Biologicals:Biologicals:A Vision for the Future of Clinical A Vision for the Future of Clinical Investigators in Evaluations of Investigators in Evaluations of New Biological ProductsNew Biological Products

Karen Midthun, MD Karen Midthun, MD Acting DirectorActing Director

Center for Biologics Evaluation And ResearchCenter for Biologics Evaluation And Research February 25, 2010February 25, 2010

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Biologics Control Act, Biologics Control Act, 19021902The Horse CBER Rode in OnThe Horse CBER Rode in OnDiphtheria antitoxin from a milk horse named JimDiphtheria antitoxin from a milk horse named Jim

• 1901: Anti-toxin from Jim was contaminated with tetanus1901: Anti-toxin from Jim was contaminated with tetanus

• Serum made in St. Louis with no central or uniform controls to Serum made in St. Louis with no central or uniform controls to

ensure potency and purity; no inspectionsensure potency and purity; no inspections• Serum bottled & used, resulting in the deaths of 13 childrenSerum bottled & used, resulting in the deaths of 13 children• Camden, NJ: 9 children died from tetanus-tainted smallpox Camden, NJ: 9 children died from tetanus-tainted smallpox

vaccine vaccine

• Biologics Control ActBiologics Control Act: government regulation of biologics; : government regulation of biologics;

required licensure of products/facilities; authority to inspect required licensure of products/facilities; authority to inspect

and to withhold, suspend, or revoke licensesand to withhold, suspend, or revoke licenses

One of the first One of the first bottles (1895) of bottles (1895) of diphtheria antitoxin diphtheria antitoxin produced at the produced at the Hygienic LaboratoryHygienic Laboratory

Biologics – definitionBiologics – definition ((PHS Act, section 351PHS Act, section 351))

• Virus, therapeutic serum, toxin, Virus, therapeutic serum, toxin, antitoxin, vaccine, blood, blood antitoxin, vaccine, blood, blood component, or derivative, allergenic component, or derivative, allergenic product, or analogous product …product, or analogous product …

• Applicable to prevention, treatment, or Applicable to prevention, treatment, or cure of a disease or condition of human cure of a disease or condition of human beingsbeings

Products Regulated by CBERProducts Regulated by CBER

Somatic Cell & Gene

Therapies

Blood Derivatives

Selected Devices

Whole Blood

Human Tissues Xenotransplantation Products

Vaccines (preventive and therapeutic)

AllergenicExtractsBlood

Components

How are Biologics Different?How are Biologics Different?• Traditional drugs• Low molecular wgt. (<1

kDa)• Usually organic synthesis

• Fewer critical process steps • Well-characterized• Drug substance

homogeneity• Maximal tolerated dose• Linear dose response• Usually more specific

mechanisms of action• Usually metabolized• May have p450 interactions• Usually not immunogenic

Biological productsBiological productsHigh molecular weight (>50 High molecular weight (>50

kDa)kDa)Made with/from live Made with/from live

cells/organismscells/organisms inherent & contamination inherent & contamination

riskriskMany critical process steps Many critical process steps Less well-characterizedLess well-characterizedComplex heterogeneous Complex heterogeneous

mixturesmixturesOptimal biologic doseOptimal biologic doseNon-linear dose responseNon-linear dose responseMultiple or even unknownMultiple or even unknown mechanisms of actionmechanisms of actionDegradedDegraded

No P450 interactionsNo P450 interactions

Often ImmunogenicOften Immunogenic

Clinical Trial ConsiderationsClinical Trial ConsiderationsVaccines for Healthy ChildrenVaccines for Healthy Children

• Pivotal studies: typically large RCTs, Pivotal studies: typically large RCTs, e.g.e.g., several thousand , several thousand to many thousand children (>70,000 infants in Rotateq to many thousand children (>70,000 infants in Rotateq rotavirus vaccine trial)rotavirus vaccine trial)

• Control: typically placebo or active control (e.g., a licensed Control: typically placebo or active control (e.g., a licensed vaccine that may or may not be active against infectious vaccine that may or may not be active against infectious disease of interest)disease of interest)

• Live virus & bacterial vaccines or vectored vaccines assessed Live virus & bacterial vaccines or vectored vaccines assessed for shedding of the organisms (quantity & duration, risk of for shedding of the organisms (quantity & duration, risk of transmission to unvaccinated)transmission to unvaccinated)

• Adjuvants: vaccines may contain an adjuvant, need to Adjuvants: vaccines may contain an adjuvant, need to evaluate safety evaluate safety andand efficacy of vaccine as a whole efficacy of vaccine as a whole

• Vaccines intended for predominantly healthy populations, Vaccines intended for predominantly healthy populations, informs informs risk/benefit considerationsrisk/benefit considerations

Products for Rare Diseases: Use Products for Rare Diseases: Use of Flexible Study Designsof Flexible Study Designs

• Historical controls sometimes used, e.g.,Historical controls sometimes used, e.g.,─Natural history of disease is well characterized & Natural history of disease is well characterized &

understoodunderstood

• Sequential trialsSequential trials─Early stopping for strong negative or positive Early stopping for strong negative or positive

cumulative datacumulative data

• Adaptive trialsAdaptive trials─Ongoing adjustments to treatment regimen, Ongoing adjustments to treatment regimen,

dosing, participant allocation, and/or sample sizedosing, participant allocation, and/or sample size• Crossover trialsCrossover trials─Study participants serve as own controlsStudy participants serve as own controls

Historical Safety IncidentsHistorical Safety Incidents Underscore need for control of Underscore need for control of manufacturing process, product testing, manufacturing process, product testing, pre pre andand post-market safety surveillance, post-market safety surveillance, proactive stance re EIDsproactive stance re EIDs

