Should a Doctor Prescribe Drugs that are Unapproved by the FDA?

Here’s an interesting clinical dilemma brought to my attention by another physician.

She was asked to refill a prescription for a drug called domperidone to help a patient with lactation. Domperidone is not FDA approved in the United States for any indication. However, in Europe and in Canada it is approved as a promotility agent for patients with a condition called gastroparesis, which causes the stomach to empty very slowly and results in chronic nausea and vomiting. As a side effect the drug is also known to increase the production of prolactin, a hormone that stimulates milk production. In the case of this physician’s patient, she had adopted a child and found that the medication had effectively enabled her to produce milk and nurse, with seemingly no untoward effects. It’s unclear who had initially prescribed the drug, but various online lactation support forums discuss it as an option  for women who have trouble with lactation.

The questions: Is it legal, ethical or good medical practice for a physician in the United States to write a prescription for domperidone for a patient who has been using it for lactation with good results? How about for gastroparesis? Where does one get the drug? Is it even legal to sell the drug in the United States?

I’ve cared for at least two patients who have used domperidone. In both instances it was ordered by prescription from an overseas source by a local gastroenterologist. In these two cases my patients had tried just about everything on the market in the United States for gastroparesis and were still struggling with debilitating symptoms. In one case, my patient had required hospitalizations and ultimately a feeding tube because of intractable vomiting. The drug was ineffective in both patients and it was eventually discontinued.

As I read more about this medication I discovered that the FDA cautions:

“FDA warned healthcare professionals and breastfeeding women not to use an unapproved drug, domperidone, to increase milk production (lactation). The agency is concerned with the potential public health risks associated with domperidone. FDA took these actions because it has become aware that some women are purchasing this drug from compounding pharmacies and from foreign sources. Although domperidone is approved in several countries outside the U.S. to treat certain gastric disorders, it is not approved in any country, including the U.S., for enhancing breast milk production in lactating women and is also not approved in the U.S. for any indication.”

The concern over domperidone is its potential to induce potentially fatal cardiac arrhythmias through QT prolongation (an alteration of electrical activity in the heart). This risk has been recognized in Europe and is currently under study. Nonetheless, at least one expert panel in Canada has endorsed the safety of the drug for use in lactation (though not currently approved for this use in Canada).

As my colleague and I discussed the situation with her patient we both concluded that it would not be prudent to refill this prescription for the purpose of lactation. In fact, it would likely be construed as medical malpractice, in light of the drug’s status with the FDA, should the patient or her baby suffer any toxicity. However, clearly there are gastroenterologists who feel that prescribing this medication in United States for cases of severe gastroparesis is justifiable—and I would concur that in certain situations this might be a compassionate and reasonable option despite the regulatory concerns.

To further extend this discussion—physicians do frequently prescribe drugs that are on the market and FDA approved for off-label use. For example, just yesterday I prescribed gabapentin for hot flashes. One interesting study published in Archives of Internal Medicine in 2006 by Radley, Finkelstein, and Stafford found that 21% of sampled medications were being prescribed for off-label use.

The authors concluded:

“The Food and Drug Administration (FDA) focuses on market entry for prescription drugs rather than regulating physicians’ prescribing practices, allowing off-label use of medications for indications beyond those formally evaluated by the manufacturer. Off-label prescribing of medications is legal,1 often thought to be supported by scientific evidence,2 and common in certain clinical settings.3– 4 Although this practice provides a pathway to innovation in clinical practice, it raises key concerns about risks to patients and costs to the health care system.5– 7

Whereas prescribing approved medications for off-label use falls into the realm of acceptable clinical practice, one has to be very circumspect about prescribing drugs that are not deemed adequately safe or effective to market in the United States for any indication. Unfortunately for those who feel that the FDA is too slow, political, or conservative in its approval process, these are the regulatory constraints under which physicians must practice in the United States.

Juliet Mavromatis is a general internist based in Atlanta, GA. She blogs at DrDialogue, where this post first appeared.

7 replies »

  1. Absolutely, our licensed medical doctors should have the right to prescribe medication as they deem beneficial and safe for their patients. I took Domperidone as prescribed by my gastroenterologist for two or more years and it worked like a charm. My digestive issues included severe gastroparesis and vomiting. Finally, he was banned from ordering it for his patients and many of us fell back to our sick and miserable unhealthy lives!

