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Recent rapid responses
Rapid responses are electronic letters to the editor. They enable our users to debate issues raised in articles published on bmj.com. Although a selection of rapid responses will be included as edited readers' letters in the weekly print issue of the BMJ, their first appearance online means that they are published articles. If you need the url (web address) of an individual response, perhaps for citation purposes, simply click on the response headline and copy the url from the browser window.
Displaying 1-10 out of 12 published
Public and professional trust in the pharmaceutical industry is low, and the responses here show why. A recent study of doctors’ (dis)trust of the pharmaceutical industry funded by the Edmond J. Safra Center for Ethics at Harvard University found that they trust even well-designed trials less if sponsored by the industry.[1] Stephen Whitehead, one of the respondents and the
Chief Executive for the Association of the British Pharmaceutical Industry, wrote as if our data-based analysis was just a one-sided polemic and therefore did not challenge our facts, while he offered one of his own: companies invest one third of sales in R&D. We challenged him to verify such a staggeringly high amount, but he has not done so. Instead, he wrote to discredit our “lack of understanding” and reported the industry invested one third of profits, a much smaller amount. Another tall tale cut down to size. He cited the ONS 2010 Business Enterprise Research and Development Report for exact figure of 34.3%.
Once again, we cannot trust Mr. Whitehead to check his facts. That Report contains no such figure that we can find, and in reply to an inquiry, Mr. Jim Nicholls, an officer at the Office of National Statistics wrote to say that “Unfortunately, we do not collect/publish sales or profit figures…” So even the cut-down claim of R&D investment has no basis in the ONS R&D report. We then searched the ABPI for the missing figures on sales and profits but found none. We called, and a nice lady said someone would call back, but no one has. We emailed too, but no reply. Who knows what trustworthy, verified facts would show to be the pharmaceutical industry’s investment in R&D?
Now a more nuanced and thoughtful response has come from a senior team from the European Federation of Pharmaceutical Industries and Associations, led by Richard Bergström, but there are more inaccuracies. We thank Mr. Bergström for his comments but we also take issue with much of what he has to say. First, we need to be clear that the ending of the Norwegian “medical need clause” in 1996 had nothing to do with predictions about the future value of new drugs being “unfeasible”. The Norwegian model was abandoned because Norway harmonized its drug regulatory system with that of the European Union and the EU that did not have a medical need clause.
Second, we reject the claim that predictions are not possible. While occasionally some drugs prove to be more valuable than initially thought [2], in general most new drugs provide little to no new therapeutic value. As documented in our article, an independent detailed assessment of the postmarket value of all new products (and new indications for existing products) over the last decade found only 76 out of 991 (7.7%) new products and indications offered any significant therapeutic gain [3]. Mr. Bergström continues the industry myth that equates innovation with a new molecular entity (NME), when most are not therapeutic advances.
Third, if as Mr. Bergström says, new drugs cannot be adequately evaluated until they are in clinical use in the real world, why then do drug companies spend hundreds of millions of dollars promoting the early adoption of these new products rather than waiting to see how valuable they actually are? Why do drug companies persist in running clinical trials on highly selective patient groups rather than testing them in a more real world environment?[4]
Finally, many drug candidates “fail to survive” clinical trial testing because companies withdraw them for economic reasons (43%) rather than for reasons of efficacy (31%) and safety (21%).[5] Even then, most clinical trial results do not show that the products being tested are outright failures but yield mixed results that lead companies to discontinue their development. The word “failure” is part of pharmaceutical mythology and should be replaced by the more accurate word, withdrawal.
Competing interests: In 2007 Joel Lexchin was a consultant to a law firm acting for Apotex Inc. In 2008 he was an expert witness for the Canadian federal government in its defence against a lawsuit challenging the ban on direct-to-consumer advertising. In 2010 he was an expert witness for a law firm representing the family of a plaintiff who allegedly died from an adverse reaction from a product made by Allergan. He is currently on the Management Board of Healthy Skepticism Inc. and is the Chair of the Health Action International – Europe Association Board.
York University, 4700 Keele St., Toronto Ontario Canada M3J 1P3
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+Peter Høngaard Andersen, Chair, Research Directors Group (RDG), European Federation of Pharmaceutical Industries and Associations (EFPIA); H. Lundbeck A/S, Denmark.
Richard Bergström, Director General, EFPIA.
