compared to ordinary trials, the requirements are relaxed in specific ways to make more patients eligible for. One specific requirement for these protocols is that you not be eligible for other good trials.
      • Generally positive data from phase III or advanced phase II trials is required before NCI will consider opening a TRC protocol. This means that if a drug is available under a TRC protocol you already know there must be promising data (though this doesn’t guarantee it’s a miracle cure!).
      • Each TRC protocol is offered to all NCI designated cancer centers, and will be available at any center which decides to take part.
      • As of December 2002, there are only two active TRC protocols, one of which is to end soon, however I understand this program is expected to be the main mechanism for expanded access to specific drugs from now on.
    • Two Ways to Find TRC Protocols
      • You can find TRC protocols in the NCI’s PDQ Clinical Trials Database. Importantly, PDQ has detailed eligibility requirements for each TRC trial. To find the TRC Trials, go to the PDQ search form. Enter “CTEP-TRC” (without the quote marks) in the “Protocol ID” field and don’t change any of the other fields. Now click the search button at the bottom of the page. On the next screen just hit the display button to get the list of TRC protocols, which should be short. Click on each trial to get details.
      • The NCI’s “Compassion” page also lists active TRC protocols and there is a slight possibility they may list something not found in PDQ so it’s worth checking just in case.
  • Group C Drugs
    • Program Overview
      • Group C drugs can be released to NCI registered investigators for compassionate treatment of individual patients. Any doctor who’s recently participated in an NCI sponsored trial will be a registered investigator. This differs from the Special Exception Program in that here the drugs are pre-cleared for release. Like the other NCI compassionate access mechanisms, there has to be reasonable evidence of efficacy before a drug is given the Group C designation. Currently, there is only one Group C drug and I understand that the TRC Protocol is replacing this program.
    • Finding Group C Drugs:
      • Check the The NCI’s “Compassion” Page. Again – there is presently only one Group C drug and there may be fewer in the future!

Much of the above information is based on a conversation with staff at the NCI’s CTEP pharmaceutical Management Branch in December 2002.

Obtaining New Drugs and Treatments from Other Countries

Although American medicine is very advanced, sometimes useful drugs are approved in other countries before they are approved here, and sometimes treatments are in common use overseas before they are available here. Occasionally this presents an opportunity to get a new treatment before it is approved here including treatments which are only available in clinical trials here. There are two ways to get such treatments. First, you can travel to the country where the treatment is being used and get it there. Second, it turns out you can often import drugs by mail or overnight courier.

My Experience Helping Someone Import a Drug from Japan

In 2002, I helped obtain a new drug, Iressa, for a patient with far advanced pancreatic cancer. A friend of his, Susan Gurney, was desperately trying to find an effective treatment. Although most of the experience with Iressa was in lung cancer, Susan thought it might help her friend. Unfortunately, there were no clinical trials of Iressa in pancreatic cancer. She told me she'd found there was a compassionate use program for Iressa, but that she hadn't been able to get through their phone system.

I found the phone number for their compassionate use program on the manufacturer's website and was able to get through. They were quite willing to talk to me, but just as I feared, their program was strictly limited to non-small cell lung cancer. I didn't think we'd get far trying to persuade them to release it for a pancreatic cancer patient.

But at the Iressa Web Site, I noticed the drug had just been approved in Japan. I called Susan and suggested she might be able to import it. I actually thought she might have to travel to Japan and carry it back.

Susan quickly figured out that she could import it by overnight courier without having to travel at all. In only few hours she had contacted a friend who speaks Japanese who in turn found someone who knew an English speaking doctor in Japan who turned out to be more than willing to prescribe it and get it sent by courier. Susan also found another friend who had done business in Japan and who able to help her get the payment wired. Susan recommends that anyone in the U.S. making overseas calls to unknown clinics find someone who is a native speaker to help.

It took three days to for the doctor to arrange to get the drug from AstraZeneca and it arrived in the US only three days after that, but was held up in customs. Sadly, Susan's friend was terribly sick and died before it even arrived.

