Abstract
David Cavalla has 28 years' experience in various senior scientific and commercial roles within the pharmaceutical industry. He is currently involved with a number of biotech companies at the board level. Previously, he was founder and CEO of Arachnova Ltd., a company focused on therapeutic switching, from which he exited as a result of a trade sale. Prior affiliations included Glaxo Group Research Ltd. and Napp Research Centre, where he was head of biosciences. He is author of Modern Strategy for Pharmaceutical R&D—Towards the Virtual Research Centre and one of the first advocates of drug repurposing. He frequently contributes articles on pharmaceutical strategy and is on the editorial board of Drug Discovery Today. Formerly, he served as the chairman of the Society for Medicines Research. He obtained a first degree and PhD from Cambridge University and spent 2 years as a visiting fellow at the National Institute of Mental Health in Washington, DC. He is author/inventor of over 70 published articles and patents.
Yes, sometimes—but not always. For instance, there is a famous story of how a leper was treated with thalidomide because his doctor thought this would allow him to sleep (thalidomide was originally licensed for insomnia). The patient was on the verge of death and for 19 months had been bedridden and unable to sleep for more than 2–3 hours during the course of any 24 hours because of the pain of his disease. Suddenly, he was able to sleep for 20 hours straight. This serendipitous discovery ultimately led to the amazing reevaluation of the drug for leprosy. But, of course, leprosy is a serious disease and thalidomide is a dangerous drug. OLU should be reserved for serious conditions in which there is no licensed alternative. Unfortunately, an OLU is written for one in five prescriptions, even for nonserious conditions and when there are licensed alternatives. In some cases, like factor VIIa, which was prescribed off-label 97% of the time, only 1 in 30 prescriptions was written for its approved orphan indication, which was a rare form of inherited hemophilia. In many of these other off-label bleeding disorders, the drug was not effective and actually caused various thromboembolic reactions, including death. Overall, there are 2–3 times as many adverse events with OLU as on-label prescriptions, and when you work this out, it comes to 35,000–45,000 deaths per year associated with the practice.
Again, sometimes it is—but not always. For instance, a doctor needs to do what is in his or her patients' interest, and quite often a child may need a drug that is only approved for adult use. Freedom to prescribe outside regulatory restriction is a right cherished by medical professionals. Doctors use the relatedness principle, according to which an approved drug for one purpose would also be effective for another related purpose. However, the legal liability assumed by a pharmaceutical company is generally limited to the on-label uses and does not follow into related conditions, or related types of patients. Physicians bear a significantly greater burden of malpractice or negligence liability if they prescribe off-label, and they need to justify it by reference to the prevailing standard of care. Furthermore, the relatedness principle is not always correct. For instance, we now know that the risk of suicide and suicidal behavior is a significant problem in young patients on antidepressants. This was first discovered with paroxetine, which was approved for use in adults but used off-label in children and adolescents. It also turned out that paroxetine was not significantly effective as an antidepressant in under 18-year-olds. Now, there is a Food and Drug Administration (FDA) black-box warning for suicidal behavior in association with all antidepressants being used in under 24-year-olds, which doesn't appear to be a problem with older patients. So, in this case, we have an increased risk and decreased level of effectiveness in younger patients, a result that is surprising to many medical professionals.
As I mentioned, quite a lot of OLU is associated with pediatric care, because drugs are often approved for adults only (having been clinically tested in adults only). In recognition of this problem, about a dozen years ago regulatory authorities in Europe and North America offered various sticks and carrots for companies to expand the evidence for the use of their medicines in children and adolescents. The carrot was in the form of additional patent protection, and this has been quite effective in stimulating additional regulatory filings for pediatric medicines, including specific formulations and dosages for these patients. Unfortunately, these incentives only apply to branded medicines, and as we know, an increasing proportion of prescriptions (80–90%) are for generic drugs, which aren't captured by this legislation. So, pediatric medication is a reason why OLU is sometimes necessary. The other point to mention here is that doctors are actually highly interested in OLU and curious about other purposes that existing drugs can be used for. I should point out that a survey of new therapeutic uses for existing drugs found that 57% of them were discovered by practicing clinicians independently of both pharmaceutical company or university research.