To the Editor,
We welcome open discussion of the current drug discovery and development process and its limitations, as raised by Light and Lexchin.(1) Although we do not propose to provide a detailed response to the individual postulates and numbers put forward by the authors, we would emphasise our surprise in their claim that it is possible to predict the true value of a medicine using the so-called ‘Norway model’.(2) This model is no longer in use in Norway, since such predictions have been shown to be unfeasible, and it is recognised that estimating the value of a medicine requires the documentation of real life use. However, we would like to discuss some of the points that were raised, especially with regard to current industry constraints and proposed revision of regulatory requirements, that we propose may accelerate and streamline the drug development and approval process.
We would agree that the authors are correct in stating that there is no “innovation crisis” – there is, however, a crisis in the cost of innovation. This is particularly relevant in terms of the high attrition rate of medicines in development, which often occurs late in the development process and after significant investment. The decline in R&D productivity in pharmaceuticals in the past two decades is “associated with an increasing concentration of R&D investments in areas in which the risk of failure is high, which correspond to unmet therapeutic needs and unexploited biological mechanisms”.(3) However, despite such high practical and financial losses, 49 new innovative medicines were approved during 2011 in the EU, covering several disease areas.(4) A total of 37 new non-orphan medicines, 11 orphan medicines and one advanced-therapy medicine were approved by the EMA (5), with ‘one third of drugs launched in 2011 [being] first in class’.(4) Among these new medicines was the first new treatment for lupus erythematosus for over fifty years.(6)
The authors imply that drug developers have too much control over clinical study design and that more stringent regulatory requirements for study design are required. In fact, the real issue is that the regulatory frameworks for the review and approval of new medicines, including already stringent study design requirements, have not evolved in step with technological advances in medical research. Patients, society and industry would all benefit from greater flexibility to allow more adaptive clinical trials, which are more efficient and better reflect the real-world patients who will benefit most from treatment.
A change is certainly needed to make the drug discovery and development process more productive, more efficient and more cost-effective for society. The pharmaceutical industry is aware of the issues highlighted by the authors and is committed to bringing about positive changes in the way truly innovative drugs are developed and approved. However, this is not achievable by the industry alone. Placing arbitrary restrictions on drug approval is not the answer – collaboration is what is needed. Investment in science has been consistent in the research based pharmaceutical industry, and progress comes in waves; witness the explosion of antivirals induced by the advent of HIV/AIDS, with zero applicable treatments at the beginning of the 1980s to over 25 agents specific to four separate viral processes at the present time. Such achievements have been gained by collaboration across academia and industry, and with support from government.
Current technological advances promise step-changes for patient care in Europe and beyond. ‘Personalised medicine’ allowing the tailoring of emerging therapies to individual patients or specific populations, via economically viable ‘omics’ examinations, is becoming a practical possibility. Effective data capture, essential to allow such a level of individualised treatment, will offer not only the repurposing of established medicines for new treatments, but also the prospect of reducing side effects in their established use. Biomarkers and diagnostics can be used to select patients more effectively for treatments and improve the efficiency of the clinical process, with the essential endorsement by regulators and funding from healthcare systems.(4)
The Innovative Medicines Initiative (IMI) is the world’s largest public-private partnership and aims to improve the drug discovery and development process through collaboration at all levels and steps of the pharmaceutical value chain in order to deliver better and safer medicines for the benefit of all stakeholders, including patients and society as a whole. The IMI is undertaking a range of projects with clearly defined, measurable outcomes to advance the understanding and classification of diseases, increase the efficiency of novel drug target validation and develop new, innovative methods to predict drug safety and assess clinical effects of new drugs. Additionally, new regulatory pathways will be investigated to inform discussion on regulatory guidance. The IMI will also develop novel therapeutic agents for areas with high unmet need but low return on investment. This highlights the role that the pharmaceutical industry is taking to develop medicines in areas that suffer from a lack of financial incentives but which offer a significant potential benefit to society.
Society is facing major health care challenges and industry is facing major challenges due to the costs of innovation. New innovative medicines addressing these challenges may not be secured by adding ever more restrictions and constraints on the industry. Only through collaboration between stakeholders, regulators, academia, payers and industry, as exemplified by the IMI, will the drug discovery and development process, and related regulatory frameworks, continue to evolve and ensure that these challenges are met, so that patients and society receive the best possible treatment options in the future.
References
(1) Light DW, Lexchin JR. Pharmaceutical research and development: what do we get for all that money? BMJ 2012; 345:e4348.