It was about three weeks more until Susan got it released by producing a prescription letter from her friend's doctor and (oddly) her passport. Since her friend had already died she was not in a hurry and thinks she'd have gotten it faster if she tried.

It was expensive, $100 per pill and Susan had to pay all of the cost.

Note 1: I have not personally tried to determine whether Iressa would be likely to help people with pancreatic cancer, and have no opinion on whether Iressa is promising for pancreatic cancer.

Note 2: Iressa is now FDA approved for use in the treatment of non- small cell lung cancer

Finding Out if New Drugs or Treatments Are Available Overseas

Unfortunately, I know of no current single source of information for drugs and treatments in use in foreign countries but researching your options may reveal opportunities here if you are alert. If you are interested in a particular new drug it’s usually easy to find out if it’s been approved overseas. Just find the manufacturer’s web site using a high quality search engine like. If the drug has recently been approved in another country it’s very likely they will report this in a press release. To find press releases, check out the company’s “news” section, typically found under “investor information” or similar. If it’s not approved here but has been marketed elsewhere for a long time, you might not see anything in the press release section, but they will surely describe it in their products section.

Importing Drugs from Overseas by Mail or Courier

It is often possible to import a three month supply of a drug available elsewhere, but not approved here, if it’s imported for personal use under the supervision of a doctor. It turns out it’s actually illegal to import unapproved drugs, but the FDA is basically willing to look the other way under the right circumstances, and they have even issued specific guidelines about when to allow imports. They have four requirements.


The intended use [of the drug] is unapproved and for a serious condition for which effective treatment may not be available domestically either through commercial or clinical means.

There is no known commercialization or promotion to persons residing in the U.S. by those involved in the distribution of the product at issue.

The product is considered not to represent an unreasonable risk.

The individual seeking to import the product affirms in writing that it is for the patient's own use (generally not more than 3 month supply) and provides the name and address of the doctor licensed in the U.S. responsible for his or her treatment with the product or provides evidence that the product is for the continuation of a treatment begun in a foreign country.

The above is taken from the FDA's Information on Importation of Drugs

I expect most every real life situation where you’d want to import a legit drug not approved here for treatment of poor prognosis cancer would meet these guidelines. If treatment will require more than a three month supply of the drug, you should be able to go through the process again to obtain more drug as needed.

As a practical matter you’ll need to find a US doctor who will cooperate with you in administering the therapy, and you’ll need to get an overseas pharmacy to ship drug to you.

As far as I can tell the FDA import guidance would also apply to substances such as nutritional supplements, even they aren’t approved drugs elsewhere. Be aware though that the FDA will not permit importing so called alternative treatments if it believes they are either dangerous or quack drugs. Laetrile is an example of something they won’t allow. If you are thinking of trying to import an alternative therapy, it’d be a good idea to search FDA’s website to make sure no specific alert has been issued (I haven’t found a simple list of banned products there). I suspect that most low profile nutritional supplements would pass, but remember, FDA isn’t required to allow any imports – it just chooses to allow most.

Resources on Importing Drugs

  • “Coverage of Personal Importations” from the FDA/ORA Regulatory Procedures Manual

Traveling Overseas for Treatment

If there is a new treatment available overseas that requires you to be present to get it, travel is certainly a possibility, and I have known of patients who have traveled to other countries for treatment. Your health insurance probably won’t pay, but the good news is that medical costs are far more reasonable in most of the rest of the world than in the states. It’s important, of course, to verify that the treatment you are traveling for is legit and backed up by solid data. While the U.S. has no monopoly on new treatments for cancer, it is also true that there are quite a few foreign clinics specializing in some form of “alternative” medicine and most of these treatments are unproven, disproven, or ineffective.

This CancerGuide Page By Steve Dunn. © Steve Dunn
Page Created: December 2, 2002, Last Updated: August 5, 2004