ICT

Regulatory & Business Practice

Regulatory Requirements
Walter Janssens, Kristof Bonnarens and Greet Musch at the Federal Agency for Medicinal and Health Products, Belgium, discuss regulatory requirements in early-phase development

The number of clinical trials in early-phase development that are submitted to the Belgian Federal Agency for Medicines and Health Products (FAMHP) is relatively high. This is exemplified by the number of Phase I and Phase II studies in Table 1. Although these numbers also include clinical trials that are conducted with products that are already in further stages of development, they reflect, to a large extent, first trials in humans, and other Phase I or IIa clinical trials with the aim of establishing the doses to be used in Phase IIb and Phase III studies. The number of first-in-human trials is given separately and sometimes includes Phase II trials. This number further illustrates the relative importance of early-phase clinical trials in the clinical trial activities that were submitted to the FAMHP.
Questions have often been asked about the possibility of conducting exploratory clinical trials and microdose studies to obtain data in humans, in order to decide on the feasibility of starting full development. These trials would be conducted with limited human exposure and therefore are also supported by limited, but essential, preclinical data. At this stage, the availability of the investigational medicinal product is limited. To allow these kinds of trials, and in order to provide clear instructions, a guidance document was developed in consultation with the stakeholders. Since June 2007, exploratory clinical trial applications (eCTA), also termed Phase 0 studies, have been evaluated in Belgium according to this guidance document. The number of eCTA, which are mostly, but not exclusively, first-in-human studies, suggests

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Table 1: Clinical trial applications in Belgium during 2009 Number of trials Phase I trials Phase II trials Phase III trials Phase IV trials eCTA, including microdose studies First-in-human trials, excluding exploratory trials 134 159 197 45 17 26 Percentage of total trials 24.9 29.6 36.6 8.4 3.2 4.8

that roughly one third of the first administrations to humans are now done in exploratory studies.

EXPLORATORY CLINICAL TRIALS

The need for eCTA is recognised in the newly revised ICH M3 guideline (1). As this guideline has come into effect recently, it is anticipated that the number of eCTA may increase further. The guideline offers two methods for conducting microdose studies. One option involves the administration of a total of 100g, which may be divided over different doses and is preclinically supported by an extended single dose study, usually in rodents. The second involves administration of a maximum of 100g at a time, with a maximum of 500g in

total. Such studies require a seven-day repeated dose study, usually in a rodent species. So far, the first approach has been the preferred one. It remains to be seen whether or not the second approach will be used more often in the future, since it is now formally mentioned in the ICH M3. The guideline now also describes the conduct of a clinical trial with a single dose in the (sub)therapeutic range, which is to be supported by extended single dose studies in a rodent and a non-rodent species. So far, there have been no applications for such trials in Belgium, which may be related to the fact that the possibility was not previously mentioned in the guidelines. Alternatively, it may well be that when the available amount of substance is not an issue, companies consider it more efficient

to conduct 14-day repeated dose studies from the beginning, as opposed to conducting two extended single dose studies, and may therefore prefer to use one of the approaches that would also allow repeated administration to humans. The guideline lists two possibilities to support the conduct of exploratory clinical trials with a maximal duration of 14 days. The first possibility is based on the conduct of a rodent and a non-rodent study of 14 days. The other possibility involves a 14-day toxicity study in a justified rodent species and a confirmatory study in a non-rodent at a dose yielding an exposure similar to the rodent no observable adverse effect level (NOAEL), and with a duration of at least the clinical exposure. In addition, safety pharmacology and genotoxicity studies should be available. For further discussion of the other preclinical requirements, the ICH M3 guideline should be consulted. Whereas the ICH M3 guideline gives five examples to conduct exploratory trials, it also states that other scientifically justified possibilities may be considered. In such cases, previous consultation with the competent authority may be required. Therefore, the procedure for submission of eCTA in Belgium involves a presubmission and a scientific advice procedure can also be started.

sensitive species. When two rodent and non-rodent species are used in the toxicology testing, the starting dose should not exceed two per cent of the AUC at the highest dose in the species with the lowest exposure if no toxicity was observed. If toxicity is observed, or when toxicity relies on the rodent species with confirmatory testing in non-rodents, the NOAEL should be used to guide the selection of the starting dose. The starting dose should lead to a maximal expected exposure of two per cent of the AUC at NOAEL in the most sensitive species. It should be noted that if the non-rodent species is more sensitive to adverse effects than the nonrodent in the last approach, further testing in the non-rodent may be required.

