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- Herausgeber: John Wiley & Sons
- Kategorie: Wissenschaft und neue Technologien
- Sprache: Englisch
Today’s medicines are regulated for their efficacy and safety and, once approved, they can be marketed for certain uses as justified by the data. Regulatory bodies in developed countries are constituted by legal statute and operate as parts of government, ostensibly in the interests of the people as patients.
But once approved, medicines can be used for any purpose the prescriber thinks fit and appropriate for the patient. One in five prescriptions is therefore written outside regulatory purview.
Off-label Prescribing looks into the corners of our medicated lives, where drug regulation runs up against medical practice, and concerns the use of a drug that has been approved for one use (in medical parlance, ‘indication’) being used for a different indication; alternatively, being used on a different set of patients from the ones it is approved for, or at a different dose. Usually the patient is unaware of what is going on, having not been informed by their doctor of this aspect of his or her prescribing choice.
The book examines how and why this occurs, what the various medical professions have to say about it, and how pharmaceutical companies benefit by moving into this poorly regulated area. Off-label Prescribing pulls these complex issues together in one volume, to highlight current practice, its advantages and weaknesses and how the author suggests practice should evolve in the future. It will therefore be of interest to all those who prescribe (and receive) medicines, combined with a greater objective to provide more transparency and discussion for professionals.
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CONTENTS
Cover
Title page
Copyright page
Dedication page
Foreword
Acknowledgement
Author’s note on the cover design
Introduction
Chapter 1: What is off-label medication, and how prevalent is it?
What is ‘off-label’ medicine?
Scope of the issue
Chapter 2: Where it all went right: new uses for existing drugs supported by good evidence
Examples where products have been through regulatory approval for a secondary use
Examples where evidence is uncertain and not to regulatory standards
Chapter 3: Shared decision making and consent
Viewpoint of the patient
Viewpoint of the prescriber
Diagnosis
Chapter 4: Gaming the system: the role of the pharmaceutical industry
Normal drug development and drug repurposing development
DTC advertising
Patents and genericisation
Conclusion
Chapter 5: Do no harm: Safety and efficacy
Relative safety
Fatal ADRs
Quality of evidence
Chapter 6: Liability, injustice and reimbursement: who should pay?
A prescriber’s ethical and professional duties
A prescriber’s legal position
Reimbursement
Cost, as a driver for off-label medicine
Chapter 7: The role of regulation in off-label medicine
Regulators do not regulate medical practice
Off-label marketing
Chapter 8: Justifying unapproved medicine
Constraints on making changes
A partial solution: clinical trial transparency
A solution based on increased regulatory supervision
My solutions
Conclusion
References
Index
End User License Agreement
List of Tables
Chapter 04
Table 4.1 Summary of orphan legislation around the developed world.
Table 4.2 Orphan indications for some top-selling drugs.
Chapter 05
Table 5.1 Summary of studies showing increased risk of ADRs in paediatric patients treated with off-label medicine compared to treatment in accordance with approved status.
Table 5.2 Drug use, by on- and off-label status and level of supporting evidence, ranked by decreasing order of off-label uses with inadequate evidence.
Table 5.3 Approved indications for TNF blockers.
Table 5.4 Indications in whose pathophysiology TNF has been implicated, but for which TNF blockers are not clinically effective.
Chapter 07
Table 7.1 Significant fines in relation to illegal off-label promotional activities of major pharmaceutical companies imposed by the US Department of Justice.
Chapter 08
Table 8.1 The dilemma of regulatory drug approval.
Table 8.2 Potential additional uses for statins supported by evidence in human situations, from retrospective trials, case reports or prospective studies.
List of Illustrations
Chapter 01
Figure 1.1 Off-label mentions by therapeutic class. Graph drawn from data in Ref. [9].
Figure 1.2 Levels of off-label use and scientific evidence, by therapeutic area. Graph drawn from data in Ref. [9].
Figure 1.3 Costs associated with the prescribing of antipsychotic medications in the United States, 2002 through 2008, categorised by off-label status and level of supporting evidence.
Chapter 02
Figure 2.1 Pseudohermaphroditism; photographs of afflicted males before and after puberty.
Chapter 04
Figure 4.1 Life expectancy in the United States.
Figure 4.2 Percentage success of compounds entering first human studies (Phase I) that are successful in progressing to subsequent stages of development.
Figure 4.3 Use of Lidoderm for approved orphan and non-approved uses.
Figure 4.4 Use of Provigil for approved orphan, approved non-orphan and non-approved uses.
Figure 4.5 Neurontin (gabapentin) prescriptions, by indication.
Figure 4.6 Average relative price of generic to brand. FDA analysis of retail sales data from IMS Health, IMS National Sales Perspective (TM), 1999–2004, extracted February 2005 (http://aspe.hhs.gov/sp/reports/2010/GenericDrugs/ib.shtml).
Chapter 05
Figure 5.1 Suicide attempt among adolescents and young adults (under 25 years) before and after receiving new antidepressant prescriptions from primary care physicians or psychiatrists or starting psychotherapy.
Figure 5.2 Really?
Figure 5.3 The COX-2 selective drug Vioxx reduced the gastropathy risk of the non-selective NSAIDs but substituted it with cardiovascular risk. Ibuprofen and naproxen, both non-selective NSAIDs, share similar gastropathy risks, but ibuprofen also carries a similar cardiovascular risk to Vioxx – the worst of both worlds.
Chapter 06
Figure 6.1 The flow of prescriptions from physician to patient is matched by a reverse flow of payment from payer to producer. The payer also determines the level of copayment by the patient, if any. The total payment is made up of the copayment and the reimbursement.
Chapter 08
Figure 8.1 Generic and branded products, used on- and off-label, and whether they are likely targets for clinical data transparency (a) accessibility of data and (b) volume of prescriptions. The areas of the rectangle relate to numbers of prescriptions, normalised to 100%.