• 1901:1901: Contaminated diphtheria antitoxin lot Contaminated diphtheria antitoxin lot 13 fatal 13 fatal tetanus cases; led to Biologics Control Act of 1902tetanus cases; led to Biologics Control Act of 1902

• 1955:1955: Deficient viral inactivation (“Cutter incident”) - some Deficient viral inactivation (“Cutter incident”) - some lots of inactivated poliovirus vaccine lots of inactivated poliovirus vaccine cases of poliomyelitis cases of poliomyelitis in >200 vaccinees and contactsin >200 vaccinees and contacts

• 1970's-’85:1970's-’85: HIV transmitted through contaminated blood, HIV transmitted through contaminated blood, blood components, and plasma derivatives; donor deferral blood components, and plasma derivatives; donor deferral and testing introduced, significantly reducing riskand testing introduced, significantly reducing risk

• 1990s:1990s: Variant Creutzfeldt-Jakob Disease (vCJD) recognized; Variant Creutzfeldt-Jakob Disease (vCJD) recognized; risk-based donor deferral implemented; vCJD transmission risk-based donor deferral implemented; vCJD transmission by blood/blood products subsequentlyby blood/blood products subsequently recognized in UKrecognized in UK

• 1999:1999: Intussusception after licensure of first rotavirus Intussusception after licensure of first rotavirus vaccine; led to vaccine withdrawal; very large safety studies vaccine; led to vaccine withdrawal; very large safety studies conducted pre-licensure for subsequent rotavirus vaccinesconducted pre-licensure for subsequent rotavirus vaccines

Complexity of Complexity of Manufacturing Process: Manufacturing Process: gene therapy examplegene therapy example

Allogeneic PBMC

CD34+Selection

Retroviral vector Growth Factors

CD34+ Expressing New

Gene

Anti-CD34+ MoAB

Multiple Cytokines and/or

CD34+ transduction

Fibronectin coated flasks

Investigational Gene Therapy Investigational Gene Therapy ProductsProductsPotential risks and benefitsPotential risks and benefits

• Risk of detrimental inflammation:Risk of detrimental inflammation: fatal hepatotoxicity in fatal hepatotoxicity in teenager after gene therapy trial for genetic enzyme teenager after gene therapy trial for genetic enzyme deficiency using adenovirus vector (deficiency using adenovirus vector (1999) 1999)

• Risk of proliferationRisk of proliferation

• 11stst gene therapy trials for SCID-X1 w/o compatible stem cell gene therapy trials for SCID-X1 w/o compatible stem cell donor (Europe) donor (Europe) T cell leukemia arose in 5/20 (construct T cell leukemia arose in 5/20 (construct integrated into a proto-oncogene regulating T cell integrated into a proto-oncogene regulating T cell proliferation - 1 died, 3 cured, 1 still being treated), proliferation - 1 died, 3 cured, 1 still being treated), BUTBUT

• Potential for cure: good immunity restored in 17/20 (for at Potential for cure: good immunity restored in 17/20 (for at least 5-8 years), 12/20 lost need for IV IgG (unusual after least 5-8 years), 12/20 lost need for IV IgG (unusual after stem cell transplant), only 1/20 did not develop any T cells stem cell transplant), only 1/20 did not develop any T cells

R

Cell Scaffold Products:Cell Scaffold Products: Another Group of Complex Another Group of Complex BiologicalsBiologicals

• Autologous or allogeneic cells on Autologous or allogeneic cells on collagen or synthetic resorbable collagen or synthetic resorbable matrix for wound repairmatrix for wound repair

• Cell seeded scaffolds for Cell seeded scaffolds for cardiovascular repaircardiovascular repair

• Encapsulated pancreatic islet cells Encapsulated pancreatic islet cells

• Expanded autologous cells on a Expanded autologous cells on a matrix for collagen repairmatrix for collagen repair

Example: Autologous stem cells (selected using monoclonal antibodies, expanded in culture, matured with cytokines, then given back to patient).

Potential benefits of therapy:

• Potential for much greater potency

• Applicable to a wide range of very difficult to treat diseases

• Potential for fewer adverse effects than conventional therapies

• More targeted

Potential risks oftherapy:

• Tumorigenicity• Cellular contaminants• Adventitious agents• Safety of reagents• Sterility• Product stability• Product variability

Investigational Cellular Therapy

Example: Coagulation factors derived from either human plasma or culture media from genetically engineered cells for replacement therapy to treat patients with congenital deficiencies (e.g. hemophilia)

Potential Benefits of Therapy:

• Effective in controlling bleeding episodes that are life threatening

Potential Risks of Therapy:

• Infections due to adventitious agents

• Development of neutralizing antibodies due to modifications in the molecule

• Allergic reactions to impurities

Investigational Blood Product

Synthetic peptides can be manufactured with very high degrees of product consistency, but variability with autologous or allogeneic cellular products can be enormous (sometimes >100 fold)

Consistency of manufacturing: may vary by product

SUMMARYSUMMARY• Biologicals: diverse, complex products for Biologicals: diverse, complex products for

the treatment and prevention of a broad the treatment and prevention of a broad range of common and rare diseasesrange of common and rare diseases

• Complex processes for manufacture, Complex processes for manufacture, product testing, product testing, andand for evaluation of safety for evaluation of safety and efficacyand efficacy

• Include many products for healthy peopleInclude many products for healthy people –– informs risk-benefit considerationsinforms risk-benefit considerations

• Include highly innovative products (great Include highly innovative products (great potentialpotential benefits benefits butbut risks not fully defined) risks not fully defined)

• Clinical trial designs may vary with productClinical trial designs may vary with product