Clinical pharmacology in neuroscience drug discovery:quo vadis?David G Trist1, Adam Cohen2 and Alan Bye3

Available online at www.sciencedirect.com

ScienceDirect

Clinical Pharmacology in Neuroscience Drug Discovery in

recent years has concentrated on First Time in Human safety

and pharmacokinetics. The more traditional pharmacological

research in humans has been reduced mainly as a response to

the difficulty of developing human pharmacology models in

neuroscience diseases. As a consequence, opportunities are

being missed to aid in target selection and in target validation.

The decision of big Pharma to reduce investment from the

Neurosciences has had implications for clinical

pharmacologists in this area. It remains to be seen whether

academia, government laboratories and contract houses will

respond to the challenge of carrying out increased Clinical

Pharmacology in the Neurosciences.

Addresses1 Via N. Sauro 24, 37047 San Bonifacio, Italy2 Centre for Human Drug Research, Zernikedreef 10, 2333CL Leiden,

The Netherlands3 Alan Bye and Company Limited, Horsham, West Sussex, UK

Corresponding author: Cohen, Adam (ac@chdr.nl)

Current Opinion in Pharmacology 2014, 14:50–53

This review comes from a themed issue on Neurosciences

Edited by David G Trist and Alan Bye

1471-4892/$ – see front matter, # 2013 Elsevier Ltd. All rights reserved.

http://dx.doi.org/10.1016/j.coph.2013.11.008

IntroductionWork carried out by basic pharmacologists is not a singular

activity. One can loosely classify the activities undertaken

as those performed in vitro and those performed in vivo.

In the former case, this can be at the molecular level,

cellular level, tissue level or whole organ level. In the

latter case, animal studies, amongst many, are undertaken

to understand basic physiology/pathology, to develop

mechanistic animal models, to set up animal models of

disease, to express human receptors/enzymes in animals

and to delete receptors and enzymes in animals. Like-

wise, clinical pharmacology is not based on one activity.

Aronson [1,2�] describes a similar list of human pharma-

cology activities, from molecular to individual studies.

However, he goes on to broadly classify clinical pharma-

cology much wider than one would classify preclinical

pharmacology [1,2�,3,4]. In fact, it has been suggested

that this classification is ‘too broad for any of us to

accomplish the totality with any degree of comfort’ [5].

Current Opinion in Pharmacology 2014, 14:50–53

These activities include pharmacokinetics, drug metab-

olism, clinical toxicology, pharmacovigilance, among

others, that are not normally the remit of the preclinical

pharmacologist. Historically, interest in drug metabolism

and pharmacokinetics can be traced back to two events.

The first is due to FDA guidelines issued from 1984 [6]

that recognized that many molecules were failing due to

metabolic or kinetic reasons. This was also reported by

Prentis et al. in 1988 [7] where they showed that the

majority of failures for UK: Pharma between 1964 and

1985 was due to inappropriate pharmacokinetics (�40%).

The second was that medicinal chemists were discovering

that candidates with good preclinical efficacy were often

metabolized easily or had poor absorption or rapid elim-

ination. Thus, it became important to know as early as

possible that molecules had the right metabolic and

kinetic profile in man. This impacted on early phase

human studies that were limited to pharmacokinetics

and the determination of obvious clinical adverse effects

(often called safety and tolerability). Today, in drug

discovery an important function of clinical pharmacology

is to determine the pharmacokinetics and pharmacologi-

cal activity of molecules at the early stages of the process.

This requires methodological studies and the develop-

ment of translational models. However, more recently,

the major cause of failure in neurosciences has been lack

of efficacy or differentiation from gold standard medicines

[8�]. This heightens the worry that pharmacokinetic/

pharmacodynamic (PK/PD) skills are disappearing just

at the time when there has been a greater emphasis on

systems biology and biomarkers [9].

This article looks at the present situation for carrying out

clinical pharmacology in neurosciences and suggests what

the future might be in a world where the identification of

reliable targets in psychiatry and neurology is particularly

complex and changing [10��].

A stark reality

Neurosciences represent another layer of complexity.

There is a general division into neurology and psychiatry.

Within each category there are diverse diseases with a

very wide range in the level of understanding of the

pathophysiology. This leads to diagnostic problems.

Especially for some of the diseases like depression or

schizophrenia the available biomarkers for disease

activity are predominantly clinical, although proteomics

is showing some potential [11]. Additionally, disease

states cannot be experimentally induced in all diseases.

This means that typical human pharmacological studies

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Clinical pharmacology in neuroscience drug discovery Trist, Cohen and Bye 51

are feasible in insomnia, acute pain and headache

[12,13,14]. Psychiatric diseases such as major depression,

schizophrenia, bipolar disorder have been much more

difficult.

A case in point for psychiatric diseases is shown by the

problems with Diagnostic and Statistical Manual of

Mental Disorders of which edition 5 (DSM-V) has

recently been published. DSM provides a common

language and standard criteria for the classification of

mental disorders and is used in the United States and

frequently in the rest of the world. DSM has been

criticized as being not based on etiology, neurobiology,

epidemiology, genetics, or response to medications, but

rather on criteria based on clinical observation [15].