Figure 8.2 Possible development route to convert an off-label medicine into one with regulatory approval. Additional involvement of pharmacovigilance data comes from ongoing regulatory assessment of the product according to the original approval. Commercial engagement is incentivised either as a branded medicine by pricing, or if a generic medicine by exclusivity arrangements.
Figure 8.3 Merck’s two products containing the drug finasteride were for prostate enlargement and hair loss. The second product (Propecia) was developed under a method of use patent and contained a different dose of finasteride than was contained in Proscar.
Guide
Cover
Table of Contents
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Off-label prescribing – justifying unapproved medicine
David Cavalla
This edition first published 2015 © 2015 by John Wiley & Sons, Ltd.
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Cavalla, David, author. Off-label prescribing : justifying unapproved medicine / David Cavalla. p. ; cm. Includes bibliographical references and index.
ISBN 978-1-118-91207-2 (cloth) I. Title. [DNLM: 1. Off-Label Use. 2. Drug Approval. 3. Pharmaceutical Preparations. QV 748] RM300 615.1–dc23
2014028488
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Cover image: © Dan JubbCover design by Dan Jubb
This book is for patients, who for too long have been misled about the fact that many of the prescriptions that are written for them are for unapproved for their circumstance. We are all patients, or potential patients, so really this book is for everyone.
Foreword
NORD (The National Organisation for Rare Disorders) estimates that 25 000 000 Americans, 8% of the population, have a life-altering disease for which there is no currently effective therapy. Globally, 8% of the population would yield over 500 000 000 people similarly affected. Yet, under the current system, with all the knowledge, technology and money we have to invest in this problem, most people with diseases for which there are no, or only poor, treatment options have little hope of receiving an effective treatment in their lifetimes. Healthcare costs round the world keep rising, and a significant portion is spent on palliative care for diseases with no truly effective treatment. Those costs, plus lost productivity costs and the emotional trauma for patients and their families, directly or indirectly impact all of us.
The for-profit medical research industry is our current ‘solution’, but it can only work for some patients, and many serious conditions are left unaddressed. The major pharmaceutical companies invest more than US$ 70 billion per year in R&D to bring to market about 30 new drugs or drug improvements annually. Development takes 10–14 years and costs US$ 1.5 billion or more per new drug. Industry generally makes a lower investment in rare diseases, acute diseases, prevention and diseases of the poor where it cannot make a suitable profit. This is essentially a market failure, which restricts many patients from receiving solutions to their medical problems, and makes it unlikely that the for-profit system can conquer most of the 7000 diseases waiting to be addressed.
Other factors compound the problem. Academic research for diseases of the poor and rare diseases receive limited funding. Researchers often cannot or would not collaborate due to intellectual property and authorship concerns, so the limited funds that are available are not leveraged by collaboration. And philanthropic and venture funders are often stymied in their efforts to find the best treatment ideas and creating the research partnerships required to create treatments for these underserved patients and diseases.
Physicians, patients, payers, government and industry are all searching for solutions to this gaping treatment hole. One stopgap measure employed with regularity around the globe is to use drugs approved for one disease to treat another disease for which formal approval has not been obtained: this is called ‘off-label’ medicine. While on the surface repurposing of our existing therapeutic armoury has great appeal, when one examines this in more detail, significant peril is exposed. In practice, the freedom to prescribe off-label has often been abused by prescribers and industry: products have been used with inadequate evidence for trivial conditions, and commercial interests have trumped patient welfare. In order to sort this out, we need to differentiate the acceptable off-label uses from the unacceptable. But how?
David Cavalla examines, in great detail and with clear support, the issues of off-label drug prescribing. His evaluation is both broad and deep. He notes the value and the pitfalls of the practice, and offers cogent and feasible solutions to create greater value for patients. Most importantly, while sharing his expertise, he gives the reader the chance to draw his or her own conclusions. This is a very important book, because catastrophic diseases do or will impact many of us. At some point in each of our lives, we are likely to be faced with the need to find a medical solution to an unresolved disease, either for ourselves or for someone we care about. And that solution might involve what David Cavalla calls ‘An Unapproved Medicine’. Armed with the knowledge in this book, you might make a different set of decisions or make the same decision better informed.
Dr. Bruce E. Bloom
President and Chief Science Officer,Cures Within Reach
Acknowledgement
In writing this book I would like to thank all of the people who have given me help and advice, including specifically my wife, my daughter Anna and father John, who read and reviewed the early draft of the manuscript. I am also most thankful for the expert advice from Drs David Erskine, Janice Steele and Michael Clementson from the delivery end of medicine, as pharmacists and practitioners.
Author’s note on the cover design
Off-label medicine is the technical term for medicines which have not been approved for the therapeutic purpose for which they are prescribed. It is a term with which most patients are unfamiliar, yet it can be likened to something with which is much more recognisable: off-piste skiing. The likeness, depicted on the cover of this book, extends on the one hand to the fact that neither practice is strictly illegal, and on the other to the fact that both practices are less safe and well-described than the authorised alternatives. Off-label uses of medicines are not regulated, so we have much less information about the safety and efficacy of the treatments. But sometimes, like off-piste skiing, there is no other way to travel.
To justify the use of an off-label treatment, there is one and only one person to bear in mind: the patient. But disposing of the other interests in the delivery of medicine, for example the pharmaceutical company that makes the product, the doctor who prescribes it and the government or insurance company who pays for it, is not an easy task.
Introduction
When becoming authorised to practise, the Hippocratic Oath requires a doctor to swear to ‘…use treatments for the benefit of the ill…but from what is to their harm and injustice…[to]…keep them’[1].
It is common knowledge among the medical profession and the public at large that the Oath requires the doctor to essentially ‘Do no harm’; however, the requirement to keep their patients from injustice is much less appreciated. This book will identify issues that relate to the justice of the relationship between doctor and patient, as well as a wider consideration of other aspects of the complex ways in which medicines travel from scientist’s bench to the bedside.
Most importantly, it will deal with the way in which around one in five of prescriptions today are written outside regulatory purview – in other words, the treatments have not been approved by the regulatory agencies. This is what I mean by unapproved medicine. Given that there were over four billion prescriptions written in the United States in 2011 [2], it is a very significant issue. * In certain areas, the proportion of unapproved prescriptions is much higher even than this, reaching three quarters or even 90% of prescriptions in some types of patients or with certain conditions.
