Professor Jochen Kulhmann, Head of the Institute of
Clinical Pharmacology at Bayer, opened the conference. He set the tone and
the central themes for the conference - pharmaceutical companies can no
longer afford to continue to late phase III with drugs that do not work,
or drugs that are not any better than existing therapies. With the
advances within drug discovery - genomics, high-throughput screening,
combinatorial chemistry - we are at the ‘tip of the molecular iceberg’
with an increasing number of new candidates being delivered to
Development’s doorstep. Clinical pharmacology thus finds itself in a
pivotal position - between Research and Development, between an increasing
input and an increasing responsibility to make an early decision on a
project’s future - in which it is the key player in the ‘go/no go’
decision. To improve the quality of such decisions a certain number of
strategies were elucidated, to be later expanded on during the conference,
notably:
After this introduction Dr John Posner (Bios) shared
his thoughts on the use of surrogate markers in clinical pharmacology. He
gave the definition of surrogate markers as ‘a clinical measurement
known to be statistically associated with, and believed to be
pathophysiologically-related to, a clinical outcome’. Again the tone of
the presentation echoed that of the introduction - the sooner we identify
losers the greater chance we have of backing winners. After giving a
summary of markers that have been used, he concluded that they can
contribute to exploratory-phase decision making by helping establish the
scientific basis of drug action, justifying the dose range and improving
the accuracy with which the benefit/risk ratio is estimated. This with the
caveat that the sensitivity and specificity of surrogate markers should
always be established and their predicted power for the therapeutic
outcome should always be questioned. These two points were discussed later
in the conference with delegates and presenters recognising that the
search for, and the validation of, markers needs to be started early in
preclinical evaluation if there is to a chance of having a useable marker
in clinical development. Examples were also given of successful use of
such markers with, notably, one clear example of unsuccessful use. This
was given by Dr Stefan Adamus (Boehringer Ingelheim) who showed data from
a compound showing clear effects in a healthy volunteer model of airflow
resistance. This compound exhibited nice dose-response curves in a
validated model, yet the compound was not efficacious in asthmatic
patients. This was a clear warning for those that want to believe too much
in their surrogate markers.
The first day continued with a mixed bag of subjects
allied to phase I/II clinical trials. Dr Michael Zuehlsdorf (Bayer) gave
an interesting presentation on the benefits of incorporating
pharmacogenomics into clinical development. He stated the truism that the
future aim of the industry is to find the right drugs for the right
patients at the right dose, a move away from the ‘Blockbuster’ drug to
a more individualised therapy. Pharmacogenomics is the study of how
genetic factors affect the pharmacokinetics and pharmacodynamics of drugs.
If there is a variation in drug efficacy due to genetically regulated
differences in, for example, metabolism or receptor sensitivity and
abundance, then we should understand this difference and develop the
compound accordingly. This can save time and money, and such differences
if unidentified will cause variability in clinical response raising
patient numbers in studies and possibly giving misleading results. In an
ideal scenario the drug dose-response would be established according to
genotype and clinical studies would take this into account in the patients
included and doses given. Subsequent drug labelling would also target the
drug at the responder population. That this is still an ideal scenario was
illustrated during the question and answer session where a delegate wanted
to know whether Bayer would give different dose recommendations according
to ethnic group in large US phase III studies. This question was adeptly
ducked; the gist of the reply being that this remains a ‘future
challenge’.
Next up were three predominantly pharmacokinetic
presentations – an overview of this topic from Dr Bob Ings (Pharmacia
and Upjohn), drug interactions, covered by Dr Alain Patat (Wyeth Ayerst)
and choice of first dose in man from Dr Bruno Reigner (F Hoffmann-La
Roche). Dr Patat focussed our attention on the importance of interaction
studies by quoting the findings of a recent study that purports to show
that death due to adverse drug reactions is between the fourth and sixth
leading cause of death in America. This being so, interaction testing is
an important component of drug development and, as always, the earlier the
better. An early start in vitro followed up by studies in phase I and II
will speed up phase III through an improved knowledge of the safety margin
and facilitated patient recruitment.
In the next presentation Dr Reigner promoted the
importance of a team approach in choosing a first dose to give to man,
using a plurality of calculation methods with the pharmacokinetic-based
methods being favoured.
A change of subject ensued with an interesting talk on
the electrocardiographic QT interval given by Dr Robert Hermann (Asta
Medica AG). Prolongation of this interval is linked to a potentially fatal
ventricular tachycardia known as torsade de pointes. This issue has been
the subject of increasing scrutiny, due largely to the highly publicised
terfenadine/erythromycin interaction, culminating in the 1997 CPMP
guideline ‘The assessment of the potential for QT interval prolongation
by non-cardiovascular medicinal products’. Dr Reigner’s talk was an
evenly paced review of issues related to the QT interval – its
measurement, clinical relevance and significance of changes – ending
with a critique of the CPMP guideline. His strongest reservations over
this guideline lay in the stated requirement that manual ECG reading by
experience cardiologists is necessary for QT interval measurement. Given
the marked inter-observer variability in this measurement and the
implications for study resources (time, availability of experienced
personnel) this seems impractical. Especially as more reliable automatic
methods are now available which tend, if anything, to overestimate the QT
interval thus giving conservative results, erring on the safe side. It is
important is to build QT interval assessment early into the drug
development programme and not wait for surprises in later studies.
