Transcript The_new(ish)

The new(ish) model of drug
development
Contract research organizations and
the clinical trials industry
Outline
1. The drug development pipeline: a (very) brief
introduction
2. The rise of CROs
3. When experiments travel
4. Some implications
1. The drug development pipeline
From discovery to approval: some
numbers
• Estimated average time from synthesis to
approval: 9-12 years
• Estimated cost: $500 million-$2 billion*
• 1 in 5,000 compounds screened at early-stage
will reach the market
• Only about 20% of compounds that enter
human trials are successful; though estimates
vary.
*For an introduction to the controversy over these numbers, see: Collier 2009,
CMAJ 180(3):279.
The cost of clinical trials: some
industry figures
• The average number of patients studied per drug rose from
about 3,000 in the 1980s to nearly 5,000 today.
• Development costs more than quadrupled – from $104 million
in the 1980s to $467 million in the 1990s
• From 1995-2000, one of every eight compounds entering
Phase I reached approval –a 13% success rate.
• From 2000-2003, one of every 13 entering compounds gained
approval – a success rate of only 8%.
From Quintiles: reinventing the clinical trial: http://www.quintiles.com/elements/media/whitepapers/reinventing-clinical-trial.pdf
And some more figures
• From the 1980s to the 1990s, clinical trial
costs rose 5 times faster than preclinical costs
• Over the same time period, the average cost
of developing a drug rose at a rate 7.4%
higher than inflation- and clinical trials were
responsible for most of that
Collier 2009, CMAJ 180(3):277
Clinical trials: the various types
• Prevention trials
• Screening trials
• Diagnostic trials
• Treatment trials: test experimental
treatments, new combinations of
drugs, or new approaches to
surgery.
• Quality of life trials
• Compassionate use trials: provide
experimental therapeutics prior to
final FDA approval to patients whose
options with other remedies have
been unsuccessful.
Clinical trials: Phase 1 (first-in-man)
Initial studies to determine:
• the actions of drugs once in humans
(pharmacokinetics)
• the side effects associated with increasing doses
(dose-ranging)
• early evidence of effectiveness
• may include healthy participants and/or patients.
• Duration: <1 year
• Sample size: 20-80
Clinical trials: Phase II
Phase II trials are designed to evaluate:
• Safety in the target patient group
• Effectiveness
• Efficacy at various doses
• Short-term side effects
• Drug-drug and drug-disease interactions
Duration: Several years
Sample size: 200-300
Clinical trials: Phase III
Phase III trials are designed to evaluate:
• Effectiveness
• Risk-to-benefit ratio in a demographically diverse sample
• Efficacy and safety for subgroups
Has two or more “arms”, can be placebo-controlled or active-controlled
Forms the principle evidence for a New Drug Application (NDA)
The most time-consuming and expensive phase in drug development; perhaps twothirds of true R&D costs
Duration: Up to 5 years
Sample size: 300-3,000+
Clinical trials: Phase IV post-marketing
• Done after the drug or treatment has been
granted marketing authorization
• Designed to gather information on the drug's
effect in various populations and any side
effects associated with long-term use.
• In practice, post-marketing surveillance has
been under-regulated and under-funded.
Clinical trials regulation: the FDA
Marketing approval in the US is
granted by the Food and Drug
Administration.
FDA regulations have been
one of the primary drivers of
standardized drug
development procedures,
and now form the basis of
corporate drug testing in the
developed world.
Despite numerous criticisms
of its processes, the FDA
remains the gold standard
in regulatory stringency
Clinical trials regulation: the FDA (cont.)
Economists and industry
alike have criticized the
FDA for imposing
excessive requirements.
So have patient groups,
many of whom have
successfully lobbied for
earlier access to
experimental treatments
More development time lost to
FDA mandated procedures = less
time to exploit patent exclusivity =
barriers to innovation
Clinical trials regulation: the FDA (cont.)
Political pressure from industry and
patient groups led to a number of
reforms in the 1990s designed to
shorten approval time and reduce
regulatory burdens*
Percentage of new drugs receiving
FDA approval within 6 months of
NDA rose from 4% in 1992 to
28% in 1999
Average approval time for nonpriority review drugs was at 18
months in 2008
*See, for example: Prescription Drug User Fee Act 1992; FDA Modernization Act 1997
In sum…
Clinical trials are getting bigger and more
complex
They’re getting much more expensive
Regulatory burdens in developed countries are
seen by industry as being heavy
The industry solution?
2: The rise of CROs
The contract research industry grew out of
consultancies established in the early 1970s. Quoted
from Petryna 2007:
“They were a cottage industry, people working out of
garages with a few computers- scientists who came
out of the industry with experience and said I can
take on some of this data management work or trial
monitoring on a contract basis. But pharma did not
trust these people with anything large or
complicated.”
The Rise of CROs (cont.)
• Early 1980s: pharma
routinely outsourcing
lab and clinical
services.
• Mid-1990s: research
industry booming,
many CROs go public
• CRO market size
currently estimated at
$17.8 billion, and
revenue is increasing
at an annual rate of 1416%*
*Source: ACRO 2009 http://www.acrohealth.org/
The Rise of CROs (cont.)
• Today, biopharmaceutical companies
outsource approximately 25% of all clinical
trials. This figure is expected to increase to
35% over the next five years.
