2024年5月7日发(作者：)

ANALYSIS

How to improve R&D productivity:

the pharmaceutical industry’s grand

challenge

Steven M. Paul, Daniel S. Mytelka, Christopher T. Dunwiddie, Charles C. Persinger,

Bernard H. Munos, Stacy R. Lindborg and Aaron L. Schacht

Abstract | The pharmaceutical industry is under growing pressure from a range of

environmental issues, including major losses of revenue owing to patent expirations,

increasingly cost-constrained healthcare systems and more demanding regulatory

requirements. In our view, the key to tackling the challenges such issues pose to both the

future viability of the pharmaceutical industry and advances in healthcare is to substantially

increase the number and quality of innovative, cost-effective new medicines, without

incurring unsustainable R&D costs. However, it is widely acknowledged that trends in

industry R&D productivity have been moving in the opposite direction for a number of years.

Here, we present a detailed analysis based on comprehensive, recent, industry-wide data

to identify the relative contributions of each of the steps in the drug discovery and

development process to overall R&D productivity. We then propose specific strategies

that could have the most substantial impact in improving R&D productivity.

New molecular entity

(NME). A medication

containing an active ingredient

that has not been previously

approved for marketing in any

form in the United States. NME

is conventionally used to refer

only to small-molecule drugs,

but in this article we use the

term as a shorthand to refer to

both new chemical entities and

new biologic entities.

Lilly Research Laboratories,

Eli Lilly and Company,

Lilly Corporate Center,

Indianapolis, Indiana

46285, USA.

Correspondence to: S.M.P.

e-mail:

smpaulmd@

doi:10.1038/nrd3078

Published online

19 February 2010

The pharmaceutical industry is facing unprecedented

challenges to its business model. Experienced observers

and industry analysts have even predicted its imminent

demise

1–3

. Over the past decade, serious concerns about

the industry’s integrity and transparency — for example,

around drug safety and efficacy — have been raised,

compromising the industry’s image, and resulting in

increased regulatory scrutiny

4,5

. This erosion in confi-

dence in the industry and its products has resonated

poorly with patients, health-care professionals, payers

and shareholders. Indeed, the industry’s price/earnings

ratio, a measure of the current valuation of the industry,

has decreased below that of the S&P 500 index and has

remained more or less flat, as have share prices for the

past 7 years.

The industry’s profitability and growth prospects

are also under pressure as healthcare budgets become

increasingly strained. Generic drugs, although clearly

helping to keep drug prices in check, are currently

approaching 70% of all prescriptions written in the

United States

6

. Moreover, key patent expirations between

2010–2014 have been estimated to put more than US$209

billion in annual drug sales at risk, resulting in $113

7

billion of sales being lost to generic substitution. Indeed,

for every dollar lost in declining product revenues due

to patent expirations by 2012, it has been estimated

that large-cap pharmaceutical companies will only be

able to replace on average 26 cents with new product

revenues

8

.

Simply stated, without a dramatic increase in R&D

productivity, today’s pharmaceutical industry cannot

sustain sufficient innovation to replace the loss of rev-

enues due to patent expirations for successful products.

A key aspect of this problem is the decreasing number

of truly innovative new medicines approved by the

US Food and Drug Administration (FDA) and other

major regulatory bodies around the world over the

past 5 years (in which 50% fewer

new molecular entities

(NMEs) were approved compared with the previous

5 years)

9

. In 2007, for example, only 19 NMEs (including

biologics) were approved by the FDA, the fewest

number of NMEs approved since 1983, and the number

rose only slightly to 21 in 2008. Of the 21 new drugs

approved by the FDA in 2008, only 6 were developed by

the 15 largest pharmaceutical companies and only 29%

would be considered ‘first-in-class’ medicines. In 2009,

24 new drugs were approved, 10 of which were devel-

oped by large pharmaceutical companies and only 17%

of which could be considered first-in-class. Some have

argued that the number of approved ‘mechanistically

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DRUG DISCOVERY

© 2010 Macmillan Publishers Limited. All rights reserved

ANALYSIS

innovative’ and first-in-class NMEs have remained

stable at about 5–6 per year. However, the number of

potential revenue-generating drugs (innovative or

other wise) as a percentage of R&D expenditures has

undeniably fallen sharply.

