Making medicines evergreen

BMJ 2012; 345 doi: (Published 29 November 2012)
Cite this as: BMJ 2012;345:e7941

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We completely agree with the recommendations given by Hitchings and colleagues concerning the importance of being suspicious when it comes to newer versions of drugs to replace the older versions on the bases of theoretical additional benefits. The call for evidence through comparative effectiveness assessments to back these claims is crucial, because the introduction of such drugs, lacking such evidence, will be detrimental not only to patients but society as well.

The most appropriate evidence is supposedly the head-to-head trials between older and new versions of the drug. However, the available evidence from head-to-head trials might be biased because these trials are most often sponsored by the same pharmaceutical company which produces the evergreened drugs. Industry sponsorship could pose the problem of meta-bias in meta-analyses, and it was shown previously that the choice of comparator and the choice of drug dose could be inappropriate (1-3). In a recent case study of evergreening, we assessed the antidepressant couple citalopram and its chiral switch escitalopram, both produced by Lundbeck pharmaceuticals as an ideal example for this practice. Efficacy, which was based on 7 head-to-head trials, was significantly better for escitalopram than citalopram (combined odds ratio (OR) 1.60 (95% confidence interval 1.05 to 2.46)). However, for the adjusted indirect comparison of 10 citalopram and 12 escitalopram placebo-controlled trials, efficacy was similar for the two drug forms (combined indirect OR 1.03 (0.82 to 1.30)) (4). Nevertheless, in our analysis, all head-to-head trials, except one, were sponsored by the Lundbeck/Forest Lab. This trial was an institutional funded trial, and did not find any evidence of difference between the two drugs.

Besides evergreening impact on patients, evergreening could have a detrimental impact on society as well. The lack of proper evidence of additional benefit and the aggressive marketing strategies pursued by the drug producers poses a large burden on national health insurance agencies. For instance, the reimbursement cost for escitalopram reached 96.8 million Euros in 2010, compared to 4.4 million Euros for the branded citalopram and around 20 million Euros for citalopram’s generic forms(4).

Moreover, this is not an exclusive to a one time only practice, but more like Groundhog Day movie’s plot, meaning that the scenario of evergreening could go over and over on the same drug. This was indeed the case with the Fenofibrate produced by Abotte pharmaceutical for instance (5); and because this is not an isolated phenomenon, we searched evergreening in Medline and Google Scholar for other evergreened drugs and we listed the potentially suspicious medication in a separate table.

Finally, we suggest that comparative effectiveness assessments, including both direct and indirect evidence, should be made available for each suspicious drug separately, and it should be examined and questioned by health technology assessment agencies for any potential existing bias before given the green light for a patent approval.

1. Lundh A, Sismondo S, Lexchin J, Busuioc OA, Bero L. Industry sponsorship and research outcome. Cochrane Database Syst Rev;12:MR000033.
2. Lathyris DN, Patsopoulos NA, Salanti G, Ioannidis JP. Industry sponsorship and selection of comparators in randomized clinical trials. Eur J Clin Invest Feb;40(2):172-82.
3. Lexchin J, Bero LA, Djulbegovic B, Clark O. Pharmaceutical industry sponsorship and research outcome and quality: systematic review. BMJ2003 May 31;326(7400):1167-70.
4. Alkhafaji AA, Trinquart L, Baron G, Desvarieux M, Ravaud P. Impact of evergreening on patients and health insurance: a meta analysis and reimbursement cost analysis of citalopram/escitalopram antidepressants. BMC Med;10:142.
5. Downing NS, Ross JS, Jackevicius CA, Krumholz HM. Avoidance of generic competition by Abbott Laboratories' fenofibrate franchise. Arch Intern Med May 14;172(9):724-30.

Competing interests: None declared

Ali Al khafaji, Clinical Reseacher

Ludovic Trinquart

Centre d' 'Epidemiolgie Clinique , Hôpital Hôtel Dieu, Parivs Notre Dame, 75004, Paris/ France

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In response to the correspondence arising from this article:

Managing the end of life cycle for a declining product which is essential for the patient population is a complex and expensive process. The most important consideration for patients was to maintain Phenytoin Sodium Flynn capsules on the market, which would not have been possible at the old price. Had the product been discontinued, patients would have had to switch to other, more expensive formulations, with the inherent risks associated with a change of formulation of a Narrow Therapeutic Index Product (NTIP). These issues were discussed with the Department of Health before the price increase was implemented.

At the current price of 80p per 100mg capsule, Phenytoin Sodium Flynn capsules are considerably less expensive than the generic tablet presentations currently available. The drug tariff for generic phenytoin tablets 100mg (for which there are a number of MA holders) is 33% higher than our current price and has been at this level for many years.

