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SAFETY IMPLICATIONS SAFETY IMPLICATIONS FOR BIOTECH FOR BIOTECH

PRODUCTSPRODUCTS

Peter Feldschreiber &Peter Feldschreiber &

Leigh-Ann MulcahyLeigh-Ann Mulcahy

Four New SquareFour New Square

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CONVENTIONAL MEDICINES CONVENTIONAL MEDICINES AND BIOTECH PRODUCTSAND BIOTECH PRODUCTS

Biotech – effects usually known at start of Biotech – effects usually known at start of development, but effects in experimental development, but effects in experimental animals may be different to those anticipatedanimals may be different to those anticipated

Therefore:Therefore:

Important to identify mechanism of actionImportant to identify mechanism of action

Standard pre-clinical safety tests could result Standard pre-clinical safety tests could result in release of compounds into clinical trial in release of compounds into clinical trial without adequate warning of adverse effects without adequate warning of adverse effects in manin man

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SCIENTIFIC PROBLEMS WITH SCIENTIFIC PROBLEMS WITH SAFETY EVALUATIONSAFETY EVALUATION

Problems with long term testing Problems with long term testing because of antibody productionbecause of antibody production

Species specificity makes Species specificity makes extrapolation of animal data to man extrapolation of animal data to man difficult or even impossibledifficult or even impossible

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PRINCIPAL CATEGORIES OF PRINCIPAL CATEGORIES OF PRODUCTSPRODUCTS

Colony stimulating factors; growth factors; Colony stimulating factors; growth factors; hormones for human therapyhormones for human therapy

Interferons and interleukins: diverse Interferons and interleukins: diverse proteins from leukocytes and related cellsproteins from leukocytes and related cells

Monoclonal antibodies: proteins from Monoclonal antibodies: proteins from single copy of human antibodysingle copy of human antibody

Gene therapyGene therapy

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Safety IssuesSafety Issues

CSF/GF/Hormones: homologues of CSF/GF/Hormones: homologues of human endogenous protein (eg human endogenous protein (eg insulin); analogues with minor amino insulin); analogues with minor amino acid sequence change and/or acid sequence change and/or pharmacologically active peptide pharmacologically active peptide fragmentsfragments

Type of safety study will vary on case Type of safety study will vary on case by case basis – precludes generic by case basis – precludes generic mandatory requirements for mandatory requirements for protocolsprotocols

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Interferons/InterleukinsInterferons/Interleukins Diverse group of proteins – amplify maintain and Diverse group of proteins – amplify maintain and

terminate differentiation proliferative and effector terminate differentiation proliferative and effector phases of the immune response – multiple phases of the immune response – multiple biological effectsbiological effects

Possess immuno-modulatory and anti-proliferative Possess immuno-modulatory and anti-proliferative effectseffects

Recombinant human interferons major potential in Recombinant human interferons major potential in infective disorders, immune disorders and infective disorders, immune disorders and malignancymalignancy

However problems with species specificity, altered However problems with species specificity, altered pharmacokinetics, immune complex lesions, pharmacokinetics, immune complex lesions, changes in systemic exposure due to differences in changes in systemic exposure due to differences in administration, toxicity due to exaggerated administration, toxicity due to exaggerated pharmacological effects pharmacological effects

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Polyclonal immunoglobulins IgGPolyclonal immunoglobulins IgG

Historically Ig (polyclonal Historically Ig (polyclonal immunoglobulins) from multiple immunoglobulins) from multiple donors donors

Little or no purification; large doses Little or no purification; large doses with large doses of impure protein with large doses of impure protein from immunogenic foreign species; from immunogenic foreign species;

Risk of serum sickness, additional Risk of serum sickness, additional infection from blood born pathogens; infection from blood born pathogens; HIV/hepatitisHIV/hepatitis

