January 6, 2017
Division of Dockets Management
5630 Fishers Lane
Rockville, MD 20852
Comments of National Center for Health Research on “Manufacturer Communications Regarding Unapproved Uses of Approved or Cleared Medical Products”
(Docket No. FDA-2016-1149)
The National Center for Health Research is a non-profit think tank focused on research and policies that improve the quality of medical care in the United States. We strongly oppose the off-label promotion of approved or cleared medical products. For patients, the evidence clearly indicates that off-label use increases the chances of adverse events and decreases the likelihood of benefit.1 For companies, widespread off-label use of medical products provides substantial financial benefit and a clear disincentive to conduct research to determine whether those off-label uses have benefits that outweigh the risks. The easier it is for companies to sell products for off-label uses, the less likely those companies are to submit applications for new indications to the FDA. In other words, most of the benefits of off-label promotion are to companies and their stockholders, and not to patients or consumers.
Even more worrisome, most patients are not adequately informed when devices or drugs are used off label. We have trained hundreds of patient advocates, and a recurring story is that patients are not told that a medical product was being recommended, prescribed, or used for an indication that was not approved by the FDA. Patients should always be informed about the risks and benefits of any medical device, prescription drug, or biologic. In addition to clear and understandable information that the physician explains orally to the patient, the physician should provide a short, understandable informed consent form for patients to read and sign whenever a medical product is prescribed or will be used off label.
Advocates of off-label promotion claim that it is essential for good medical care. There is no evidence to support that. Advocates also claim that as long as off-label communications are truthful and scientifically sound, they should be permitted. In an ideal world perhaps the FDA could carefully monitor off-label promotion to ensure that it is truthful and scientifically sound. Clearly, the FDA does not have the resources to do that and notifying patients or physicians about the risks of off-label use has not been a priority. As a result, patients are being harmed, in some cases catastrophically.
Some posit that if a study is published, especially in a peer-reviewed journal, that is a reasonable standard of being truthful and scientifically sound. Numerous staff at our Center have published in peer-reviewed journals and also serve as peer reviewers for a wide range of medical, public health, and health policy journals. We know from experience that peer reviewers have limited information about the scientific accuracy of the articles they review. Their ability to judge the scientific accuracy of a manuscript is completely different from FDA scientific reviewers, who have the opportunity to scrutinize the data provided by the sponsors and can even reanalyze data using different statistical tests. We also know that the results presented in these publications are often biased by design, execution, or selective reporting. Clinical evidence, although it can be informative, is subject to even more bias. Moreover, medical journals exist that will publish almost anything submitted. In fact, the president of our research Center has been invited to be an editor of several journals specializing in medical issues she knows nothing about. Numerous Coalition members serve as peer reviewers, and have reported that even publication in a peer-reviewed journal does not guarantee that the study results and interpretation are unbiased and accurate.
It is easy to talk about adverse events that result from inappropriate off-label use of medical products, but that abstract concept is insufficient. Below are photos that explain the issue much better. In 2008, the Journal of Neurosurgery: Pediatrics published a case report describing a terrible complication from the off-label use of Infuse, a recombinant human bone device that is approved for adults and contraindicated in children. This off-label disaster occurred at Washington University’s St. Louis Children’s Hospital. You can see how the child’s scalp and face became dangerously swollen as a result.
One would expect that this published article would have resulted in a warning from the FDA about the off-label use of this product in children, but it didn’t. Two years later, a girl treated at Cincinnati Children’s hospital had the same adverse reaction from the same off-label use of the same product, Infuse. Her photo is below.
How did the FDA respond? At first, they did nothing. After years of being urged to issue a warning by a patient advocate, the agency finally did so, but the warning wasn’t designed to get much attention or even to be understandable to physicians or families. Instead of specifying that the warning was for Infuse, the FDA warning says the following:
Certain recombinant proteins and synthetic peptides mimic bone growth substances normally found in the body and may be added to a carrier or scaffold to be used as bone graft substitutes. Once combined, these products are surgically implanted in a patient with a bone defect to promote new bone growth or to replace or heal existing bone.