At this point, you, the Reader, will surely say: No, he is wrong. This cannot be. We have a highly regulated and legally constituted system by which the safety and efficacy of medicines is ensured before they are taken by patients. I do know that medicines sometimes have side effects, sometimes do not work and sometimes even the regulators get it wrong, but I simply cannot believe that prescriptions cannot be written without regulatory say-so. And on this scale, it beggars belief!
You will also say: How can I not have heard of this before? If it is true, why have the press not highlighted it more? What is the point of medicines regulation when nearly a quarter of prescriptions are not regulatorily approved? Being perhaps well read in this area, you may also say: I have heard there are issues of data being hidden from the public by pharmaceutical companies, but I thought companies were obliged to have all their products approved by regulators before they are dispensed. And, you go on: if this is so, why are regulators not more stringent with the rules, to prevent it happening?
If this is your response, please do read on, because what I say is true. And, for the most part, it is all perfectly legal. It is my intention that by the end of the book, readers will be able to judge whether, from the patient's perspective, our current practice of medicine and its prescription meets the standard of justice espoused in the Hippocratic Oath.
This book explores the nooks and crannies of our medicated lives, where drug regulation runs up against medical practice, and concerns the use of a drug that has been approved for one use (in medical parlance, ‘indication’) being used for a different indication; alternatively, being used on a different set of patients from the ones it is approved for, or at a different dose. It is now time to shed some light on this somewhat dark area. As you will see, not only does this mean that the evidence base for the drug's benefit is suspect, but there are safety issues too. Usually the patient is unaware of what is going on, having not been informed by their doctor of this aspect of his or her prescribing choice. I will tell you what the various medical professions have to say about this, how they respond to regulatory bodies and how pharmaceutical companies benefit by moving into this poorly regulated area. The issues are complex and resist simplistic headline-grabbing sound bites; but I hope you will persist to the conclusion of this book, since, in addition to pointing out the problems, by the end I will also leave you with some proposals to improve the way medicines are prescribed and evidence gathered to support the ways they are used.
Note
*
Using data from the OECD (OECD Health Policy Studies Pharmaceutical Pricing Policies in a Global Market; OECD Publishing, 2008. DOI: 10.1787/9789264044159-en), the relative volume of pharmaceutical utilisation can be obtained across the OECD countries. This is then normalised according to the population and the known number of prescriptions in the United States in 2011, which is 4.02 billion according to Ref. [2]. The total number of prescriptions across the United States, Japan, France, Germany, Spain, the United Kingdom, Italy, Korea, Canada, Australia, Mexico, Poland, the Netherlands, Sweden, Portugal, Austria, Hungary, Czech Republic, Switzerland, Norway, Finland, Denmark, Ireland, Slovakia, New Zealand and Iceland is then estimated to be 10.85 billion. Twenty-one per cent of this is over two billion prescriptions per year, a number I shall refer to later in the book.
Chapter 1What is off-label medication, and how prevalent is it?
The practice of medicine has been regulated since Hippocrates, who first told doctors (physicians, clinicians, general practitioners [GPs] and so on) how they should behave with regard to their patients. His Oath, written nearly 2500 years ago, is the most famous text in Western medicine. Though most people do not know exactly what it says, they believe it to say something along the lines of ‘Doctor, do no harm’. That is only partly true, as I shall now explain.
But before I do, there are actually many versions in the public mind of what Hippocrates said, including the view recounted by one UK doctor of an elderly patient who believed the Oath instructed doctors never to tell patients the truth. This book will describe circumstances in which this patient is often correct, namely, that GPs do not tell the truth to their patients, but of course incorrect in that Hippocratic Oath does not say that.
The Oath starts: ‘I swear by Apollo the physician and by Asclepius and Hygieia and Panacea… to bring the following oath to fulfilment’. According to Greek mythology, Apollo is the god of healing, Asclepius is his son and Hygieia and Panacea are his granddaughters. As with Zeus his father, Apollo had many love affairs with goddesses and mortals. One of his amours was Coronis, who was the daughter of the king of the Lapiths. Dwelling on a higher plane, Apollo was not able to be beside Coronis on earth, so he sent a white crow to look after her. Unfortunately, while she was pregnant by Apollo, Coronis fell in love with another man, and the crow informed Apollo of the affair. Appalled at her infidelity, in his anger, Apollo turned the crow black.
Artemis, Apollo’s twin sister, shot an arrow to kill Coronis. While Coronis’ body was burning on the funeral pyre, Apollo removed the unborn child, who was called Asclepius and became the god of medicine. When he grew up, Asclepius had two daughters, Hygieia, the goddess of health, and Panacea, the goddess of cures: medicine ran in the family. The words ‘hygiene’ and ‘panacea’ clearly have their etymological origins in these mythological figures.
According to legend, Hippocrates was a descendant of Asclepius; this gives more weight to Hippocrates’ proclamations, particularly when he pronounces on medical matters. Part of the Oath instructs the doctor to treat his teachers as his parents and to pass on the art of medicine to the next generation of healers. This is clearly relevant to Hippocrates’ ancestry, going all the way back to Apollo. But it is the next part of the Oath that is most relevant to this book and indeed to the practice of medicine.
It continues: ‘And I will use treatments for the benefit of the ill in accordance with my ability and my judgment, but from what is to their harm and injustice I will keep them’.
It is the two words, ‘harm’ and ‘injustice’ which I ask you to bear in mind as we go forwards.
What is ‘off-label’ medicine?
