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Guide for conduction of nonclinical and clinical studies for registration of alphainterferon as biological product by comparability development
1. Guide for conduction of nonclinical and
clinical studies for registration of alpha-
interferon as biological product by
comparability development
2. National Health Surveillance Agency | Anvisa
Guide for Conduction of Nonclinical and
Clinical Studies for Registration of
Alpha-Interferon as Biological Product
by Comparability Development
Brasilia 2011
4. Table of contents
1 Introduction.................................................................................................................................................... 4
2 General Considerations ...................................................................................................................................4
3 Nonclinical studies.....................................................................................................................................5
4 Clinical studies ...........................................................................................................................................6
5 Immunogenicity ..........................................................................................................................................7
6 Indication Extrapolation..........................................................................................................................7
7 Pharmacovigilance Plan ..........................................................................................................................7
8 References .................................................................................................................................................8
Guide for conduction of nonclinical and clinical studies for registration of heparins as biological product in development by comparability 3
5. 1
Introduction
This guide outlines the clinical and nonclinical requirements for registration of recombinant human alpha-interferon in Anvisa
[National Health Surveillance Agency] as biological product, using the route of individual development. The nonclinical section
deals with the pharmaco-toxicological requirements, and the clinical section addresses the requirements for pharmacokinetic,
pharmacodynamics, efficacy and safety studies, as well as pharmacovigilance aspects. Suggestions of nonclinical and clinical
protocols are also presented.
In this guide, we will bring general directions for the conduction of nonclinical and clinical studies for registration of recombinant
human alpha-interferon by comparability. However, if the researcher/institution is able to evidence the efficacy and safety of these drugs
through other scientific and technically more feasible studies, the data presented will be evaluated by ANVISA and the deviation
from the guide’s directions must always be justified.
This Guide will address only the requirements for nonclinical and clinical studies applicable for registration of recombinant human
alpha-interferon by comparability, being that the other items of the specific standards must be complied with for health registration
of the product.
2 General
considerations
Recombinant human alpha-interferon (2a a n d 2 b ) i s a known and well characterized protein made up of 165 amino acids.
The non-glycosylated protein has a molecular weight of approximately 19.240 Da. The protein contains two disulfide
bridges, one between the cysteine residues 1 and 98 and another between the cysteine residues 29 and 138. The sequence
contains potential O-glycosylation sites. Physical, chemical and biological methods are available for protein
characterization.
Recombinant human alpha-interferon is approved for different indications like hepatitis virus B and C, leukemia, lymphoma, renal
cell carcinoma and multiple myeloma and can be used separately or in combination with other drugs. Alpha-interferon can have
different pharmacodynamics effects. The importance of these pharmacodynamics effects in each one of the clinical applications is still
unknown. Generally, the use of alpha-interferon in oncology has reduced considerably and is being replaced by other treatments.
The dose and therapeutic scheme required to obtain the desired response vary greatly according to the different indications.
Alpha-interferon is normally used subcutaneously, although it can also be used intramuscularly or intravenously. Treatment with
alpha-interferon 2a and 2b is associated with different adverse reactions like fever, discomfort, fatigue, myalgia and can also be
associated with psychiatric, hematological and renal adverse events.
Therapy with alpha-interferon can lead to development of auto-antibodies. A variety of autoimmune disorders like problems in the
thyroid, rheumatoid arthritis, systemic erythematous lupus, neuropathies and vasculitis have been observed with the use of alpha-
interferon.
Both neutralizing and non-neutralizing antibodies were observed during use of alpha-interferon.
This guide does not address the quality requirements. For aspects related to quality, the principles are applied as set forth in the Guide
for conduction of the comparability exercise for registration of biological products by comparability and Resolution RDC No. 55/10
and its updates.
According to RDC 55/10, the comparer biological product (CBP) cited in this guide is recombinant human alpha-interferon
registered at Anvisa through presentation of a complete dossier.
6. 4 Guide for conduction of nonclinical and clinical studies for registration of heparins as biological product in development by comparability
7. 3 Nonclinical studies
Before starting the clinical development, nonclinical studies must be conducted. The nonclinical studies must be comparative and
designed to detect differences in the pharmaco-toxicological response between the alpha-interferon to be registered and the CBP, and
not just to evaluate the response per se. The approach adopted must be fully justified in the nonclinical summary.
