Opinion
Challenges and opportunities of drug
repositioning
Natalia Novac
Global Knowledge Management, External Innovation, Merck Serono, Merck KGaA, Frankfurter Strasse 250, D64293,
Darmstadt, Germany
Drug repositioning is an innovation stream of pharma-
ceutical development that offers advantages for drug
developers along with safer medicines for patients. Sev-
eral drugs have been successfully repositioned to a new
indication, with the most prominent of them being
viagra and thalidomide, which have generated histori-
cally high revenues. In line with these developments,
most of the recent articles and reviews on repositioning
are focused on success stories, leaving behind the chal-
lenges that repositioned compounds have on the way to
the clinic. Here, I analyze repositioning as a business
opportunity for pharmaceutical companies, weighing
both challenges and opportunities of repositioning. In
addition, I suggest extended profiling as a lower-risk
cost-effective repositioning model for pharmaceutical
companies and elucidate the novel collaborative busi-
ness opportunities that help to realize repositioning of
shelved and marketed compounds.
Introduction
According to the recent Pharma R&D Factbook from CMR
International, the number of drugs which were terminated
in Phase III of clinical development has doubled in the past
5 years, reaching 55 compounds in the period from 2008 to
2010 (http://cmr.thomsonreuters.com/pdf/2012-cmr-fact-
book-exc_cbr-en.pdf). This figure is particularly disturbing
because the new active substance entries into development
phases have also been steeply declining at a rate of ap-
proximately 50% for each phase compared to 2007. The
primary reason for drug failures in late development is
poor efficacy in the larger population of Phase III clinical
studies, whereas safety reasons are the primary cause of
attrition in earlier development phases [1,2]. The idea of
recycling late-phase-failed compounds to a new indication
is an attractive opportunity from both business and social
standpoints. A repositioned compound with proven bio-
availability and known safety profiles would benefit from
an accelerated R&D process, reduced development cost,
decreased failure rate due to safety, and should contribute
to a productivity boost by filling pipeline gaps [3]. From a
social point of view, reutilization of knowledge generated
by patient data for future indications is highly ethical,
maximizing the use of patient information.
Corresponding author: Novac, N. (Natalia.Novac@merckgroup.com).
Keywords: repositioning; extended profiling; repurposing; new use of old drugs;
compound reprofiling.
0165-6147/$ – see front matter
ß 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.tips.2013.03.004
Repositioning in biotech
By the mid-2000s, with the excitement of the first success
stories of sildenafil (Viagra1) repositioned from angina to
erectile dysfunction, and thalidomide repositioned from
morning sickness to multiple myeloma, huge interest in
repositioning fostered biotech and pharma entrepreneur-
ship that resulted in the creation of several startup com-
panies focused on repositioning (Table 1).
To understand the outcome of these efforts toward
repositioning, I have analyzed the fate of these specialty
pharma companies and further explored their success
strategy. As seen in Table 1, the majority of the reposition-
ing startups have not survived. One-third of the companies
no longer exists and cannot be found in the market space
any longer (i.e., they either stopped trading or filed for
bankruptcy). The cause of commercial failure of these
biotech repositioning companies is difficult to track. In
most cases, companies never fail to communicate about
their positive results but do disappear from the market
without any press release. Sometimes, causes of attrition
can be deduced from the results of clinical trials (if pub-
lished). Thus, one could assume that Avera Pharmaceuti-
cals closed due to lack of clinical efficacy of its leading
compound AV608 in social anxiety disorder [4]. Other
potential failures, such as inability to find commercial
partners because of poor commercial prospects of reposi-
tioned assets or inability to raise funds, might be the cause
of the disappearance of the rest of the companies; however,
those failures are much less likely to be communicated
publicly.
Another one-third of the companies specialized for repo-
sitioning were acquired by bigger companies with various
successes. CeNeS Pharmaceuticals was acquired by Paion
for $21 million, whereas Aspreva was bought by Galenica
for a 30-fold higher amount. The reason for such an accom-
plishment was because the Aspreva successful deal with
Roche incurred royalties from off-label use of the drug
mycophenolate mofetil in a new indication of lupus nephri-
tis [5–7].
