You’ve heard the term, “cure-all”, I’m sure, but as we all know, there is no real “cure-all” in life. If you ever watched the movie, “My Big Fat Greek Wedding”, then you are all too familiar with the father of the bride who believes that Windex is the “cure-all” for everything. As he states in the movie, “from psoriasis to poison ivy, put some Windex on it!” Windex, however is not a magic potion. It is simply intended for cleaning windows, mirrors, glass shower doors, glass top stoves and more as stated on their website. In fact, Windex in high concentrations can be very caustic, because it contains ammonia! Maybe the father of the bride should have done some research before promoting Windex’s unapproved uses!

In the medical field, doctors, like the father of the bride in the movie, use many products for unapproved uses. In our industry, the Food and Drug Administration (FDA) requires that medical devices, drugs, biologics and combination products be used according to its labeling of approved (or “on- label”) uses. Oftentimes, however, doctors end up using products for “off-label” use. With this FDA requirement, how is it that doctors are able to use these products for unapproved uses?

Good question, right? Well, let’s first take a look at how the process works.

Who are the participants?

1. The FDA – The FDA has established premarket review/approval processes to help prevent harm to public health from unsafe and ineffective medical devices, drugs, biologics and combination products. The process requires a review of safety and effectiveness of each product before distribution for approved/market cleared uses and the product’s labeling must include directions for each use.
2. Drug or Medical Device Manufacturers – Manufacturers follow the process required by the FDA and pull together all the data and documentation to support the safety and effectiveness of each product for each use. They may not manufacture a product for commercial distribution until FDA approval/market clearance. Manufacturers can promote “on-label” uses, but cannot promote “off-label” uses.
3. Doctors – The FDA regulates drug approval and medical device market clearance as described above, but interestingly, does not regulate drug or medical device prescribing. Doctors can prescribe for “off-label” uses, which is legal, if they believe it will benefit the patient and thus the public health. Again, “off-label” use means the product is being used in a manner not prescribed in the manufacturer’s FDA approved/market cleared packaging label or insert. The label is a document that details the instructions applicable to the uses/doses, as applicable, which are based on clinical study data or other pertinent documentation submitted to the FDA to support the safety and effectiveness of each product for each use.
4. Public Health – The entire public health can be a patient at some point in their lives. During that point, the patient population receives a diagnosis and treatment from a doctor, which may include the “off-label” use of a drug or medical device. Even more interesting, the doctor is not required by law to inform the patient that the “off-label” use is not included on the product label or that there may be no clinical data to support that use. This is not illegal or unethical when it is deemed “medically appropriate” by the doctor.

“Off-label” use is very popular among doctors. Interestingly enough, it’s the doctor’s prerogative to weigh the risks and benefits to determine the best care for patients. So here’s the question, would you want to use the drug or medical device in or on your body if there was no clinical data to support the safety and effectiveness of the product? What kinds of issues can arise?

When is “off-label” use an issue?

1. Lack of Clarity – often there is some confusion among doctors regarding the product’s approval/market clearance. For instance, they may believe that the product is approved for one use, when it is really not. The doctors think they are going for an “on-label” use when technically, it is an “off-label” use. Lack of clarity around the “on-label” use can increase the risks to the patient and lead to very serious outcomes.
2. Adverse Effects – if an adverse event occurs related to a product, doctors may be involved in legal claims if the patient believes they were harmed and the physician deviated from the standard of care.
3. Misbranding – When a manufacturer promotes an “off-label” use, the FDA could cite them for misbranding, meaning its labeling is false or misleading in some way.

Where is “off-label” use happening?

Off-label use is happening all over the world. In many parts, there have been examples where common off-label uses have later proved to be unsafe and/or ineffective, with dreadful consequences to public health.

Why would doctors choose “off-label” uses?

