88 Drivers and Barriers of TM

advanced tools and processes for evaluating how ES cell-based

products planned for humans will perform.
Another example where the FDA is trying to make a difference
is with the development of companion diagnostics, i.e. the tests
that are used to determine whether a particular therapy may work
for a particular patient. A good example is the recent approval
of Crizotinib, approved for locally advanced or metastatic non-
small cell lung cancer (NSCLC) that is anaplastic lymphoma kinase-
positive as detected by an FDA-approved test. The FDA issued the
draft guidance entitled In Vitro Companion Diagnostic Devices on
July 14, 2011, to communicate to industry how the FDA defines
these devices and to assist sponsors in understanding the Agencys
perspective on them. As a follow on to the In Vitro Companion
Diagnostic Devices guidance, the FDA is also developing a draft
guidance outlining strategies for clinical trial design and regulatory
considerations for co-developing a novel companion diagnostic and
therapy simultaneously, where the approval and subsequent use
of the therapy would incorporate a requirement for the diagnostic
test. This draft guidance will include recommendations for the
strategic use of biomarkers for patient selection and screening, as
well as clinical trial designs that allow for ethical patient selection
strategies. The FDA is also producing an internal plan for how it will
review applications using co-development strategies for product
development to accompany both guidances and ensure the Agency
meets the special needs of these types of products in a timely
way.

4.2.3 Emphasis on Preclinical Pharmacology

For a long time there has been a missing link between preclinical
information and the understanding of human pharmacology and
individual variations in clinical response to therapeutic interven-
tions. There is a need for a new discipline that can promote
pharmacology-based drug development and effectively link pre-
clinical pharmacology to human pharmacology in a quantitative
manner. The current lack of systematic translation of nonclinical
findings is exemplified by a relatively recent example. The first-in-
man Phase 1 clinical trial with the monoclonal antibody TGN1412,

  
 
  
 
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which ended in the near-death inflammatory response called

cytokine storm, prompted scientists and regulators to look back
and investigate whether this disaster could have been avoided from
the information generated in pre-clinical testing. The animal safety
testing revealed that the preclinical safety testing was conducted
in a non-responsive species with improper antigen presentation.
In particular, little attention was paid to understanding the CD28
binding differences, and subsequent signal transduction, between
human and cynomolgus monkey. There was more focus on the
knowledge that TGN1412 binds with high affinity to a 6 amino
acid epitope on an extracellular loop of the CD28 molecule that
is entirely conserved between man and macaques. Subsequently,
the drug developer may have incorrectly considered cynomolgus
macaques to be the most relevant species for pre-clinical safety
testing.
Most drugs fail due to lack of clinical efficacy. This is difficult
to comprehend considering major advances in basic science sup-
porting target identification, lead generation, and preclinical phar-
macology models. Predictions for novel interventions in preclinical
stages of development often suffer from lack of understanding of
validation in preclinical research and an overly optimistic reliance
on a narrow piece of favorable evidence that sways decision-
makers to promote drug candidates for clinical testing. For example,
in the case of AstraZenecas failed stroke drug NXY-059, use of
normotensive rodents in preclinical development may have led to
spurious predictions of clinical activity [10]. One widely recognized
target for the development of drugs to treat Alzheimers disease
is the prevention of amyloid-beta accumulation in the brains of
Alzheimer patients. Semagacestat, a gamma secretase inhibitor Eli
Lily was developing, was screened and designed to target amyloid-
production and expected to be effective against dementia. However,
results from two long-term Phase 3 studies showed it did not slow
disease progression and was associated with worsening of clinical
measures of cognition and the ability to perform activities of daily
living. Retrospectively, it is noted that trials were launched on the
basis of molecular, rather than behavioral, endpoints; which raises
questions about the validity of preclinical investigations in making
clinical generalizations [11].

  
 
  
 
 90 Drivers and Barriers of TM

4.3 Impact of TM on Regulatory Decision Making and

Barriers to TM

The FDA is increasingly utilizing concepts of TM into regulatory

decision making to supplement the information generated from
confirmatory trials. Advances in this area are providing unique
opportunities for the FDA to adopt a risk-based regulatory approach
toward drug approval that is increasingly driven by concepts from
TM. Over the last few years, the FDA has been increasingly relying on
biomarkers/surrogates and pharmacometric approaches to review
and approve new drug applications. This has been to facilitate
the streamlining of drug development based on translational
strategies and mechanistic understanding, with the expectation
that it will lead to significant cost savings and reduction of
development time and, at the same time, get novel and much-needed
therapies quickly to patients. Qualified biomarkers can enrich
clinical trials by demonstrating benefits, establishing unmet medical
needs, and identifying patients with a predisposition to adverse
events.
For example, the utility of hemodynamics in assessing treatment
response in children with pulmonary arterial hypertension (PAH)
that are unable to perform exercise testing, has recently attracted
considerable attention as an alternative to the gold standard of
exercise capacity to determine a medicines efficacy (see FDA
Advisory Committee Briefing Document for Revatio 2010). Work
recently carried out by both Pfizer and the FDA indicates that drug-
induced changes in exercise capacity were associated with drug-
induced changes in pulmonary vascular resistance index (PVRI) in
patients with PAH. This suggests that drug-induced changes in PVRI
might be used to make an informed assessment of treatment benefit
of Revatio (sildenafil) for PAH in children of all ages. The relationship
seems to be consistent across drugs of several classes and in control
groups. This highlights the effective utilization of a practical clinical
surrogate.
Evidence supporting clinical utility becomes a key driver for
clinical adoption and personalized medicine. However, the question
boils down to how much evidence one needs and how that evidence