Maintaining the same formulations and the identicodes on the capsules were considered important to reassure patients that there was no risk resulting from the change of ownership of the product.

There have been some supply issues over the years, a situation which often gets worse with old products as volumes decline. We are introducing a number of measures to increase the resilience of the supply chain with the intention of fully satisfying future demand.

Competing interests: Director of Flynn Pharma Ltd

David Walters, Director

Flynn Pharma Ltd, Hertlands House, Primett Road, Stevenage, Herts SG1 3EE

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The popular myth created by the drug industry that it costs around $1 billion to develop a new drug never dies (1), although it has been refuted countless times. In reply to the BMJ paper mentioning this, Stephen Whitehead, Chief Executive, Association of the British Pharmaceutical Industry, even claimed that the true cost was $1.6 billion (£1 billion) (2).

These estimates are false and build on seriously flawed methods, including debatable accounting theory, and premised on blind faith in the confidential information supplied by the drug industry to its economic consultants at two universities who were paid by the same industry to do the job (3-5). The true cost is likely to be below $100 million (3).

Drug companies spend only 1% of revenues on basic research to discover new molecules, net of taxpayer subsidies, and more than four fifths of all funds for basic research to discover new drugs and vaccines come from public sources (6).

The profit per unit sold has always been much higher in the drug industry than in other industries, e.g. 11% in 1960 compared to 6% in all the Fortune 500 companies, big pharma included (7). In the 1980s, when the marketers took over from the scientists in the drug industry, its profits skyrocketed and was 19% in 2011. In 2002, the combined profits for the ten drug companies in Fortune 500 exceeded the profits for all the other 490 businesses put together (4).

Thus, there is no need to "understand" and even less need to accept that drugs are so expensive. It has nothing to do with what it costs to develop them. It builds on a cool calculus - a kind of extortion - what our politicians are prepared to pay for drugs to avoid becoming pointed at in the news as cold-hearted people who deny patients access to medicines and only think of our national budget.

1 Hitchings A, Baker E, Khong T. Making medicines evergreen. BMJ 2012;345:e7941.

2 Whitehead S. Making medicines evergreen (rapid response). BMJ 2012 Dec 17.

3 Relman AS, Angell M. America's other drug problem: how the drug industry distorts medicine and politics. The New Republic 2002 Dec 16:27-41.

4 Angell M. The truth about the drug companies: How they deceive us and what to do about it. New York: Random House, 2004.

5 Goozner M. The $800 million pill: The truth behind the cost of new drugs. Berkeley: University of California Press, 2005.

6 Light DW, Lexchin JR. Pharmaceutical research and development: what do we get for all that money? BMJ 2012;344:e4348.

7 Gagnon M-A. The nature of capital in the knowledge-based economy: the case of the global pharmaceutical industry. Dissertation, York University, Toronto, May 2009.

Competing interests: None declared

Peter C Gøtzsche, Professor

Nordic Cochrane Centre, Rigshospitalet, Copenhagen

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21 December 2012

We thank Mr Whitehead for his contribution on behalf of the Association of the British Pharmaceutical Industry. We are grateful for his industry perspective and are reassured that many of his observations concur with those stated in our paper.

We agree with Mr Whitehead that the process of developing medicines is risky, costly, and time-consuming; and that incremental changes can be beneficial for patients. The cited costs were chosen to provide an illustration of the scale of investment necessary to bring a medicine to market, in a way that would be readily interpretable by clinical readers. Accounting of costs, and indeed profits, is clearly a complex issue. Whilst the cited figure may not include capital or opportunity costs, it similarly does take into account — for instance — of sunk costs, allowances for depreciation, or tax relief for research and development. In our article, we acknowledge the need to support adequate investment for on-going innovation of new therapies. However, irrespective of its development costs, we do not believe a drug that may be detrimental to patients or the health service should be adopted.

Mr Whitehead correctly points out that producing a follow-on product does not alter the patent term for the original product. However, the 'new' product (which may have the same active ingredient) may be protected by a new patent. Through strategic marketing techniques that promote brand-switching before market entry of generics, this follow-on product may be used to resist the effect of generic competition (without necessarily providing additional benefit for patients). Our figures illustrate how this may play out in practice.

Finally, he disagrees that the GMC guidance concerning off-label prescribing is too restrictive. The reality in clinical practice is that drugs are frequently prescribed off-label, and often (though not always) with good supporting evidence and clinical experience. Where such evidence exists (or is equivalent to that for a newer licensed product), we believe there should not be additional barriers to the use of a drug that is both cheaper and has a more extensive safety database. The proposed changes to the GMC guidance (1), which are broadly in line with this, suggest that our view is an important one and shared more widely.