With an estimated $50 billion in collective annual

R&D spending by the large pharmaceutical companies,

and appropriate allocation over time to the successful

discovery and development of NMEs, the average cost

for these companies to bring an NME to market is now

estimated to be approximately $1.8 billion (see below for

details underlying this estimate), and is rising rapidly.

Moreover, there is little evidence that the average costs

of successfully launching an NME vary significantly

between large pharmaceutical or small biotechnology

companies

10,11

.

Although R&D productivity has been declining

for a number of years

2

, the unprecedented combina-

tion of reduced R&D output in the form of success-

fully launched truly innovative NMEs, coupled with

diminishing market exclusivity for recently launched

new medicines and the huge loss of revenues owing to

generic competition over the next decade, suggest that

we may be moving closer to a pharmaceutical ‘ice age’

and the potential extinction of the industry, at least as it

exists today

12,13

. Although this might be welcomed by the

industry’s critics, the impact on the health and well-being

of patients owing to delayed or even lost opportunities

to introduce the next generation of innovative medicines

could be devastating. In this regard, we underscore the

findings of Lichtenberg

14

on the effects of medical inno-

vation (including controls for the impact of obesity and

income), which indicate that ~40% of the 2-year increase

in life expectancy measured from 1986–2000 can be

attributed to the introduction and use of new drugs. It

took approximately 3 years for NME launches to have

their maximal impact on longevity — this effect was

not observed for non-NME (older) drugs. One can only

speculate as to the impact on longevity and quality of life

that new drugs now in clinical development for cancer

and Alzheimer’s disease might have. Without these new

medicines, and given the rise in diseases such as diabetes

and childhood obesity, it is possible that life expectancy

may actually decrease over time

15

.

Among all the challenges faced by the pharmaceutical

industry, we argue that improving R&D productivity

remains the most important. The environmental factors

that are reducing the industry’s profitability can only

be mitigated by substantially and sustainably increas-

ing the number and quality of innovative, as well as

cost-effective, new medicines; but only if accomplished

at reasonable R&D costs. So, the key questions are

where, how and by how much can R&D productivity

be improved? Here, we present a detailed analysis of

R&D productivity by first defining and modelling the

essential elements of contemporary drug discovery

and development that account for the current cost of

a new medicine, and discuss the rate-limiting steps of

the R&D process that are contributing to reduced R&D

productivity. We then propose, and illustrate, ways to

improve these factors.

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© 2010 Macmillan Publishers Limited. All rights reserved

How do we define R&D productivity?

R&D productivity can be simply defined as the relation-

ship between the value (medical and commercial) created

by a new medicine (considered here to be an NME)

and the investments required to generate that medicine.

However, R&D productivity can in our view best be

elaborated in two important dimensions: inputs leading

to outputs, or R&D efficiency; and outputs leading to

outcomes, or R&D effectiveness

(FIG. 1)

.

R&D efficiency represents the ability of an R&D

system to translate inputs (for example, ideas, invest-

ments, effort) into defined outputs (for example, inter-

nal milestones that represent resolved uncertainty for

a given project or product launches), generally over a

defined period of time. If launching (gaining regulatory

approval and commercializing) an NME is the desired

output, how can this be achieved with greater efficiency

(that is, at a lower cost)?

R&D effectiveness can be defined as the ability of the

R&D system to produce outputs with certain intended

and desired qualities (for example, medical value to

patients, physicians and payers, and substantial com-

mercial value). Thus, R&D productivity can be viewed

as an aggregate representation of both the efficiency and

effectiveness of the drug discovery and development

process; the goal of a highly productive R&D system is

to efficiently translate inputs into the most desired and

valuable outputs. For a more detailed description of these

definitions, see Supplementary information S1 (box).

With this definition of R&D productivity in mind, we

have further adapted a productivity relationship or

‘pharmaceutical value equation’, which includes the key

elements that determine both the efficiency and effec-

tiveness of the drug discovery and development process

for any given pipeline (see equation 1).

P