(2) Joldal B. Regulation for need - the Norwegian experience. Journal of Social and Administrative Pharmacy 1984; 2:81-84.
(3) Pammolli F, Magazzini L, Riccaboni M. The productivity crisis in pharmaceutical R&D. Nat Rev Drug Discov 2011; 10(6):428-438.
(4) EFPIA Annual Review of 2011 and Outlook for 2012, www.efpia-annualreview.eu/uploads/efpia.pdf
(5) EMA Monthly statistics report Dec 2011, www.ema.europa.eu/docs/en_GB/document_library/Report/2012/02/WC500123265...
(6)EMA Benlysta (belimumab), EPAR summary for the public, www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Summary_for_the_pub...
We would like to thank the following for their counsel in preparing this response: Dr Ismail Kola (UCB); Dr Martin Mackay (AstraZeneca); Professor Trevor Jones (Allergan Inc.); Professor Mads Krogsgaard Thomsen (Novo Nordisk); and Dr Patrick Vallance (GlaxoSmithKline).
Competing interests: None declared
Lundbeck, Ottiliavej 9, 2500 Valby, Denmark
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+There is a very elementary error here. Stephen Whitehead begins by claiming one third of sales are devoted to R&D and then refers to ONS figures demonstrating it is one third of profits.
Competing interests: None declared
N/A, London, SW6
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+Would it be possible for the BMJ to set up a head-to-head debate between Stephen Whitehead and David Healy?
Competing interests: None declared
NHS, Forth Valley
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+Mr Light,
Your claims of 11 September only serve to demonstrate a lack of understanding of the modern requirements of medicines discovery and development and how this is largely funded by the pharmaceutical industry. The statistic in question, namely reinvesting a third of profit into future R&D, is a statistic supplied by the Office for National Statistics in their 2010 Business Enterprise Research and Development report, with the exact figure for 2010 being 34.3%. I think most people would agree, this is a reliable and independent source of information.
Competing interests: Chief Executive of the Association of the British Pharmaceutical Industry
Association of the British Pharmaceutical Industry, 105 Victoria Street, SW1E 6QT
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+11 September 2012
A recent article in the BMJ used FDA data to show that the pharmaceutical industry does not face the innovation crisis it has so widely publicized to make the public and legislators think it needs more subsidies and government protections from free-market competition than it already has. http://www.bmj.com/content/345/bmj.e4348.full?ijkey=Y1g4ZVUImIbtXOI&keyt... The pharmaceutical industry benefits more from government welfare than all the university students struggling to get ahead and single mothers combined.
If you click Read Responses on the BMJ website, you will see that Stephen Whitehead, Chief Executive of ABPI, the industry’s powerful trade association in London, emphasizes how many advances we get “for all that money” paid for pharmaceuticals to improve people’s lives and he urges “…that we remember the pharmaceutical industry invests one third the value of sales into research and development…”
The BMJ article acknowledges the small stream of superior new medicines, but one-third of sales for R&D is unbelievable. It is much more than claimed by the American pharmaceutical trade association, PhRMA and two and a half times more than the best independent figures we have, from the authoritative survey of R&D investments by industry by the National Science Foundation (NSF). http://www.nsf.gov/statistics/infbrief/nsf12309/
I challenge Mr. Whitehead to submit figures to back his claim and have them verified by the Chartered Institute of Public Finance and Accountancy. What counts as “sales” and “R&D” should be defined carefully to avoid dividing a too-large numerator into a too-small denominator. Otherwise, we can assume that Mr. Whitehead and the companies he represents are simply misleading members of Parliament and the European Parliament as well as readers.
Mr. Whitehead’s claim of so much money for R&D also insults pharmaceutical researchers who are being laid off left and right as ABPI companies claim to be spending so many billions in R&D. If a third of sales were being spent on R&D, companies would be hiring researchers, not closing entire research facilities in the UK and elsewhere.
Over in the U.S., the pharmaceutical trade association, PhRMA, claims that 21 percent of sales goes to R&D, half again more than the NSF figure based on its careful, time-tested and consistent criteria for what counts as R&D. (See http://www.phrma.org/media/releases/phrma-statement-flawed-british-medic...) Are UK companies spending much more money but being much less innovative than the US companies?
