1 SAFETY IMPLICATIONS FOR BIOTECH PRODUCTS Peter Feldschreiber & Leigh-Ann Mulcahy Four New Square

2 CONVENTIONAL MEDICINES AND BIOTECH PRODUCTS Biotech – effects usually known at start of development, but effects in experimental animals may be different to those anticipated Therefore: Biotech – effects usually known at start of development, but effects in experimental animals may be different to those anticipated Therefore: Important to identify mechanism of action 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 Standard pre-clinical safety tests could result in release of compounds into clinical trial without adequate warning of adverse effects in man

3 SCIENTIFIC PROBLEMS WITH SAFETY EVALUATION Problems with long term testing because of antibody production Problems with long term testing because of antibody production Species specificity makes extrapolation of animal data to man difficult or even impossible Species specificity makes extrapolation of animal data to man difficult or even impossible

4 PRINCIPAL CATEGORIES OF PRODUCTS Colony stimulating factors; growth factors; hormones for human therapy Colony stimulating factors; growth factors; hormones for human therapy Interferons and interleukins: diverse proteins from leukocytes and related cells Interferons and interleukins: diverse proteins from leukocytes and related cells Monoclonal antibodies: proteins from single copy of human antibody Monoclonal antibodies: proteins from single copy of human antibody Gene therapy Gene therapy

5 Safety Issues CSF/GF/Hormones: homologues of human endogenous protein (eg insulin); analogues with minor amino acid sequence change and/or pharmacologically active peptide fragments 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 Type of safety study will vary on case by case basis – precludes generic mandatory requirements for protocols

6 Interferons/Interleukins Diverse group of proteins – amplify maintain and terminate differentiation proliferative and effector phases of the immune response – multiple biological effects 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 Possess immuno-modulatory and anti-proliferative effects Recombinant human interferons major potential in infective disorders, immune disorders and malignancy 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 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

7 Polyclonal immunoglobulins IgG Historically Ig (polyclonal immunoglobulins) from multiple donors Historically Ig (polyclonal immunoglobulins) from multiple donors Little or no purification; large doses with large doses of impure protein from immunogenic foreign species; 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 Risk of serum sickness, additional infection from blood born pathogens; HIV/hepatitis

8 Monoclonal antibodies Proteins synthesised from a single copy of a human antibody. Proteins synthesised from a single copy of a human antibody. Circumvent classical safety issues of therapeutic immunoglobulins. Circumvent classical safety issues of therapeutic immunoglobulins. Have high potency and specificity 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 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 High risk severe side effects: 50% serum sickness like symptoms

9 Gene therapy Sophisticated methods of gene delivery Sophisticated methods of gene delivery Need for reliable assessment of risk to avoid adverse clinical outcomes 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 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 Basic principles for design of protocols: nature of gene, nature of vector, appropriate species, validation of clinical/surrogate endpoints and/or biological markers

10 Pharmacogenomics EMEA/CPMP/3070/01: ‘Study of individual variation in DNA sequence related to drug response’ 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 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 sub- populations Use to predict efficacy in population, individualise doses and avoid toxicity in sub- populations Example – warfarin and anticoagulant control Example – warfarin and anticoagulant control

11 Product safety & biotech products 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 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 Very difficult to determine long term safety effects

12 Impact of A v. National Blood Authority (2001) Greatest risk of liability is under CPA/PLD Greatest risk of liability is under CPA/PLD A imposes onerous liability to ensure safety A imposes onerous liability to ensure safety Blood = non-standard; “natural” product – parallels with biotech products? 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 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. Where generic/potential risk of harm known or can be known-> defective. Avoidability irrelevant.

13 A v. NBA contd How do you reduce legitimate expectations of users of natural products? How do you reduce legitimate 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 probability of serious adverse events Hypotheses/mechanisms that predict probability of serious adverse events Need for strategic protocols for investigation, assessment and basis of scientific/technological decision-making Need for strategic protocols for investigation, assessment and basis of scientific/technological decision-making

14 Tension between CPA and regulatory strategies 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? 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 Tension between need for time/cost effective development and regulation and risk of product liability litigation