• CROs can contract for almost every aspect of
drug development, but their core business is
clinical trials
The Rise of CROs: Driving factors
•
•
•
•
•
•
Changing industry structure
Explosion of INDs
Rising cost and complexity of trials
Changes in US clinical trials regulations
Data exclusivity and patent law developments
International harmonisation of regulatory and ethical
standards
• Increasing commercialization of scientific research
• The emergence of the global clinical trial
3: When experiments travel
• More than 50,000
clinical trials are
currently being run
worldwide
• An estimated 40% of
those are taking place
in “non-traditional
research environments”;
that is, low and middle
income countries
Density of actively recruiting clinical sites of biopharmaceutical clinical
trials worldwide as of 2007 Density is in per country inhabitant (in millions;
based on 2005 population censuses); darker orange/red denotes a higher density.
The trial density and average relative annual growth rate in percent is shown for
selected countries. The countries in grey had no actively recruiting
biopharmaceutical clinical trial sites as of 12 April 2007.
• Estimates vary widely, and
trends are difficult to quantify
because trial registry is not
adequately standardized
• However, the pace of expansion
into LMICs is accelerating, and
is likely to continue doing so.
• As of Nov 2007, approx. 1/3 of
phase III trials sponsored by the
20 largest pharma companies
are being conducted solely
outside the US.
• The majority of the sites for
these studies were outside the
US.
Why?
Several reasons
•
•
•
•
•
•
•
Cost
Large “treatment-naïve” patient pools
Epidemiological transition
Hierarchical doctor-patient relationships
Inadequate health systems
Presence of underpaid, qualified local researchers
Less stringent government oversight (regulatory
arbitrage)
• Government policies designed to attract the clinical
trials industry
5. The implications
For scientific research:
• Norms that emphasize speed over quality
• Uncertain lines of accountability
• “De-skilling” of the research enterprise
• Conflicts of interest
• Stronger, more complex controls over IP
• Changes in the role and function of publication
• Re-ordered goals of research in general
5. The implications
For the public
• More me-too drugs, and a possible decrease
in overall innovation
• Increased chances of ineffective or unsafe
drugs gaining FDA approval
• Emergence and codification of “ethical
variability”
• Increased risk of exploitation of research
subjects
Questions?
Further reading
On drug development:
•
Collier 2009. Drug development cost estimates hard to swallow”. CMAJ. 180(3): 277-280.
http://www.cmaj.ca/content/vol180/issue3/
•
Singh 2008. “Drug development challenges”.
http://www.pharmafocusasia.com/strategy/drug_development_challenges.htm
On clinical trials:
•
The ADVANTAGE Seeding Trial: a review of internal documents. Annals of Internal
Medicine. 149(4):251-258 http://annals.org/cgi/content/full/149/4/251
•
Collier 2009. “Rapidly rising clinical trial costs worry researchers; CMAJ. 180(3): 277-280.
http://www.cmaj.ca/content/vol180/issue3/
•
Collier 2009. “Clinical trial registries becoming a reality, but long-term effects remain
uncertain”. CMAJ 180(10): 1007-8. http://www.cmaj.ca/cgi/content/full/180/10/1007
•
Fisher 2007. “Ready to recruit or ready to consent populations?: Informed consent and the
limits of subject autonomy”. Qualitative Enquiry. 13(6): 875-894.
•
Abraham 2007. “Drug trials and evidence bases in international regulatory context.
BioSocities. 2:41-56.
On contract research:
•
Lenzer 2008. “Truly independent research?” BMJ. 337: 602-6.
http://www.bmj.com/cgi/content/extract/337/aug21_1/a1332
•
Mirowski and VanHorn 2005. “The Contract research organization and the
commercialization of scientific research.” Social Studies of Science. 35(4): 503-548.
http://sss.sagepub.com/cgi/content/abstract/35/4/503
Further reading (cont.)
On contract research:
•
Fisher 2006. “Coordinating ethical clinical trials: the role of research coordinators in the
contract research industry.” Sociology of Health and Illness. 28(6):678-694.
•
Petryna 2005. “Ethical variability: drug development and globalizing clinical trials”.
American Ethnologist 32(2):183-197.
•
Petryna 2007. “Clinical trials offshored: on private sector science and public health”.
BioSocieties. 2: 21-40.
http://journals.cambridge.org/download.php?file=%2FBIO%2FBIO2_01%2FS1745855207
005030a.pdf&code=20678702f93af21cec9cdaa4de02bcf5
•
Petryna 2009. When Experiments Travel: the clinical trial and the global search for human
subjects. Princeton University Press.
•
Rettig 2000. “The Industrialization of clinical research”. Health Affairs. 19(2): 129-146.
http://content.healthaffairs.org/cgi/content/abstract/19/2/129
•
Schuchman 2007. “Commercializing clinical trials—risks and benefits of the CRO boom”.
NEJM. 357(14):1365-8. http://content.nejm.org/cgi/content/full/357/14/1365
•
Normile 2008. “The promises and pitfalls of clinical trials overseas”. Science. 322: 214-6.
On ethics in developing country research
1.
Wendler et al. 2004. The Standard of care debate: can research in developing countries
be both ethical and responsive to those countries’ health needs?