PhRMA should also submit figures to the Chartered Institute of Public Finance and Accountancy to verify that we get so much R&D for paying so much for patented drugs. It would be fun to see how the Chartered Institute would reconcile the data on these two, divergent claims, based substantially on the same global corporations that belong to both trade associations.
American companies too are laying off researchers, closing labs and killing research projects, while telling members of Congress how they create high-skill research jobs.
Meantime, neither ABPI nor PhRMA talks about the evidence in the BMJ article on the prevalence of a Hidden Business Model of Big Pharma. Companies turn out scores of minor variations, price them high, and make billions getting doctors to prescribe them. These eat up about 80 percent of increased expenditures on drugs.
Could we please get pharmaceutical policy on an accurate, verifiable footing?
Competing interests: None declared
Edmond J. Center for Ethics, Harvard University, 124 Mt. Auburn St. Suite 540, Cambridge, MA 02138
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+Professors Light and Lexchin cogently expose the myth of the pharmaceutical innovation crisis, and the diverse strategies that the drugs companies use to maintain their handsome profit levels, whilst the focus on more cost effective and safer medicines has been lost. As they point out, re-focussing on the latter means stopping approvals of so many drugs of little therapeutic value, as well as reviving the old Norwegian ‘medical need’ clause and not rewarding innovation through the high prices generated by patent protection.
Unfortunately, the UK is going in the opposite direction. The last budget introduced a 10% corporation tax rate on profits from patented products (Finance Act 2012, section 19 and Schedule 2). According to KPMG, the rules will be phased in over five years with 60% of the benefits available in 2013 increasing to 100% in 2017. So as well as higher prices on patented medicines, resulting profits will be taxed at a this much-reduced rate. This will provide a big incentive for pharmaceutical companies to push for yet more patents, but cost effectiveness and safety are not patentability requirements.
There appears to have been very little debate on the likely effects of this lower tax rate on public health.
Competing interests: None declared
Queen Mary, University of London, Centre for Primary Care and Public Health, 58 Turner Street, London E3 4DS
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+Perhaps the authors would care to provide us a list of the drugs that have been produced in the last 50 years to back up their claim that 85-90% have produced no benefit? Would that be the view of patients with rheumatoid arthritis treated with infliximab or those with chronic myeloid leukaemia treated with imatinib? What about HIV, 20 years ago an untreatable condition? It is hard to escape the impression that the authors' main and possibly only objective is the denigration of the pharmaceutical industry for ideological reasons. What happens to actual patients is of little or no importance. Naturally I am shocked that the BMJ accepts advertisements from such companies and I hope Dr Godlee will explain how this is compatible with its pure and unsullied principles.
Competing interests: None declared
Imperial College, Department of Clinical Pharmacology, St Mary's Hospital, London, W2 1NY
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+I strongly disagree with the claims made about the pharmaceutical industry in both these papers and I am disappointed with how little regard has been given to balance or fairness.
There is little understanding here of the nature of innovation in science. Medical research has always rested on gradual, small steps forward rather than breakthrough advances which have always been very rare. Take HIV – it was once terminal within just years after infection. But thanks to incremental improvements in its treatment, it is now a manageable chronic disease which patients can live with until their old age.
The authors’ discussion of research and development of medicines seems more reminiscent of polemic than analysis. The methods used to measure the expenditure required to bring a new medicine to market are widely acknowledged by mainstream economists and the suggestion that these standard techniques are somehow biased or skewed, is simply misleading. It is vital that we remember the pharmaceutical industry invests one third the value of sales into research and development, ten times more than the UK average.
Finally, the claim that medicines are only ever compared to a placebo and not to an existing medicine, is simply not the case. It is in the interests of companies to compare their treatment with existing medicines, particularly the "gold standard" treatment, so that they can assess relative effectiveness of their product.
Most of the figures and arguments raised in these papers apply in a non-UK context, which does make me question why the British Medical Journal has chosen to give them so much prominence.
Competing interests: Chief Executive of the Association of the British Pharmaceutical Industry
Association of the British Pharmaceutical Industry, 105 Victoria Street, SW1E 6QT
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+16 August 2012
Light and Lexchin recently argued that the widely held innovation crisis in the pharmaceutical industry is a myth.(1) They correctly diagnose the issue; however, the drug approval data they provide in support of the argument tells only half of the story. Total numbers of new drugs brought to market did increase considerably in the 1990s, and have declined considerably in the past decade. However, contrary to the conclusions of Lexchin and Light, the pharmaceutical industry has also been producing fewer “me too” drugs today than they have in the past.