Pharmacodynamic studies
In vitro studies:
In order to compare the changes in the activity between the alpha-interferon to be registered and the CBP, one must provide data on a
series of comparative bioassays (bond with receptor, antiviral effect in cell culture, anti-proliferative effects in tumor cell lineages),
being that several of these assays will already be part of the quality dossier in the comparability exercise.
In vivo studies:
One must compare the in vivo pharmacodynamics activity of the alpha-interferon to be registered and of the CBP in:
• a suitable animal pharmacodynamics model (e.g. evaluation of the effects on pharmacodynamics markers, like 2’-5’-
oligoadenylate synthetase activity in the serum). If possible, these evaluations must be conducted as part of a toxicity
study.
and/
or
• suitable tumor animal model and/or
• suitable antiviral animal model
Toxicology Studies
Data on at least one repeated dose toxicity study in relevant species must be provided. The study must have duration of at least 4
weeks.
Toxicokinetic studies must be conducted as part of the repeated dose toxicity study and must include evaluation of the antibody
formation potential.
Data on the local tolerance in at least one species must be provided. If possible, these local tolerance tests can be conducted as part of
a repeated-dose toxicity study.
E Pharmacological studies on safety, reproductive toxicology, mutagenicity and carcinogenicity are not routine requirements for the
nonclinical tests of a biological drug product containing recombinant human alpha-interferon.
For the case of nonclinical development, comparative studies must be conducted using the alpha-interferon elected as comparer product
(alpha-interferon registered at Anvisa through presentation of a complete dossier) and the alpha-interferon to be registered. At least
two relevant species should be used if available and local tolerance, acute toxicity and repeated dose toxicity studies must be
conducted. Comparative evaluation of pharmacokinetic, pharmacodynamics and immunogenicity (whenever possible) parameters are
also required.
Guide for conduction of nonclinical and clinical studies for registration of heparins as biological product in development by comparability 5
8. 4 Clinical studies
Pharmacokinetic/Pharmacodynamic Studies
The pharmacokinetic/pharmacodynamics properties of the alpha-interferon to be registered and of the CBP must be compared in a
randomized, single-dose study in health volunteers. The primary pharmacokinetic parameters recommended are area under the curve
(AUC) and the secondary parameters are Cmax, T1/2 and CL/F.
The equivalence margins must be pre-specified and appropriately justified.
Pharmacodynamic Studies:
Different pharmacodynamics markers are available, like β2 microglobulin, neopterin and 2’-5’- oligoadenylate synthetase activity
in the serum, which are relevant to measure the interaction between alpha-interferon and the immune system. The doses selected must
be in the ascending linear region of the dose response curve. Even though the importance of these pharmacodynamics effects is still
unknown in the different indications, a complete comparative evaluation after administration of epoetin alpha to be registered and the
CBP can provide useful data.
After conducting the necessary nonclinical studies with satisfactory results, the conduction of a Phase I, comparative, double-blind
study is recommended with health volunteers and a wash-out period of 4 weeks. The aim of this study is comparison of the
pharmacokinetic and pharmacodynamics parameters and gathering of preliminary safety data.
Clinical Efficacy
Study population
The action mechanism of alpha-interferon includes a series of different unrelated effects.
Demonstration of effect similarity between the product to be registered and the CBP is required. This can be done in a virgin
population of treatment with hepatitis C (HCV), as outlined by the indication of the CBP. Other populations must be studied
according to the indications desired.
Study outlining and duration
A parallel, randomized group study for comparison of the products for at least 48 weeks is recommended. The study must be double-
blind at least up to the point in which the data from the primary analyses is generated. If this is not possible, a justification must be
presented and all actions to eliminate possible biases must be clearly identified in the protocol.
The posology (dose, administration route and administration methodology) must be the same as for the CBP. The alpha-interferon
must be administered together with the standard treatment for hepatitis C used together with the CBP.
The study must be outlined so as to allow conduction of the primary efficacy analysis in the twelfth week for all recruited patients. A
homogeneous population is preferably recommended, for example, a single viral genotype. If a heterogeneous population is selected,
stratification must be conducted according to the viral genotype.