The remaining one-third of the companies that still exist
in the open market went through turbulent times reflected
by their name changes (Combinatorx, Biomedicine, Faust
Therapeutics) or a drastic headcount reduction (Somaxon,
which in the end of the unusually lengthy development
phase became a one-man company to bring the reposi-
tioned drug silenor to approval) [8,9].
Looking at the high rate of failure of biotech companies
specialized in repositioning, the question arises on how it
Trends in Pharmacological Sciences, May 2013, Vol. 34, No. 5 267
Opinion Trends in Pharmacological Sciences May 2013, Vol. 34, No. 5

Table 1. List of companies focusing on repositioning founded before 2006 and their current status collected from business news
and former or existing company sites
Company name
Avera Pharmaceuticals
Arakis
Arachnova
Dynogen Pharmaceuticals
Sention Inc.
Bionaut
Aspreva
Cypress Biosciences
Hypnion
Vela Pharmaceuticals
Genaissance Pharmaceuticals
ChemGenex Therapeutics
Saegis Pharmaceuticals
CeNeS Pharmaceuticals
Applied Genetics
KineMed
QUATRx
Somaxon
Corcept Therapeutics
Vanda Pharmaceuticals
Vivia Biotech SL
Sosei Co., Ltd
Verva Pharmaceuticals
BioMedicines, Inc.
Faust Therapeutics
CombinatoRx, Inc.
Current status
No longer existing
No longer existing
No longer existing
No longer existing
No longer existing
No longer existing
No longer existing
No longer existing
No longer existing
No longer existing
No longer existing
No longer existing
No longer existing
No longer existing
No longer existing
Still trading
Still trading
Still trading
Still trading
Still trading
Still trading
Still trading
Still trading
Trading under different name
Trading under different name
Trading under different name
Comment
Since January 2012 no longer trading
Since 2008 not found in any registries (a major partner Sosei)
Since February 2008 Arachnova Ltd was presumed to be no longer
trading
In February 2009 the company filed for bankruptcy
Since February 2006 Sention was presumed to be no longer trading
Since August 2010 the website is no longer available
Acquired by Galenica in 2007 for $915 million
Acquired by Ramius in January 2011 for $255 million
Acquired by Eli Lilly in April 2007 for $315 million
Acquired by Pharmos in 2006 for $29 million
Acquired by Clinical Data in 2005 for $56 million
Acquired by generic company Teva
Acquired by Lundbeck in 2006 for $27 million
Acquired by Paion in 2008 for $21 million
Acquired in 2008 by Estee Lauder
Proprietary biomarker discovery technology
Obtained own research via merging with Harmos
After drastic headcount reduction finally launched Silenor after 6
hard years in clinical development
Mifepristone for Cushing’s syndrome approved in 2012
First product Fanapt approved for schizophrenia in September 2012
Proprietary fluorescence activated cell sorting (FACS) technology
(discovery in autoimmune diseases)
One launched product (contraception)
A part of Chemgenex fused to adipogen to form Verva (Phase II)
Now called Intarcia (proprietary technology for implant
formulation for diabetes)
Now called Domain Therapeutics (proprietary platform for target
identification)
Now called Zalicus Inc. (proprietary high-throughput technology
for combinatorial screening)

compares with de novo drug development and whether
long-term survival rate of other biotech companies is simi-
lar. According to a recent report by Canadian Biostatistics,
35% of Canadian biotech–pharma companies exit the busi-
ness over a long-term period of 10 years [10]. In a more
dynamic world of California’s biotech industry, as much as
48% of biotech companies ceased their existence over a
similar 10-year period [11]. Thus, although the biotech
business is associated with a high failure rate, reposition-
ing strategies represent an even greater risk for small
biotech companies.