Today, medicines are regulated for their efficacy and safety, and once licensed for sale, they can be marketed for certain uses as justified by the data. Regulatory bodies in developed countries are constituted by legal statute and operate as parts of government, ostensibly in the interests of the people as patients. But once approved, medicines can be used for any purpose the prescriber sees fit and appropriate for the patient. In other words, regulatory authorities are the gatekeepers to prevent the medical use of unapproved products, but then leave the gate entirely wide open regarding unapproved indications or uses of approved products. To be succinct, medicinal products require regulatory approval, but the practice of medicine does not. There remain restrictions on the marketing of these products, but these are considerations for the producer, not the prescriber. Later on, I will explain the nuance that distinguishes between the marketing and the use of medicines and how, in my opinion, pharmaceutical companies game the system.
The ways in which medicines are prescribed, and administered, outside the terms of the marketing authorisation are called ‘off-label’ uses. They have not been justified by the regulatory authorities, which determine the label for the product, hence the title of this book. As was said, a ‘general off-label use of drugs is the death of the idea of regulation’ [3]. The importance of the regulatory justification is not merely because these public authorities spend a lot of time, money and manpower examining the evidence behind the safety and efficacy of the medicines we take: it is because these authorities are put in place to implement certain standards to which the patient expects his or her therapy to accord. The regulatory approval is also the patient’s approval, the basis for their consent to being treated with the prescribed medication. Drug regulation is a complex decision about the balance of safety and efficacy,1 benefit and risk – a world of shades of grey, not black and white. In the real world, the prescribing doctor has a lot of flexibility as to what s/he can prescribe; that flexibility can be put to good use, but patients are rarely aware that their off-label medicine has not been approved for their affliction, with consequences to the quality of their care.
So, off-label prescriptions are not illegal, and from the doctor’s perspective, they may not even be seen as unethical; in fact, according to the Hippocratic Oath, they may fulfil a doctor’s moral imperative, for instance, in situations of rare diseases where there is no approved product. However, the evidence behind off-label medicine rarely fulfils the patient’s expectations that a formal regulatory assessment of safety and efficacy has been performed, and this is the first sense in which I mean off-label medicine seems to be unjustified. Later, in Chapter 6, I shall deal with other consequences, such as who pays for the medicine, and what happens in cases where things go wrong. But before doing so, let us consider the scale of the issue.
There are lots of examples of secondary uses for existing drugs. The story of how a proposed treatment for angina and heart failure ended up as the world’s first treatment for erectile dysfunction is well known. The company behind the drug (Pfizer), now known as Viagra™, recorded that when the product, then known as UK-92480-10, or sildenafil, was first tried on male volunteers in a Welsh clinic, they reported physical excitation on seeing the nurses in the ward, requiring them to roll on their stomachs. In this case, the intended development for cardiovascular diseases was curtailed, and the product entered into medical practice for the treatment of erectile dysfunction instead (and in 2012, generated over $2 billion in revenue for Pfizer). Because the decision to develop for erectile dysfunction occurred before Viagra was approved for any use, this is not an example of off-label medication. However, even though this story is somewhat anecdotal, it does show that drugs often do more than one thing. In fact, there is a sequel to the first approval indication for sildenafil, in which it was subsequently developed for a second indication (or third, depending on how you look at it), as we shall see in Chapter 2.
I have strong interest in this area, having investigated this area of secondary uses for existing drugs, now called drug repurposing, for over 15 years. I have collated over 2300 proposed new uses for existing drugs, either marketed products or investigational compounds. This is freely accessible on the internet at http://www.drugrepur-posing.info. But the level of support for such new uses can vary enormously. In some cases, we have human data, such as clinical trials to support the effect. In many others, there is only information from experiments in vitro (literally ‘in glass’, this refers to test tube experiments) or in vivo (in animals). Some information even derives from a computer assessment of the shape similarity of drugs, but predictions like this based on in silico analysis are merely hypotheses, starting points for research programmes lasting years or even decades to deliver validation in regulatory studies that would be needed for market approval. As we shall discover in Chapter 4, most of the normal scientific hypotheses upon which drug discovery programmes are based turn out to be wrong.
We now realise that there are very few, if any, drugs with only one activity and/or only one conceivable therapeutic use. But even though there is vast promise from making better use of the drugs we currently have on hand, most of the early-stage predictions fail to be realised in practice. Sometimes this is for commercial reasons, but it is also for experimental reasons of safety or efficacy. As this area becomes more widely used as a means to discover new therapeutics, it is all the more likely that the current medicines that we all use will become increasingly investigated for new uses. New discoveries of this kind can be enormously helpful to the armoury of therapeutics available to the patient. However, it is unsafe to suppose that a theory deriving from an animal experiment, or anecdotal case report from one patient, really translates into a safe, efficacious treatment of general merit: it needs to be proven. Prescribers have enormous freedom to uncover whether the early science suggestive of a human benefit really works in a patient. As this book will show, the current legal framework, regulatory controls and ethical norms in medicine do not provide the best environment for delivering such new therapeutics to patients, and the consequences of its misapplication can be gravely injurious.
There are two main types of off-label medicine: use of drugs for unapproved diseases or conditions (which, in the medical profession, are called ‘indications’), and use of drugs for unapproved patient groups. Off-label use can also include prescribing different dosages, lengthening or shortening the interval between treatments or using different routes of administration from those indicated on the drug label.2
There are three main areas of therapy where off-label medicines are most widely used. The first is the use of products licensed for adults, on the basis of clinical trials in adults, for children. The second is of psychiatric medicines, and the third is in oncology treatment. We started with a broad statement that off-label use constitutes ‘20% of all prescriptions’, but the prevalence varies enormously, and among these broad classes lie salient examples where off-label use reaches staggering proportions. Getting consistent statistics can be difficult: a review of international studies in ambulatory care reports rates of 13.2% and 29%, in paediatric wards between 18% and 60% and in neonatal units between 14% and 63% [4]. Another international literature review reports that rates for off-label medicine use vary between 11% and 80% [5]. A study from the Netherlands reports that 44% of all prescriptions in a paediatric ward are off-label [6]. In Germany, around 40% of under 18s were prescribed at least one off-label medicine among a study of 17 000, with no significant differences according to region, urbanity, migrant background and social class [7].