  
 
  
 
 Impact of TM on Regulatory Decision Making and Barriers to TM 91

should be generated. It is important to keep in mind that the ma-

jority of evidence generated to support the clinical utility of a drug
and companion diagnostic has occurred incrementally over time
[12]. Incremental benefits should not be held against widespread
adoption. Clinical utility is often a matter of judgment; depending
on a stakeholders perspective of the supporting evidence. That
certainly does not mean that we should not strive for a higher
level of evidence to establish clinical validity and support clinical
implementation for a positive public health outcome. Evidence
generation leads to the much-needed discussion of study design
(e.g., enrichment design) and regulatory framework (pre- vs. post-
approval) that create opportunities for the generation of useful data
[13]. This can potentially facilitate improved integration of drug and
diagnostic tests into clinical practice.
The recent example of slow uptake of genetic testing for warfarin
in the clinic illustrates this struggle. The label for warfarin has
been updated with biomarker information, which needed the
clinical practice to change in order to be comprehensively adopted
(http://www.accessdata.fda.gov/drugsatfda docs/label/2011/0092
18s107lbl.pdf). However, very few patients get tested for VKORC1
and CYP2C9 when prescribed warfarin, despite much observational
evidence of clinical utility of this information for optimum dosing. In
a recent observational pharmacogenomic-warfarin dosing study led
by Medco and Mayo Clinic, researchers found that hospitalizations
due to any cause, as well as due to blood clots or excessive bleeding,
for heart patients taking warfarin dropped by approximately
30% when genetic information was available to doctors [14].
However, critics raised the possibility that the 30% reduction in
hospitalizations in the study may have been due to the effect of
closer attention to the patient rather than the effect of genotyping
prior to dosing [15]. Experts in the field wondered whether we could
achieve similar goals simply by using a dosing algorithm that takes
age, gender, body surface area, and early INR response into account.
These are valid arguments considering the cost of genetic testing
and the feasibility of obtaining the test results in real-time without
significant inconvenience to patients and health-care providers.
In addition, there are enough conflicting reports from clinical
trials, including prospective randomized controlled investigations,

  
 
  
 
 92 Drivers and Barriers of TM

to polarize this debate. The first randomized prospective controlled

trial to compare genotype-guided dosing to standard empirical
dosing has produced negative results of no difference in proportion
of out-of-range INRs between intervention and control groups.
However, the same study enumerated several key findings to
support the use of genetic testing that have been discussed in detail
by Lesko [16].
Clinical data seems to follow a hierarchy of evidence, with
meta-analyses and randomized controlled trials constituting the
highest level of evidence and expert opinion being the lowest
[17]. This has been the case with abacavir hypersensitivity, where
clinical adoption has been relatively rapid and widespread for
HLA-B*5701 prescreening to identify patients for the at-risk allele
prior to initiating therapy. Positive and unambiguous data from
a randomized controlled trial [18] provided evidence of clinical
utility, which not only led to speedy adoption into clinical guidelines
but also paved the way for positive reimbursement decisions from
insurance companies and rapid acceptance by both the physician
and patient communities [19]. We also often see that having a strong
causal relationship between genetic evidence and clinical outcome is
not enough to encourage clinical adoption.

4.4 Concluding Remarks

Experience at the FDA suggests that failure to utilize prior

knowledge about the drug and the disease often accounts for
trial failure, which is either lack of differentiation with placebo or
identification of unanticipated adverse effects. TM can make the
drug development process more quantitative and science-driven;
provide important clues and opportunities to look at the early data
and make any necessary corrections in the confirmatory stage, such
as how to get the correct dose for the most appropriate patient.
The National Center for Toxicological Research (NCTR) is playing an
important role in conducting FDA mission-critical, peer-reviewed,
translational research to develop a scientifically sound basis for
regulatory decisions and reduce risks associated with FDA-regulated
products. This NCTR research evaluates the biological effects of

  
 
  
 
