Off-Label Use & Safety
 

Off-Label Use & Safety

BART COBERT

MARCH 19, 2014

There has been a lot of discussion regarding the off-label use of drugs.  This has been a focus of interest for FDA, EMA, MHRA and other health agencies around the world and certainly has been an issue and concern at companies over the years.  This is a complex issue with implications for public health, patient safety, corporate profit, innovation and medical care.

Let’s look at some of the basics first.

In most jurisdictions (the US, Canada, EU and elsewhere) a drug, biologic, device or other product is approved for a particular use or disease (“indication for use”).  The approval indication may be very specific (“pneumococcal pneumonia”) or more general (“severe pain”).  What this means is that clinical testing (usually) has shown that using the product in this approved indication, at the approved dosage and route of administration, for the approved length of time, in the approved patient population will have more benefits than risks.  It is, of course, not a guarantee that the product will work or that there will be no adverse events.

Also in most jurisdictions a prescriber can use any product for any patient for any indication.  That is, the prescriber, usually a physician, can determine in his or her judgment that a product can be used for a non-approved use or at a dosage that is higher or lower than what is in the official labeling.  There should be good reasons to do this though this is not always the case.  Sometimes these reasons are based on reports in the medical literature for new uses for an approved drug. Sometimes the physician has particular experience using this product in non-approved indications.  Sometimes the new indication is under review at the health agency with approval expected at some point.  Sometimes the patient clamors for the drug – though this is not always a good reason to prescribe it.  Sometimes a drug is approved for a particular indication in another country but not in the physician’s country suggesting there is a good basis for its use.  Sometimes the non-approval was controversial and the vote on the advisory committee, for example, was very close.  And, of course, sometimes there really is no good justification at all for its use.

In some areas, particularly oncology, where there are dying patients who have failed previous surgical and drug treatments, the oncologist will use drugs not approved for that malignancy or at that dosage but for which there may be some justification for its use or for pushing a dose beyond the labeled limits.  Sometimes this is done in desperation as the last hope for a dying individual.  If the risks and benefits (if any) are well described, with all parties understanding that the treatment is not sanctioned by the health agency, the justification for this seems very reasonable.

On the other hand, there are situations where off-label use of an approved drug is tolerated and expected.  I’ve seen many situations where a new drug can be studied and likely approved for several indications though not all at the same time.  The sponsor company has a choice of looking at one or more indications in their clinical trials.  So how do they decide which to do and how quickly? Sometimes the company will use its limited resources to study the indication which is most common, easy to study and enroll patients.  At other times, the company (often small companies) will choose the indication that will be the fastest to market feeling that they need to generate income to finance further work and make some profit for shareholders.  Deep pocket companies may study several indications at once.

The rub here is that once the drug gets on the market it can be used for all or any indication in most jurisdictions.  The health agencies are well aware of this and, in my experience, there is some level of ambivalence.  The agencies really do want to get innovative new products, particularly new chemical entities or products where there is a no good treatment, onto the market.  The agencies are aware that getting a new indication for a product can take years and meanwhile the results of the successful clinical studies are being published in major journals, presented at medical meetings and, of course, being talked about on-line by patients, disease support groups and others in the social media.
This introduces some very awkward situations.  For governments, there is use by patients and prescribers that is not approved but which may represent good medical practice.  For patients, this may be life-saving or disease-mitigating new therapy.  For companies, this may be more sales and profit.

For some companies it may not pay to pursue a new indication as the patent will be expiring soon, the drug will be generic, the costs are too high, there are too few patients with the disease, the company doesn’t have the money to do more trials, other companies are developing new products which will make ours obsolete soon etc.  So there are often very legitimate reasons for companies not to pursue new indications even though there is general agreement by the health agencies, the company, the prescribers and the patients that this is a worthwhile new indication to pursue.  This is one of the weaknesses of the current system of drug development.

This then can produce bad behavior.  Companies might promote the off-label use (illegally) either knowingly or, wink, wink, nod, nod, unofficially allowing plausible deniability for their management.  One need only look at some of FDA’s Warning Letters to see that certain advertising is going beyond the labeled indication and FDA forces the company to stop that promotion.  Do sales reps ever present unapproved indications as possible uses for their drugs to prescribers using articles they pulled themselves from the internet without corporate knowledge…..?

So off-label use is not simply a question of a company trying to make more money or a physician foolishly doing something incorrect and harmful.  It is a complex area where some off-label use is appropriate and some is not from the medical (but not legal or regulatory) point of view.
There are other interesting aspects of off label use including the question of whether the FDA has the right to limit First Amendment protected free speech.  That is, the US Constitution’s First Amendment limits the government from stopping or limiting  free speech.  This raises the question of whether the FDA can legally prevent a company from disseminating information and scientific articles on off label use.  The FDA issued a draft guidance in 2011 and has just issued a revised draft guidance on Distributing Scientific and Medical Publications on Unapproved New Uses — Recommended Practices, February 2014.  Although these do not address safety per se, the guidance does help the company understand what it can and cannot do in terms of off label use and promotion.  Of course, this will lead to more use off label and more adverse events.
This area has arisen in court cases and may change over the years as courts interpret the law.

See, for example, Wikipedia.

Implications for Safety
Obviously, using a drug for an unapproved indication means venturing into an area where little or nothing is known about the safety profile of the drug.  There may be contraindications to use which are not yet known; there may be drug interactions involving other medications the patient is taking which will prove to be harmful; there may be nuances in the diagnosis, dosage, duration of treatment etc. which are unknown and which may harm the patient.  In other words, this off-label use is an “n of 1” experiment in each patient given the drug.

For this reason, it is prudent for practitioners, patients and the pharmaceutical companies to make extra efforts to track down adverse events and safety issues in off-label use.  Companies should routinely, when collecting adverse event information from the patient or health care practitioner, get the indication for use as well as the full drug use data (start and stop dates, dosing, benefits, AEs, lot number etc.).

Companies should routinely, as part of the signaling process, review off-label use looking for patterns and safety concerns.  There is usually not much data available and large scale data mining is usually not too helpful.  It is here that medically trained and savvy individuals should examine these cases looking for trends and signals.  The threshold for concern should be low; that is, start worrying sooner if something looks problematic!  Since there may be little or no other data in the database or medical literature to help in the safety analysis, individual cases become more important in the analysis.
These cases should be kept in the signal list and, of course, reported to the FDA and other health authorities if the cases meet expedited reporting requirements.  Be conservative and, if in doubt, report the case.

Keep in mind that off-label safety information must now be included in PSURs/PBRERs and, if required, in REMS and RMPs.  Also keep in mind that FDA’s definition of an AE (21CFR312.32(a)) includes off label use.  So health authorities are aware of and interested in off-label use.  Be sure, if you are in a company, that you are keeping FDA and the health agency up to date on safety concerns with off label use.  Be sure also that the company is complying with the laws and regulations (and guidances) covering this area in all markets.

The Bottom Line:Off-label use is real and will not go away and is, in some cases, a good thing for public health.  From the safety perspective, careful attention must be paid to off label use.  Strong follow up and data collection should be done and careful analysis done for safety trends and signals.  Senior management should be kept well aware of any safety issues.
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