1. Doctors may be inclined to treat a patient’s life-threatening illness with a logical treatment on the market even though the FDA has not approved or market cleared the “off-label” use.
2. Doctors may be driven to use a treatment for one condition if the pathologic or physiologic features of this condition, compared to a second condition, are similar.
3. Doctors may feel compelled to utilize a treatment for one population that was not included in a clinical study, but was studied and FDA approved or market cleared for another population.
4. Doctors may be determined to treat a patient with two doses per 12-hour period over one dose per 12-hour period as FDA approved (“on-label”).

Certainly manufacturers could submit amendments to drug and medical device applications (or Investigational Device Exemptions – IDEs or New Drug Applications – NDAs). These activities could be very costly and might never justify the cost of the “off-label” use, especially because of the new clinical data that would be required to support safety and effectiveness.

How do approval/premarket clearance requirements help?

There are many reasons why these requirements help make “on-label” uses safe:

1. Collecting vigorous scientific data will support safety and efficacy of medical device, drug, biologic and combination products for particular uses. (Otherwise, a firm could obtain approval/clearance for one use, but then doctors would use its products for unapproved uses, without having any scientifically robust clinical studies to assess the safety or efficacy of the unapproved uses.)
2. Requiring review of data before marketing/promotion of products for those particular uses in order to prevent harm. This better ensures that doctors have a valid basis for making treatment decisions, before use by public health.
3. Providing a review of safety and efficacy data by a third party to assure that claims are appropriately supported.
4. Requiring a development of labeling that provides information necessary for the safe and effective use of the product.

Opponents of “off-label” uses?

Off-label uses are perfectly legal, at least for now, and the FDA does not mandate doctor prescribing. Knowing this, why shouldn’t drug manufacturers be able to market their products for unapproved uses? For one, if manufacturers promoted their products for “off-label” uses, then the safeguards designed to protect the public health would be compromised and could lead to patient harm, including:

1. Harm from a product that is unsafe for “off-label” use and lacks adequate directions for this use.
2. Harm from a product that is ineffective for “off-label” use and might be used in place of another product for “on-label” use based on data showing safety and effectiveness (worsening of a disease that would have responded to another therapy to a point that makes it more difficult or impossible to treat the disease).
3. Exposure of patients to the risks of an ineffective treatment.

The past few decades has shown that acceptance of “off-label” use is no guarantee that a product is safe or effective for that use. It also exposes patients to many risks. This is why the FDA requirements are so important. Robust clinical trial testing, FDA-required labeling and careful approval/market clearance by the FDA are in place to make the public health feel good about using a product. There have been many instances where acceptance of “off-label” use has later been shown to be unsafe and/or ineffective, sometimes with devastating consequences to public health.

Opponents want to regulate “off-label” use without unjustifiably overwhelming clinical innovation. Some opponents feel that doctors would make a treatment decision based on clinical data, experience and a personalized analysis of the patient’s needs, but others would also like to have even more evidence-based prescribing, with stricter rules governing off-label drug use.


Proponents of “off-label” uses?

Proponents, on the other hand, struggle with the fact that if “off-label” use is regulated, this could impede patients’ early access to novel therapeutic treatments. Some proponents also argue that “off-label” use leads to reduced costs. The manufacturers have less regulatory costs, which can be translated down the line. Furthermore, if the “off-label” uses could be promoted by the manufacturer, this would lead to the open flow of information, users are informed of all options and makes off-label treatments available to patients.


Final Thoughts

Although there are competing interests of the opponents and proponents of “off-label” use of medical device, drug, biologic and combination products, the good of the public health is what most important and that means ensuring the safety and efficacy of the product. To ensure this happens, the FDA needs to provide guidance for “off-label” use and promotion.

The manufacturers should also participate in preparing the guidance documents to ensure that the least burdensome approach is taken, but is statistically sound. The doctors need to realize that medical device, drug, biologic and combination products are not Windex – they are not a cure-all for all that ails, and they should document scientific rationale in their medical records for use of an “off-label” use for each patient. It is this basis whether an independent clinical test, evidence-based test or peer study will hold up in a court of law. The court’s job is to practice prudence and sound judgment, keeping their eye on the public health, which is what all the players in the medical field should be doing too.