Preclinical Safety Evaluation of Biotechnology-Derived Pharmaceuticals

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Regulatory Issues for CROs Evaluation
ofBiotechnology-Derived Pharmaceuticals
K.K. Tripathi, PhD Adviser and Member Secretary,
RCGM Department of Biotechnology Ministry of ST,
GOI kkt_at_dbt.nic.in The views expressed in this
presentation are those of the author and they
have nothing to do with the regulatory
authoriries in place and GOI
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• Structure of the Presentation
• Basics
• Defining Biotech Medicines, Biopharmaceuticals,
  Biogenerics Biosimilars !!!
• EU and USA scenario and perspectives
• Indian Viewpoint
• Regulation
• EU and USA
• India

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• What are Biopharmaceuticals? Compared to drug
• Biopharma industry-25 yrs old with gt350 marketed
  products.
• Term widely used but hardly defined by users
• Over 4 million entries on Google search
• Involves use of biotechnology and pharmaceutical
  compared to drug
• Antsense oligos, RNAi, synthetic peptides and
  other products mimic biopharma as well drug

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Worldwide off Patent Biotech Medicines often
referred as Generic Biophamaceuticals,
(USA) Biogenerics, (USA) Follow-on Biologics,
(USA) Biosimilars, (EU) (rDNA hybridoma
derived) Off Patent Biologicals, (All)
and so on ,,,,,,,,,,,,,,, Definition is Market
and Commerce based
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What Are Biotech Medicines?
Biotech medicines often replace or supplement a
natural protein produced by the body, satisfying
medical needs previously unmet by chemical
medicines
More than 325 million patients worldwide have
been helped by biotech medicines More than 50
of medicines in development are biotech medicines
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EU View Biosimilars are not generic
pharmaceuticals Generics are clinically
identical to their reference products Biosimilars
can never be identical to their reference
products ??Due to the complexity variability of
a biological, the quality profile is determined
by the manufacturing process 'the product is the
process' ??Differences in process are inevitable
between different manufacturers minor process
differences can lead to marked differences in
clinical profile
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Biosimilars are similar, not identical, to
original biotech products
Biosimilars are similar.
.Not Identical
Different cell lines Different mfg process
Small differences in substrate and mfg process
may affect patient safety and clinical efficacy
of the product
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• Impact of small differences among biotech
  products on efficacy and safety is unpredictable
• Safety and efficacy can differ significantly with
  small changes in protein biophysical
  characteristics or formulation of the drug
  produc
• Long term safety profile of biosimilars has yet
  to be established
• Prescribers and patients should be aware of this
  to ensure appropriate introduction into clinical
  practice
• Need to recognize safety and efficacy issue in
  both approval process and introduction into
  clinical practice of biosimilars

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• INDIAN Scenario
• No Biosimilar, only Biogeneric as in USA
• No Guidelines
• Schedule Y of Drugs and Cosmetics Act
• EMEA/ICH Guidelines
• More than 20 products approved so far
• Guidelines to be put in place soon

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Biogeneric products approved so far in India
Sal No 1 2 3 4 5 6 7 8 9 10 11 12 Molecule Human insulin Erythropoietin Hepatitis B vaccine Human growth hormone Interleukin 2 Interleukin 11 Granulocyte Colony Stimulating Factor Colony Stimulating Factor Interferon2Alpha Interferon 2Beta Interferons Gamma Streptokinase Sal No 13 14 15 16 17 18 19 20 Molecule Tissue Plasminogen Activator Blood factor VIII Follicle stimulating hormone Teriparatide (Forteo) Drerecogin (Xigris) alpha Platelet Derived Growth factor (PDGF) Epidermal Growth factor (EGF) Eptacogalpha (r-F VIIa) r-coagulation factor
Refer DBT Website www.igmoris.nic.in
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The Primary Goals of Preclinical Safety
Evaluation are

• Identify an initial safe dose and subsequent dose
  escalation schemes in humans
• Identify potential target organs for toxicity and
  for reversibility
• Identify safety parameters for clinical monitoring

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The Test Materials

• Monoclonal antibodies, Cytokines, Growth
  factors, Vaccines, Fusion proteins, Hormones,
  Chemically synthesized peptides, Enzymes, Plasma
  derived products, Receptors, Oligonucleotides,
  proteins extracted from human tissue,
  biotransformed drugs with small molecular weight
  as generic products of Pharma, and Guess what
  more !!!!!!