To summarise these figures, one could say that higher rates are seen in younger patients and in hospital settings, and that a figure of 20% lies at the lower end of these reports. However, consistent estimates of the prevalence of off-label use are made more difficult because they are often not recorded in a patient’s notes; this in turn may reflect the fact that they are associated with increased liability for physicians. Thus, it is quite possible for an audit of physician practice to deliver a result indicating a falsely low rate of off-label prescriptions and, where there is a range of figures, to suspect the higher proportion to reflect more accurately the real situation [8].
In fact, in many areas, off-label use is more common than use according to the approved label, bringing to mind the point that in such circumstances the pharmaceutical regulatory system is not fit for purpose. But also, even though this is clearly a very large issue, getting hold of reliable statistics is something of a problem in itself. Off-label medicine is not universally shady, but it does have shady patches, and few practitioners will admit to having participated in the darker regions of the practice any more than they absolutely have to. So there are questions about the statistics, but if they are wrong, one would suspect them to be under- rather than overestimates. Very few doctors would voluntary admit to prescribing off-label when they have not. That also tells you something about the perceived ethics involved. Nevertheless, to avoid criticism, I have erred on the side of caution in my overall statement that it constitutes ‘20% of all prescriptions’. A widely referenced article looked in detail at the issue and came to a similar conclusion; they also assessed the proportion of off-label use by therapeutic class [9] (Figure 1.1).
Figure 1.1 Off-label mentions by therapeutic class. Graph drawn from data in Ref. [9].
To give you some simple examples, the prescription of antibiotics for colds and flu is almost entirely without patient benefit but at significant cost to the NHS in the United Kingdom (and equivalent payers in other countries) and raises concern in an era of increasing bacterial resistance; the prescription of antipsychotics to dementia patients without their consent and at their increased risk is a scandal that led to a recent UK government report and action; and the prescription of antidepressants to children and adolescents when they had only been licensed for adults revealed age-related increases in suicide risk, with increasing risk for young patients but not for old.
Off-label medication is not always a bad thing, and it would be a grave mistake to ban the practice entirely. I certainly would not advocate its prohibition, far from it. In my work on the area of secondary and tertiary uses for existing drugs, I have come to realise the huge potential of this area of study. A main purpose of this book is to ensure that the beneficial discoveries made by doctors in the privacy of their patient consultations are properly validated and widely disseminated. The advantages of this approach are shown clearly by the story that follows, representing one of the strangest examples of a bad drug made good through off-label prescription, coupled with a strong element of serendipity.
The drug is thalidomide, a name which connotes some of the worst aspects of pharmaceutical industry misbehaviour and patient harm. Thalidomide was first introduced in 1957 by the West German company Chemie Grünenthal GmbH with the trade name Contergan, a potent and apparently safe sleeping pill. In laboratory rodents, unlike barbiturates – with which it was compared at the time – thalidomide proved remarkably ‘safe’, insofar as it was almost impossible to administer a single lethal dose. As we know now, these tests were insufficiently broad to cover the full range of toxicological consequences of the drug’s long-term administration. Clinical testing in Germany was unsystematic, with pills distributed to employees and samples given to local doctors. With its apparent safety advantages compared to other sleeping pills like barbiturates, which can be lethal at small multiples of their therapeutic dose, thalidomide gained widespread popularity in Europe and Canada; it could even be purchased without a prescription. This was an era of burgeoning use of pharmaceuticals, and their use in psychiatric conditions, as the Rolling Stones recognised so acutely in ‘Mother's Little Helper’, a song about the widespread use of diazepam (Valium™). It was also an era of minimal regulatory supervision of the pharmaceutical industry. Later on, in addition to its use as a sleeping pill, thalidomide also became popular in the treatment of pregnancy-related morning sickness.
The first ‘thalidomide’ baby was born on Christmas Day, 1956, before the drug went on the market; she was born with no ears as the daughter of an employee of Chemie Grünenthal who had given his pregnant wife some of the free tablets. Around the same time, physicians and neurologists reported an increased incidence of peripheral neuritis (tingling hands and feet) in adult patients who were taking the sedative. The connection between these cases and the use of thalidomide was not yet clear, but the neuritis effect prevented the approval of the drug by the Food and Drug Administration (FDA) in the United States.
The Australian obstetrician William McBride was instrumental in connecting the use of thalidomide with its toxicity to the unborn child (teratogenicity). He prescribed the drug for women suffering from morning sickness and then suspected a causal link in the malformed babies he delivered months later. McBride led the uncovering of the scandal, which included overcoming the initial intransigence of the drug companies that were involved and the important role of journalists in securing proper compensation for the victims. One estimate is that thalidomide caused malformations in between 8000 and 12 000 infants, 5000 of whom lived to adulthood. In addition, over 40 000 people suffered from peripheral neuritis. Thalidomide was banned by the World Health Organization (WHO) in 1962 and withdrawn from the market in Europe and Canada, and one would have thought that would be the end of its medical life.
But in 1964, a critically ill patient with erythema nodosum leprosum (ENL), a complication of multibacillary leprosy, was referred to Dr. Jacob Sheskin, who was at Hadassah University in Jerusalem by the University of Marseilles, France. The story is brought to life in the eminently readable Dark Remedy: The Impact of Thalidomide and Its Revival as a Vital Medicine, by Trent Stephens and Rock Brynner [10]. Leprosy (Hansen’s disease) is a chronic, infectious disease of human beings that primarily affects the skin, mucous membranes and nerves. This bacterial disease is caused by Mycobacterium leprae, and is normally contracted through the respiratory tract and is similar to the bacillus that causes tuberculosis.
‘My discovery’, said Dr. Sheskin,
came about only by chance. In 1964, we had a letter from the University Hospital in Marseilles saying that a Moroccan immigrant from the Atlas Mountains on his way to Israel had been hospitalized there with Hansen’s disease. They requested permission to allow the patient to continue his travels to Israel [11]. Through the Jewish Agency we answered that since the man was a Jew he was entitled to return to Israel. A separate plane was hired, and the patient, his wife, a son of a previous marriage also suffering from Hansen’s disease, and several children of the wife’s previous marriage were put on the plane in isolation and sent to Israel.
