Rheumatology Advance Access originally published online on May 22, 2006
Rheumatology 2006 45(8):935-936; doi:10.1093/rheumatology/kel145
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EDITORIAL |
A patient-centred approach to drug regulation
Freeman Hospital, Newcastle NE7 7DN and 1 Department of Rheumatology, University of Liverpool, University Hospital Aintree, Longmoor Lane, Liverpool L9 7AL, UK
Correspondence to: Dr Walker. E-mail: david.walker{at}nuth.nhs.uk
It would be naïve, indeed, to expect to be able to inhibit a biological system that exists because it has increased its chances of survival to procreation age and not expect to pay a biological price for it. Drugs, whose effects are mediated by such inhibition, will therefore inevitably have the potential for causing side effects, and the ‘perfect’ fully safe yet effective drug is yet to be produced. It is, therefore, of paramount importance to balance drug efficacy with safety—but of late it appears that patients' needs do not occupy the forefront of this important process, as they should.
The recent withdrawal of drugs such as rofecoxib [1], valdecoxib [2] and coproxamol [3], which were widely used to treat pain in arthritis, have led to many serious repercussions in the delivery of care to patients with arthritis. Many patients have been left in more pain and with less satisfactory treatment than they previously had. Many more patients and their physicians, are confused about the safety of painkillers and are worried about either taking or prescribing such drugs. We, and presumably most rheumatologists, are currently spending long periods in the clinic discussing these issues with patients and, outside the clinic, advising other physicians. Often, the patients came to use one of these drugs only after they had tried many similar prescriptions that were discontinued because of unacceptable side effects or lack of efficacy and finally finding a drug that suited them best only to see it being withdrawn. In this article, we will debate whether the current situation is appropriate and discuss what might be done by the pharmaceutical industry and drug regulators to prevent similar occurrences in the future if they were to use a more patient-centred approach.
Drugs such as coproxamol and coxibs are primarily aimed at symptom control in arthritis with pain, which is in most individuals the paramount problem [4]. The patient is, therefore, in the best position to judge their actual benefit. It is well-known that individual patients perceive large differences in the efficacy of these painkilling drugs although conventional therapeutic trails are not designed to detect this. Many patients ‘swear by’ the effect of one drug and not that of another. Unfashionable as this is, it is the universal experience of all practitioners who prescribe significant quantities of these drugs.
The structure of British medicine in the National Health Service (NHS) is evolving to empower patients to play a greater role and take more responsibility in their care [5]. However, this is tempered by the unrealistic expectation of many that drug therapy can be effective yet 100% safe. This in turn leads to a covert (if not overt) defensive prescribing policy from many doctors, particularly in primary care [6]. We believe that if patients are provided with good information on the potential risks and how these may apply to them as individuals, they are in the best position to decide whether to continue a drug or not. In the case of coproxamol, the risk may in fact be to others and not to the patient—provided they do not wish to take an overdose, which is extremely rare in conditions such as rheumatoid arthritis (RA) [7]. In our experience, most patients stable on coproxamol at the time of its withdrawal elected to continue it—a fact mirrored in clinical interactions throughout the country everyday.
A major concern of drug regulatory bodies is the greater good of the population as a whole. However, there is plenty of choice of drugs and chemicals, such as aspirin and acetaminophen, which are very dangerous in overdose, available over-the-counter (OTC) [8], and it seems unlikely that the withdrawal of coproxamol will have much effect on suicide rates. It seems cruel to withdraw drugs that are a lifeline to certain patients and are less toxic than OTC drugs. If it were judged, as presumably it has been, that less coproxamol in circulation is good for society as a whole, then why should there not be a mechanism whereby existing patients who wish to remain on it can continue to be supplied with it? This could be done on a named-patient basis, but if this is not appropriate, perhaps new legislation should be produced.
In the case of the rofecoxib and valdecoxib, it is the manufacturers who have unilaterally withdrawn the drugs, and caused similar problems [1, 2].
The pharmaceutical industry, responsible to shareholders, will make decisions for commercial rather than clinical reasons. We suggest that they should be similarly constrained to continue the supply of drugs to patients currently taking them in cases in which the risk is justified by the benefit and the patient wishes to continue.