So what is the success strategy of survivors? It seems
obvious that most of the companies that were formed based
on sole expertise of their founders did not survive in the
long run. The survivors, in turn, backed up their reposi-
tioning projects with a proprietary technology, which they
also offer as a service for other companies. For example,
Zalicus (formerly CombinatoRx), in addition to its reposi-
tioning pipeline, developed the proprietary combination
high-throughput screening (cHTSTM) technology allowing
for screening compound combinations in phenotypic mam-
malian cell-based assays [12,13]. Similarly, Intarcia (for-
merly BioMedicines) has a unique technology for diabetic
drug formulation, and KineMed offers the proprietary
heavy water labeling-based biomarker discovery platform
[14]. The above examples teach us that to be a successful
268
repositioning company, it needs to rely not only on experts
but also on technological intellectual property that allows
the company to bridge hard times.
Repositioning in pharma
According to recent reviews and market research reports,
repositioning constitutes 10–50% of R&D spending and is
viewed as an important part of product life-cycle manage-
ment [15,16]. Several pharma companies, such as Pfizer,
AstraZeneca, and GlaxoSmithKline, have created units
dedicated to systematic scanning of repositioning oppor-
tunities.
In contrast to apparent investments, success stories of
repositioned drugs coming from big pharmaceutical compa-
nies have drastically declined in recent years. Table 2
represents repositioning examples together with the year
of approval for the new indication. The approval dates of the
repositioned drug show that most successful big pharma
repositioning happened before the development of system-
atic efforts (e.g., year 2006), suggesting that the repositioned
drugs resulted from serendipitous discovery. Possibly, it is
too early to evaluate the success of more recent repositioning
efforts due to the lengthy development process. It may also
be that the obvious candidates for repositioning have been
exhausted and a much more thorough analysis and invest-
ment has to be done to reposition the rest of the candidates.
Opinion Trends in Pharmacological Sciences May 2013, Vol. 34, No. 5

Table 2. List of repositioned compounds updated and supplemented with information on compound approval
Drug Original indication New indication Year a
Amphetamine Stimulant Hyperkinesis in children (attention deficit hyperactivity disorder, ADHD) 1943
Allopurinol Tumor lysis syndrome Gout 1967
Zidovudine Cancer HIV/AIDS 1985
Minoxidil Hypertension Alopecia 1988
Bupropion Depression Smoking cessation 1997
Sibutramine Depression Obesity 1997
Finasteride Benign prostatic hyperplasia Alopecia 1997
Methotrexate Cancer Rheumatoid arthritis 1999
Fluoxetine Depression Premenstrual dysphoric disorder 2000
Atomoxetine Parkinson’s disease ADHD 2002
Thalidomide Morning sickness Multiple myeloma 2003
Cymbalta Depression Diabetic peripheral neuropathy 2004
Topiramate Epilepsy Migraine 2004
Paclitaxel Cancer Restenosis 2004
Sildenafil Angina Erectile dysfunction 2005
Requip Parkinson’s disease Restless legs 2005
Lumigan Glaucoma Hypotrichosis simplex 2009
Dapoxetine Analgesia and depression Premature ejaculation 2009
Milnacipran Depression Fibromyalgia syndrome 2009
Phentolamine Hypertension Dental anesthesia reversal agent 2009
Lidocaine Local anesthetic Arrhythmia 2010
Mifepristone (RU486) Pregnancy termination Cushing’s syndrome 2012
a
Year of first approval in new indications.

Interestingly, the most recent repositioning successes of
2009–2012 have originated from the surviving specialty
pharma industry such as Corcept, whose repositioned
mifepristone was approved for Cushing’s syndrome in
February 2012 [17,18]. It is also notable that most of the
recently approved repositioned compounds are targeting
either novel or orphan indications, such as premature
ejaculation, dental anesthesia reversion, hypotrichosis
simplex, or fibromyalgia syndrome, all of which represent
an attractive market niche [19–21].
Major challenges and potential for drug repositioning
The limited number of star-performing repositioning pro-
jects from big pharma companies in recent years reflects a
plethora of challenges for drug repositioning.
