SAFETY IMPLICATIONS FOR BIOTECH PRODUCTS

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 anticipatedTherefore: • 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

3. SCIENTIFIC PROBLEMS WITH SAFETY EVALUATION • Problems with long term testing because of antibody production • 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 • Interferons and interleukins: diverse proteins from leukocytes and related cells • Monoclonal antibodies: proteins from single copy of human antibody • 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 • 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 • 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

7. Polyclonal immunoglobulins IgG • 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

8. Monoclonal antibodies • 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

9. Gene therapy • 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

10. Pharmacogenomics • 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 sub-populations • 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 • 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 • 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.

13. A v. NBA contd • How do you reduce legitimate expectations of users of natural products? • 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

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