 References 93

potentially toxic chemicals or microorganisms; defines the complex

mechanisms that govern their toxicity; aids in understanding critical
biological events in the expression of toxicity; and develops new
scientific tools and methods to improve assessment of human
exposure, susceptibility, and risk [20].
In the United States, drug-induced liver injury (DILI) is now the
leading cause of acute liver failure (ALF), exceeding all other causes
combined. Because of this, DILI has been identified by the FDAs
Critical Path Initiatives [21] as a key area of focus in a concerted
effort to broaden the agencys knowledge for better evaluation tools
and safety biomarkers.
In August 2007, the FDA entered a 2-year Cooperative Research
and Development Agreement (CRADA) with Entelos, a leader in
predictive biosimulation, to develop a virtual patient computer
model simulation to predict whether new drugs will produce
DILI. The goal is to use this in silico platform to guide the
development of clinical biomarkers and preclinical assays to
identify patient types and drug combinations that increase the
risk of liver injury. In addition to the CRADA, the FDA issued
a contract with Entelos, Inc, in September 2008 to perform an
exhaustive review of the scientific literature and produce the
first implementation step of the computer model, describing the
currently known and hypothesized mechanisms for DILI (ref: FDA
website; http://www.fda.gov/aboutfda/partnershipscollaborations/
publicprivatepartnershipprogram/ucm231122.htm).
There are several venues for TM to revolutionize drug develop-
ment enterprises by applying advanced tools to optimize dosing,
identifying the right patient population for drugs in development,
and providing the means to apply informed clinical trial design to
answer the most pertinent questions. Together, these can help to
reduce attrition, minimize failure and appropriately define clinical
utility.

References

1. Eichler, H.G., et al. (2010). New drug approval success rate in Europe in
2009, Nat. Rev. Drug Discov. 9, 355356.

  
 
  
 
 94 Drivers and Barriers of TM

2. DiMasi, J.A., et al. (2010). Trends in risks associated with new

drug development: success rates for investigational drugs. Clinical
Pharmacology & Therapeutics 87 (3), 272277.
3. Hooper, M. and Amsterdam, J.D. (1998). Do clinical trials reflect drug
potential? A review of FDA evaluation of new antidepressants. Paper
Presented at Annu. NCDEU Meeting., 39th, Boca Raton, Fla., 1114 June.
4. Honig, P. and Lalonde, R. (2010). The economics of drug development:
a grim reality and a role for clinical pharmacology, Clin. Pharmacol.
Therap. 87(3), pp. 247251.
5. Lee, WM, et al. (2005) Hepatic findings in long-term clinical trials of
ximelagatran, Drug Saf. 28(4), pp. 35170.
6. Goldkind, L. and Laine, L. (2006). A systematic review of NSAIDs
withdrawn from the market due to hepatotoxicity: lessons learned from
the bromfenac experience, Pharmacoepidemiol. Drug Saf. 2006 15(4),
pp. 213220.
7. Stein, C.M., et al. (1997). Vasodilation in black Americans: attenuated
nitric oxide-mediated responses, Clin. Pharmacol. Therap., 62(4), pp.
436443.
8. Kalydeco label at Drugs@FDA: http://www.accessdata.fda.gov/
scripts/cder/drugsatfda/index.cfm?fuseaction=Search.DrugDetails.
9. Sai-Hong Ignatius, Ou. (2011). Crizotinib: a novel and first-in-class
multitargeted tyrosine kinase inhibitor for the treatment of anaplastic
lymphoma kinase rearranged non-small cell lung cancer and beyond,
Drug Des Devel Ther. 5, pp. 471485.
10. Bath, P.M.W., et al. (2009). Effects of NXY-059 in experimental stroke: an
individual animal meta-analysis, Br. J. Pharmacol., 157, pp. 11571171.
11. Kimmelman, J. and London, A.J. (2011). Predicting harms and benefits
in translational trials: ethics, evidence and uncertainty, PLoS Med 8 (3),
p. e1001010.
12. Woodcock, J. (2010). Assessing the clinical utility of diagnostics used in
drug therapy, Clin. Pharmacol. Therap. 88, pp. 765773.
13. Temple, R. (2010). Enrichment of Clinical Study Populations, Clin.
Pharmacol. Therap. 88(6), pp. 774778.
14. Epstein, R.S., et al. (2010). Warfarin genotyping reduces hospitalization
rates: results from the MM-WES (Medco-Mayo Warfarin Effectiveness
Study), J Am Coll Cardiol, 55, pp. 28042812.
15. Turna, R. (2010). Clinical utility of PGx-guided Warfarin dosing not
proven in Mayo-Medco study, reviewer concludes at cardiology meeting,
Yahoo Finance News.

  
 
  
 
 References 95

16. Lesko, L.J. (2008). The critical path of Warfarin dosing: finding an
optimal dosing strategy using pharmacogenetics, Clin. Pharmacol.
Therap. 84(3), pp. 303305.
17. Harbour, R. and Miller, J.A. (2001). A new system for grading
recommendations in evidence based guidelines, BMJ 323, pp. 334336.
18. Mallal, S., et al. (2008). PREDICT-1 Study Team. HLA-B*5701 screening
for hypersensitivity to abacavir, NEJM 358, pp. 568579.
19. Lesco, L.J. and Zineh, I. (2010). DNA, drugs and chariots: on a decade of
pharmacogenomics at the US FDA, Pharmacogenomics, 11(4), pp. 507
512.
20. NCTR Strategic Plan, available at https://www.hsdl.org/?view
&did=28370).
21. FDA (2006) Critical path opportunities report, US Department of Health
and Human Services, March, 2006, http://www.fda.gov/downloads/
ScienceResearch/SpecialTopics/CriticalPathInitiative/CriticalPath
OpportunitiesReports/UCM077254.pdf.