Transcript SAFETY IMPLICATIONS FOR BIOTECH PRODUCTS

SAFETY IMPLICATIONS
FOR BIOTECH
PRODUCTS
Peter Feldschreiber &
Leigh-Ann Mulcahy
Four New Square
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CONVENTIONAL MEDICINES
AND BIOTECH PRODUCTS
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Biotech – effects usually known at start of
development, but effects in experimental
animals may be different to those anticipated
Therefore:
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Important to identify mechanism of action
Standard pre-clinical safety tests could result in
release of compounds into clinical trial without
adequate warning of adverse effects in man
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SCIENTIFIC PROBLEMS WITH
SAFETY EVALUATION
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Problems with long term testing because
of antibody production
Species specificity makes extrapolation of
animal data to man difficult or even
impossible
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PRINCIPAL CATEGORIES OF
PRODUCTS
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Colony stimulating factors; growth factors;
hormones for human therapy
Interferons and interleukins: diverse proteins
from leukocytes and related cells
Monoclonal antibodies: proteins from single copy
of human antibody
Gene therapy
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Safety Issues
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CSF/GF/Hormones: homologues of human
endogenous protein (eg insulin);
analogues with minor amino acid
sequence change and/or
pharmacologically active peptide
fragments
Type of safety study will vary on case by
case basis – precludes generic mandatory
requirements for protocols
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Interferons/Interleukins
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Diverse group of proteins – amplify maintain and
terminate differentiation proliferative and effector phases
of the immune response – multiple biological effects
Possess immuno-modulatory and anti-proliferative effects
Recombinant human interferons major potential in
infective disorders, immune disorders and malignancy
However problems with species specificity, altered
pharmacokinetics, immune complex lesions, changes in
systemic exposure due to differences in administration,
toxicity due to exaggerated pharmacological effects
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Polyclonal immunoglobulins IgG
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Historically Ig (polyclonal
immunoglobulins) from multiple donors
Little or no purification; large doses with
large doses of impure protein from
immunogenic foreign species;
Risk of serum sickness, additional infection
from blood born pathogens; HIV/hepatitis
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Monoclonal antibodies
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Proteins synthesised from a single copy of a
human antibody.
Circumvent classical safety issues of therapeutic
immunoglobulins.
Have high potency and specificity
Example of use in cancer: MAB investigated to
attack cells of one type of cancer without
harming normal cells – rituximab in treatment of
non-Hodgkins lymphoma, but
High risk severe side effects: 50% serum
sickness like symptoms
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Gene therapy
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Sophisticated methods of gene delivery
Need for reliable assessment of risk to avoid
adverse clinical outcomes
Pre-clinical studies to guide dose escalation and
define clinically relevant parameters for
assessing potential toxicity
Basic principles for design of protocols: nature
of gene, nature of vector, appropriate species,
validation of clinical/surrogate endpoints and/or
biological markers
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Pharmacogenomics
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EMEA/CPMP/3070/01: ‘Study of individual
variation in DNA sequence related to drug
response’
Study of variability of expression of individual
genes relevant to disease susceptibility as well
as drug response at cellular, tissue, individual or
population level
Use to predict efficacy in population,
individualise doses and avoid toxicity in subpopulations
Example – warfarin and anticoagulant control
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Product safety & biotech
products
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No formulaic recipe for safety programme
– must be based on scientific necessity
tailored to each type of molecule/therapy
– no provision for mandatory regulation as
to content of programme
Very difficult to determine long term
safety effects
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Impact of A v. National Blood
Authority (2001)
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Greatest risk of liability is under CPA/PLD
A imposes onerous liability to ensure safety
Blood = non-standard; “natural” product –
parallels with biotech products?
Held public entitled to expect 100% safety and
severely restricted reliance on Art 7(e) defence
Where generic/potential risk of harm known or
can be known-> defective. Avoidability
irrelevant.
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A v. NBA contd
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How do you reduce legitimate
expectations of users of natural products?
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Warnings? Education of public?
But = unlawful restriction on liability (Art 12)?
Hypotheses/mechanisms that predict
probability of serious adverse events
Need for strategic protocols for
investigation, assessment and basis of
scientific/technological decision-making
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Tension between CPA and
regulatory strategies
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Will CPA test of expectation of safety and
lack of predictability of individual adverse
events hinder development and
authorisation of major and potentially life
saving advances?
Tension between need for time/cost
effective development and regulation and
risk of product liability litigation
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