The withdrawal of two of the Coxibs was related to the potential for serious cardiovascular side effects, with the risk of myocardial infarction (MI) or stroke increased with the dose and duration of treatment with rofecoxib [9] or for potential cutaneous side effects with valdecoxib [2]. However, the data leading up to these concerns may not be as robust as is generally thought to be. Coxibs, in common with all NSAIDs, are well-known for their potential adverse effects, in some individuals, on renal function, fluid retention, and hypertension [10]. Many large-scale studies with these drugs have not demonstrated a significant cardiovascular risk, unless particularly high doses are employed—yet trials in patients at high risk of bowel malignancies have suggested otherwise [11]. It may be of particular relevance, but not widely appreciated, that in this latter population there is evidence that even aspirin—widely used to prevent thrombotic events—is associated with a higher incidence of cardiovascular toxicity [12]! One must wonder if it is appropriate to extrapolate findings from a potentially unusual population, who are deriving no symptomatic benefit from the drug, to patients with arthritis, where one benefit of the treatment may be to allow them to comply with their cardiac rehabilitation programme post-MI. Moreover, the premature closure of the studies has meant that it will not be known if these risks were outweighed by the reduction in malignant transformation or, indeed, the reduced risk of serious or fatal gastrointestinal toxicity observed with conventional NSAIDs.
The overall situation has not been helped by the general lack of objectivity and tendency for scaremongering by the press—both national [13] and, sadly, medical [14]. Information allowing a sensible discussion and weighing of risks has been sparse and hard to find, if present at all. Some studies of interest, but with significant methodological flaws, have been hyped up to imply extrapolated outcomes that are somewhat exaggerated [15]. To say to a general practitioner (GP), in effect, that a drug may cause problems and he or she had better be very careful prescribing it makes it much easier and for them less risky to simply stop the drug and allow the patient to suffer. The alternative is to risk having a patient on the drug suffer a vascular event, whether or not related to the drug, and feel responsible (or medicolegally liable) for causing it. In this risk-averse climate it is ‘safer’ for GPs to make conservative decisions.
This is a classical situation in which good leadership is required. Simply withdrawing a drug might not be the best solution. In addition to causing undue suffering to patients in chronic pain, this also leads to confusion in prescribers—as it is unreasonable to expect non-specialist doctors to be sufficiently aware of the data to make a fully informed decision without help. Recent advice from the regulators that coxibs should not be used in patients with established ischaemic problems in heart, brain or limbs is unhelpful as there is no mention of benefit, dose or duration. Can a man with a previous MI and osteoarthritis of his knees really not take an anti-inflammatory before he plays golf?
We would suggest that formal advice from regulatory bodies should include some mention of benefit, better information on the alternatives available and, especially, what is known and, importantly, not known about their risks. Current advice only includes coxibs even though there is no data to show that the conventional NSAIDs are any safer. We are in a position, embarrassing to the scientific-evidence-based practice we aspire to, and are encouraged to withdraw drugs, such as coproxamol and some of the coxibs, where there is only modest evidence for toxicity in patients with arthritis, and swap them for traditional NSAIDs, where there is a gaping hole in data for safety—it is as though we are advised to go for the devil we do not know rather than the devil we do know [16]. How can it be that, 10 yr ago, patients were taking much higher gastrointestinal (GI) risks with conventional NSAIDs without gastroprotection and judging that the risk was worth it and, now, it is judged that a smaller risk of cardiovascular disease cannot be justified?
Although extremely desirable, it is, sadly, highly unlikely that studies investigating off-patent medication to address these important questions will ever be performed. The best evidence otherwise, therefore, comes from large observational databases such as Kaiser Permanente [17]. These suggest that many conventional NSAIDs have similar side-effect profiles, with the exception of significant reduction in life-threatening gastrointestinal toxicity in coxibs. Many patients may therefore have been pushed out of the frying pan into the fire when changing to traditional NSAIDs as they are exposed to both cardiovascular and GI risks. It is entirely possible that, in the fullness of time, the coxibs will be shown to be safer than conventional NSAIDs across the entirety of adverse events. Mysteriously, this no data equals neo risk is not extrapolated to Celecoxib 200 mg daily, where there are no data to show an increased risk. We think that it is likely that, if the advice is taken, we will see an increase in gastrointestinal side effects and no fall in cardiovascular events. We seem to have forgotten how many deaths are caused with conventional NSAIDs and how many patients were unable to tolerate them [18].
