deductible from a manufacturer’s tax base, claiming that this omission overestimates the cost, to a pharmaceutical company, of developing a new drug.
In the context of this discussion, neither of these criticisms is justifiable. The inclusion of the ‘opportunity costs’ that accrue during the lengthy period of drug development is an accepted accounting practice. And although tax relief can give financial advantage to a developer, it does not alter the estimates of the out-of-pocket costs — to society as a whole — of developing a new drug: someone has to pay! I therefore, albeit with some reluctance in view of incomplete disclosure of the data, accept that the average cost of discovering and developing a new drug is now in excess of US $800 million.
The commercial developer of a drug needs to recoup the R&D costs, recover the losses from those products abandoned during development (either due to inefficacy or adverse safety findings) and make a reason-able profit. There is a convention, in the pharmaceutical industry, that to recoup R&D investment a product needs to bring in peak annual sales of US $500 million. Although I am unaware of the formal evidence to support such a claim, I have encountered it so often (both privately and publicly) that it seems likely to reflect the industry’s broad position and is, consequently, a major driver for both investment decisions and price-setting. (This figure is also quoted, again without supporting data, in the BCG report1.) Indeed, a study of
the returns to R&D on new drug introduc-tions found that the sales of only about 30% of products were sufficient to recoup their original development costs5.
The increasing cost of drug development is likely to promote the situation whereby com-panies invest only in the development of those new drugs that are expected to yield peak annual sales greater than US $500 million. It is also worth noting that completely novel drug development — that is, against unproven disease targets — poses a greater risk of failure than developing drugs against proven targets. This provides additional incentive for com-panies to focus on improving on approaches that have been clinically and financially suc-cessful, and a disincentive to develop products for unmet medical needs.
In summary, the fact that the discovery and development of a new drug now costs in excess of US $800 million, and is rising at an annual rate of 7.4% above general price inflation2,
raises concerns. If the pharmaceutical indus-try’s R&D efforts become concentrated solely on high-selling products, the outlook in many areas of pharmacotherapy — in particular models of disease and bioinformatics should
facilitate the processes of drug discovery and development. And ‘personalized medicine’, based on pharmacogenetic approaches, has the potential to optimize the efficacy and minimize the toxicity of therapeutic agents. Yet, despite the promise, it increasingly seems that these hopes will not be realized without dramatic changes in the way that new medi-cines are discovered and developed. The cost of drug development is so great that new medicines are in danger of becoming unaf-fordable for either manufacturers to develop or consumers to purchase.
The problem
Two recent studies1,2suggest that the average
cost of discovering and developing a new drug is now in excess of US $800 million. The approaches used by the authors of these studies seem to be different. The methods and results of the Boston Consulting Group (BCG) study1are provided only in the briefest
form, as an appendix to a report on the impli-cations of genomics for pharmaceutical R&D. The text of the report does, however, provide some data on the apportionment of expendi-ture at the different stages of drug discovery and development. The study by DiMasi and colleagues2 gives much greater detail,
although these authors do not apportion costs to the individual components of non-clinical development. The overall conclu-sions of the two studies, however, are broadly similar (TABLE 1).
In neither study do the authors disclose the identities of the products they examined, and the BCG study is seriously weakened by the absence of every important detail. In deriving their final estimates, both studies estimated the out-of-pocket costs and added the ‘capitalized’ cost, which represents the revenue that would have been generated, over the period of development, if the out-of-pocket expenses had been invested in the equity market.
These findings have led to some contro-versy3,4. Relman and Angell3, in particular,
criticize the DiMasi study2for including
capi-talized cost in their final estimate. They also take issue with this study for failing to take account of the R&D expenses that are
The cost of drug development has risen markedly in the past 30 years, with studies now reporting values exceeding US $800 million. As these spiralling costs threaten to make the development of new drugs increasingly unaffordable for both developing companies and consumers, it is clear that efforts should be made to address this problem. All aspects of the drug discovery and development process should be examined for potential cost savings, but I focus here in particular on the current regulatory requirements.