We are very grateful to Dr Brunet for highlighting the recent 24-fold increase in the price of Epanutin (phenytoin) capsules. We agree with him that although the manufacturer technically has done nothing wrong, it does appear unethical, and ought to be known about more widely.


1. General Medical Council. Good practice in prescribing and managing medicines and devices. Draft for consultation, 2011.

Competing interests: Please see main article; none directly relevant to this response.

Andrew W Hitchings, Specialty registrar in clinical pharmacology

Emma H Baker, Teck K Khong

St George's, University of London, Cranmer Terrace, London SW17 0RE

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Hitchings and colleagues' excellent analysis of the methods used by pharmaceutical companies to maximise profits omitted a recent example of a novel tactic which has resulted in additional annual costs to the NHS of £46 million.

The technique involves exploiting the fact that the price of generic medicines is not negotiated with the Department of Health, as market forces are intended to keep prices competitive. However, medical treatments do not always obey the usual rules of the market, and where there are significant clinical safety reasons for prescribing by brand, the generic market may not prevent excessive price rises.

In September 2012 Pfizer announced the sale of the marketing rights of the epilepsy drug Epanutin (phenytoin) to another company, Flynn-Pharma. The drug was still to be made by Pfizer and would be identical in all respects - even to the extent of having the name Epanutin stamped on the capsules. However, it would now be packaged under a different name, and, crucially, Flynn-Pharma were able to describe the product as generic. This meant that the previous price controls were lifted and the price could be increased more than 23-fold. The cost of 28 capsules rose from 66p to over £15.

The reality is that there is no generic market for phenytoin. Pfizer are the only company to make the capsules in the UK, and were another company to start to manufacture or import them, doctors would not be able to switch on cost grounds, as the recommendation is to prescribe by brand in order to reduce the risk of destabilising a patient's epilepsy. For a condition where the stakes are high - the consequences of a single seizure can lead to death or serious injury and the prohibition from driving for a year - this is a risk that no doctor should take.

The exploitation of this loophole has cost the NHS a significant amount of money in times when budgets are being reduced, caused considerable anxiety among epilepsy sufferers worried about changes to their medication, and has no clinical justification whatsoever. I have raised the issue in the media ( and with the Health Secretary. Disappointingly, the Department of Health is not inclined to investigate.

Competing interests: None declared

Martin D Brunet, General Practitioner

Binscombe Medical Centre, 106 Binscombe, Godalming, GU7 3PR

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I am disappointed to read your article which repeats tired and hackneyed arguments about the ‘evergreening’ of medicine patents and which downplays the risks and costs associated with research and development. The article begins by stating that on average R&D costs for each new medicine runs at £550m. But this fails to take in to account capitalised costs which should always be included in any serious economic model. When these costs are taken in to account the research and development costs are around £1bn. This is important, because by misrepresenting the huge investment made in creating medicines, it is more difficult to appreciate why it is so important that companies make a good return on their investment to discover further new medicines.

The article also overlooks and downplays many other important factors relating to medicine patents. Crucially, it glosses over the fact that if a company makes an improvement to a medicine, the length of the patent for the existing medicine is in no way affected and manufacturers are free to produce generic copies of this product as normal. This is a crucial point, because a medicine cannot be continually protected from generic competition by small modifications to the medicine.

I also take issue with the charge that GMC guidance on the use of off-label prescribing is ‘overly constraining’ and that cheaper medicines should at times be used to treat a disease even it does not have a license for that indication. Loosening the regulations in this area would not only put patient safety at risk, it would also undermine the entire regulatory process which is in place to protect public health.

Finally, it is wrong to dismiss small, iterative improvements to medicines based on the perception that they provide little added value. These slight modifications are absolutely crucial to improving patient care and central to making significant advances in treatment over a period of time. So while a seemingly small change to a product – for instance reducing the dosage, will often lower the chance of side effects and make it more likely that patients will adhere to their treatment. Incremental modifications to medicines, over many years, can also transform the way we treat disease. Take HIV medicines. By continually making minor improvements, and then building on these improvements year after year, we have transformed a disease which was once terminal, into a condition that can be lived with long in to old age. Discovery in science is nearly always evolutionary rather than revolutionary. It is essential we recognise this is just as true for the development of medicines.

Competing interests: None declared

Stephen Whitehead, Chief Executive

Association of the British Pharmaceutical Industry, 105 Victoria Street, SW1E 6QT

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