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Monoclonal antibodiesMonoclonal antibodies Proteins synthesised from a single copy of Proteins synthesised from a single copy of

a human antibody.a human antibody. Circumvent classical safety issues of Circumvent classical safety issues of

therapeutic immunoglobulins.therapeutic immunoglobulins. Have high potency and specificityHave high potency and specificity Example of use in cancer: MAB Example of use in cancer: MAB

investigated to attack cells of one type of investigated to attack cells of one type of cancer without harming normal cells – cancer without harming normal cells – rituximab in treatment of non-Hodgkins rituximab in treatment of non-Hodgkins lymphoma, butlymphoma, but

High risk severe side effects: 50% serum High risk severe side effects: 50% serum sickness like symptomssickness like symptoms

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Gene therapyGene therapy

Sophisticated methods of gene deliverySophisticated methods of gene delivery Need for reliable assessment of risk to Need for reliable assessment of risk to

avoid adverse clinical outcomesavoid adverse clinical outcomes Pre-clinical studies to guide dose Pre-clinical studies to guide dose

escalation and define clinically relevant escalation and define clinically relevant parameters for assessing potential toxicityparameters for assessing potential toxicity

Basic principles for design of protocols: Basic principles for design of protocols: nature of gene, nature of vector, nature of gene, nature of vector, appropriate species, validation of appropriate species, validation of clinical/surrogate endpoints and/or clinical/surrogate endpoints and/or biological markersbiological markers

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PharmacogenomicsPharmacogenomics EMEA/CPMP/3070/01: ‘Study of individual EMEA/CPMP/3070/01: ‘Study of individual

variation in DNA sequence related to drug variation in DNA sequence related to drug response’response’

Study of variability of expression of Study of variability of expression of individual genes relevant to disease individual genes relevant to disease susceptibility as well as drug response at susceptibility as well as drug response at cellular, tissue, individual or population cellular, tissue, individual or population levellevel

Use to predict efficacy in population, Use to predict efficacy in population, individualise doses and avoid toxicity in individualise doses and avoid toxicity in sub-populationssub-populations

Example – warfarin and anticoagulant Example – warfarin and anticoagulant controlcontrol

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Product safety & biotech Product safety & biotech productsproducts

No formulaic recipe for safety No formulaic recipe for safety programme – must be based on programme – must be based on scientific necessity tailored to each scientific necessity tailored to each type of molecule/therapy – no type of molecule/therapy – no provision for mandatory regulation as provision for mandatory regulation as to content of programmeto content of programme

Very difficult to determine long term Very difficult to determine long term safety effectssafety effects

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Impact of Impact of A v. National Blood A v. National Blood Authority (2001)Authority (2001)

Greatest risk of liability is under CPA/PLDGreatest risk of liability is under CPA/PLD A A imposes onerous liability to ensure safetyimposes onerous liability to ensure safety Blood = non-standard; “natural” product – Blood = non-standard; “natural” product –

parallels with biotech products?parallels with biotech products? Held public entitled to expect 100% safety Held public entitled to expect 100% safety

and severely restricted reliance on Art 7(e) and severely restricted reliance on Art 7(e) defencedefence

Where generic/potential risk of harm known Where generic/potential risk of harm known or can be known-> defective. Avoidability or can be known-> defective. Avoidability irrelevant.irrelevant.

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A v. NBA A v. NBA contdcontd How do you reduce legitimate How do you reduce legitimate

expectations of users of natural products?expectations of users of natural products? Warnings? Education of public?Warnings? Education of public? But = unlawful restriction on liability (Art 12)?But = unlawful restriction on liability (Art 12)?

Hypotheses/mechanisms that predict Hypotheses/mechanisms that predict probability of serious adverse eventsprobability of serious adverse events

Need for strategic protocols for Need for strategic protocols for investigation, assessment and basis of investigation, assessment and basis of scientific/technological decision-makingscientific/technological decision-making

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Tension between CPA and Tension between CPA and regulatory strategiesregulatory strategies

Will CPA test of expectation of safety Will CPA test of expectation of safety and lack of predictability of individual and lack of predictability of individual adverse events hinder development adverse events hinder development and authorisation of major and and authorisation of major and potentially life saving advances?potentially life saving advances?

Tension between need for time/cost Tension between need for time/cost effective development and regulation effective development and regulation and risk of product liability litigationand risk of product liability litigation