Humankind has reaped extraordinary bene-fits from the pharmacological revolution of the twentieth century. Conditions such as poliomyelitis, diphtheria and whooping cough have been largely eliminated in devel-oped countries by immunization. Many lethal communicable diseases can be readily cured with antimicrobial agents. Complex surgical procedures, beyond the imagination of our forefathers, are now safely and effectively undertaken using modern anaesthetics. And drugs have improved the quality of life for many people with chronic diseases to an extent that would have been unthinkable in the nineteenth century.
Nevertheless, there remains massive unmet medical need in both developed and developing countries. For example, there is a pressing requirement for effective vaccines against HIV/AIDs, malaria and tuberculosis. We have little to offer those with neurodegen-erative disorders such as Alzheimer’s disease,
Parkinson’s diseaseor Huntington’s disease. Current treatments for many psychiatric disorders leave much to be desired. And the outlook for patients with the most common advanced malignancies, such as lung, breast, prostate and colorectal cancers, is still poor.
It could be argued that the prospects for satisfying unmet medical needs, however, have never been brighter. Advances in molec-ular genetics and molecmolec-ular biology offer the possibility of identifying novel, druggable targets that could be modulated to prevent, control or cure of many of the conditions highlighted above. The application of tech-niques such as combinatorial chemistry, high-throughput screening, sophisticated animal
Cutting the cost of drug development?
Michael D. Rawlins
underlying the current regulatory framework in the United States, namely the Federal Food, Drug and Cosmetic Act of 1938 and the 1962 amendments) have been confined to history. Nevertheless, drug regulation comes at a price that is ultimately paid by consumers.
The time is now right for an exhaustive examination of the requirements of drug regulatory authorities. There needs to be a rigorous examination of the ‘rituals’ associated with drug development9. Every step in the
drug development pathway should be tested against two separate criteria: is there a clear evidence-base to support the continuing inclusion of the measure in the requirements of regulatory authorities?; and does each regulatory requirement offer value for money? Evidence-based drug regulation Many of the requirements of drug regulatory authorities are based on the opinion of experts, rather than on formal evidence. By ‘formal evidence’, I mean that the basis for the particular requirement is founded on fact rather than hypothesis; and that there is a robust body of evidence to support the contin-uing inclusion of the measure as a regulatory requirement. Although I concentrate on the preclinical safety studies and the clinical trial programmes, the same principles apply to the chemical and pharmaceutical aspects of drug development.
Preclinical safety studies. The preclinical safety
studies, undertaken during the development of a new drug, are mainly based on biological plausibility rather than on any formal quanti-tative assessment of their predictive powers9.
This approach is unsound, and inadequate, for the twenty-first century. The current pre-clinical safety studies involve four types of investigation: exploration of the potential pharmacological effects of a drug on biological processes other than those intended for its therapeutic effects (the pharmacological ‘screen’); pharmacokinetic investigations of the drug in the species likely to be used for formal toxicology testing (studies of absorption, distri-bution, metabolism and excretion (ADME)); single- and repeat-dose toxicity testing; and those in which the risk of failure is high — is
bleak. Not only will less common conditions be ignored, but many of the potential benefits of pharmacogenetics will not be realized.
Some have put forward the view that the application of genetics will reduce the costs of drug development (see, for example,REF. 1), although others remain unconvinced (see, for example,REF. 6). The problem, as I see it, is this. A pharmacogenetic approach to drug discovery is likely to result in the fragmenta-tion of condifragmenta-tions that are currently regarded (and treated) as single diseases. Some believe that the commercial disadvantage of market segregation, on the basis of pharmacogenetic data, might be offset by a lowering of devel-opment costs resulting from more targeted clinical trials. I do not share this optimism. The conventional preclinical components of drug development would largely remain in place, and the number of patients enrolled in clinical studies would be unchanged if con-temporary approaches to confirming efficacy and safety remain unaltered.