In addition to not naming the product, instead of issuing a strong warning to doctors or families about the off-label use in children, the warning is very understated:
The FDA has approved these products for orthopedic and dental use only in patients over the age of 18 who are done growing (skeletal mature). The labeling for each product provides the specific indications for use.
These products are not approved for any use in patients under the age of 18 who are still growing (skeletally immature).
Even the FDA’s recommendations are very understated, referring to the fact that the product’s “safety and effectiveness has not been reviewed” for children, rather than stating that children had been irreparably harmed by Infuse.
The FDA recommends against routine use of these products in patients under age 18 because their safety and effectiveness has not been reviewed or approved for use in this population.
Consider alternatives such as autograft bone, allograft bone, and bone graft substitutes that do not contain recombinant proteins or synthetic peptides before using bone graft substitutes containing recombinant proteins and synthetic peptides in patients under age 18.
Carefully consider the benefits and risks before using these products in any patient. If considered the best or only option, inform parents/guardians and patients about the risks and benefits of using the product when discussing surgical options.
The above warning can’t be justified as lack of FDA resources or FDA’s lack of knowledge of how to get reporters’ attention and physicians’ attention. A quick look at the FDA website homepage shows how FDA relies on press releases and press conferences to let the world know when they approve a new product, and how they use public relations terms like “breakthrough” or “first new treatment in over a decade” to make sure the public will pay attention. Unfortunately, the FDA rarely uses their press and communications teams to warn physicians, patients, or family members about the dangerous off-label use of medical products, whether it is devices like Infuse or drugs that have been found to be ineffective or unsafe for popular off-label uses.
Patients deserve better and so do physicians. In the case of Infuse, the product is sold to children’s hospitals, where its use is always off-label. That means that the company that makes Infuse, Medtronic, is already promoting its off-label use by reaching out to children’s hospitals to sell their product. Has the FDA ever contacted children’s hospitals to warn them? That would be a relatively easy strategy.
As previously noted, companies currently have very little incentive to test their drugs, biologics, or devices for new indications once they are on the market. If off-label promotion is allowed by the FDA, the companies have even less incentive to conduct well-designed studies and submit applications for approval for those other indications.
Companies and their lawyers argue that off-label promotion is a free speech issue. This seems hypocritical, since the very same companies have made it almost impossible for patients harmed by their drugs and devices to talk about their experiences. Instead, companies that settle with patients who have been harmed by their products, either for approved indications or off label, insist on non-disclosure agreements that make it impossible patients to exercise free speech and share information with other patients and their physicians.
These non-disclosure agreements help explain why it is so rare for the FDA to hear from patients harmed by medical products, whether devices or drugs. Companies actively recruit patients to lobby on their behalf, to Congress and to the FDA, but they do what they can through legal strategies and settlements, to keep patients who have been harmed from speaking up. In addition, patients who were harmed, especially those seriously harmed, are unlikely to have the resources they would need to know when opportunities are available to contact the FDA about an important issue, such as off-label promotion. They are even less likely to have the resources needed to attend FDA public meetings.
The FDA knows that medical product manufacturers frequently provide misleading information to promote off-label uses. Major drug manufacturers have been fined billions of dollars for off-label marketing tactics. For example, many companies making atypical antipsychotics have promoted their use for dementia patients, despite the lack of efficacy and the known risk of fatalities. Unfortunately, these fines are perceived as just the cost of doing business. If the FDA loosens the current restrictions on off-label promotion of medical products, even more patients will be harmed.
As a nonprofit think tank that does not accept funding from companies that make medical products, the National Center for Health Research scrutinizes research to determine the treatments, programs, and policies that improve health care. Based on research showing the clear risks and relatively modest benefits to patients, and the even greater costs to public health when there is inadequate evidence to make informed decisions, we strongly oppose allowing companies to promote medical products for off-label uses. These views are based on evidence and have been confirmed by speaking with hundreds of patients harmed by medical products that they did not know were being used off label.