The patient arrived in a terrible state, suffering from extreme lepra reaction with all the classical symptoms. I have never seen a leper in worse condition. For 19 months he had been bedridden and had not slept for more than 2–3 hours during the course of any 24 hours. The pain he was suffering was unbearable. He had cachexia3 and was on the verge of death. I had read in the literature that women mental in-patients were being given thalidomide to make them sleep, and that the drug was effective where nothing else had helped. Since the patient was in such a hopeless state, I decided to try thalidomide to sooth him.
After 1 day of the thalidomide – two pills – he slept for about 20 hours without waking. When he woke he said he felt so much better that he wanted to get off the bed to go to the toilet! I only had 20 thalidomide tablets: the drug had already been condemned all over the world and had been withdrawn from the market. I gave him two more pills and made him stay in bed for another 24 hours. This time, the pain, which had been so great, had disappeared almost entirely. After another 3 days of treatment, I decided to stop the pills to see what would happen.
All the symptoms returned, the pain, the insomnia, and the inflammation of the eyes. So I started the pills again. Once again, his condition improved dramatically. I then knew that it was not by chance that he had gotten better but because of the thalidomide. I secured more thalidomide and started to give other patients in the Hospital suffering from extreme lepra reaction the thalidomide treatment. All recovered dramatically.
Because of the disastrous effects of thalidomide on foetuses, we did not give the drug to fertile women lepers. We did not want any more deformed thalidomide babies. So we gave the pills only to women rendered infertile. But there are still about 12 million lepers in the world, half of whom are not being treated at all. Much remains to be done to reach them’.
To confirm his findings, Sheskin needed to travel to Venezuela, where there were many more lepers and where thalidomide was still available. There he conducted clinical tests with patients whom he had treated in the past and for whom he had records. He ended up treating 173 patients, and over 90% were symptomatically cured. His unexpected discovery led to further research on the discredited drug; scientists began to ask if it could be useful in other inflammatory conditions? In so doing, they revealed that thalidomide could modify certain immune reactions and could be useful also for those infected with HIV/AIDS and in other autoimmune conditions. More widely, research in cancer revealed that it could inhibit the proliferation of blood vessels associated with the development of tumours, thus slowing tumour growth. This effect paralleled the original effects of the drug on the growing foetus, where it was shown to interfere with the blood supply to the developing limbs of the foetus. We seem to have a common mechanism for the teratogenicity and the oncological activity.
As far as leprosy was concerned, the development was taken up by the US pharmaceutical company Celgene, and after some confirmatory placebo-controlled trials, thalidomide was finally approved in 1997 by the FDA for treatment of ENL. It subsequently became approved for cancer of the bone marrow, or multiple myeloma. To enhance its safe application and use, a special educational booklet was created, called System for Thalidomide Education and Prescribing Safety, to which patients must adhere. As a further indication of its concern about safety and to remind patients of the terrible former history of the new treatment, Celgene wanted to retain the name ‘Thalidomide’ as a trade name for its product, so that people would recognise its potential problems and avoid them.
This is a remarkable story, elements of which I shall refer to in later parts of this book. Firstly, it is profoundly apposite for my subject matter, since off-label uses refer to the use of medicines outside regulatory purview. Thalidomide was the reason why our current system of medicines regulation exists. Regulatory bodies around the world were drastically strengthened after the tragedy in order to prevent it happening again. A whole range of additional preclinical toxicology tests became necessary before experimental drugs could be first tested on humans. Drug regulation nowadays is all about risk and reward, safety and efficacy. It is a complex process, and enormous amounts of information are accrued and evaluated in order to make the assessment as accurate as possible. However, we recognise that no drug is perfect, and all have side effects. We need to minimise the risk and optimise the reward, but we are never going to have a completely safe or a completely efficacious treatment. It is a balance, infinite shades of grey. The system got it wrong with the first life of thalidomide, but got it right in the second.
So secondly, this story makes another important point. We should recognise that thalidomide’s old uses, for inducing sleep and for morning sickness, are troublesome for those affected, but not more than this: they are hardly life-threatening. People who are not treated are likely to be more tired, or nauseous, but these are natural processes which to a certain extent are self-correcting. Patients with insomnia eventually fall asleep; pregnant women with morning sickness eventually move into their third trimester, and the symptoms normally resolve. In comparison, leprosy and multiple myeloma are very serious conditions. They do not self-correct; left untreated, patients with these conditions often die as a result of them. This difference is vital if we are fully to understand and find better systems to deal with off-label uses for existing drugs.
But in another respect, this is a good demonstration of off-label prescription leading to patient benefit, rather than the reverse. So, where then is the harm?
Scope of the issue
Clearly from the thalidomide example, serendipity plays a central role in the history of the development of medicines. Indeed, Dr Sheskin’s motivation for prescribing thalidomide to the leprous patient was to enable him to sleep, given that the patient had not been able to do so before coming into his care. Long before the modern era, treatments were often applied to patients in all sorts of conditions in order to discover whether they worked. If you look at the potential uses proposed for herbal medicine, which often derived from folk medicine, you can see the huge range of ailments which they are proposed to work for.
In William Withering’s An Account of the Foxglove, written in 1785, the author is a practising doctor who tries his treatment on all sorts of patients. Included in the account are examples of diseases we can recognise, like asthma or gout, as well as ones which are difficult to decipher, like dropsy (an old word for oedema, or swelling) or anasarca (which is extreme generalised swelling). These latter two are symptoms of a number of possible illnesses. He informs us in particular that the preparation has beneficial effects on urine production. In days of bladder stones and other urinary problems, the delivery of ‘a healthy flow’ was generally considered a very good thing. It would particularly be so for patients with extreme general swelling, which could be due to liver failure, kidney failure, heart failure as well as severe malnutrition or protein deficiency. Nowadays, we recognise the active ingredient of the foxglove (Digitalispurpurea) to be digoxin, which is used both directly and as its derivative, digitoxin, for the treatment of heart failure. But it is not useful for liver failure, or malnutrition, and when used in excess, digoxin and digitoxin are both poisonous.