  2. Today we were able to develop a drug that can reverse cirrhosis of the liver and remove the hepatitis B virus. We give a guarantee of treatment or a refund, surely says a lot.
    But we do not have huge funds for research, so we have to sell our medicine without registration.

  3. Sorry Al, you don’t have your facts even close to right. FDA approval isn’t for use of a drug. FDA approval just allows a company to claim their product can be used in a certain fashion in their promotional and marketing materials.

    The FDA has no authority to define what physicians do. They are not in that line of work.

    What the FDA approves is the ability for a pharmaceutical company to market a drug for a specific indication. FDA “approval” means that the company paid some people to do a study and they think that it showed it was safe and effective, and the FDA is satisfied by their claims.

    Not all drugs are even FDA approved! Many of our bread and butter drugs predated the Pure Food Drug and Cosmetic Act (e.g. phenobarbital). Many of our first line drugs are used for reasons which the manufacturer has not sought approval (and in many cases, will never).

    The FDA does not provide any sort of endorsement or recommendations to physicians. The most they can do is either not approve the drug, remove the approval, or require the manufacturer to put more warning information in the package insert/label.

    Now lets talk about what the studies actually show. First, they only have to show they are not worse than some standard (so called non-inferiority studies) or not more toxic, or both. Second, the studies are designed by the drug companies, paid for by the drug companies, analyzed by the drug companies, and promoted at scientific meetings by people who are paid as part of the drug company’s speakers bureau. The FDA cannot do any of its own research (but they do their own analysis, as best they can). Third, research costs the typical drug company about as much as they spend on marketing. That is a lot of money! Drug companies are not going to pursue a market where they cannot return on the investment (typically to their shareholders). Fourth, higher quality research is typically done funded by NIH without the self-interest of the drug company funded work. Fifth, if the manufacturer’s drug is already being used (e.g. if it was recommended by some advisory panel or professional society, or there was compelling research to support a use) they may be happy letting other promote their drug and not bother getting FDA approval. Finally, once a drug goes off patent, and becomes a generic, no new indications get added unless someone spends all the money to get approval for marketing it for a new use. Since everyone who makes the drug will benefit, but only one would pay, whoever approved this would be fired (and likely the officers of the company would be sacked by the board of directors/shareholders).

    The decision to seek marketing approval is not based on whether or not a drug works well or is safer than alternatives. It is based on whether or not the company thinks it can make a profit on the drug. The FDA has no authority to request or require a drug company spend its own money to investigate some new indication, even if it is clearly in the public’s best interest.

    Even if we know a drug is the best treatment for a patient, with better safety and better outcomes, it may never be FDA approved for this because of the regulatory process and the financial responsibility drug company executives have to their shareholders.

    FDA approval does not give much assurance that a drug is safe or that a drug works. Many new, highly marketed, and highly touted drugs have been pulled from the marketplace because subsequent studies show them to be a liability to the bottom line of a drug company.

    I base my decision on which drugs I do, and do not, use based on compelling, unbiased evidence. I do not base it based on what a representative from a drug company tells me or what some advertisement says.

    It is quite common to see a later study done w/o manufacture funding shows drugs to be less effective and/or more toxic than what the manufacturer’s hired investigators found. It is also the case that high quality research is done on uses of drugs which are not one which the manufacturer has sought marketing approval.

    It is, and has always been, and will remain, acceptable for physicians to use drugs consistent with community standard of practice. Drugs are used based on the best knowledge available, which often have nothing to do with the FDA approval process. Many of our most important drugs are used for indications which the FDA will never receive an application from a manufacture to market the drug for this indication.

    I think most would agree that it is critical to patient safety and wellbeing that physicians prescribe drugs based upon sound evidence, not on what someone is allowed to say in a promotion of their drug.

    Do you think patient drug choices should be relegated to the marketing department at a drug company beholden to their shareholders, or to their physician who has a fiduciary responsibility to you?

  4. Why not? The US Government requires that we use EHR devices that have not been approved by the FDA.

  5. A really good question. I think the physician is taking a lot of personal risk in doing so. Doubt the liability insurance would cover a lawsuit. And if this became common practice it would be difficult to draw a line. There are many arguments against it.

    On the other hand there is the patient…

    Perhaps the answer is to tell someone about it and write that you aren’t endorsing it but it is there if someone is willing to go through the effort of finding it and ordering it on their own