Similar to any other project, a repositioning effort needs
an upfront investment, and it is notoriously difficult to
persuade management to invest in assets that were un-
lucky initially. Perhaps this type of organizational mental-
ity led to repositioning of thalidomide by Celgene and not
by the inventor company Grünenthal, who had one of the
most prominent failures in drug development history. The
reason for the initial failure of thalidomide was the incor-
rect population selection, namely women in their first
trimester of pregnancy. This resulted in birth defects of
newborns, reflecting the teratogenic effect of the drug that
was unknown at the time of its approval. Exclusion of
pregnant women from the patient population led to suc-
cessful approval of thalidomide in multiple myeloma and
erythema nodosum leprosum and its current development
in several indications by Celgene [22].
Organization of pharmaceutical R&D around specific
therapeutic areas creates another issue for repositioning
projects that develop a compound for an indication outside
of the strategic focus of the company. The design and
execution of proof-of-concept (POC) clinical trials
requires a substantial amount of clinical expertise.
Out-licensing of such compounds for a defined indication
or conduction of investigator-sponsored trials (studies
initiated and conducted by interested clinicians) are
potential options to address this hurdle. However, the
choice of contract research organizations (CROs) or small
biotech companies that could take the risk to conduct
such POC studies is limited. This ‘reversed’ business
model, in which pharma companies act not as a source
of cash for in-licensing or acquisition, but rather as a
source of ideas and compounds for out-licensing, is un-
common and might need time for adoption. An additional
complexity is introduced by repositioning projects for
medical conditions that have never before been consid-
ered as independent indications, such as erectile dys-
function or restless leg syndrome. These special
repositioning projects need field experts outside of the
usual repertoire of a pharmaceutical company [23,24].
Repositioning of assets that failed in the later stages of
development is always combined with the limited time for
development in the new indication. The initial so-called
‘composition of matter’ (COM) patent protects the com-
pound for 20 years (http://www.wipo.int/treaties/en/ip/par-
is/trtdocs_wo020.html). However, the hard road of drug
development started by compound discovery takes at least
13 years until the drug is on the market [25]. Approximate-
ly six of the first years are spent in research, meaning that
the development phase is the lengthiest one, in part be-
cause of strong regulation from governmental authorities.
With these time lines, it is obvious that repositioning of a
compound after it has failed in the initial indication is
extremely risky time wise. Therefore, it is wiser to design a
branched development program, in which the compound is
developed in several indications in parallel, minimizing
269
Opinion
the pipeline risk and the possibility of imminent expiration
of intellectual property (see below).
An opportunity to get around the existing COM patent is
filing a combination of two old drugs for a new indication.
The repositioning company Zalicus is pursuing exactly this
approach using a proprietary combination screening plat-
form for the new combination discovery and developing
among others a combination of prednisolone and cyclospor-
ine (prednisporin) for the treatment of allergic conjuncti-
vitis. This discovery led to the recent in-licensing of
prednisporin by Sanofi (http://www.businesswire.com/
news/home/20121025005302/en/Zalicus-Licensee-Sanofi-
Status-Update-Prednisporin-FOV1101).
Changing the dosage or route of administration of a
patented drug is yet another prospect for breathing new
life into old compounds and creating a business incentive
boosted by the novel COM patent protection. This tactic is
used by Arcion, which is developing clonidine, an oral drug
first approved for hypertension in 1950, for the topical
application in painful diabetic neuropathy [26].
An alternative way to extend patent protection is
through generation of secondary patents such as ‘method
of use’ (MOU) patents, which specify a new use of a
compound. However, most COM patents protect com-
pounds for a broad range of indications, making MOU
generation difficult. Generation of MOU patents is partic-
ularly difficult for marketed compounds, which are often
reported in single case studies to be effective in indications
different to the one where they are approved. These physi-
cian practice-derived reports prevent pharmaceutical com-
panies from the generation of a new MOU patent, thereby
averting clinical trials that would analyze the efficacy of
the compound in larger population cohorts. Even in the
ideal case of no reports published about the potential new
use of the compound, repositioning of marketed compounds
could be halted because of the differential pricing policy for
different indications. There is no incentive for a pharma-
ceutical company to reposition from a low-price indication,
such as alcohol abuse or hypertension, to a more expensive
one, such as oncology, despite the potential medical and
financial value for patients.
