Guide for conduction of nonclinical and clinical studies for registration of alpha-

interferon as biological product by comparability development

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

Copyright © 2011. National Health Surveillance Agency. Partial or full reproduction of this works is allowed provided the source is mentioned. Legal deposit in the National Library, according to Decree No. 1.825, dated December 20, 1907. 1st edition.

CEO CEO’s Assistant

Dirceu Aparecido Brás Barbano Luiz Roberto da Silva Klassmann

Directors Directors’ Assistants

Jaime César de Moura Oliveira Luciana Shimizu Takara

José Agenor Álvares da Silva Neilton Araujo de Oliveira

Maria Cecília Martins Brito Luiz Armando Erthal

Head of Cabinet

Vera Maria Borralho Bacelar

General Drug Management

Norberto Rech

Safety & Efficacy Assessment Management

Laura Gomes Castanheira

Biological Product Registration Coordination

Marcelo Mário Matos Moreira

Direct participation: Brenda

Gomes Valente Bernardo Luiz

Moraes Moreira Fanny

Nascimento Moura Flávia

Regina Souza Sobral Daniela

Marreco Cerqueira Juliana

Bertoli da Silva

Laura Gomes Castanheira Marcelo

Mário Matos Moreira Marcos

Fernando Galves da Silva Maria

Fernanda Reis e Silva Thees

Neemias Silva de Andrade

Patrícia Ferrari Andreotti

Raimundo Nonato Vieira Júnior

Rodrigo Martins Bretas

Silmara Crisitane da Silveira

Elaboration and editing

AGÊNCIA NACIONAL DE VIGILÂNCIA SANITÁRIA

SIA Trecho 5, Área Especial 57, Lote 200

71205-050, Brasilia –

Federal District

Phone: (61) 3462-6000

Home page: www.anvisa.gov.br

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

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 2b) 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.

4 Guide for conduction of nonclinical and clinical studies for registration of heparins as biological product in development by comparability

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

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

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

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

Ministry of

Health