Acta Poloniae Pharmaceutica ñ Drug Research, Vol. 65 No. 6 pp. 641ñ645, 2008 ISSN 0001-6837
Polish Pharmaceutical Society
THE SCOPE AND REQUIREMENTS RELATED TO PRECLINICAL AND
CLINICAL STUDIES OF A NEW MEDICINAL PRODUCT, INCLUDING
BIOTECHNOLOGICAL AND BIOSIMILAR PRODUCTS
MTZ Clinical Research Sp. z o.o., 5 PawiÒskiego St., 02-106 Warsaw, Poland
Abstract: The article presents an outline of the requirements concerning the planning of preclinical and clini-
cal studies, necessary for the legal approval of a medicinal product. It describes the clinical research plan of
innovative and generic pharmaceutical products, taking into account the specific situations in which the assess-
ment of biological equivalence of a generic product is not possible based on pharmacokinetic parameters. The
article also discusses the guidelines which determine the scope of studies which are necessary in the process of
registration of biotechnological and biosimilar products.
Keywords: preclinical studies, clinical studies, innovative medicinal product, generic medicinal product, bio-
logical products, similar biological products
Introduction and definitions lence studies) together with a comparative assess-
A number of basic concepts must be defined ment of the pharmacokinetics or the therapeutic
before we describe the scope and requirements of effect, with the aim to prove similarity. No preclini-
preclinical and clinical studies which must be car- cal research is carried out on generic products.
ried out in order for the pharmaceutical product to Biopharmaceuticals ñ are pharmaceuticals pro-
gain a legal approval and the marketing authoriza- duced according to biotechnological methods,
tion. although no widely accepted definition exists. This
Innovative medicinal product ñ i.e. an original group of products includes:
one, is a product whose effects are based on either recombinant proteins, (monoclonal) antibodies, vac-
new, unknown or previously unused active compo- cines, blood and plasma-derived products, products
nents or on components which, in comparison with obtained from the cells of: bacteria, yeasts, insects,
the products available on the marked, improve the plants, and mammals, as well as of genetically mod-
effectiveness, safety, or comfort of the therapy. ified plants and animals; products used in gene ther-
Such a product is registered on the basis of a apy (vaccines based on DNA, oncological treatment,
complete set of registration documents including, in Parkinsonís disease and other neurodegenerative
addition to the chemical, biological and pharmaceu- diseases), somatic cell therapy, tissue engineering.
tical part, the results of original research, as well as Registration of these medicinal products is based on
pharmacological and clinical assessment. To fulfill a complete set of registration documents including
these requirements it is necessary to carry out a bat- preclinical and clinical data.
tery of preclinical studies, as well as studies of phase Medicinal biosimilar products ñ (terms used:
I, II, III, and IV. similar biological medicinal product/biosimilar,
Equivalent medicinal product ñ i.e. a generic biotechnological generics, biogenerics, follow-on
one, is a product therapeutically equivalent to the biologics ñ the terminology is not synonymous due
innovative product. It is assumed that a product is to a great variety of products) medicinal products of
therapeutically equivalent if it is pharmaceutically biotechnological origin whose quality, safety and
equivalent and biologically equivalent. efficacy in relation to the original (referential) prod-
Such a product is registered on the basis of a uct has been proven, and which have obtained mar-
set of registration documents including, in addition ket authorization. The concept of biogenerics was
to the chemical, biological and pharmaceutical part, introduced by EMEA in 2004 (the review of the
the results of original clinical studies (bioequiva- European pharmaceutical law ñ Pharma Review).
* Corresponding author: e-mail: email@example.com
642 TERESA BRODNIEWICZ-PROBA
This gives the basis for submitting the so-called sim- the first in men administration, another part is con-
plified registration applications. It is necessary to tinued parallelly with the studies of subsequent
prove the similarity to biological products registered phases.
