4/4/13 Why Do Clinical Studies on Immune Products? The Regulatory - PDF document

4/4/13 Why Do Clinical Studies on Immune Products? The Regulatory and Immune Product Landscape Keys to understanding clinical studies on nutrition and the immune system 1. Increased scrutiny of the FTC and FDA over immune health claims. 2. The existing regulatory frameworks are not coordinated and differ among geographies. Don Cox, Ph.D. Senior Vice President, Research & Development, Healthcare Group 3. Evolving regulatory framework includes a shared perspective among Biothera, the immune health company leading geographies on health claim regulatory requirements. 4. Foods & beverages can be delivery vehicles for immune health ingredients. Sponsored by Topics to be Covered Before We Begin: Steps to Approval ü Laying the foundation for success ü Types of studies Clinical data • Physical health ü Elements of study design Pre-clinical • biomarkers proof of concept Mechanism of ü Understanding outcomes • Health benefits action • Possible biomarkers Safety/Tox data ü Examples (our studies and others) ü Summary Timeline (multiple years) 1

4/4/13 Laying the Foundation Lay the Foundation: Safety & Tox • There are standard methods used for • Published safety & toxicology data many of these studies. ( Food & Chem. Tox., 45:1719-1730 2007 ) • Two 90-day subchronic rat toxicology studies • We will use studies completed with a • Acute toxicity study (1,000 times standard dose, particular strain of beta 1,3/1,6 glucan as completed in Japan) examples. • Geno-toxicology studies • Multiple studies are often required to • Safety demonstrated in multiple human achieve the technical objective, we clinical studies. present a summary. Lay the Foundation: Lay the Foundation: Know the MOA Pre-clinical research Example The lethal anthrax model used is the well-known mouse (Balb/c) model 1) Taken orally, the specific beta previously described by Welkos et al. (Infect. Immun. 51:795-800, 1986) 1,3/1,6 glucan is taken up into the Dose 8 days pre -exposure & post body via the Peyer ’ s Patches in the intestines. * 2 and 20 mg/kg 100 WGP Glucan % Survival 2) Immune cells called macrophages 80 with the beta 1,3/1,6 glucan travel 60 to the immune organs throughout Control 40 the body. * p<0.016 20 3) Macrophages break down the 0 beta 1,3/1,6 glucan into smaller Oral Administration 0 1 2 3 4 5 6 7 8 910 fragments that bind to neutrophils, WGP Glucan Days Post -Infection (2 & 20 mg/Kg ) B. anthracis Challenge the most abundant immune cell in (strain Vollum 1B) 300 the body. spores, s.c. Survival Monitored 4) Neutrophils more quickly recognize Day -8 -1 0 1 2 3 4 5 6 7 8 9 10 11 and kill foreign challenges. JANA 5:1-5, 2002 Hong et al 173:797-806, 2004 2

4/4/13 Validated Science Topics to be Covered Dozens of Peer-Reviewed Published Studies on Technology ü Laying the foundation for success ü Types of studies ü Elements of study design ü Understanding outcomes ü Examples (our studies and others) ü Summary Types of Studies Types of Study – Designs • Two basics types of clinical studies exist: 1) Observational 2) Intervention- randomized, controlled trial (RCT) Open label Single blind Double blind • RCT is a managed study that can provide compelling evidence that a study treatment (intervention) causes an expected outcome Specialty studies • Observational studies are less convincing because • Safety evaluation Crossover they observe people & correlate observations to • Dose titration human health • others 3

4/4/13 Types of Study & Design Questions Suggested flow of clinical objectives • Study design is critical to eliminating • Clinical studies to show basic unintentional bias. Demonstrate a product efficacy • Single blind, open label, double physical health benefit blind, and crossover study designs all have merits. • Explore, confirm, evaluate Identify • Double-blind study is considered to ingredient- be the best. specific biomarkers • A crossover design reduces variations • Clinical support for between treatment groups. correlative biomarkers Clinically evaluate biomarker • Properly powered, response well-designed studies Clinical studies combining health benefit & biomarkers Assess the Clinical Research Topics to be Covered • Consistent results build credibility ü Laying the foundation for success • Multiple studies replicate benefit ü Types of studies • Multiple P.I.’s for independent verification ü Elements of study design – A key objective is to achieve significant scientific agreement… ü Understanding outcomes • Use validated methods & surveys ü Examples (our studies and others) ü Summary 4

4/4/13 Requisite Elements of a Elements of RCT Design Clinical Study Protocol Placebo- Randomized Blinded controlled Design Primary & (dbl-blind, Statement of • Subjects are • Single –subjects • Placebo is an secondary objective crossover, etc.) randomly do not know if inert substance outcome(s) assigned to they are lacking the treatment or receiving effect of the placebo placebo or treatment treatment Subject Inclusion & • Use a statistically • True “pharma” exclusion criteria Study Product, valid random • Double-subjects studies often use Study plan dose, placebo, number and investigators “standard of • Informed consent (Varied format) study duration generator do not know… care” rather than placebo Statement of Objective Primary and Secondary Outcomes • “…To determine the effects of 10 days of specific One Primary Outcome Secondary Outcomes strain of beta 1,3/1,6 glucan supplementation on Leukocytes, Cytokines, and Salivary Immunoglobulins following up to 120-min of walking/jogging in a warm, humid environment in Proportion of subjects who present with two or Cumulative days with infectious symptoms more of any of the following confirmed bacterial subjects with below average 'fitness.” or viral infections • .. to conduct a randomized, double-blind, placebo- Cumulative number of infection episodes controlled clinical trial in young children (1-4 years old) to investigate the effects of yeast beta-glucan Proportion of subjects that require, and average duration of: a) antiviral treatment, b) antibiotic on common childhood infections in young children. treatment, and c) hospitalization Adverse Events 5

4/4/13 Study Design Subject Inclusion and Exclusion Criteria Example Inclusion criteria • Age 18-70 Open label Single blind Double blind • Frequent traveler • Generally healthy • Agree to study visits, procedures and compliance, informed consent signature Exclusion criteria Specialty studies • Current symptoms of illness • Safety evaluation Crossover • Liver or kidney disease • Dose titration • Allergy or other inflammatory disease • others • Cigarette smoker • >20 lb. weight loss or gain in past 3 months • Unable to understand protocol Investigation Study Product Typical Study Plan-Format Study plan: V 0 V 1 V 2 V 3 V 4 • “…Investigational study or control will be provided in -15 to -7 day Study days 0 30 60 90 numbered bottles. When randomized, subjects will before V1 Subjects’ data and be given the lowest available randomization x medical history number.” Clinical examination x x x x • Randomization code held by Sponsor, not shared Eligibility criteria x with P.I. Informed consent x Supplementation start x • Known serving size (or dose) Subject interview, Diary x x x x • Placebo should closely match color, flavor, physical Innate immunity (Blood x x x x and saliva collection) characteristics of study product. Symptoms of URTI / ... → → → → | moridity Medical symptom ... → → → → | confirmation 6