Meeting Highlights

2003 © Ashley Publications Ltd ISSN 1474-0338 609

Ashley Publicationswww.ashley-pub.com

1. Preliminary considerations

2. Regulatory concerns

3. Preclinical issues

4. Clinical applications

5. Case studies

6. Conclusions and insights

Biologics Safety Preclinical, Clinical and Regulatory9 – 10 September 2003, London, UK

Renald HennigChiron Vaccines, PO Box 1630, 35006 Marburg, Germany

Biologicals offer particular challenges for all concerned, whether they be sci-entific researchers, profit-oriented companies (including not yet profit-pro-ducing start-ups), public health-focused regulators, physicians, or, mostimportantly, patients. One of the most important of these challenges issafety. Hence, this conference was organised by Vision in Business (the trad-ing name of Analysis and Networking Ltd) to provide practical solutions andadvice for comprehensive, effective safety testing. It provided a wide spec-trum of presentations, ranging from the usefulness of animal models for bio-logicals safety predictions, to an FDA perspective on implications of its recentrestructuring, to a real-life case study on erythropoietin and pure red cellanaemia. For anyone seriously interested in the safety of biologicals, this wasa very good opportunity to gain an overview of all major aspects of biologi-cals safety, broaden existing expertise and to network with those concernedwith these issues.

Keywords: biologicals, immunogenicity, regulators and safety, safety, safety testing

Expert Opin. Drug Saf. (2003) 2(6):609-611

1. Preliminary considerations

As K Sikora (Hammersmith Hospital, London, UK; AstraZeneca Oncology)pointed out, over the coming years, a large number of novel targeted cancer drugswill enter clinical trials. New and creative partnerships between academia and indus-try will be required. ‘In silico’ drug design has allowed the creation of specific inhibi-tors for each member of a gene family, for example, protein kinases. Currently, morethan 500 molecules are investigated in clinical trials, a number that is expected toincrease significantly. The market for cancer drugs is expected to triple by 2010.New issues have arisen, such as the possibility for pharmacodynamic assays formolecular patient effectiveness and the need for different end points (e.g., stabilisa-tion rather than tumour shrinkage). Surrogate end points – defined as substitutemeasurements of benefit – may be measured using biomarkers. Predictive markerswill stratify patient populations by likelihood of response to an agent, for example,the presence of hormone receptors, or surface marker expression. All of this requiresvalidation, however, and will have a major impact on registration procedures andtreatment structures.

M Wadhwa (National Institute for Biological Standards and Control,South Mimms, UK) cautioned about product comparability of biologicals afterchanges in production – and the immunogenicity issue. Guidance has been issued byboth the US FDA and the European Agency for the Evaluation of Medicinal Products(EMEA). Possible product-affecting changes range from expression systems, fermenta-tion, culture and purification processes, to formulation and filling, and product condi-tions such as storage and shipping. Potency, pharmacokinetics and/or immunogenicitymay be affected. If comparability is claimed to a ‘similar’ product, biologicals are differ-ent: there will most likely be differences in the cell banks, processes, equipment, andanalyses, with significant effects on product properties. Hence there is a need for

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extensive comparability studies. EU (European Union) patentprotection will expire for erythropoietin, IFN-γ and IL-2 withinthe next 2 years, and the markets are in the billion-dollar rangeworldwide for these products. Immunogenicity may also beaffected by a range of possible changes. These include changesin glycosylation, protein folding or extraction and purificationprocesses in the manufacturing process of therapeutic proteins.Even minor changes in impurities and/or excipients may have asignificant impact on immunogenicity, which is a particularconcern for new products claiming comparability with licensedproducts. Wadhwa presented a wide range of examples, with afocus on granulocyte–macrophage colony-stimulating factor(GM-CSF) and various antibody responses studied.

