Biotherapy Drug Circulation Regulation in the Republic of Belarus. Current Status and Long-Term Prospects

http://www.rceth.by/

Andrian Victorovich Nadzharian, M.D., Assistant Professor

Originator medicine means medicine that differs from all earlier registered medicine by the pharmacologically active substance or a combination of such substances

http://www.rceth.by

LAW OF THE REPUBLIC OF BELARUSof July 20, 2006, No. 161-Z

ON MEDICINESAdopted by the Chamber of Representatives on June 23, 2006

Approved by the Republican Council on June 30, 2006(in the version of Laws of the Republic of Belarus dated August 5, 2008, No. 428-Z,

dated June 15, 2009, No. 27-Z, dated December 22, 2011, No. 326-Z)

Generic medicine means medicine containing the same pharmaceutical substance or a combination of pharmaceutical substances in the same dosage form as the originator medicine, equivalent to the originator medicine and therapeutically interchangeable with it

http://www.rceth.by

LAW OF THE REPUBLIC OF BELARUSof July 20, 2006, No. 161-Z

ON MEDICINESAdopted by the Chamber of Representatives on June 23, 2006

Approved by the Republican Council on June 30, 2006(in the version of Laws of the Republic of Belarus dated August 5, 2008, No. 428-Z,

dated June 15, 2009, No. 27-Z, dated December 22, 2011, No. 326-Z)

Pending agreement

Biotechnology medicine is a medicine obtained using biotechnological processes, including:

- recombinant DNA technology,- method of controlled expression of genes coding production

of biologically active proteins,- Hybrid and monoclonal antibody method Biosimilar medicine is a biotechnology medicine that is similar

to the first manufactured (originator) medicine and presented after the patent for the originator medicine expired.

http://www.rceth.by

www.rceth.by

BASICS

RESOLUTION OF THE MINISTRY OF HEALTH OF THE REPUBLIC OF BELARUS

of May 8, 2009, No. 52

ON REQUIREMENTS TO DOCUMENTS FOR MEDICINES AND PHARMACEUTICAL SUBSTANCES SUBMITTED FOR STATE REGISTRATION

(RE-REGISTRATION) AND DOCUMENTS PROVIDED FOR MAKING AMENDMENTS TO THE REGISTRATION FILE FOR A MEDICINE

(PHARMACEUTICAL SUBSTANCE) EARLIER REGISTERED IN THE REPUBLIC OF BELARUS AND FOR RECOGNITION OF THE RESOLUTION OF THE MINISTRY OF HEALTH OF THE REPUBLIC OF BELARUS DATED

NOVEMBER 21, 2008, No. 199, AS NULL AND VOID

(in the version of resolutions of the Ministry of Health dated November 20, 2009, No. 129, and dated September 13, 2010, No. 124)

www.rceth.by

BASICS

For a biotechnology medicine (including biosimilars) - comprehensive information on pre-clinical medicine study and on medicine clinical trials in accordance with Good Clinical Practice, unless the applicant confirmed the biomolecule’s primary, secondary and tertiary structure identity to the starting compound, quantitative and qualitative parameters of all concomitant identified impurities and the cell line, in which this biomolecule was obtained

Priority

www.rceth.by

www.rceth.by

Example: LMH (low-molecular heparins)

EXPERT OPINIONon the registration file documents that describe quality, efficiency and safety of *****PARIN (foreign, biosimilar medicine) – medicine submitted for registrationExpert examination of documents that describe quality, efficiency and safety of the medicine:Trade name: *****PARIN

International name: ****parin

Dose delivery system: Solution for injection, 20 mg/0.2 ml, in syringes, in blister, in No. 1 package x 1

Solution for injection, 40 mg/0.4 ml, in syringes, in blister, in No. 1 package x 1

Solution for injection, 60 mg/0.6 ml, in syringes, in blister, in No. 1 package x 1

Solution for injection, 80 mg/0.8 ml, in syringes, in blister, in No. 1 package x 1

Applicant:

Manufacturer of officinal drugs:

Manufacturer that carries out pre-packing/ packing:

Manufacturer in charge of quality:

The expert examination established that:I. ATC codeThe ATC B01AB** ****parin code assigned by the applicant does not meet the acceptable code under the international non-proprietary name1:

European Medicine AuthorityLondon, March 19, 2009

EMEA/CHMP/BMWP/118264/2007COMMISSION ON HUMAN MEDICINAL PRODUCTS

(CHMP)

GUIDELINES ON PRE-CLINICAL AND CLINICAL TRIALS ON BIOSIMILAR BIOLOGICAL MEDICINAL PRODUCTS

CONTANING LOW-MOLECULAR HEPARINS

DRAFT AGREED WITH THE BIOSIMILAR MEDICINE WORKING GROUP (BMWP)

April 2008

CHMP APPROVAL FOR PRODUCTION FOR COMMENTING PURPOSES

April 2008

END OF CONSULTANCY (CUT-OFF DATE FOR COMMENTS)

October 2008

AGREEMENT WITH BMWP February 2009

CHMP’S APPROVAL March 2009

EFFECTIVE DATE October 2009

KEY WORDS:

Low-molecular heparins, biosimilar biological medicinal products, comparability, pre-clinical trials, clinical trials, indication, extrapolation

7 Westferry Circus, Canary Wharf, London E14 4HB, CKTel. (44-20) 74 18 84 00, facsimile: (44-20) 74 18 86 13

email: mail@emea.europa.eu; hpp://www.emea.europa.eu© European Medicine Department, 2008

Reproduction and/or distribution of this document shall only be allowed for non-for-profit purposes, subject to reference to the

source (EMEA)

Example: LMH

LMH

The applicant proved:1. Equivalency of physical and chemical properties

2. Equivalency of the starting material in the chemical selectivity of de-polymerization, according to the drug product marking.

3. Equivalency of structural elements in di-sacharides.

4. Equivalency in biochemical and biological trial.

In vitro comparison vs coagulation effect is provided.

www.rceth.by

COMMENTS ON PRE-CLINICAL TRIALS:I. No comparative pharmaco-dynamic in vivo trials have been

provided.II. Chronic toxicity has not been studied.III. No specific immunogenicity trials have been conducted. Local

tolerance data obtained at least for one species must be provided.

LMH

Clinical trials:1.Comparative trial of drug pharmaco-kinetics/ pharmaco-dynamics in healthy adult male volunteers in fasting.

2.Bio-equivalency trial of two LMH types in healthy volunteers.

3.Comparative trial when applied as blood clot prevention in cardiopulmonary bypass during haemodialysis.

www.rceth.by

Enoxaparin

www.rceth.by

LMH

www.rceth.by

COMMENTS ON CLINICAL TRIALS:I. CLINICAL EFFICIENCY DATA:• Therapeutic equivalence should be shown in at least one randomized

double blind clinical trial with the appropriate study power, in parallel groups.

• Efficiency in venous thromboembolism (VTE) prevention in patients who undergo surgeries with a high VTE risk has not been shown: comparative efficacy and safety of two drugs using a ‘surrogate’ composite endpoint consisting the total quantity of thromboembolism manifestations (the total number of cases of ТГВ, ТЭЛА and VTE-related death) has not been estimated.

• Clinical safety has not been duly studied. II. No immunogenicity data was provided.

Immunogenicity

www.rceth.by

London, December 13, 2007Doc. Ref. EMEA/CHMP/BMWP/14327/2006

COMMISSION ON HUMAN MEDICINAL PRODUCTS(CHMP)

GUIDELINES ON ASSESSMENT OF IMMUNOGENICITY OF BIOTECHNOLOGICALLY-DERIVED THERAPEUTIC PROTEINS

APPROVED BY CHMP JULY 2006

ACCEPTED FOR CONSULTATION JANUARY 2007

END OF CONSULTATION (TIMING FOR SUBMISSION OF COMMENTS) JULY 2007

APPROVED BY CHMP OCTOBER 2007

ACCEPTED BY CHMP DECEMBER 2007

EFFECTIVE DATE APRIL 2008

KEY WORDS Immunogenicity, adverse immune response, biotechnologically-derived proteins, immunogenic risk factors, opinions, clinical efficiency and safety, risk management

European Medicine Authority

Compliance with the Instruction on Medical Application and SmPC of the Originator Drug

www.rceth.by

Conformity (identity) of information in the medical application instruction proposed for the Republic of Belarus and information available in the drug application or overall product characteristic (SmPC) instruction approved by competent governmental authorities of the country that issued a certificate for pharmaceutical product (CPP).

