Belgium Phase 1 Requirements

8/3/2019 Belgium Phase 1 Requirements

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RegulatoryRequirements

Walter Janssens, Kristof Bonnarens and Greet Musch at the Federal Agency for Medicinal

and Health Products, Belgium, discuss regulatory requirements in early-phase development

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

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.



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 M3guideline (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

100µg, 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 100µg at a time, with a maximum of 500µg 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

Number of trials Percentage of total trials

Phase I trials 134 24.9

Phase II trials 159 29.6

Phase III trials 197 36.6

Phase IV trials 45 8.4

eCTA, including microdose studies 17 3.2

First-in-human trials, excluding exploratory trials 26 4.8

Table 1: Clinical trial applications in Belgium during 2009




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 a14-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.

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 insuch 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 theminimal 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

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 mostsensitive species. It should be noted that if the non-rodent

species is more sensitive to adverse effects than the non-

rodent 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 anexploratory 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.

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 NOAELin 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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beyond the limits that are proposed in the guideline. In

general, this would require an amendment to the protocol to

be submitted.

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 sensitivethan 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.

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 mayneed 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.

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 theagency, 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.

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 escalationmay 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

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.




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.

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 studiessuch 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 requirea 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.

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. Ingeneral, 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

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

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 inthe 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: [email protected]

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 andBiomedical 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.

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.



should lead to the most eff icient and patient friendly way to

conduct the first 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 specif ic guidelines

depend on the nature of the product should be applied. Theactive 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 activitiesfor 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 specif ic 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.

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

2. EMA/CHMP/SWP/28367/07, Guideline on strategies toidentify and mitigate risks for first-in-human clinical

trials with investigational medicinal products

3. 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

4. FDA Guidance for Industry. Estimating the Maximum

Safe Starting Dose in Initial Clinical Trials for

Therapeutics in Adult Healthy Volunteers

5. EMA/CHMP/ICH/302/95, Note for guidance on

preclinical safety evaluation of biotechnology-derivedpharmaceuticals

6. EMA/CHMP/ICH/646107/2008, Note for guidance on

nonclinical evaluation for anticancer pharmaceuticals

7. EMA/ CHMP/QWP/185401/2004, Guideline on the

requirements to the chemical and pharmaceutical

quality documentation concerning investigational

medicinal products in clinical trials

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Belgium Phase 1 Requirements