Make your own free website on



Streamlining phase I/IIa Trials

April 13 and 14, 1999, Munich, Germany

This two-day conference was organized by IIR, under the banner headline of

‘Achieving Speedy Phase I/IIa Trials, Maintaining Quality & Reducing Costs: how to achieve all three’.

The conference publicity listed quite disparate conference aims, from assessing the methodological reliability of QT dispersion prolongation to learning how to re-engineer phase I process and organizational structure.

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:

  • discovery experiments geared more to critical evaluation of the compound

  • ‘killer’ experiments being done as early as possible

  • genotyping of clinical trial patients to select patient groups which are likely to respond (pharmacogenetics)

  • modeling and simulation of clinical trials

  • integration of pharmacokinetic and pharmacodynamic principles into drug development (the PK/PD guided approach)

  • increasing use of surrogate markers/pharmacodynamic endpoints for rapid clinical feedback

  • involvement of the target population as soon as possible

  • co-operation with high quality centres (CROs/hospital)

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.

Send questions or comments to
Copyright © 2004 FIPACIAN  Page last modified: 10/07/04