DOSE ESCALATION
After the establishment of a safe starting dose, it is equally important to consider the dose escalation procedure. It is indeed possible that adverse effects to humans may not manifest themselves at the first low dose, but they may become more prominent when really active doses are reached during dose escalation. Fortunately dose escalation can be guided by the observations at the lower doses in humans with regard to pharmacokinetics, first indications of the magnitude of the pharmacodynamic effect, measurement of biomarkers related to potential adverse effects or the first signs of evolving untoward effects in addition to the existing animal data. Since exploratory clinical trials are not supposed to aim to establish the maximal tolerated dose, the occurrence of adverse effects may be a reason to halt dose escalation. Anyway, clear stopping rules should be given in the protocol, based on the preclinical findings. Effects, whether considered pharmacodynamic or adverse, that occur during an exploratory trial should be monitorable and be neither severe nor serious. If unexpected adverse effects occur during the conduct of an exploratory clinical trial, this would certainly be considered a clear sign that further dose escalation is not possible or at least must be reconsidered.

STARTING DOSE
The establishment of a safe starting dose is the first concern that needs to be addressed. First of all, a pharmacodynamic rationale should be provided indicating that there is scientific support for potential therapeutic effects. This should be based on knowledge of the disease process and on the package of in vitro and animal in vivo data showing that the substances concerned influence target organs, cells or mechanisms in such a way that they can be assumed to modify the pathology. This package should also allow the concentrations or exposures that can be presumed to cause such a therapeutic effect to be determined. Importantly, the lowest exposure level that would cause a biologically relevant effect should also be estimated from these data. This is of particular importance if the substance is a first-in-class product that addresses a new target that has not yet been investigated in humans or where relatively little knowledge has so far been accumulated. Such knowledge would be needed to implement the EMA guideline on the mitigation of risks in first-in-human clinical trials, because the starting dose should then definitely take the minimal anticipated biological effect level into account (2). It is obvious that in such cases the animal species that were used should be justified, and the similarities and differences between the animal target and the human target should be described. In cases where interference with the target can be predicted, the pharmacodynamic action should still be taken into account to choose the starting dose. Indeed, the anticipated effect should remain within limits that are predicted to be safely tolerated by the healthy volunteers or patients involved in the trial; this will allow a decision to be made on whether further development is warranted or not. The other important determinant of the starting dose is the NOAEL in the most

MAXIMAL DOSES
The maximal dose that may be administered in an exploratory clinical trial is determined in the first place by the limits given in the guideline. The limit is obvious in the case of microdose studies; otherwise the maximal dose is defined by the NOAEL in animals. The exposure in humans should not surpass one half of the AUC at NOAEL in rodents or the AUC at NOAEL in non-rodents, whichever is lower. In those cases where no toxicity is determined in animals, it is not possible to monitor for potential prodromes of adverse effects, but on the other hand the substance under investigation may have a large safety margin. To remain on the safe side, the maximal exposure in humans in this case should not exceed one tenth of the lowest AUC at NOAEL in the most sensitive species. As indicated above, the observed effects during the dose escalation may also result in an upper boundary to the allowable dose in humans. If the animal data predict that adverse effects will be monitorable and limited in magnitude, the observations in humans may allow escalation of the dose

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In Belgium, a presubmission procedure has been agreed between the agency and the different stakeholders. This means that in the conduct of exploratory trials, the applicant is supposed to provide an outline of the project, indicate what preclinical data will be available and identify potential issues that may be discussed before the submission of the actual trial application.
beyond the limits that are proposed in the guideline. In general, this would require an amendment to the protocol to be submitted.

PRESUBMISSION PROCEDURE
In Belgium, a presubmission procedure has been agreed between the agency and the different stakeholders. This means that in the conduct of exploratory trials, the applicant is supposed to provide an outline of the project, indicate what preclinical data will be available and identify potential issues that may be discussed before the submission of the actual trial application. This will allow a face-to-face meeting, teleconference or written discussion between the agency, applicant and ethics committee when needed, to discuss diversions from the guideline and on safety issues when a substance with a new mechanism of action is involved. In a large majority of cases, such a formal meeting was not deemed necessary after the presubmission procedure was activated. On the other hand, it should be noted that only in exceptional cases were major issues raised by the agency during the evaluation, possibly because any issues were cleared beforehand. In general, the presubmission procedure does not seem to cause time delays and the regular 15-day deadline foreseen by Belgian Law for review of a Phase I CTA can also be maintained for eCTAs.