It is with these thoughts in mind that I believe it is now imperative to make major efforts in reducing the costs of bringing new drugs to the market. There are a number of facets of the drug development process that could be targeted in this respect — such as improving strategies for identifying likely failures as early as possible to reduce the cost due to them, and addressing inefficiencies in the conduct of clinical trials — but I focus here on the current regulatory requirements. Drug discovery
Drug hunting is as much an art as it is a science. The decision to adopt one specific approach to a particular therapeutic problem is grounded in science, but the choice of approach, and the particular target, is a matter of judgement. The extent to which this can be made easier and simpler is questionable.
Some commentators7,8 have recently
pointed out that there seems to be a trend for many new drug discoveries to be made by small companies supported by venture cap-ital, or in academic settings, rather than in the laboratories of major pharmaceutical compa-nies themselves. I do not regard this as either inappropriate or indicative of failure by the
pharmaceutical industry. The trend, during the latter years of the twentieth century, for drug hunting to be the provenance of indus-try is unhealthy. Pluralism offers opportunities for innovative discoveries that should be supported enthusiastically, rather than derided or deplored, even though the subsequent development programme will require the resources of a major manufacturer.
Despite this encouraging move towards a broader base for drug hunting, I doubt, overall, that significant reductions in the costs of drug discovery are likely. Instead, it is in the development phase that we should be seeking savings.
Drug development
Once a candidate molecule has been identified, major costs are incurred in its development. The breakdown, derived from the BCG1and
DiMasi2data, is shown in TABLE 2. Although
the table reveals some differences between the two studies, it is obvious that each component of the drug development process consumes substantial resources.
Drug regulatory authorities, particularly in North America and Europe, have made sub-stantial contributions to public health. Failures of pharmaceutical quality are now rare. It is almost unique for inefficacious new products to reach the market, although the clinical effectiveness of some (such as the cholinergic agents for Alzheimer’s disease and β-interferons for multiple sclerosis) are modest. And, although the assessment of safety at the time a new product becomes generally available is necessarily provisional, subsequent market withdrawals (for safety reasons) are unusual9.
I am confident that tragedies such as the sulphanilamide or thalidomide disasters (which spurred much of the legislation
Table 1 | Estimates of the overall costs of drug discovery and development
Costs* Boston Consulting Group (2001)1 DiMasi et al. (2003)2
Out-of-pocket cost – 403
‘Opportunity cost’ – 399
Total cost 880 802
*US $ million.
Table 2 | Estimates of the component costs of drug development
Component Pre-approval costs: US $ million (%)
Boston Consulting Group (2001)1 DiMasi et al. (2003)2
Biology 370 (42%) – Chemistry 160 (18%) – Preclinical safety 90 (10%) – Overall preclinical 620 (70%) 335 (42%) Clinical 260 (30%) 467 (58%) Total 880 (100%) 802 (100%)
dose(s) proposed for marketing, and can encompass studies of comparative efficacy with current ‘best practice’.
Phase II and III studies are almost invari-ably conducted using a randomized, con-trolled, blinded, parallel-group design. The evidence supporting such study designs is overwhelming and (usually) ensures freedom from bias11,12, even though the generalizability
of the results can sometimes remain uncertain. Regulators, manufacturers, clinicians and con-sumers can, therefore, generally be re-assured that the results and conclusions are reliable.
Despite the clear evidence base to support conventional clinical trial designs, alterna-tives need to be explored if costs are to be decreased. If the numbers of patients in pre-marketing clinical trials could be reduced without compromising knowledge of safety and efficacy, and if the time taken to conduct such studies could be significantly diminished, substantial cost-savings would be achieved.