Recently, the National Institute of Mental Health said

it was withdrawing support for the manual due to a lack of

validity of DSM-5 [16]. The potential fall-out of this

action indicates that diagnoses will become even more

heterogeneous.

A major problem around measuring drug effects in

humans is that there are few ‘hard endpoints’. In psy-

chiatry, it is mostly subjective observation on either the

part of the patient or the clinician or both.

Much excitement has been generated around the hunt

for biological markers (surrogates) of disease. Whereas, in

non-neuroscience diseases ‘notably oncology’ the bio-

chemistry and genetics behind the pathology is leading to

significant progress in markers, knowledge of the dis-

eases of the neurosciences are mainly poor in terms of

pathohysiology. New technologies, whilst shedding light

in some diseases, have brought their own complexities.

All of the above have not encouraged classical clinical

pharmacology in the neurosciences, thus reinforcing

Figure 1

Target Lead Candidate FTIHPhase I

Pre-Clinical

| Clinical Pharm

AB C

Simplified representation of the drug discovery process from target to post la

Clinical Pharmacology functions from the point of First Time in Human (FTIH) o

Phase III. The blue arrows designate potential information feedback from clinic

the potential information that can help going forward, for example in selecting

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the movement towards pharmacokinetics rather than

pharmacodynamics.

Recently, a number of large pharmaceutical companies

have reduced investment in drug discovery in the neuro-

sciences [17]. This is discussed in more detail below when

thinking to the ‘Future’. Part of the explanation for this

decision has been that neurosciences lack basic knowl-

edge in disease pathologies to find valid targets and that

clinical trials are difficult and expensive [17]. As men-

tioned above this has led to a high number of Phase III

study failures [18].

A process problem?

Drug Discovery is mainly carried out in industry, in-

cluding specialized contract research organisations

(CROs). This does not mean that academia is not playing

its part. However, most of the observations discussed here

are related to industry activity.

Fig. 1 shows a schematic representation of the classical

drug discovery process. It is often shown as a highly

efficient linear process with a series of handovers from

one discipline to the next. Firstly a target is identified

(mainly from pre-clinical data) that leads to the gener-

ation of a molecule (candidate) that if possessed of the

right selectivity, safety, pharmacokinetic data will enter

into the clinic passing from human volunteers to full

Phase III studies involving thousands of patients. Clinical

pharmacology (as mentioned above) presently tends to be

involved in Phase I studies looking at initial human safety

and pharmacokinetics in a prescriptive, stereotyped pro-

cess. In Pharmaceutical companies it is usual to find most

of this activity contracted out. Also most companies have

scaled back or disbanded their Clinical Pharmacology

groups. Where appropriate, clinical pharmacological

Phase II Phase III FileApproval

Launch Phase IV

Clinical

acology |

D

Current Opinion in Pharmacology

unch into the market showing the central role of clinical pharmacology.

nwards through the clinical stages designated Phase I, Phase II, and rarely

al pharmacology studies in Phase I, and Phase II. The red arrows indicate

dose or targeting disease populations in later bigger clinical trials.

Current Opinion in Pharmacology 2014, 14:50–53

52 Neurosciences

research is also carried out in a limited number of volun-

teers or patients (Phase II), depending on a large extent

on the disease. These studies might often be a translation

of the pre-clinical models into man. However, where

there is a strong drive to get into formal clinical trials

the worth of these studies in aiding the drug discovery

process for a specific target is often considered minimal as

they are informative rather than decision-making and

only seen as delaying the pivotal trials. Of course, such

a drive is motivated by the optimistic expectation that

such a study is positive and that further translational

research would only delay the undoubted blockbuster

sales. Unfortunately as many of the large pharmaceutical

companies have discovered the so called ‘late stage fail-

ure’ particularly in the CNS area is more often the result

of this optimism than a blockbuster drug.

This means that an early prediction of potential for

success of a new drug has value even if it delays the

pivotal clinical trials. Surely the best initial indicator of

success is that the drug has its maximal pharmacological

effect in the brain. Without this it would be difficult to

imagine how a large clinical trial could ever be positive.

Classical human pharmacological studies of a new target

can add much to the process.

With the present focus on pharmacokinetics and safety

findings at the ‘first time in human’/Phase I stage this is

not the case. Feedback of data will be confined to the

candidate selected, either positively or negatively (arrow

A in Fig. 1). However, any volunteer or patient clinical

pharmacology efficacy studies carried out have the poten-

tial to give information on the target validity itself (arrows

B and C of Fig. 1). Thus, translation in the upstream

direction to pre-clinical becomes more important than

simply developing animal models in man.

This should now lead to a more cyclical process map.

Thus, clinical pharmacology could be considered pivotal

in the drug discovery process by cycling information back

as far as target selection and forward as far as Phase III and

beyond. Importantly, clinical pharmacology can reset the

‘Fail fast, fail cheap’ concept into the clinic and not at a

stage in the process reliant on preclinical data that may be

poorly validated and may result in a missed opportunity.