There are many, many examples of OLU that are trialed in a doctor's surgery but are not more widely disseminated. Some of them could provide very valuable findings. We have a real problem with publication of these events, partly because there is some skepticism about the robustness of such discoveries. However, it is part of a doctor's duty to “pass on his or her art for the benefit of others,” so we need to find better ways of encouraging these types of disclosure, since they are the seed for wider testing and take-up. Another major problem in this area is that, even though there is potential for new method of use patents, innovations in OLU are often prevented from commanding a commercial return because of off-label generic substitution. This is best exemplified with aspirin, which is approved for the first two of its uses (as a painkiller and for the prevention of strokes), but not for the third, prevention of colon cancer, and potentially other cancers. Any aspirin manufacturer who invests in further trials for this latter use will have his or her rewards diluted among all the other competitor companies who don't similarly invest. So, there is no commercial incentive, and we have to rely on public funding to carry this work forward. In practice, this takes decades. Examples like aspirin (and many others) deny patients cheap and effective treatments or substantially delay them.
Unfortunately, pharma has seen OLU, when applied to its patented drugs, as a huge commercial opportunity to sell products without proper approval. This is countered by regulatory sanction and, to a certain extent, by poor public relations. If a company is marketing a drug for one use, but the drug could be used for another, the company can sell it (but not promote it) at the same unit price but without providing the normal evidence base associated with an approved drug. This is a very gray area, with regulators like the FDA being very aggressive in what they see as protecting patients (remember what I said earlier about the greater risks of OLU). The FDA is prohibited from regulating physicians, who can prescribe OLU perfectly legally, so in conjunction with the Department of Justice, they exert their impact in this area by fining companies. The first really big FDA action started with Neurontin, which was largely sold for the treatment of pain and psychiatric disorders, whereas at the time it was only approved as an adjunctive treatment for epilepsy. This practice has continued so that most of the many billions of dollars extracted from pharma in the past 15 years have been primarily related to OLU marketing activities. Incidentally, they are aided in this effort by whistleblowers who are able to claim up to 30% of any recovery. There now seems to be a limit to the extent to which FDA can police this practice, since a recent judgment allowed a defense based on free speech. And in any case, despite the fines, the opportunities are often worth it. So, although Pfizer was fined $400 million in 2004 regarding Neurontin, the company apparently was undeterred from continuing the practice since they were subsequently fined even larger amounts for off-label promotion of other drugs in 2009 and 2013. In many cases, the level of OLU exceeds the level of “on-label” use, which makes a mockery of our regulatory systems. These high levels of OLU become imprinted on physician behavior, so even after OL promotion has ceased, or the drug becomes generic, the practice continues.
The real problem with OLU is evidence or lack of it. Roughly three quarters of OLU is supported by no, or poor scientific evidence. This means that the two or three times greater adverse events are for drugs that largely do not work! Regulators know this, which is why they are concerned; after all, their role is to ensure that the public gets the safe and effective drugs they need but are protected from the snake oil. Physicians can prescribe, and can even justify their prescriptions, on the basis of a small trial, whereas much more robust levels of evidence are required for regulatory approval. The outcomes from these trials can be based on biomarkers of dubious merit, and indeed this whole area is open to the abuse many pharma critics have posited, around biased evidence and ghostwritten articles. You will note that even the recent pharma proposals regarding opening access to clinical trial data stop when it comes to trials around OLU. It is vital that we find new ways to promote the gathering of robust data to support OLU or refute it. We need to recognize that much of this data will need to bridge from the single case report to the large regulatory trials necessary to support license approval. And we need to encompass not just branded medicines but also generic ones. I have some ideas for this, such as marketing exclusivity for expanded uses of generic drugs based on regulatory filings and different prices for OL versus approved uses, which I shall be writing about in a book to be published later in the year, called Justifying Unapproved Medicines.