During the past two decades, the size of clinical programmes to support drug approvals has increased significantly. For example, the average number of subjects involved in clinical trials conducted to support a New Drug Application for approval to market a drug in the United States has more than doubled2. The desire to obtain
informa-tion that differentiates the drug from its poten-tial competitors, in ways that are clear to both doctors and patients, is an important force driving the increase in clinical programme size13, especially in therapeutic areas for which
there are already many marketed drugs. However, the regulatory policies governing the quality and quantity of data required for drug approval clearly also have a major impact on the size of a clinical programme.
Drug regulatory authorities, such as the US FDA, have generally required at least two Phase III randomized controlled trials (RCT) to confirm a new drug’s safety and efficacy. As recently noted by Peck and colleagues14, in the
case of the FDA this arose from an interpreta-tion of a passage in the 1962 amendments to the Food, Drug and Cosmetics Act requiring “adequate and well-controlled investigations to determine substantial evidence of effectiveness required for approval of a new drug.”However, the 1997 Food and Drug Administration Modernization Act amended this to requiring “data from one adequate and well-controlled investigation and confirmatory evidence.”Peck et al. suggest that their proposals for imple-menting this amendment would provide “more rational, more efficient and more infor-mative clinical drug development”14. To
sum-marize briefly, for a single controlled trial and confirmatory evidence to provide substantial The predictive power of the current
pack-age of short-term mutpack-agenicity studies (that is, the ‘mutagenicity package’) has a reason-able scientific basis and I doubt whether changes would be warranted. The value of in vivo carcinogenicity studies with non-mutagenic compounds is much less com-pelling. Either an unexpected tumour type is expressed which, after extensive investigation, is shown to be irrelevant to humans, or it reveals a tumour type that is entirely pre-dictable from the compound’s pharmaco-logical properties, and for which hyperplasia has often been observed in the repeat-dose toxicology studies.
Clinical studies. According to the estimates
shown in TABLE 2, the cost of the clinical development of a new drug is in the region of US $300–450 million. Is such a massive expenditure necessary?
Phase I studies with a new drug have a crucial role in the design of subsequent clinical trials. They examine whether the pharmaco-logical effects seen in experimental animals are expressed in humans; they provide crucial dose–response data; and the pharmacokinetic investigations provide invaluable information about the dosage regimens to be used in clini-cal trials, as well as equally valuable data about routes of elimination. Well-conducted Phase I studies with new drugs are irreplaceable.
Phase II studies are intended to indicate whether, and at what dose, a new drug’s anticipated therapeutic benefits are observed in patients; and to provide some preliminary indication of its safety in humans. Phase III studies provide confir-mation of a drug’s therapeutic efficacy and safety in a wider patient population at the special toxicity testing (such as mutagenicity,
carcinogenicity and reproductive toxicity tests). Of the preclinical safety studies, the pharmacological screen seems, intuitively, to be of the most value. Yet I have never encoun-tered a robust analysis (either generally or specifically) of its predictive power, nor am I aware of any objective basis for the presumed safety margins that arise from such studies.
The acute- and repeat-dose toxicology studies warrant closer examination. Some form of acute toxicology is clearly necessary, if only as a preliminary to designing repeat-dose studies. Yet the predictive powers of the repeat-dose toxicology tests, as presently conducted, are largely unknown. Their justifi-cation and interpretation relies, largely, on the corporate memory of industry and regulatory toxicologists, rather than on a careful scrutiny of the totality of the available data. The ques-tions that need to be asked include the follow-ing. First, to what extent are the current regulatory requirements for repeat-dose studies based on biological plausibility, rather than formal evidence? Second, to what extent does ‘target organ’ toxicity, as identified in relevant experimental animals (usually the rat and the beagle dog), reflect likely toxicity in humans? If so, what are the predictive powers? Third, are the current protocols demanded by drug regulatory authorities supported by a detailed scrutiny of the totality of the available evidence? What, for example, is the real pre-dictive power of repeat-dose studies lasting more than three months? Last, what is the evidence base for the ‘safety margins’ assumed by toxicologists? The answers to these ques-tions require a full analysis and assessment of the mass of data held in the vaults of US and EU drug regulatory authorities.