To shed light on drug development trends, we tracked US FDA approvals of therapeutic new molecular entities (NMEs) from 1946-1950 through to 2006-2010.(2) We classified each of the 1,027 NMEs into one of three categories: first-of-kind drugs, the drugs first approved within their respective chemical subgroups of the World Health Organization’s Anatomical Therapeutic Chemical (ATC) classification system and first-of-kind biologics; early follow-ons, drugs approved within 10 years of respective first-of-kind drugs; and, late follow-ons, approved more than 10 years after respective first-of-kind drugs.
The five-year averages of each type of drug approval are shown in Figure 1. Following a post-war boom in drug development that subsided over the late 1960s, total new drug approvals rose from averages of approximately 10 per year in the 1970s to averages over 35 in the 1990s. Since the 1990s, total NME approvals have fallen sharply, to an average of 20 per year over the past 5 years. As is shown in Figure 1, however, little of the rise and fall in total new drug approvals is attributable to changes in the number of first-of-kind drugs being approved. Approvals of first-in-class drugs have been relatively stable since the 1970s. In contrast, rates of follow-on drug approvals have changed much more dramatically.
That the rise and fall of follow-on drug development explains most of change in total drug development over the past 20 years suggests that the spike in the 1990s was not merely a result of the US FDA clearing a regulatory backlog. The backlog itself was just a symptom of an industry wherein there were significant opportunities for follow-on competition. Such opportunities result from a combination of market factors, including the technical ability to produce technologies that are related to but distinct from a radical innovation, the legal ability to innovate around the intellectual property of a pioneer, and end the commercial ability to sell follow-on technologies at sufficient prices to recoup the cost of follow-on technological development.(3)
The recent decline in follow-on drug development – an “imitation deficit” – is likely the result of the sector’s transition from small molecule drug development for large, primary care drug classes to an era of much more specialized drug development.(4) In blockbuster drug classes established by traditional pharmaceutical pioneers of the past, such as medicines to treat hypertension, competition has likely exhausted most of the therapeutic and economic opportunities for follow-on development. Meanwhile, a growing wave of “personalized” biotech medicines is coming to market, led by a wave of molecularly targeted antineoplastic discoveries. Cancer drugs accounted for just 9% of all NMEs approved prior to 2000 but have accounted for 15% of all NMEs approved since. This trend is likely to continue given that roughly 30% of all drugs currently under clinical development are cancer treatments.(5)
It is important to note that Biotech drugs may be less prone than traditional pharmaceuticals to follow-on drug development because of technical considerations. It may be more difficult to innovate around patents protecting first-of-kind biotech products. It may also be the case that, in contrast to markets for drugs to treat chronic diseases or reduce common risk factors, the target markets for emerging biotech drugs may simply be too small to support significant follow-on competition.
Light and Lexchin are correct in pointing out that pharmaceutical sector is returning to long-term trends in drug development. Indeed, first-in-class drug development rates have not significantly deviated from long-term trends. It would be a mistake, however, to pretend that the sector today bears resemblance to that of just a decade ago. Much has changed in terms of the underlying paradigm of drug development. Improvements in regulatory science and transparency would most certainly be welcome in today’s market; however, regulatory solutions such as Norway’s medical need clause or innovation prizes may not have much effect in the increasingly specialized but nevertheless lucrative pharmaceutical marketplace.
References
1. Light DW, Lexchin JR. Pharmaceutical research and development: what do we get for all that money? BMJ 2012;345.
2. FDA/Center for Drug Evaluation and Research. Drugs@FDA. In. Silver Spring, MD: Department of Health and Human Services (HHS); 2011.
3. Achilladelis B, Antonakis N. The dynamics of technological innovation: the case of the pharmaceutical industry. Research Policy 2001;30(4):535.
4. Aitken M, Berndt ER, Cutler DM. Prescription Drug Spending Trends In The United States: Looking Beyond The Turning Point. Health Affairs (Millwood) (Project Hope) 2009;28(1):w151-160.
5. PhRMA. New Medicines in Development Database. 2010 [cited 2010 September]; Available from: http://www.innovation.org/index.cfm/FutureOfInnovation/NewMedicinesinDev...
Competing interests: None declared
University of British Columbia, 201-2206 East Mall, Vancouver, British Columbia, Canada, V6T 1Z3
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