MINISTRY OF HEATHCARE OF THE REPUBLIC OF BELARUS ORDERdated June 23, 2009, No. 610

ON APPROVAL OF THE INSTRUCTIONS ON EXPERT EXAMINATION OF DOCUMENTS FROM THE REGISTRATION FILE FOR A MEDICINE/

PHARMACEUTICAL SUBSTANCE AND DOCUMENTS SUBMITTED FOR MAKING AMENDMENTS TO THE REGISTRATION FILE OF AN EARLIER

REGISTERED MEDICINE/ PHARMACEUTICAL SUBSTANCE

(in the order versions of the Ministry of Health dated March 14, 2001, No. 237, dated May 8, 2012, No. 519)

LMH

CONCLUSION ON REGISTRATION POSSIBILITY:

With the view to the clinical trials held in the Republic of Belarus, when data on drug pre-clinical study (comparative pharmaco-dynamics in vivo, study of chronic toxicity and immunogenicity) is provided, the medicine may be registered for the single indication:

Blood clot prevention in cardiopulmonary bypass during haemodialysis in patients above 18.

The entire medical administration instruction needs to be corrected taking into account one indication.

www.rceth.by

www.rceth.by

The entire development and production system for biosimilar medicines is intended to ensure equivalency to the reference product

Clinic

Clinical immunogenicity

Pharmaco-kyneticsand pharmaco-dynamics

Structural and functional features

Large-scale clinical trials

Pre-clinical

Biological description

Physico-chemical description

Animal trials

Purpose: proof of comparability to the originator product at all stages

www.rceth.by

Main Parameters of Recombinant Human Granulocyte Colony Enhancing Factors Assessment (in Pre-Clinical Trials)

Pharmaco-dynamic trials

Toxicological trials

Comparative pre-clinical trials:

in vitro trials:at the receptors’ level, based on sufficient dilutions to fully describe the response to concentration.

1. The trial duration is not less than 28 days per repeated dose.2. Data on local tolerance in at least one species. 3. Reproduction toxicology, mutagenicity and carcinogenicity.

in vivo trials: in natural conditions, using neutropenic and non-neutropenic rodents as a model

www.rceth.by

Main Parameters of Recombinant Human Granulocyte Colony Enhancing Factors Assessment (Clinical Trials)

Comparative clinical trials:

Pharmaco-kynetic trials: main AUC parameter and secondary parameters Сmax and T1/2.

Clinical efficiency trials

Severe neutropenia prevention after cytotoxic chemotherapy in a homogenous patient group; comparable trials in two parallel groups.

Pharmaco-dynamic trials: absolute neutrophil count (ANC). Comparative pharmaco-dynamic trials in healthy volunteers should be provided.

www.rceth.by

Main Parameters of Recombinant Human Granulocyte Colony Enhancing Factors Assessment (Clinical Trials)

Clinical safety

Comparative clinical trial: the overall impact should meet the exposure of an ordinary chemotherapy treatment course; the overall duration of supervising patients should be at least 6 months. The number of patients should be sufficient to assess adverse impact, in particular, bone ache and laboratory deviations. Immunogenicity data should be collected in accordance with the principles set forth in the appropriate guidelines (period: 12 months)

www.rceth.by

BASICS: X Drug Registration

АТС L03AA02 filgrastim code assigned by the applicant meets the accepted code by international non-proprietary name:

[1] http://www.whocc.no/atcddd/

www.rceth.by

BASICS: X Drug Registration

COMMENTS ON PRE-CLINICAL TRIALS:I. Comparative pharmaco-dynamic in vitro trials have not been provided by

the applicant.II. Comparative pharmaco-dynamic in vivo trials on a neutropenic model

have not been provided.III. Chronic toxicity was studied during 21 days, while at least 28-day trials

are required.IV. No specific immunogenicity trials have been held.