Box 1 | The frequentist approach in clinical trials
Conventional clinical trials involve testing a new treatment against either placebo or an active comparator. The statistical issue, then, is whether any difference between the two treatments is real or not.
The Fisherian approach is to calculate the likelihood that the difference is due to chance. By convention, if the probability (the ‘P’ value) of this being due to chance is less than 5% (that is, P <0.05), it is regarded as ‘statistically significant’.
The Neyman–Pearson approach estimates the chances of making various types of error in drawing conclusions from the study. The chance of a type 1 error (‘α’) is the likelihood of concluding there is a difference where none exists. As with the Fisherian approach, this is conventionally set at 5% or (sometimes) at 1%. The chance of a type 2 error (‘β’) is the likelihood of concluding there is no difference when one exists. It is usually expressed as 1 – β with a P value of 80% or (sometimes) of 90%. The factors determining 1 – β are the size of difference between the two treatments, and the number of patients recruited into the study.
The P value (the probability that any difference between two treatments has arisen by chance) is arbitrarily set at 5%. Those inexperienced with statistics might draw three erroneous conclusions from a P value: that if P <0.05 there is a real difference between the treatments; that the larger the P value, the greater the difference; and that if a difference is ‘statistically’ significant, it is also ‘clinically’ significant.
cost US $15 million over three years. I asked whether there had been any problems. I was told there had been none: during a seven-year period, during which millions of ampoules had been produced, no quality problems had been encountered. When I asked why the regulatory authority was insisting on this measure, I was told it was precautionary. When I asked why the company were not challenging it, I was told that it was not worth their while fighting with their regulator.
For the particular company, US $15 million is small change, but it will add a modest increment to the cost of the product, which will ultimately be passed on to consumers. Will it be worth it? Will the expenditure offer value for money? I doubt it!
Conclusions
The outlook for pharmacotherapy in the twenty-first century should be golden. Our capacity to meet unmet clinical need should be great. We are, though, in danger of jeopar-dizing this potential if we do not make every attempt to reduce the cost of drug develop-ment. It will not be easy; nor will it be uncon-troversial. There will be political, social and legal challenges to be addressed. But if we do not work towards this goal, we will fail future patients, their families and society as a whole.
Michael D. Rawlins is at the Wolfson Unit of Clinical Pharmacology, The Medical School, University of Newcastle upon Tyne, Newcastle upon Tyne NE2 4HH, UK. e-mail: m.d.rawlins@ncl.ac.uk
doi:10.1038/nrd1347
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evidence of effectiveness, they propose to initially undertake at least one well-designed randomized, blinded dose–response Phase IIb trial to demonstrate pharmacological action, clearly prespecifying all endpoints, covariates, and modelling and analysis procedures to be used; and then to undertake (on the basis of the Phase II results) a single Phase III RCT of sufficient size to establish a clinically beneficial treatment effect and to provide evidence of the same pharmacological action14. The combined
results of the two trials would provide substan-tial evidence of effectiveness. As the authors note, this proposal does not provide enhanced efficiency for assessing safety. Nevertheless, if widely adopted, such a scheme would clearly reduce costs, but more radical proposals should also be considered.
The randomized, controlled, blinded, parallel-group clinical trial is not the only possible approach to investigating the safety and efficacy of a new drug. The international community should embark on collaborative methodological research to critically evaluate alternatives. This requires an experimental approach, rather than just a theoretical analysis, with formal comparisons of the results of studies comparing novel and tradi-tional (RCT) designs. Some possibilities, albeit with a different purpose in mind, have been recently been advanced15. They include
various forms of sequential, adaptive, decision-based and risk-decision-based designs, as well as Bayesian techniques. We should even re-examine old heresies such as observational studies16, including historical controlled trials,
and confirm or refute the circumstances under which they might be appropriate17.