The story of Digitalis shows how one herbal product was generally used in a number of indications, but over the years, its utility focussed upon one indication. The evidence base closed in around heart failure. Dr Withering, in the late eighteenth century, played his part in this process by providing a written account of his experiences. Nowadays, drugs are subjected to randomised, controlled trials to find out whether they actually do any good and then first introduced for one indication alone, to be given to a specified patient population, at a specified dose and in a specified form. Subsequent to that introduction, experimental efforts are made to expand the limits of these specifications. Sadly, unlike Withering’s treatise, not all of the experiences in that process of expansion are documented in modern medical practice. Generally, the prescription of a drug in an off-label fashion, based as it is on limited evidence, does not itself result in the enlargement of the evidence base; the result of the prescription is not written and disseminated for future cohorts exposed to similar treatment. This problem is further dealt with in Chapter 8, where I discuss whether it is right that off-label medication should be categorised as different from a clinical trial, as it currently is, and how we can routinely document off-label uses, so that we can build the evidence base for safety and efficacy upon which future prescribers can depend.
One of the major classes of off-label drug use is for paediatric therapy. For legal, ethical or practical reasons, clinical trials are usually not performed on children (nor are they routinely conducted on other patient groups, such as pregnant women or senior citizens). In paediatric respiratory care, many drugs are not available in formulations suitable for infants and toddlers, having been tested predominantly on older children. However, respiratory drugs are frequently used in children for common diseases like asthma, upper and lower respiratory tract infections, rhinitis (allergies) and sinusitis. Three-quarters of marketed prescription drugs have no labelling indications for children, although their inclusion in clinical trials is enlarging [12]. Among medicines which were newly licensed by the European Medicines Evaluation Agency (EMA) between 1995 and 2005, only one-third was specifically licensed for children [7]. Thus, off-label use is particularly widespread in paediatric situations, and over half of children in Europe who are prescribed medicines in hospital receive a medication that is either ‘unlicensed’ or ‘off-label’ [13]. Other studies put the figure at 40%, 45% or 76% [6,7,14], and the area has been comprehensively reviewed [15]. To summarise these statistics, the younger the patient and the more critical and rare their illness, the more likely they will be treated off-label. This may be because the licence is for older children, whereas the prescription is for a younger child. It may also be for a different use than that on the approved label; or it may be because the dose is different or its schedule of administration is different from the approved use. Commonly, it is believed the problem is that the drug is approved for adults, having been tested only in adults. There are regulatory incentives available to producers through the regulatory system, and the extent to which this can be improved is dealt with more thoroughly in Chapter 7.
So what? Do these statistics amount to anything of real patient import, or am I just demanding unrealistic standards of pointless box-ticking by our medical practitioners? Of course, if there were no adverse consequences, there would be little to complain about (apart from the waste of money). So, for one thing, let me point out that there is an increased rate of adverse drug reactions (ADRs) associated with off-label use. A study from France in paediatric care showed that there were over three times as many ADRs associated with off-label medication as with ‘on-label’ alternatives [16]. The relationship does not just apply for ADRs overall; it is particularly concerning that a Swedish study showed that off-label drug use in children was associated with a significantly higher number of serious adverse reactions [17]. A study from Liverpool, United Kingdom, also showed that the rate of adverse reactions associated with off-label medication, at 6.0%, was significantly higher than on-label comparators, at 3.9% [18]. Another report from Derbyshire, United Kingdom, cited two studies, one of which suggested that five out of eight severe ADRs were associated with the off-label use of a medicine. This study suggested that the percentage of unlicensed and off-label drug use was significantly associated with the risk of an ADR. The other study found that 14 of 19 drug prescriptions associated with 17 severe ADRs were either unlicensed or off-label [19]. In a study of ADRs in children and adolescents over a 10-year period in Denmark, 60% of ADRs reported for medicines prescribed off-label were serious, and, in contrast, 35% of ADRs reported for ‘on-label’ medicine use were serious. Thirteen of the off-label serious ADRs resulted in a fatality [20].
So, safety in paediatric medicine is something that we will need to pay close attention to as we go forwards in our consideration of patient consent and the ethics of off-label medication (see Chapter 3), especially as safety is a paramount consideration when children are concerned, and consent often has to be given by the patient’s parents, most of whom are acutely sensitive to safety concerns.
Psychiatric care is another common area of off-label use. A US study looked at psychotropic drugs over a decade-long period from 1998 through 2009: the average proportion of all uses that occurred off-label was 23.3% for antidepressants, 60.7% for antipsychotics and 54.2% for mood stabilisers [21]. At these high levels, there are more drugs being prescribed off-label than in accordance with the regulatory approval; in this situation, this ‘is the death of regulation’ [3]. But it gets worse, as we now see.
In November 2009, the UK Department of Health issued a report on the prescribing of antipsychotic drugs to people with dementia [22]. With a rare exception, no antipsychotic is licensed in the United Kingdom for treating the behavioural and psychological symptoms of dementia; the approved label is generally limited to the treatment of schizophrenia and bipolar disorder. This therefore constitutes off-label medication except in the rare and unfortunate event that the demented patient also has a co-morbid psychotic illness. The report had been commissioned in recognition of widespread concern about the overprescription of antipsychotic drugs to patients with dementia, a concern felt particularly among patients and their families who had not been consulted before such antipsychotic treatment began; neither were they aware that the prescription was being administered in an off-label fashion. Subsequently, the UK National Institute for Health and Care Excellence (NICE) conducted its own evaluation [23]. It was suggested that up to a quarter of people with dementia had been prescribed antipsychotics in addition to their normal medication, up to 180 000 people at a cost of £90 million a year. In formal care, the proportion of dementia patients being prescribed antipsychotics rose to nearly a half [24]. The vast majority of these, 8 out of 10, derived no benefit from antipsychotic treatment, and NICE advised against the use of any antipsychotics for non-cognitive symptoms or challenging behaviour of dementia unless the person is severely distressed or there is an immediate risk of harm to them or others.