under the centralized procedure. There is no need to The set of toxicity tests includes a test for local
carry out a whole battery of studies as it is in the tolerance, in which the way the product is adminis-
case of original products. tered must be identical to the one in the planned study
Europe has worked out a system of recommen- involving human subjects. Another type of study is
dations concerning the scope of preclinical and clin- genotoxicity testing, whose purpose is to detect any
ical studies (general and detailed, prepared by potential mutations or chromosomal damage by
CHMP ñ Committee for Medicinal Products for means of tests performed on cells. The results must be
Human Use). The USA has been working on the known before the start of phase II studies. Similarly,
legalization of this system. before the start of phase II studies, an assessment of
the effects of the product on the male and female
Research and development in the pharmaceutical reproductive systems must be carried out. In some
industry and the risks associated with them cases, an additional study on the potential carcino-
It takes on average 13.4 years from the discov- genic effects is performed. This study may be con-
ery of a compound to the registration. The process of ducted after the registration of the product. If there are
developing a new medicinal product is very expen- doubts concerning the safety of the product, the scope
sive and the risk of failure is very high. The risk for of the study shall be appropriately extended (1).
various phases of the research is estimated as fol-
lows: preclinical phase ñ 61%, phase I / II ñ 78%, Clinical studies of medicinal innovative pharma-
phase IIIó51%. ceutical products
Preclinical studies of innovative pharmaceutical Phase I
products The aim of phase I of clinical studies is solely
Preclinical studies are conducted only for inno- a research (exploratory) one, rather than therapeutic.
vative products. Their aim is to discover the toxic The participants of the study are essentially healthy
effects, especially their impact on particular organs. volunteers (10 ñ 20 persons), unless administration
Moreover, the studies have to examine the relation of the medicinal product to healthy people would be
between the impact of the toxic effect and the length unethical, regarding its profile.
of the exposure to the tested product, as well as the The aim is to make initial estimates as to the
reversibility of the impact. safety after a single and repeated administrations,
discovering the pharmacokinetics of the product
Pharmacological studies of safety (absorption, distribution, metabolism, and excre-
These studies assess the impact of the product tion), and discovering the pharmacodynamic effect
on the functions of, for example, the cardiovascular (i.e. the effects of the product on the organisms of
system, the central nervous system, and the respira- healthy or sick people). Sometimes it is possible to
tory system. plan the study in such a way as to preliminarily esti-
mate the potential therapeutic effect.
Toxicokinetic and pharmacokinetic studies
These studies help to obtain information on Phase II
absorption, distribution, metabolism, and excretion. The aim of phase II clinical studies is to dis-
The results of these studies are analyzed before the cover the therapeutic properties of the product. The
start of phase I studies. study is carried out on a selected group of patients.
A typical participantsí group in this study phase is
Toxicity tests small and very homogeneous, (typically up to 100
The first step are studies of acute toxicity after participants in 1 ñ 3 research centres). During the
the administration of a single dose or increasing study, the size of the doses (through an increase in
doses to two species of mammals. In the next step dosage) which will be used in phase III is deter-
there are the so-called chronic toxicity tests, which mined. An important aim of phase II is to verify the
must be adequate to the planned manner of adminis- end points that will be used in phase III.
tration to humans. The product is given to two Phase III
species of mammals, of which only one may be a The aim of phase III studies is to prove the
rodent. A part of the study must be completed before expected therapeutic benefits. The selection of par-
The scope and requirements related to preclinical and clinicalstudies of... 643
ticipants is not as strict as in phase II, although cer- product and reference product they should fall
tain criteria for acceptance or exclusion apply. between 80 ñ 125%.
Studies of this phase are usually multi-centre, there
may be even a few thousand participants. During the Comparative clinical studies of pharmaceutical
study, a further assessment of the relation between products based on pharmacokinetic parameters
the size of the dose and the therapeutic effect is per- Comparative clinical studies of pharmaceutical
formed, moreover, the effects of the medicine products based on pharmacokinetic parameters are
applied together with other medicinal products is carried out when the concentration of the active
assessed. The results of phase III studies will serve component in the body fluids is sufficient. The sub-
as the basis for the registration of the product. jects of such studies are a limited number of healthy
(with some precisely described exceptions) partici-
Phase IV pants. This number, depending on the intersubject
During this postregistration phase further stud- variability (CV), usually varies between 24 and 110.
ies on the administration safety and the relation After the administration of the product under strict-
between the administration and the effects of the ly specified conditions, samples of body fluids are
product are carried out. The participating patients do taken at set times, and then, the concentration of
not undergo any selection; the only criteria are the these products is measured. Obtained pharmacoki-
indications / contraindications written on the prod- netic parameters: the AUC, Cmax and Tmax are ana-
uctís information leaflet. This phase of the study lyzed, and then, as a result of comparison, a conclu-
involves thousands of participants. sion on the biological equivalence can be drawn.