ESTIMATING HUMAN DOSES

One of the ways to transform animal doses into human doses remains the classic scaling method that takes body surface into account, and can always be used to check human doses calculated in other ways (3,4). If there is a large discrepancy between modelled human doses and scale doses, this should be justified. Nowadays, companies often use models that should predict human exposure at a certain dose, based upon observations in animals. Measured exposures in animals at NOAEL and at doses indicative for therapeutic efficacy can further be used to predict human doses that will be marginally active, will have pharmacodynamic effect or may cause adverse effects. In vitro concentrations to induce activity and plasma concentrations in animals at effective or toxic doses may further be used to refine predictions of the starting dose. Since these estimates will be subject to a number of uncertainties, and humans may be more sensitive than expected or may reach higher exposure, a safety factor should be taken into account. Once the first data in humans has been obtained, the predictions can be further refined. A pause when nearing potentially critical exposures in humans may be required.

CLASSIC PHASE I TRIALS

The main difference between exploratory clinical trials and Phase I trials is that the potential toxicity is better defined in the animal experiments. Usually the safety pharmacology, and in particular the cardiovascular safety pharmacology, will be better addressed in a dedicated study, whereas for exploratory trials this may be studied in the course of the toxicology studies. The augmented degree of documentation of effects allows the substance to be dosed higher, and dose escalation may go up to the maximal tolerated dose in classic Phase I studies. Obviously the severity and seriousness of expected adverse effects at a given exposure should be taken into account in order to determine the maximal dose that can be administered. With regard to the starting dose and dose escalation, the same rules as for exploratory clinical trials can be applied and the same guidelines should be followed. Whereas exploratory clinical trials mostly seem to be performed when there is a choice to be made between different substances and it allows projects to be terminated in a very early phase when relatively little investment has already been made, the classic Phase I study allows easier connection to further development and, if there is no choice to be made, may save some time. Whereas there is no presubmission procedure
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MAGNITUDE OF PHARMACODYNAMIC EFFECTS

In exploratory clinical trials, a certain predefined pharmacodynamic effect may be required. When the substance under investigation targets a new mechanism that has not yet been explored in humans, the maximal effect may need to be set at a lower level, or be approached in smaller steps than with a known mechanism of action. The decision on what effect is acceptable also depends on whether the effect aimed at is, for instance, a receptor or enzyme occupation, inhibition or activation of the target, which organs and organ systems are likely to be affected, and how target occupation is correlated to a physiological effect. In this context, it is also important to consider whether healthy volunteers will be involved in the trial, with the advantage of better control and less variability, or whether stable, otherwise healthy patients with moderate disease will be involved. The latter may allow better prediction of target involvement and potential therapeutic benefit, in addition they may tolerate a pharmacodynamic effect better.

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Most studies with biotechnology-derived products are conducted according to a classic Phase I approach. This may be linked to the fact that the ICH S6 guideline is the most important guidance for such products and the amount of preclinical testing needed may already be relatively limited, therefore the exploratory approach does not always provide major advantages.
for classic Phase I trials, the Belgian agency has a scientific advise procedure in place when an applicant wants to address issues that may arise beforehand. is maximally active may not yield much additional therapeutic effect. This may be addressed in the preclinical setting to a certain extent. Thus, careful consideration of the amount and type of preclinical data that will be available

BIOTECHNOLOGY-DERIVED PRODUCTS
For biotechnology products, the ICH S6 guideline provides guidance to the preclinical requirements that addresses issues like the species specificity of the interaction of the product with its target, the need to conduct some studies such as genotoxicity studies, and particular aspects of safety pharmacology testing (5). This guidance document is currently in a revision process and the procedure for scientific advice may be helpful to discuss unclear issues if these may have major repercussions. Most studies with biotechnology-derived products are conducted according to a classic Phase I approach. This may be linked to the fact that the ICH S6 guideline is the most important guidance for such products and the amount of preclinical testing needed may already be relatively limited, therefore the exploratory approach does not always provide major advantages. Furthermore, the fact that such products require a complex production process and thus there is often no choice to be made between different products may in part explain that limited numbers of eCTAs were submitted in the past with these products.