It would be perverse to expect the phar-maceutical industry to undertake such a pro-gramme: it would only, at least in the short term, further increase the costs of drug devel-opment. Rather, it requires a public–private partnership with close collaboration between the industry, public bodies (such as the Medical Research Council and the National Institutes of Health), and not-for-profit organizations (such as the Wellcome Trust and CancerUK).
Clinical trials are generally undertaken using a so-called ‘frequentist’ statistical approach (BOX 1). They are designed from a Neyman–Pearson standpoint but analysed from a Fisherian perspective18. The
Neyman–Pearson approach is focused on the chances of making various type 1 or 2 errors. The Fisherian approach is concerned with estimating the evidence against a speci-fied null hypothesis and expressed as a P value. Overemphasis on hypothesis testing, and of the inferences drawn from P values,
has been widely criticized18–20. Other
approaches to the analysis of both conven-tional and novel clinical trials are therefore needed. In particular, Bayesian approaches should be examined, experimentally, in order to re-assure sceptics (and others) whether their potential to allow for sequential analyses, non-prespecified sub-group analyses and flexible modelling of evidence from a variety of sources, can be achieved15,19,20.
Value for money
Drug regulatory authorities in almost all developed countries base their decisions on three criteria: quality, efficacy and safety. They take no account of the actual or potential price of the product to consumers. This absence of a ‘fourth hurdle’ is appropriate for two reasons. First, in a democracy, it would be wrong for any state to deny its individual citizens the right to purchase goods merely because the price was deemed to be too great. Second, there is a very real danger that drug regulators, either consciously or unconsciously, would confuse the decisions, and when confronted with a difficult cost–effectiveness problem would retreat behind arguments about efficacy, safety or the balance between the two.
This does not mean, however, that drug regulatory authorities can ignore the cost implications of their licensing requirements. Safety comes at a price. Consequently, in addition for a need to undertake a radical review of regulatory requirements, there is an equal imperative to examine the value for money of those that seem to have a robust and valid basis.
To some extent, regulatory authorities already, and implicitly, recognise this. If, for example, the safety of a new drug were to be explored more fully during its clinical devel-opment, regulatory authorities would have a case to demand at least a tenfold increase in the number of exposed patients in the pre-authorization period. They do not do this. Regulatory authorities recognize that such a demand would deny patients of newer effec-tive medicines, and drive pharmaceutical companies into extinction.
This approach needs to be adopted much more widely. Some requirements, even if soundly based, might have to be eliminated because they offer so little value for money. This applies, with equal force, to manufactur-ing as to preclinical safety studies. A few weeks ago I visited one of the manufacturing sites of a major pharmaceutical company. While watching the production of a sterile product, it was explained to me that the national regu-latory authority required an additional step to be incorporated into the process. This would
Competing interests statement
The author declares that he has no competing financial interests.
Online links
DATABASES
The following terms in this article are linked online to: Online Mendelian Inheritance in Man:
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=OMIM Alzheimer’s disease | Huntington’s disease | multiple sclerosis | Parkinson’s disease
FURTHER INFORMATION
Alzheimer’s Association: http://www.alz.org Hereditary Disease Foundation:
http://www.hdfoundation.org
Parkinson’s Disease Foundation:
http://www.pdf.org
Access to this interactive links box is free online.
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Challenges (Institute of Medicine, Washington DC, 2001)
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N. Engl. J. Med. 323, 1343–1348 (1990).
18. Senn, S. Statistical Issues in Drug Development (Wiley,
Chichester, 1997).
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20. Speigelhalter, D. J., Myles, J. P., Jones, D. R. & Abrams, K. R. Bayesian methods in health technology assessment: a review. Health Technol. Assess. 4 (38), (2000).