Preclinical studies of generic pharmaceutical Comparative clinical studies of pharmaceutical
products products based on pharmacological parameters
In the case of generic products, in principle, no Comparative clinical studies of pharmaceutical
preclinical studies are carried out. products based on pharmacological parameters are
carried out when there is insufficient concentration
Clinical studies of biological equivalence of ge- of the tested (active) substance in the body fluids.
neric pharmaceutical products Typical examples are studies of local effect of der-
The aim of the study of biological equivalence, matological preparations containing corticosteroids.
preceded by studies designed to demonstrate the The study avails itself of the fact that the preparation
pharmaceutical equivalence, is to demonstrate phar- penetrates the epidermis and the stratum corneum,
macological equivalence, and thus therapeutic causes vasoconstriction and thus blanching of the
equivalence ñ and hence also therapeutic inter- skin. The above mentioned pharmacodynamic effect
changeability which provides the basis for the regis- is proportional to the time which has elapsed from
tration of the generic product. the application of the preparation and to the thera-
In other words, biological equivalence indicates peutic effect. The participants of this type of studies
pharmacological equivalence, and thus, on this basis also comprise a relatively limited number of healthy
conclusions about biological equivalence can be drawn. volunteers (between 60 and 100). The findings, i.e.
An evaluation of the biological equivalence is AUEC (area under effective curve), Cmax and Tmax,
carried out according to an analysis of the following are compared using the same principles as in the
parameters: pharmacokinetic, pharmacological, the case of pharmacokinetic studies, and conclusions
results of comparative therapeutic studies concerning the biological equivalence are drawn.
Analyzed parameters Comparative clinical studies of medicinal prod-
Parameters of primary importance: AUC ñ area ucts based on therapeutic data
under the curve; Cmax ñ maximum concentration. Comparative clinical studies of medicinal prod-
Secondary parameters: Tmax ñ the time of maximum ucts based on therapeutic data are carried out when the
concentration from the administration; T1/2 ñ the tested substance is not present in sufficient concentra-
time of achieving half of the maximum concentra- tion in the body fluids, and when there is no pharma-
tion of the active component; MTR ñ mean resi- codynamic effect which could be easily compared.
dence time; % of extrapolated AUC value. An example of such a study may be the study of
When comparing these parameters a 90% con- a pharmaceutical product containing mesalazine
fidence interval is applied for the relation between which practically does not leave the colon after
average AUC and Cmax parameters. For the tested administration. 280 patients participated in the cited
644 TERESA BRODNIEWICZ-PROBA
study. The comparative assessment of AUC, Cmax, the reproductive system, as well as mutagenicity is
and Tmax was performed on the parameters of the ther- not a routine requirement.
apeutic effect. The study lasted longer than 2.5 years. In the case of biosimilar insulin, in vitro tests
are carried out first. Their aim is to detect any dif-
Preclinical studies of innovative and biosimilar ferences in the bonding to the receptor. Then a test
biopharmaceuticals for cell proliferation is performed. The in vivo stud-
Preclinical studies of innovative biotechnolog- ies are carried out in rodents (as the model here
ical products (biopharmaceuticals) serve rats deprived of the pituitary gland). They esti-
Preclinical studies of innovative biotechnolog- mate the weight increase or the length of the femur.
ical products have a different scope for products of Toxicological studies involve administration of the
different origins. The scope of the studies is regulat- product for 4 weeks at least 2 times a week. They
ed by EMEA directives. assess the local tolerance. The studies that are not
Products such as cytokines, recombinant coag- required: assessment of safety pharmacology, repro-
ulation factors, enzymes, hormones, recombinant ductive toxicology, mutagenicity, and carcinogenic-
proteins, and plasma-derived products are tested in a ity (2-4).
different way than heparins, vitamins, DNA vac-
cines, or products for cell therapy. Clinical studies of innovative biotechnological
The study begins with tests in the in vitro sys- products
tem, during which the presence of receptors on cells Clinical studies of innovative biotechnological
and the affinity to them is determined, the rules for products are planned and carried out in a manner
pharmacological effects are set, and information analogous to clinical studies of innovative medicinal
useful when selecting species of animals for phar- pharmaceutical products.
macological studies is obtained (e.g. the animals Due to the nature of the products, the safety,
used in studies on monoclonal antibodies have an and particularly the immunogenic potential of the
epitope to which the tested monoclonal antibody has products of biological origin, is thoroughly analyzed.