If, in the USA, some such noncommercial repositioning
trials are sponsored by the National Institutes of Health
(NIH), no similar governmentally sponsored body exists in
Europe. As the majority of academic institutions cannot
afford expensive clinical development, currently patients
themselves consolidate their forces in the form of patient
advocacy groups, participating as alternative sponsors for
clinical development. Collaboration of pharma companies
with patient advocacy groups, particularly in niche indica-
tions, could lead not only to financial risk-sharing but
significantly accelerate patient accrual and access to key
networks of opinion leaders maintained by patient advo-
cacy groups [27,28].
More than 7000 rare diseases affecting cumulatively 6–
7% of the population have a great prospect for drug repo-
sitioning [29]. The US Orphan Drug Act (ODA) protects the
developers in this field by 7 years of market exclusivity, tax
credits for certain development costs, and application fee
waivers. Similarly, European legislation gives the drugs
with orphan designation 10 years of market exclusivity,
270
Trends in Pharmacological Sciences May 2013, Vol. 34, No. 5
reduced fees for regulatory activities, and development
grants. These benefits are helpful to overcome the intellec-
tual property expiration challenge (described above) and
indeed lad to successful repositioning of several com-
pounds to rare diseases, with imatinib being one of the
most successful examples that is now approved in seven
separate orphan oncological indications (http://www.phar-
ma.us.novartis.com/product/pi/pdf/gleevec_tabs.pdf). An-
other incentive for the industry in repositioning for an
orphan indication is the premium pricing typically used
for orphan drugs and therefore generating significant rev-
enues despite the small market.
Effective drug repositioning
The conventional model of drug repositioning is compound
‘recycling’ after it has failed in later stages of development
or reached the market (Figure 1A) [30,31]. Such a model
requires additional investment into a compound that has
already used significant resources, as well as a solution for
intellectual property expiration. A more effective business
model of drug repositioning, ‘extended profiling’, allows
testing of the compound in the most promising potential
indications immediately after a successful first-in-man
study. To realize POC studies without a significant in-
crease in resources, a company relies on several collabora-
tive models such as investigator-sponsored trials, out-
licensing, and codevelopment with specialty pharma or
private–public partnership (Figure 1B). Extending com-
pound profile early on gives developers an opportunity to
learn not only about the efficacy in alternative indications
but also about potential side effects associated with certain
comorbidities, thereby derisking the pipeline. This model
is also more cost effective compared with the conventional
one. The average cost per patient for a Phase II study is
US$36 000 with an approximate involvement of 100 to 500
patients, whereas the average cost per patient for a Phase
III study is approximately US$47 000 where the number of
patients varies between 1000 and 5000 patients [32]. Even
the most modest calculations using the minimum number
of patients in a Phase III study will prove that the invest-
ment into several POC studies early in the development
and continuing with the most promising indication will be
more commercially attractive than reinvestment after the
compound has failed in a large Phase III confirmatory
study. The developmental history of the recently approved
Pfizer compound crizotinib (Xalkori1) might be considered
as an example of the extended profiling model. The drug
was initially designed to treat anaplastic large cell lym-
phoma (ALCL) because it is an inhibitor of the anaplastic
lymphoma kinase and its fusion proteins. However, by the
time the compound was entering the clinic, other types of
cancers were found to carry ALK5-fusuon mutations.
Based on the latest discoveries, several Phase I/II studies
were initiated profiling the drug in three indications in
parallel: ALCL, inflammatory myofibroblastic tumour
(IMT), and in non-small cell lung cancer (NSCLC). As
described in the model, here the collaborative development
was in place from the beginning, that is, the ALCL study
was carried out in collaboration with the National Cancer
Institute (NCI) and Children’s Oncology Group, the study
in IMT was done as a form of investigator-sponsored trial
Opinion
(A) Convenonal reposioning business model:
Discovery and preclinical Ph I Ph II
(B) Alternave extended profiling business model:
Discovery and preclinical Ph I Ph II Ind1
IST
PPP
Alternave
indicaon
COL
plan
EXT
Figure 1. Repositioning business models. (A) Conventional business models, when a compound failed in the last stages of development or marketed compounds are
reintroduced into the pipeline for research and development in a new indication. (B) Extended profiling business model, where each compound that proved to be safe in a
Phase I study is a subject for an alternative indication plan (AIP) derived from the reassessment of public and proprietary data and prioritization of the most promising
indications. According to the AIP, a compound is tested in several indications in the form of IST (investigator-sponsored trial), PPP (private–public partnership), COL
(collaboration with the other pharma or academic body), or EXT (out-licensing for the limited indication with the back acquisition/milestone payment option).
