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/white-papers/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 interactionsDuration: Several yearsSample size: 200-300

Clinical trials: Phase IIIPhase 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 two-thirds 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 FDAFDA 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

Marketing approval in the US is granted by the Food and Drug Administration.

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

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 non-priority review drugs was at 18 months in 2008

*See, for example: Prescription Drug User Fee Act 1992; FDA Modernization Act 1997

Clinical trials regulation: the FDA (cont.)

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 14-16%*

*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%2FS1745855207005030a.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 research1. Wendler et al. 2004. The Standard of care debate: can research in developing countries

be both ethical and responsive to those countries’ health needs?