an affinity, and a cross-reactivity profile that is sim-
ilar to that of a human). Comparative clinical studies of biosimilar prod-
The next step is usually the safety test with two ucts.
species of animals. The choice of animals with an When planning clinical studies of biosimilar
epitope involved in a specific reaction is very impor- products, designed to prove the similarities, the fol-
tant. The way of administering the product is the lowing principles must be applied:
same as in the planned clinical study, and the size of ● selecting the reference product and its character-
the dose is a multiplication of the dose administered istics;
in the clinical study. The immunogenic profile of the ● demonstrating the similarities in the in vitro and in
product is analyzed in a particular way. The vivo models in preclinical studies;
immunogenic potential is checked by several highly ● demonstrating the safety and efficacy through
specialized and selective methods. limited clinical studies (Phase I and III);
● demonstrating the safety of the product through
Preclinical studies of biotechnological generic, i.e. immunological research.
biosimilar products The rules which apply to the planning of clini-
Preclinical studies of biosimilar products are cal studies of biosimilar products:
not as extensive as the studies of innovative prod- ● demonstrating the physicochemical and biologi-
ucts. One can track them by looking at the examples cal similarities to the reference product (preclinical-
of studies, recommended by the EMEA, of biosimi- ly) are as follows:
lar erythropoietin and insulin. ● demonstrating the relation between the pharmaco-
In the case of biosimilar erythropoietin in vitro dynamic and therapeutic effect, and the dose;
tests examining the bonds to receptors and differen- ● determining the possibility of using surrogate
tiation of cells should be carried out. The in vivo endpoints and their relation to the dose and the con-
studies involve tests with the use of policystemic or centration of the product in fluids and tissues;
normocystemic mice. ● statistical proof of the efficacy at a 95% level of
Toxicological studies involve a 3-month long confidence in relation to the extent to which bioe-
administration of the product to animals, and assess- quivalence is accepted, fulfillment of the test sensi-
ment of local tolerance in at least one specie. The tivity requirements, taking into account the inter-
evaluation of safety pharmacology, toxicology of changeability determined by standard deviation, and
The scope and requirements related to preclinical and clinicalstudies of... 645
meeting the requirement concerning adequate test Phase III. Comparative study confirming efficacy
power; and safety
● an analysis of the potential immunogenicity and The scope of biological equivalence is relative-
the creation of neutralizing antibodies ly narrow and defined a priori. It refers to a signifi-
cant therapeutic effect by setting clinically meaning-
Examples of biosimilar products with legal ful endpoints. The power of statistical calculation is
approval and those in the course of development: usually fixed between 80-90%. The number of
recombinant growth hormone (EMEA recommen- patients, often determined on the basis of pilot stud-
dations are available); recombinant erythropoietin ies, may even be more than a thousand people. In the
(EMEA recommendations are available); recombi- case of various indications, separate studies are rec-
nant insulin (EMEA recommendations are avail- ommended to prove the therapeutic effects and safe-
able); recombinant hormone stimulating the growth ty for each indication.
of granulocytes (EMEA recommendations are avail-
able); monoclonal antibodies; genes; cells for cell SUMMARY
The nature and origin of a medicinal product
Rules for conducting clinical studies of biosimilar determines in advance the scope and requirements
products concerning the clinical studies necessary to obtain
Phase I. Study showing pharmacokinetic equiva- legal approval of the product. In turn, the exactly
lence outlined clinical studies strategy imposes certain
The purpose of the study is to demonstrate the aspects of preclinical studies, although, in general,
pharmacokinetic equivalence, mainly in terms of AUC their scope is defined by existing guidelines.
and Cmax (80 ñ 125%) or broader (in justified cases). The aim of the performed studies is to create a prod-
An example of applying the analysis of phar- uct that is comprehensively tested, maximally safe
macodynamic parameters (PD) may be a compari- for the patient, and which has new therapeutic (or
son of the well-known PD effect such as measuring generic) possibilities of a medicinal product.
the concentrations of glucose for insulin, the meas-
urement of the anti-viral effect for interferon, meas- REFERENCES
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generic products. The studies typically involve for the Conduct of Human Clinical Trials of
about 30 or more participants (healthy or sick). Pharmaceuticals.
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III is performed. Sometimes, between phase I and ñDerived Pharmaceuticals.
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