The remainder of the day was dedicated to talks related
to the CNS, asthma and cardiovascular therapeutic areas. Of these, Dr
Christian de Mey (Applied Clinical Pharmacology Services) gave a
particularly animated and entertaining view of opportunities and pitfalls
in cardiovascular clinical pharmacology. His summary of clinical
pharmacology ‘we’re in-between 5 years in rats and cats and dogs and
many more years n patients and we’re expected to do the job in months
and at no cost’ rang true. Amongst other subjects to get the sharp-end
of Dr de Mey’s tongue were PK/PD ‘a justification for buying more
expensive computers’ and food-effect studies ‘most of the meals used
for food interaction studies are causing nausea’. He emphasized that we
need to develop the expertise and qualifications to do good clinical
pharmacology work in man, illustrating his talk with examples of how all
measures are estimates, for example blood pressure, sensitive to a
method/effect/subject interaction.
The second day opened with a talk from Dr Rainer Schulz
(Quintiles) who reminded us of the communication problems that we all face
on a daily basis and that it is of course people that are critical to the
success of any project. Though he gave an entertaining review, proposals
for solutions to these eternal problems were thin on the ground.
A panel discussion followed, debating the relative
merits of in-house clinical pharmacology units (CPUs) and the use of CROs.
The opposite ends of the spectrum were represented by Pfizer (in Europe)
and Synthelabo. Pfizer do 70% of their European phase I work in house,
with CPUs in Canterbury and Brussels, whilst Synthelabo contract out all
of their studies. The view of Dr Malcolm Eve (Pfizer) was that an
‘in-house CRO’ approach paid dividends especially in the early
collaboration between the CPU staff and the clinical pharmacologists. To
be able to anticipate studies early, share knowledge and develop necessary
expertise was very valuable. Dr Eve also emerged as a champion of the CROs,
giving the delegates a good dose of common-sense regarding the use of CROs
as partners, and fervently dismissing those who ignore the depth of
knowledge possessed within CROs. Other cited advantages of the in-house
approach were cost saving - Pfizer estimated a 40% reduction compared to
sub-contracting - and reduction in monitoring costs with less associated
travel. Dr Eve remarked that the trend for pharmaceutical companies to
close down their internal CPUs could be over, and, with the opening of two
new in-house phase I units that he knew of, the tide may be turning.
The afternoon session began with a talk from Dr Bruno
Boutouyrie (Rhone Poulenc Rorer) who focussed delegates’ attention on
the importance of quality recruitment procedures. Sponsors should assure
themselves that the CROs have specifically trained staff handling all
aspects of the recruitment process. The person who answers the phone to
potential volunteers should not be a ‘call answerer’ but should be
part of the study team, with the appropriate training.
The two following talks concentrated on design aspects
of phase I/II studies and exploratory development plans. Dr Monika
Seibert-Grafe (Hoechst Marion Roussel) began by re-stating the principal
aims of early phase drug development. These include demonstration of proof
of concept and the lowering of attrition rate in later phases. Key to
successful programme design is the definition of a target product profile
(TPP) bearing in mind the labelling wanted for the putative product. A
focused development plan with decision tree can then be defined to
determine whether the product meets its TPP, with particular attention
being given to go/no go decision criteria. Dr Seibert-Grafe put an
emphasis on the up-front work that can be done in preclinical development
to improve the predictability of efficacy in patients. The early
identification and validation of surrogate markers can provide powerful
tools, improving confidence in proof of concept obtained during early
phase II.
Dr George Wensing (Bayer) gave a concise overview of
information requirements, objectives and design considerations for early
phase development. He was followed by Dr Malcolm Eve who returned to
explain some of the Pfizer strategies for moving quickly through phase I
and II. He argued for an integrated approach whereby duplication of the
time-consuming aspects is minimised. The use of a single study team to
move through phase I into phase II reduces time needed for re-learning and
re-training of key staff. Some companies write one protocol for single and
multi-dose studies, amend this to include a few patients and thereby
rapidly end up with a basic data package.
The conference closed with an insight into
computer-assisted clinical trial design (CATD) given by Dr Eric Snoeck (Pharsight).
Through the example of a retrospective study on the utility of CATD for a
urinary incontinence drug he showed how this tool could improve
development strategies and test the robustness of study designs.
This conference proved to be a useful reminder of
several key issues in exploratory drug development, with a high quality of
presentations being maintained throughout. Those experienced delegates
hoping for new insights into re-engineering their phase I process left
feeling a little disappointed. Nevertheless the magnitude of the
challenges in this area of drug development remain undisputed and was once
again highlighted by this conference.