4.1. Доклинические исследованияПеред началом клинической разработки, доклинические исследованиях должны быть выполнены. Эти исследования должны иметь сравнительный характер и должны быть разработаны для определения различий в фармако-токсикологических ответах между схожими биологическими лекарственными средствами и ссылки на опыт применения оригинального лекарственного средства не подходятФармакодинамические исследованияИсследования in vitro:На уровне рецепторов, сопоставимость результатов испытаний должна быть продемонстрирована. Очень важно, чтобы тесты, используемые для сопоставимости имели соответствующую чувствительность, чтобы обнаружить различия, и что эксперименты должны быть на основе достаточного количества разведений для полного описания реакции на концентрацию.Исследования in vivo:В естественных условиях на модели грызунов с нейтропенией и без нейтропении должны быть использованы для сравнения фармакодинамических эффектов тестирования.Токсикологические исследованияДанные по исследованию токсичности, по крайней мере, на одну повторную дозу в соответствующих должны быть предоставлены. Продолжительность исследования должна быть не менее 28 дней. Исследование должно проводиться в соответствии с требованиями "Руководством по Токсичность повторной дозы" (CPMP/SWP/1042/99) и включают в себя (I) фармакодинамические измерения и (II) соответствующие токсикокинетические измерения в соответствии с "Руководством по Токсикокинетика: Руководство для оценки системной экспозиции в токсикологических исследованиях "(CPMP/ICH/384/95). В этом контексте особое внимание следует сделать на исследование иммунного ответа на продукты.Данные о местной терпимости, по крайней мере, у одного вида должна быть предоставлены в соответствии с "Примечание для Руководство для Неклинические локального тестирования толерантности лекарственных средств "(CPMP/SWP/2145/00).Фармакология безопасности, воспроизводства токсикологии, мутагенности и канцерогенности исследования не рутинных требований к не-клиническим испытаниям подобных биологических лекарственных средств, содержащих рекомбинантный Г-КСФ в качестве активного вещества.

www.rceth.by

BASICS: X Drug Registration

COMMENTS ON CLINICAL TRIALS:I. Comparative pharmaco-kinetic trials have not been provided.II. Comparative pharmaco-dynamic trials have not been provided.III. Immunogenicity data has not been provided.

www.rceth.by

ОСНОВЫ

Comment:

The submitted draft instruction does not meet SmPC of the reference medicine. The following instruction sections should be aligned with SmPC of the originator medicine.- “precautions” (WARNINGS AND PRECAUTIONS). MANDATORY: to enter information in the same format as for the originator medicine concerning splenic rupture

-

- To include such sections as Application during Pregnancy and Breastfeeding , Paediatric Application and Geriatric Administration , which should contain information from similar sections of SmPC into the instructions for neupogene.

- -Side Effect, Overdosage and Application Method and Doses sections should be aligned.

-

www.rceth.by

BASICS

X drug cannot be registered:Comments:

COMMENTS ON PRE-CLINICAL TRIALS:I. No comparative pharmaco-dynamic in vitro trials have been provided by the

applicant.II. No comparative pharmaco-dynamic in vivo trials on neutropenic model have been

provided.III. Chronic toxicity was studied during 21 days, while at least 28-days’ studies are

required.IV. No specific immunogenicity trials have been held.COMMENTS ON CLINICAL TRIALS:V. Comparative pharmaco-kinetic trials have not been provided.VI. Comparative pharmaco-dynamic trials have not been provided.VII. Immunogenicity data have not been provided.PROVIDED DRAFT INSTRUCTION DOES NOT CONFORM TO SMPS OF THE

REFERENCE DRUG:The following sections of the instruction should be aligned with SmPC of the originator

drug:Precautions (WARNINGS and PRECAUTIONS). MANDATORY: to include information in

the same format as for the originator drug concerning splenic rupture:

www.rceth.by

Total Quantity of Biosimilar Medicines on the Market of the Republic of Belarus

Interferon alfa

Insulin (human)

Epoetin alpha

Filgrastim

Inerferon beta

Somatropin

Epoetin beta

Interleukin

Insulin glargine

0 1 2 3 4 5 6 7 8 9 10

10

9

5

4

3

3

2

1

1

Series1

www.rceth.by