The risk or benefit to the individual patient and not the risk of being sued should be the guiding principle. Sadly, one is more likely to be sued for a cardiovascular event occurring while taking an anti-inflammatory than for poor control of pain. We believe that there are benefits for individual patients that outweigh those patients' individual risks. The current advice is unsatisfactory because it does not allow sensible individual decisions to be made in consultation with individual patients. Any evidence on which to make a clinical decision needs to be interpreted to the extent that the patients recruited and the diagnoses treated reflect the patient in front of you.
Of genuine concern in this area are the diagnoses for which the prescriptions of anti-inflammatories are written. Only a very small proportion of the subjects in the Kaiser Permanente database were suffering from inflammatory arthritis—the condition in which NSAIDs are of particular importance. To explore the reasons for prescriptions and to demand a more appropriate and targeted prescribing, with significant benefit from treatment, thus reducing overall prescribing of this class of drugs, may produce more benefit than this apparent ‘witch hunt’ on newer drugs and provide an important step in the right direction. In the meantime, we mourn the (current) passing of some highly useful drugs for the management of pain in arthritis, and hope that in the future issues regarding potential drug toxicity can be dealt with in a more sensible, patient-centred and less blundering way. If these scares over a reasonably safe drug (if used in licenced doses) can bring a company the size of Merck to its knees, then where are the drugs of the future going to come from?
Potential conflicts of interest. Both authors treat many patients with pain from arthritis. Both have sat on advisory boards for the drug industry.
References
- MHRA web page: immediate withdrawal of rofecoxib 30th September 2004, http://www.mhra.gov.uk.
- MHRA web page: voluntary suspension of valdecoxhib (Bextra) by Pfizer Ltd 7th April 2005, http://www.mhra.gov.uk.
- MHRA web page: MHRA withdraws the pain killer coproxamol 21st Jan2005, http://www.mhra.gov.uk.
- Walker DJ, Griffiths ID, Leon CM. Referrals to a rheumatology unit: an evaluation of the assessments of patients; general practitioners and consultants. Ann Rheum Dis 1991;50:926–9.
[Abstract/Free Full Text] - Department of health web page: creating a patient led NHS – delivering the NHS improvement plan. March 2005. http://www.doh.gov.uk.
- Kendrick T, Burns T. General practitioners and mentally ill people in the community: the GMSC's advice is over-defensive. Br J Gen Pract 1996;46:568–9.[ISI][Medline]
- Treharne G, Lyons AC, Kitas GD. Suicidal ideation in patients with rheumatoid arthritis. Research may help identify patients at high risk. Br Med J 2000;321:1290
[Free Full Text] - Jones A. Over-the-counter analgesics: a toxicology perspective. Am J Ther 2002;9:245–57.[CrossRef][Medline]
- Bresalier RS, Sandler RS, Quan H et al. Cardiovascular events associated with rofecoxib in a colorectal adenoma chemoprevention trial. N Eng J Med 2005;352:1092–102.
[Abstract/Free Full Text] - Johnson AG, Nguyen TV, Day RO. Do nonsteroidal anti-inflammatory drugs affect blood pressure? a meta-analysis. Arch Int Med 1994;121:289–300.
- Solomon SD, McMurray JJ, Pfeffer MA et al. Adenoma Prevention with Celecoxib (APC) Study Investigators. 2005;352:1071–80. Epub 2005 Feb 15.
- Baron JA, Cole BF, Sandier RS et al. A randomized trial of aspirin to prevent colorectal adenomas. N Eng J Med 2003;348:891–9.
[Abstract/Free Full Text] - Arthritis drug may have killed thousands. Daily Mail Newspaper. London. 25/01/05.
- Topol E. Arthritis medicines and cardiovascular events—"House of Coxibs" JAMA 2005;293:doi.10.1001/jama.293.3.366.
- Press release European Medicines Agency concludes action on COX-2 inhibitors. http://www.emea.eu.int/pdfs/human/press/pr/20776605en.pdf.
- National Cancer Institute. Press Release: NIH Halts Use of COX-2 Inhibitor in Large Cancer Prevention Trial. 17 December 2004. Available at: http://www.nci.nih.gov/newscenter/pressreleases/APCtrialCOX2.
- Graham DJ, Campen D, Hui R et al. Risk of acute myocardial infarction and sudden cardiac death in patients treated with cyclo-oxygenase 2 selective and non-selective non-steroidal anti-inflammatory drugs: nested case-control study. Lancet 2005;365:475–81.[ISI][Medline]
- Cox-II inhibitors for the treatment of osteoarthritis and rheumatoid arthritis (review of existing guidance no. 27 May 2004) www.nice.org.uk.
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