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The Test Substances

• Investigational new drug or new entities
• Biologically similar to an already tested and
  used drug or molecule as a biologic
• What to term it Biogeneric? Biosimilar? Or !!!!!

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Comparability

• Evaluated on the basis of biochemical and
  biological characterization (i.e., identity,
  purity, stability, and potency).
• In some cases, additional studies may be needed
  (i.e., pharmacokinetics, pharmaco-dynamics and /
  or safety).

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Preclinical Safety Testing Requirements

• Selection of the relevant animal species
• Age
• Physiological state
• Dose, route of administration, and treatment
  regimen and
• Stability of the test material under the
  conditions of use.

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Approaches

• Conventional approaches to toxicity testing of
  pharmaceuticals may not be appropriate due to
  the unique and diverse structural and biological
  properties.
• This includes species specificity,
  immunogenicity, and unpredicted activities.
• Biological activity may be evaluated using in
  vitro assays.

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Receptor / Epitope Distribution

• Knowledge of receptor/ epitope distribution can
  provide greater understanding of potential in
  vivo toxicity .
• Relevant animal species for testing of monoclonal
  antibodies are those that express the desired
  epitope and demonstrate a similar tissue
  cross-reactivity profile as for human tissues.
• An animal species that does not express the
  desired epitope may still be of some relevance
  for assessing toxicity if comparable
  unintentional tissue cross reactivity to humans
  is demonstrated.

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Species to be Studied

• Safety evaluation programs should normally
  include two relevant species.
• one relevant species may suffice (e.g., when only
  one relevant species can be identified or where
  the biological activity of the biopharmaceutical
  is well understood).
• In addition, even where two species may be
  necessary to characterize toxicity in short term
  studies, it may be possible to justify the use of
  only one species for subsequent long-term
  toxicity studies (e.g., if the toxicity profile
  in the two species is comparable in the short
  term).

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When No RelevantSpecies Exists

• The use of relevant transgenic animals expressing
  the human receptor or the use of homologous
  proteins should be considered.
• Pharmacological mechanism(s) may differ between
  the homologous form and the product intended for
  clinical use.
• Where it is not possible to use transgenic animal
  models or homologous proteins evaluation in a
  single species, e.g., a repeated dose toxicity
  study of lt 14 days duration that includes an
  evaluation of important functional endpoints
  (e.g., cardiovascular and respiratory).

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Administration / Dose Selection

• The route and frequency of administration as
  close as possible to proposed clinical use.
• Pharmacokinetics and bioavailability of the
  product in the species being used.
• Effects of volume, concentration, formulation,
  and site of administration.
• The use of routes of administration other than
  those used clinically may be acceptable if the
  route must be modified due to limited
  bioavailability, limitations due to the route of
  administration, or to size/physiology of the
  animal species.
• Two routes otherwise is not required.

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Dosage levels

• Dosage levels should be selected to provide
  information on a dose-response relationship,
• Include a toxic dose and a no observed adverse
  effect level (NOAEL).
• Products with little to no toxicity, it may not
  be possible to define a specific maximum dose.
• In these cases, a scientific justification of the
  rationale for the dose selection and projected
  multiples of human exposure should be provided.
• Where a product has a lower affinity to or
  potency in the cells of the selected species than
  in human cells, testing of higher doses may be
  important.

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• Immunogenicity
• Antibody Formation In Humans
• Safety Pharmacology
• Pharmacokinetic studies
• Single Dose Toxicity Studies
• Repeated Dose Toxicity Studies
• Immunotoxicity Studies
• Reproductive Performance and Developmental
  Toxicity Studies
• Genotoxicity Studies
• Carcinogenicity Studies

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Carcinogenicity Studies 2

• With some biopharmaceuticals, there is a
  potential concern about accumulation of
  spontaneously mutated cells (e.g., via
  facilitating a selective advantage of
  proliferation) leading to carcinogenicity.
• The standard battery of genotoxicity tests is not
  designed to detect these conditions.
• Alternative in vitro or in vivo models to address
  such concerns may have to be developed and
  evaluated.

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Thank you