About the authors

Walter Janssens is a Zoologist and has a PhD from the University of Antwerp; he later did research at the University of Leuven in the Center for Thrombosis and Vascular Research. He then became a research scientist in the pharmaceutical industry with an emphasis on cardiovascular and gastrointestinal physiology and pharmacology and migraines. From 2002 until May 2006 he worked on toxicological aspects of the use of industrial chemicals in a regulatory context at the Scientific Institute of Public Health in Brussels. In May 2006, he became senior assessor of preclinical aspects in clinical trial applications at the R&D department of the Federal Agency for Medicinal and Health Products. He is also coordinator for early-phase development at the Agency. Email: ct.rd@fagg.be Kristof Bonnarens graduated from the University of Ghent in 2001, with a degree in Industrial Pharmacy. After a short career in the pharmaceutical industry, he joined the R&D department within the Federal Agency of Medicines and Health Products in January 2005. He is the interim Head of Division in R&D. He is a member of the EudraCT working group, and is involved in several IT-projects concerning clinical trials. Greet Musch is an Industrial Pharmacist and has a PhD in Pharmaceutical and Biomedical Sciences at the Free University of Brussels. She worked in the pharmaceutical industry for eight years, where she was responsible for all chemical and pharmaceutical analytical activities related to the development of new innovative drugs. She then moved to Federal Public Health services as a Senior Quality Assessor where she assisted in several projects related to CHMP, as well as to generics. Since August 2004 she has been in charge of the R&D department within the Federal Agency of Medicines and Health Products in Belgium, and has been Director General of Pre-Authorisation at the Agency since January 2009. She is a member of the EU Ad Hoc Group on implementing guidelines for clinical trials as well as of the Clinical Trial Facilitation Group.

CANCER PATIENTS
The ICH S9 guideline gives indications about preclinical requirements for the conduct of clinical trials in patients with advanced cancers, and it is important to keep this limitation in the scope of the guideline in mind (6). It has implications for the early-phase studies in such patients. In general, it lessens the requirements in comparison to other products. However, for such studies, a flexible dose-finding design may be a major factor to consider. Whether seamless flexible designs would be acceptable may depend on the available preclinical data and stopping criteria and needed monitoring that can be derived from it. The starting dose should be estimated as one that will cause a pharmacologic effect and is not likely to surpass the maximal tolerated dose, it is clear that preclinical pharmacodynamic, toxicological and pharmacokinetic data should be sufficient to do so. Whereas the maximal dose will generally be determined by the tolerability, it is obvious that preclinical data may be helpful in predicting that dose, moreover it could be argued that increasing the dose far above one that

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should lead to the most efficient and patient friendly way to conduct the first clinical trials.

Limited and explicitly defined production activities, only for internal use, may be envisaged after inspection.
References 1. EMA/CPMP/ICH/286/95 Revision 2, Note for guidance on non-clinical safety studies for the conduct of human clinical trials and marketing authorization for pharmaceuticals EMA/CHMP/SWP/28367/07, Guideline on strategies to identify and mitigate risks for first-in-human clinical trials with investigational medicinal products Freireich EJ, Gehan EA, Rall DP, Schmidt LH, and Skipper HE, Quantitative Comparison of Toxicity of Anticancer Agents in Mouse, Rat, Hamster, Dog, Monkey, and Man, Cancer Chemotherapy Reports 50: pp219-244, 1966 FDA Guidance for Industry. Estimating the Maximum Safe Starting Dose in Initial Clinical Trials for Therapeutics in Adult Healthy Volunteers EMA/CHMP/ICH/302/95, Note for guidance on preclinical safety evaluation of biotechnology-derived pharmaceuticals EMA/CHMP/ICH/646107/2008, Note for guidance on nonclinical evaluation for anticancer pharmaceuticals EMA/ CHMP/QWP/185401/2004, Guideline on the requirements to the chemical and pharmaceutical quality documentation concerning investigational medicinal products in clinical trials

QUALITY AND GMP ASPECTS

The guideline CHMP/QWP/185401/2004 forms the basis for evaluation of the quality of experimental medicines (7). For biotechnology-derived products, the specific guidelines depend on the nature of the product should be applied. The active substance used in exploratory trials may be synthesised in a pilot lab, but it is imperative that an adequate description of the product and the impurities that it may contain should be provided. However, once the active substance has been produced and characterised, there is no reason why the GMP rules that are in effect for classic Phase I studies should not be followed. This means that in principle the Phase I unit should apply for an authorisation for production of experimental medicinal products and that an inspection should take place before this authorisation can be granted. In Belgium, a hospital pharmacy is legally allowed to perform reconstitution and packaging activities for in hospital use. This means that if the Phase I unit where early-phase clinical trials are performed is part of the hospital, it can rely on its hospital pharmacy for such activities limited only for use in the same hospital. It could be that limited and specific production activities may be needed in a Phase I unit that, although located in a hospital, are not a part of that hospital in legal terms.

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