2. Regulatory concerns

K Wickstrom (Läkemedelsverket [Medical Products Agency],Uppsala, Sweden) offered a first glance of the regulatory view.Products developed by recombinant DNA (rDNA) technol-ogy, gene expression coding, or by hybridoma and mono-clonal antibody techniques, are classified as Part A productsrequiring the EU Centralised Procedure. The necessary degreeof preclinical testing depends on a range of factors, and a case-by-case approach is used. Differentiation between pharmaco-logical, immunological and toxic response is of particularimportance for biologicals. Whereas conventional studies ongenotoxicity, carcinogenicity and reprotoxicity may not benecessary as per biotech guidelines, potential effects and con-cerns need to be evaluated. One animal species may be suffi-cient, if highly relevant. For MabCampath® (alemtuzumab)and MabThera® (rituximab), limited in vivo studies wereaccepted by the regulator due to recognised difficulties inidentification of acceptable animal models, sufficient in vitrocharacterisation, supportive in vivo data, and, essentially,expected toxicity. Wickstrom continued with insights onassessing tumour development risk and reprotoxicity, usinginsulin analogues as an example. Some of her suggestions:think first, then get (early) advice; define problems and sug-gest solutions; stick to guidelines and correct formats; and jus-tify deviations with sound scientific rationale.

An interesting insight into the inner workings of the FDAwas provided by M Green (Center for Biologics Evaluationand Research [CBER], Rockville, USA) in a time-effectiveteleconference. The Center for Drug Evaluation and Research(CDER), Rockville, USA has recently been made responsiblefor the review of biological therapeutics for use in humans,reflecting scientific, industry, and public health needs. Theongoing restructuring is aimed at improving the efficiency andeffectiveness of the review process. The products concernedare monoclonal antibodies, cytokines, growth factors,enzymes, other therapeutic proteins, and immunotherapies.Staying within CBER are ex vivo components in the manufac-turing of monoclonal antibodies, cytokines and growth fac-tors, as well as gene therapy, human and animal cells, bloodcomponents (including recombinant versions), plasma

expanders, allergen patch tests, allergenics, venoms, vaccines,and toxoids. A range of concerns, such as review continuity,review consistency, and staffing, have been and will beaddressed. This is on top of other underlying issues, for exam-ple, standards convergence (ICH [International Conferenceon Harmonization]; CTD [Common Technical Document]).

3. Preclinical issues

As P Marinelli (Serono, Geneva, Switzerland) pointed out,protein safety evaluation includes several assays exclusive forbiotechnology compounds. In vitro testing is used to charac-terise and validate cell bank systems for production processconsistency as well as contaminants absence. Reverse tran-scriptase tests, as well as polymerase chain reaction tests, areamong those techniques provided by molecular biology toassess products derived from molecular biology technology.One such example is detection of residual DNA in purifiedbulk, of which ≤ 100 pg/dose is considered acceptable andwithout any potential patient risk. In vitro versus in vivo test-ing offers the advantages of regulatory recommendation,decreased costs, faster execution and greater standardisation.No serious safety concerns have so far been identified inpatients following administration of therapeutics fromrDNA technologies. Marinelli continued to present variousproperties of assays in use. Risk factors may still be present,such as those resulting from the change to serum-free media(to reduce BSE [bovine spongiform encephalitis] risk), prote-olytic processes after product administration, and immuno-genicity. In vitro models strongly contribute to biologicalssafety assessment.

T Bourne (Celltech R&D Ltd, Cambridge, UK) presentedon properties and preclinical safety assessment of monoclonalantibodies. By their very nature, monoclonal antibodies willoften recognise only a very limited range of non-human spe-cies. Genetically-modified animals expressing the human tar-get protein may provide useful information. However, bothavailability and suitability of relevant transgenic rodent strainsare limited, necessitating the need for primate studies. Assess-ment of plasma exposure is of particular importance due tothe often long half-lifes of antibody therapeutics. Additionalissues raised ranged from immune function assessment(including T cell responses) and reprotoxicology (do we needmore than one animal species?) to parallel reagents (affinity,isotype, and conjugation).