The futureClearly, clinical pharmacology will remain a key part of

the drug discovery process at the preclinical/clinical inter-

face. As mentioned above, clinical pharmacology is now

largely concerned with the evaluation of initial safety in

human and evaluating pharmacokinetics of new chemical

entities (candidates). The evaluation of clinical safety is

clearly impossible due to the number of (often healthy)

subjects involved and the final assessment of the safety of

a new medicine has to wait for the Phase III trial or even

Current Opinion in Pharmacology 2014, 14:50–53

post marketing. Pharmacokinetics will remain important

but, from the scientific point of view, largely routine. As

we move into an era where most new medicines have a

known biological mechanism and our knowledge of

pathophysiology increases a more sophisticated form of

early development is required. Pharmacology driven early

development will lead to better rationale for the choice of

dose and the use of challenge models can give early

information of the importance of a certain biological

mechanism for a disease. Such studies are quite common

in the pulmonary and cardiovascular field but have not

reached psychiatry and neurology. This is probably due to

the lack of pathophysiological knowledge but this also

gives direction to what needs to be done. As neuroscience

develops pathophysiological knowledge clinical neuro-

pharmacologists should be involved in the development

of companion methodology and disease models. In

addition to experimental method development, modeling

and systems biology/pharmacology allows predictions

from preclinical studies of the dose range to be first

applied in humans.

Recently, a number of Pharmaceutical companies (e.g.

GSK, AstraZeneca, Sanofi-Aventis, Merck, Pfizer) have

reduced investment in Neurosciences, particularly psy-

chiatric diseases [17]. For example, GSK has reduced its

discovery research in psychiatry and pain to focus on

neurodegenerative and neuroinflammatory diseases such

as dementia, multiple sclerosis and Parkinson’s. The

decision was due to an amalgam of pressures in psychiatry

drug discovery such as: the identification of targets, the

weakness of animal models, the nature of experimental

medicine and the development programs for these dis-

ease areas are amongst the least predictive and most

costly of any area [18]. It has been suggested that Pharma

had not invested enough in innovative projects, but

continued to produce variations on marketed mechanisms

[18].

A consequence of this industry wide reduction in these

diseases has been that the associated Pharmacology and

Clinical Pharmacology groups have also been cut back.

The vacuum may be filled by academic, government and

contract laboratories rather than just the pharmaceutical

industry [19]. This would be an inversion of that seen

until recently [20]. This might mean that for the first time

in many years traditional clinical pharmacology in neuro-

sciences drug discovery will not be the prerogative of big

Pharma, though much work will have to be done if

decisions on progressing targets (i.e. validation) will be

based on small clinical pharmacology studies, even where

there are some objective endpoints.

Previously, one of us has argued [21] that the lack of

understanding of disease pathology together with the

questionable validity of animal models of disease under-

lines the need to do studies in human at an early stage.

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Clinical pharmacology in neuroscience drug discovery Trist, Cohen and Bye 53

This is not only true for target validation, but also impor-

tantly on target identification. A hypothesis around a

target that is for a human neuroscience disease needs

to be constructed around data generated in that popu-

lation affected by the disease as well as preclinical exper-

iments. Clinical pharmacology supplying this type of

information, as it did once, could reduce target attrition

and rejuvenate neuroscience drug discovery. A possible

example from the past might be lamotrigine in bipolar

disorder. On the basis of a mechanistic rational initial

observations with lamotrigine in two cycling refractory

bipolar patients in 1993, led to a small open label study to

be undertaken in bipolar patients. Importantly, it was

recognized that animal models did not exist for bipolar

patients [22].

ConclusionsClinical Pharmacology in Neurosciences has much that it

can offer to the drug discovery process. Presently, it

fulfills an essential role in evaluating safety and pharma-

cokinetics when a candidate medicine goes First Time

into Human. Historically, clinical pharmacologists have

worked to develop human models in order to see if the

underlying science behind the chosen target translates

into human. Model development in many diseases has

proven to be very difficult due to the lack of objective

(hard) endpoints. Thus, clinical pharmacology studies

have not routinely been able to add to target selection

or to target validation in human; two areas that would

greatly benefit from data generated early in human.

Perceptions around the role of Clinical Pharmacology

in neuroscience drug discovery have on the whole looked

at translation from animal to human and tended to under-

play how human studies might be translated back to the

bench. Similarly, human pharmacology studies under-

taken in a small number of volunteers or patients have

mostly not gained acceptance as decision-making studies.

Perhaps the recent disinvestment of big pharma in neuro-

sciences will increase the role of clinical pharmacology in

academia, government laboratories and contract houses,

encouraging traditional human pharmacological research.

References and recommended readingPapers of particular interest, published within the period of review,have been highlighted as:

� of special interest�� of outstanding interest

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2.�

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One of the more up-to-date descriptions of the breadth of clinicalpharmacology in the UK.

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Current Opinion in Pharmacology 2014, 14:50–53