Zofran, an anti-nausea drug manufactured by GlaxoSmithKline, has become a commonly prescribed medicine for morning sickness. In fact, it’s active ingredient ondansetron, has been placed on the World Health Organization’s Model List of Essential Medicines. In doing so, the WHO recognized ondansetron as a necessary component of even the most basic healthcare system.
But in order to be sold in the US, every medication needs to be approved by the Food & Drug Administration (FDA). At the end of this article, we’ll cover how the FDA reviews and approves drugs, but for now we’ll only cover one basic fact:
Drugs in America are approved for specific uses.
Zofran has been approved as a treatment for:
- severe nausea and vomiting in patients receiving chemotherapy
- severe nausea and vomiting in patients receiving irradiation therapy
- nausea and vomiting in patients undergoing surgical anesthesia
The FDA has found Zofran a safe, effective treatment for those three purposes, or “indications,” and only those indications.
But as researchers found in a study published by the Journal of Clinical Outcomes Management, patients are five times more likely to be prescribed ondansetron for non-FDA-approved purposes than they are to be prescribed other “industry standard” treatments for nausea and vomiting.
In short, ondansetron is the industry standard for nausea and vomiting, whether or not those symptoms are caused by a condition for which the drug has been approved. This practice, prescribing drugs for unapproved uses, is called “off-label” prescription.
Now we can return to the question initially posed by this article, namely:
Is Off-Label Prescription Legal?
Yes, it is entirely legal, and doctors aren’t required to inform patients that their drugs are being prescribed “off-label,” either.
It’s also extremely common. In 2006, three public health researchers from Dartmouth, MIT and Stanford reviewed a huge amount of national health records. Focusing on 160 of the most-commonly prescribed drugs, their study included every time any one of those medications was prescribed in 2001.
Then, they separated each instance of prescription into one of three categories:
- drug prescribed for FDA approved use
- drug prescribed for “off-label” use, but with strong scientific support for its efficacy
- drug prescribed for “off-label” use with limited or no scientific support
21% of all prescriptions fell into those last two categories. That’s one out of every five drugs, prescribed for unapproved purposes.
But only 27% of the off-label prescriptions were supported by strong scientific evidence. In other words, more than 15% of all drugs were prescribed for uses without any scientific evidence of whether or not they would work.
Arguments For & Against Off-Label Prescription
Is that cause for concern? It depends on how you look at it, or which examples you choose to support your opinion. Many beneficial applications for drugs have been discovered through off-label use.
Beta-blockers, a class of drugs initially approved to treat high blood pressure, were prescribed off-label to patients dealing with congestive heart failure. The treatment turned out to work remarkably well, and now many beta-blockers are approved for heart failure, too.
But there have been tragic consequences, as well.
Fenfluramine hydrochloride and phentermine hydrochloride were originally prescribed as short-term treatments for obesity. Then, someone tried both medications together as a weight loss solution. It worked, and physicians began prescribing both drugs as a cocktail commonly called “Fen-phen.” Several years later, patients prescribed Fen-phen started being diagnosed with severe heart damage. By 1997, the FDA had recalled both drugs entirely.
With off-label prescription, it’s all about uncertainty. Because the FDA’s required clinical trials haven’t been conducted, there’s no way to tell which unapproved uses will work and which will have adverse effects.
You can find more cautionary, and optimistic, tales from the world of off-label prescription in this excellent WebMD article.
As we’ve seen, the FDA doesn’t regulate drug prescription, it regulates drug approval. That’s a subject we’ll cover now.
How FDA Approval Works
When prescription drug manufacturers want to sell a medication in the US, they have to test it first. But before that, they have to identify a chemical that seems to have promising benefits.
After determining which chemical they want to pursue, the manufacturer will send an application to the Food & Drug Administration. Specifically, they have to send an Investigational New Drug (IND) application to the FDA’s Center for Drug Evaluation and Research, a department within the FDA whose only mission is to make sure that drugs on the American market are:
- Safe for people to use
- Effective in treating whichever condition they are marketed for
This first application needs to include:
- information on the drug’s effects from studies on animals
- any data on the drug’s use in humans (most likely from other countries)
- a description of how the drug is made
- a plan for trials in humans, if the IND is approved
It’s only after the Investigational New Drug application is approved that a pharmaceutical company can begin testing the chemical in clinical trials. Notably, most drugs don’t even make it past this initial step.
Clinical trials aren’t performed by the Food & Drug Administration, or even its Center for Drug Evaluation and Research, but by the companies manufacturing the drug in the first place.
What Are Clinical Trials?
According to the FDA: “clinical trials are experiments that use human subjects to see whether a drug is effective, and what side effects it may cause.” Again, safety and efficacy are the two big points of interest here.
Sandra Kweder, M.D., a director at the FDA’s Office of New Drugs reports that clinical trials almost always take a long time, “usually several years.”
Once clinical trials have gathered enough evidence to prove that a drug is safe and effective, its manufacturer (or “sponsor” as they are now called within the industry) can submit another application, a New Drug Application (NDA).
NDAs need to include:
- details on how the drug is manufactured
- how stable it is (whether or not it retains its physical, chemical and therapeutic properties during storage and usage)
- its bioavailability (how much of the drug enters the bloodstream – this is important in calculating proper dosages)
- details on each of the dosages that will be marketed
- samples of packaging intended for both physicians and consumers
Next, reviewers at the FDA will check over the results of the clinical trials and determine whether or not the potential risks of the drug outweigh its potential benefits. If they do, and the drug’s marketing materials are appropriate, the new medication will be approved and go to market.
Is It The Same For Generics?
This process is the essentially the same for branded products, like GlaxoSmithKline’s Paxil, and generic versions of the same active ingredient (paroxetine in the case of Paxil, produced by as many as 26 different companies).
Generic manufacturers, though, are allowed to file Abbreviated New Drug Applications, since it’s easier to prove that a drug is safe and effective if it’s been on the market for the same indications already.