4. Clinical applications

S Kienzle-Horn (SCRATCH Services, Butzbach, Germany)offered insights on dealing with issues during the clinicalphase of biologicals development. As varied as biologicalsare, they often share one feature: that of public scepticism,especially after non-delivery of (exaggerated) early prom-ises. Official EU scientific advice should be limited to nec-essary occasions, such as dosage or unprecedented safety

Hennig

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issues. Case-by-case decisions are required. FDA draftguidelines require special safety committees with a mini-mum of three members, consisting of clinical experts and aminimum of one biostatistician. Experience with thesecommittees is limited, however, and their value may dependon charter standardisation, depth of safety evaluation andeffective communication. Despite tragic outcomes in thepast (e.g., J Gelsinger, USA, 1999), there is still no perfectanswer or common solution on how to prevent serioussafety issues. A comprehensive Safety Evaluation Plan is atleast one step in the right direction, if it uses all relevantavailable information, is continually updated, and agrees onpossible actions for – if possible predefined – identified sig-nals and risks.

G Hale (University of Oxford, Oxford, UK), spoke on rec-ognising and eliminating biologicals immunogenicity in clini-cal trials. Standardisation of assays measuring antibodyresponses has been challenging due to the inherent heteroge-neity of antibodies. Whereas bioassays measure inhibitoryantibodies only, enzyme-linked immunosorbant assays meas-ure total antibody, although even these may be standardisable.To reduce protein immunogenicity, attachment of polyethyl-eneglycol has been shown to be one successful approach. Tol-erance may also be induced either by using human products(e.g., Campath-1G versus Campath-1H), especially ifmutants with lower binding affinity are used, or by co-admin-istration of CD4 antibodies. Few, if any, controlled studiesevaluating immunogenicity of differing protein therapeuticpreparations are available. Uncontrolled studies have beenpublished far more extensively.

5. Case studies

The case studies presented put topics and issues raised intothe context of real life, real products and real patients.E Froehlich (Hoffmann-La Roche, Basel, Switzerland) gainedeverybody’s attention when he presented on cases of pure redcell anaemia (PRCA) following administration of recom-binant human erythropoietin. A very rare disease, cases ofPRCA were continually being reported, leading to an activesurveillance strategy and a label change. Despite problems ofpoor documentation and a somewhat reduced causality

assessment (temporal association alone being a sufficient indi-cator), evidence suggested eight such cases for > 600,000patient-years – making PRCA a very rare event indeed.

R Hennig (Chiron Vaccines, Marburg, Germany) related –after a brief summary of BSE concerns and how to deal withthem – experiences of a recall necessitated by bacterial con-tamination (Sphingobacterium spiritivorum) of a widely dis-tributed vaccine. This included in-house communicationissues, insightful discussions with the regulator concerned,significant economic consequences, and the unexpected out-come of the recall of a withdrawal of a batch release.

Other delegates included: C Bogedain (MediGene, Martin-sried, Germany) who presented on gene therapy vector safetyconsiderations; S Eisen (Parexel, Uxbridge, UK) who pre-sented on EU guidelines on biologicals therapy; C Nick(Parexel, Uxbridge, UK) who presented on Biogenerics: com-parability, data gathering and regulatory guidance; andB Traynor (Amgen, Thousand Oaks, USA) who presented onintegration of safety monitoring into the clinical trial process.

6. Conclusions and insights

This conference was a worthwhile experience, offering a viewof the various and sometimes challenging aspects of biologi-cals development and safety.

More questions seem to have been raised than answered,and this may well be a good thing. Biologicals offer uniquepromises for patients, even given the challenges in their devel-opment. A number of these challenges and concerns were dis-cussed at the conference, and for some of them, creative andeffective solutions were presented. More challenges willundoubtedly arise as the search for biological answers to someof the medical problems intensifies. Regulators, scientists,physicians, and companies have realised that biologicals arenot quite like other drugs; hopefully this realisation will be forthe benefit of patients.

AffiliationRenald Hennig MD MBAGlobal Head of Pharmacovigilance,Chiron Vaccines, PO Box 1630, 35006 Marburg, GermanyTel: +49 6421 39 2025; Fax: +49 6421 39 3662;E-mail: renald_hennig@chiron.com