(IST) with the Dana-Farber Institute, and the NSCLC
study was carried out by the company [33,34]. The most
successful study in NSCLC was converted into Phase III
and finished with the historically unprecedented fast ap-
proval of the drug in August 2011 [35]. Boosted by this
success, more studies are now on the way profiling the
compound in an even broader range of indications [36].
Concluding remarks
With the ever-increasing attrition rates in the pharma
industry, repositioning is one solution for pipeline derisk-
ing evidenced by several high revenue generating reposi-
tioned drugs approved and generating up to $20 billion in
annual sales [37]. However, repositioning does not elimi-
nate the risk of compound development but only reduces it,
and there are additional challenges unique to repositioning
projects reflected by the low survival rate of such startups.
New business models involving patient advocacy groups
and targeting rare, orphan, and novel indications is a great
opportunity for drug repositioning. For large pharmaceu-
tical companies, early analysis of compounds for alterna-
tive indications will not only lead to lower risk to the
pipeline via finding the best indication and a better under-
standing of the mode of action of the compound but also
ensures effective use of corporate time and resources.
References
1 Federsel, H.J. (2008) Handing over the baton: connecting medicinal
chemistry with process R&D. Drug News Perspect. 21, 193–199
2 DiMasi, J.A. et al. (2010) Trends in risks associated with new drug
development: success rates for investigational drugs. Clin. Pharmacol.
Ther. 87, 272–277
3 Padhy, B.M. and Gupta, Y.K. (2011) Drug repositioning: re-
investigating existing drugs for new therapeutic indications. J.
Postgrad. Med. 57, 153–160
Trends in Pharmacological Sciences May 2013, Vol. 34, No. 5
Ph III Launch Post-markeng
Ph III Launch Post-markeng
Ph II Ind2
Connue with the most
successful indicaon or, in
Ph II Ind3
case of broad success,
connue to develop in
Ph II Ind4 collaboraon
Ph II Ind5
TRENDS in Pharmacological Sciences
4 Liebowitz, M. et al. (2007) Safety and efficacy of AV608 in subjects with
social anxiety disorder. In 47th Annual NCDEU Meeting. June 11–14,
2007, Boca Raton, FL
5 Sinclair, A. et al. (2007) Mycophenolate mofetil as induction and
maintenance therapy for lupus nephritis: rationale and protocol for
the randomized, controlled Aspreva Lupus Management Study
(ALMS). Lupus 16, 972–980
6 Dall’Era, M. (2011) Mycophenolate mofetil in the treatment of systemic
lupus erythematosus. Curr. Opin. Rheumatol. 23, 454–458
7 Zandman-Goddard, G. et al. (2005) Novel approaches to therapy for
systemic lupus erythematosus: update 2005. Expert Rev. Clin.
Immunol. 1, 223–238
8 Patel, D. and Goldman-Levine, J.D. (2011) Doxepin (silenor) for
insomnia. Am. Fam. Physician 84, 453–454
9 Anon (2010) Low-dose doxepin (Silenor) for insomnia. Med. Lett. Drugs
Ther. 52, 79–80
10 Beaudry, C. and Levasseur, J. (2011) What influences the survival of
Canadian biotechnology firms. In Paper presented at the DRUID 2011
on Innovation, Strategy and Structure – Organisations, Institutions,
Systems and Regions. June 15–17, 2011, Copenhagen Business School,
(Denmark
11 Zhang, J. and Patel, N. (2005) The Dynamics of California’s
Biotechnology Industry. Public Policy Institute of California
12 Rickles, R.J. et al. (2012) Adenosine A2A and beta-2 adrenergic
receptor agonists: novel selective and synergistic multiple myeloma
targets discovered through systematic combination screening. Mol.