Outcomes
Primary: virological response evaluated by the number of patients with absence of HCV RNA detection by quantitative PCR in the
twelfth week. The methodology used and the cutoff applied must be justified. A decrease of 2 log in the viral growth must have a co-
primary outcome.
Secondary: virological response in the fourth week and at the end of treatment; sustained virological response (24 weeks after the end
of treatment); changes in the hepatic biochemical parameters including levels of transaminase and morbidity.
6 Guide for conduction of nonclinical and clinical studies for registration of heparins as biological product in development by comparability
9. Clinical safety
The safety data must be collected from the patients after repeated doses in a comparative study during the treatment period and
another period of 24 weeks of follow-up. The number of patients must be enough for comparison of the adverse effect profiles.
Evaluation of lab changes of immune-mediated disorders must be included. The safety profile between the alpha-interferon to be
registered and the CBP must be similar for the most common adverse events (fever, discomfort, alopecia, myalgia, leukopenia,
anemia and thrombocytopenia).
If the results of the Phase I Study are satisfactory, a Phase II/III study can be conducted to evaluate the efficacy and safety of the
alpha-interferon to be registered in relation to the comparer biological product. It must be a double-blind study to compare
non-inferiority or equivalence in patients with Hepatitis C and have minimum duration of 48 weeks. The primary outcome of
the study must be viral remission (evaluated through quantitative PCR) in the 24th week and the secondary outcomes will be
virological response in the 4th, 12th and 48th weeks (evaluated through quantitative PCR); biochemical parameters must also be
evaluated (including transaminases) and morbidity levels. Evaluation of safety (type, severity and incidence of adverse events)
and of immunogenicity must be done for the period of the study duration (48 weeks). In case of any significant finding in
relation to the safety and immunogenicity parameters, additional studies may be requested.
5 Immunogenicity
Comparative data on immunogenicity (levels of antibodies) must be collected during the study period and also during the 24-week
follow-up period. The antibodies, when present, must be evaluated for neutralizing capacity and potential impact on product efficacy.
Furthermore, any potential for neutralization of the alpha-interferon’s endogenous effect (development of autoimmunity) must be
evaluated. Any immunogenicity impact must be evaluated in patients who do not respond to the treatment, patients who present loss
of response in the primary treatment and patients who present unexpected adverse reactions or immune-mediated events.
6 Indication Extrapolation
At first, the extrapolation of therapeutic indications is possible when the action mechanism and/or receptors are the same for which the
clinical similarity was established, through comparative clinical study.
7 Pharmacovigilance Plan
Within the authorization procedure, the applicant must always present a pharmacovigilance plan and a risk reduction plan whenever
required according to the legislation in effect and pharmacovigilance guidelines.
Special attention must be paid to issues related to immunogenicity and later serious adverse effects in patients under chronic
administration of the product. Safety data must be gathered from patients covering all approved indications.
The Pharmacovigilance Plan must include follow-up of the patients included in the Phase II/III study for evaluation of relapses.
Guide for conduction of nonclinical and clinical studies for registration of heparins as biological product in development by comparability 7
10. 8 References
Guideline on similar biological medicinal products (CHMP/437/04/draft).
Guideline on similar biological medicinal products containing biotechnology-derived proteins as active substance: non-clinical
and clinical issues (EMEA/CPMP/42832/05/draft).
Note for guidance on repeated dose toxicity (CPMP/SWP/1042/99).
Note for guidance on toxicokinetics: A Guidance for assessing systemic exposure in toxicological studies (CPMP/ICH/384/95).
Note for guidance on non-clinical locale tolerance testing of medicinal products (CPMP/SWP/2145/00).
Guideline on risk management systems for medicinal products for human use (EMEA/CHMP 96286/2005).
Note for Guidance on Good Clinical Safety Data Management: Definitions and Standards for Expedited Reporting (CPMP/
ICH/377/95).
ICH Note for Guidance on Planning Pharmacovigilance Activities (CPMP/ICH/5716/03 - Final approval by CHMP on PHV).
Guidance on Planning Pharmacovigilance Activities (CPMP/
8 Guide for conduction of nonclinical and clinical studies for registration of heparins as biological product in development by comparability