Moreover, not only are these drugs ineffective, but they are dangerous in older patients. There is an approximately threefold increased risk of cerebrovascular adverse reactions (in other words, stroke) that have been seen in randomised placebo-controlled clinical trials in the dementia population with some atypical antipsychotics, including risperidone, aripiprazole and olanzapine. As a result, NICE worked out that for each 100 patients treated with atypical antipsychotics over a year, one of them died prematurely and a similar additional number suffered non-fatal cerebrovascular events, such as stroke (around half of which may be severe) as a result of adverse side effects. In the context of longer-term treatment, there were estimated to be 167 additional deaths among every 1000 people with dementia treated with antipsychotics over a 2-year period. A similar situation pertained in the United States, where the Department of Health and Human Services found that in a 6-month period in 2007, 14% of nursing home residents were given antipsychotics, presumably with similar adverse outcomes [25]. Of course, stroke is not the only side effect of antipsychotic drugs: they also produce over-sedation, which may result in falls or in patients to become ‘like zombies’ [24], and worsening of cognitive function, which is exactly the opposite of what medical treatment of dementia sufferers is supposed to achieve.
Antipsychotic prescribing is also a surprisingly common practice for active duty troops in the US military, even though psychotic illness itself would presumably not be desirable, and should have been screened out as part of the selection process. Nevertheless, antipsychotic prescription is a growing trend: it was reported [26] there has been a 682% increase in the number of psychoactive drugs – antipsychotics, sedatives, stimulants and mood stabilisers – prescribed to US troops between 2005 and 2011, despite a steady reduction in combat troop levels since 2008. Some of the off-label uses for which these drugs have been prescribed include insomnia, anxiety and aggressive behaviour. They have also been used to treat post-traumatic stress disorder (PTSD), even though the evidence for efficacy in this area is weak (for instance, one antipsychotic risperidone failed in a clinical trial examining its use as add-on treatment of PTSD symptoms [27]). Certainly, by comparison with antidepressants, which are demonstrably effective in PTSD, antipsychotics are very much the inferior option. In addition to the nearly sevenfold increase in the use of antipsychotic drugs, there has been an even bigger increase in the use of sedating anticonvulsants, an increase that is not matched in the general population, and, perversely, a decrease in the use of antidepressants. Given the comments earlier about PTSD and depression, which are both likely outcomes of active duty, the decline in antidepressant use is disturbing if they are being substituted by less efficacious antipsychotic alternatives, with consequently poorer therapeutic outcome. It is particularly disturbing given that untreated PTSD and depression are both associated with increased rates of suicide, and in soldiers involved in the Iraq war and Afghanistan mission, suicide is a greater risk than death in combat.
The overall prevalence of off-label prescribing in psychiatry is high. A study from 2000 reported that 65% of psychiatrist respondents had prescribed medication off-label within the past month [28]. A German prescription survey from 2000 reported that antipsychotic drugs were being prescribed in older patients (aged 49–70 years) almost exclusively for off-label indications [29]. Another study found the off-label use of Eli Lilly’s atypical antipsychotic Zyprexa (olanzapine) to be 45% [30]. However, one of the problems in psychiatry is the complexity and specificity of the diagnosis, together with an increasing specificity of the label. It may be helpful to think of a spectrum of use of licensed psychotropic drugs in unlicensed applications, with some off-label prescribing being nearer the label than others. Because of this very fine level of diagnostic specificity, there may be no regulatorily approved treatment for the specific condition to be treated [31]. To address this problem, I came across a blog post in the course of researching this book [32] advocating that psychiatrists should formally diagnose in accordance with the approved label in order to avoid their prescription being regarded as ‘off-label’, whatever the real patient diagnosis. The [anonymous] author of this blog appears to be a pharmaceutical industry insider or a medical professional. It is not clear whether this is a serious proposal or to what extent if reflects widespread, if unspoken, attitudes among medical professionals for their patients. However, other reports have used the term ‘diagnosis shifting’, to indicate physician behaviour in cases where they are aware that prescribing practices are being monitored. For example, when treating a patient with sinus congestion but prescribing antibiotics, a clinician might be more inclined to write it up as sinusitis, an antibiotic-appropriate diagnosis, instead of nonspecific upper respiratory infection, an antibiotic-inappropriate diagnosis [33].
Part of the problem is lack of awareness among prescribers about exactly what drugs are approved for what indications. A US survey of nearly 1200 physicians (599 primary care physicians and 600 psychiatrists) showed widespread ignorance of what drugs were actually approved for. The study was conducted in 2007–2008 and included 22 drug–indication pairs. The indications varied in their FDA approval status from on-label use, to off-label use supported by medical evidence, to off-label use deemed to be ineffective. In the area of psychiatric care, 13% of all physician respondents erroneously believed that quetiapine (Seroquel®) was FDA approved for dementia with agitation; an even higher number, 19%, had prescribed quetiapine for dementia with agitation, suggesting that roughly one-third of doctors had prescribed this indication pair knowingly off-label, with roughly two-thirds having prescribed it unknowingly [34]. These two groups may be categorised, somewhat unkindly, but not inaccurately, as the ‘ignorants’, those that do not know, and the ‘insouciants’, those that do not care. In this case, it is difficult to know which group to be most concerned about.
A common form of off-label medication in psychiatry is the prescription of drugs at higher than their approved dosage ranges. While potentially offering greater efficacy, for instance, in patients not well treated for depression, the likely adverse consequences of this practice on safety are obvious. Another factor which seems to be more prevalent in psychiatry is that the approved indications change over time, with some new uses being added to the list of approved indications (such as the expanding uses beyond depression for serotonin uptake inhibitors, [SSRIs] for anxiety and obsessive compulsive disorder), while sometimes the approved uses can be reduced (for instance, the use of fluoxetine for depression in children and adolescents) [35]. So, we need to reflect that the situation is complex and nuanced, but that in itself is not a good reason for an abandonment of concern over the scope of off-label medication in psychiatry [36].