Cancer Ther. 11, 1432–1442
13 Lin, S. et al. (2010) Identification of synergistic combinations of
F508del cystic fibrosis transmembrane conductance regulator
(CFTR) modulators. Assay Drug Dev. Technol. 8, 669–684
14 Rohloff, C.M. et al. (2008) DUROS technology delivers peptides and
proteins at consistent rate continuously for 3 to 12 months. J. Diabetes
Sci. Technol. 2, 461–467
15 Arrowhead Conferences (2011) Drug Repositioning: New Technologies,
Business Models and Strategies for Successful Development.
Arrowhead Conferences
16 Reilly, T. et al. (2006) Drug repositioning. Drug Discov. 2, 10–12
17 Anon (2012) Mifepristone (Korlym) for Cushing’s syndrome. Med. Lett.
Drugs Ther. 54, 46–47
18 Clark, R.D. (2008) Glucocorticoid receptor antagonists. Curr. Top. Med.
Chem. 8, 813–838
271
Opinion
19 McMahon, C.G. (2012) Dapoxetine: a new option in the medical
management of premature ejaculation. Ther. Adv. Urol. 4,
233–251
20 Fowler, S. et al. (2011) Reversal of soft-tissue anesthesia in
asymptomatic endodontic patients: a preliminary, prospective,
randomized, single-blind study. J. Endod. 37, 1353–1358
21 Khidhir, K.G. et al. (2013) The prostamide-related glaucoma therapy,
bimatoprost, offers a novel approach for treating scalp alopecias.
FASEB J. 27, 557–567
22 Matthews, S.J. and McCoy, C. (2003) Thalidomide: a review of
approved and investigational uses. Clin. Ther. 25, 342–395
23 Cappelleri, J.C. et al. (2000) Relationship between patient
self-assessment of erectile function and the erectile function
domain of the international index of erectile function. Urology 56,
477–481
24 Manconi, M. et al. (2012) Dissociation of periodic leg movements from
arousals in restless legs syndrome. Ann. Neurol. 71, 834–844
25 Paul, S.M. et al. (2010) How to improve R&D productivity: the
pharmaceutical industry’s grand challenge. Nat. Rev. Drug Discov.
9, 203–214
26 Campbell, C.M. et al. (2012) Randomized control trial of topical
clonidine for treatment of painful diabetic neuropathy. Pain 153,
1815–1823
272
Trends in Pharmacological Sciences May 2013, Vol. 34, No. 5
27 McNeil, D.E. et al. (2010) Duchenne muscular dystrophy: drug
development and regulatory considerations. Muscle Nerve 41,
740–745
28 Kaye, J. et al. (2012) From patients to partners: participant-centric
initiatives in biomedical research. Nat. Rev. Genet. 13, 371–376
29 Melnikova, I. (2012) Rare diseases and orphan drugs. Nat. Rev. Drug
Discov. 11, 267–268
30 Marusina, K. et al. (2011) The CTSA Pharmaceutical Assets Portal – a
public–private partnership model for drug repositioning. Drug Discov.
Today Ther. Strateg. 8, 77–83
31 Oprea, T.I. et al. (2011) Drug repurposing from an academic
perspective. Drug Discov. Today Ther. Strateg. 8, 61–69
32 Clinical Operations (PH152) (2011) Benchmarking Per-patient Trial
Costs, Staffing and Adaptive Design. Cutting Edge Information
33 Butrynski, J.E. et al. (2010) Crizotinib in ALK-rearranged inflammatory
myofibroblastic tumor. N. Engl. J. Med. 363, 1727–1733
34 Kwak, E.L. et al. (2011) Anaplastic lymphoma kinase inhibition in non-
small-cell lung cancer. N. Engl. J. Med. 363, 1693–1703
35 Shaw, A.T. et al. (2011) Crizotinib. Nat. Rev. Drug Discov. 10, 897–898
36 Mano, H. (2012) ALKoma: a cancer subtype with a shared target.
Cancer Discov. 2, 495–502
37 Tobinick, E.L. (2009) The value of drug repositioning in the current
pharmaceutical market. Drug News Perspect. 22, 119–125