A Clinical and Technical Assessment of Biologics for Moderate-to-Severe Plaque Psoriasis: Key Issues in Planning, Implementation and Reporting

1. A ClinicalandTechnicalAssessmentof Biologics for Moderate-to-SeverePlaquePsoriasis:Key Issuesin Planning,Implementationand Reporting Tahsinul Anam, Mona Ahadzadegan Ahani, Rachel Armstrong, Olayinka Abidemi Awofodu, Manuel Reyes Caballero, Neeti Galwankar, Nishreen Leila, Nicole Ricker & Lavanya Uruthiramoorthy

2. OVERVIEW OF MODERATE-TO-SEVERE PLAQUE PSORIASIS Tahsinul Anam

3. Managing Psoriasis Clinical Presentation Epidemiology and Pathophysiology

4. What is Psoriasis? • A common, life-long, genetic, autoimmune skin disease • Circumscribed areas of thick, red, scaly skin • “psoros” meaning “rough, scabby” • Term first used (along with “lepra”) by Hippocrates (460-377 B.C.) in Corpus Hippocraticum • Von Hebra first to distinguish psoriasis from leprosy in 1841

5. • Psoriatic arthritis • ~30% of patients with psoriasis • Depression and alcohol abuse • Obesity • Severe psoriasis • 7x risk for developing myocardial infarction • increased mortality • ~5 year shorter life span Psoriasis is Not Just a Skin Disease

6. • Fear of contagion from others • “modern day lepers” • Low self esteem • “something’s wrong with me” • Need to cover up • “I don’t want anyone to see” • Sexual impairment • Hand/foot lesions • Itching • Arthritis Psoriasis Significantly Impairs Quality of Life

7. 7 DERMIS STRATUM BASALE STRATUM SPINOSUM STRATUM GRANULOSUM STRATUM CORNEUM Proliferation Immaturity Neutrophil accumulation DisorganizedN O R M A L P S O R I A S I S

8. • Scalp (80%) • Elbows (78%) • Legs (74%) • Knees (57%) • Nails (10-55%) • Gluteal cleft • Palms/soles (12%) Classic Anatomic Locations for Psoriasis

9. • Chronic plaque psoriasis • Guttate psoriasis • Erythrodermic psoriasis • Generalized pustular psoriasis (von Zumbusch) • Localized pustular psoriasis • Palmaris et plantaris • Acrodermatitis continua • Inverse psoriasis Clinical Variants

10. 5 19 21 29 31 71 79 94 0 20 40 60 80 100 Other Fatigue Burning… Bleeding Tightne… Skin… Itching Scaling Percentage of respondents (n = 17,425) Symptoms of Psoriasis • Adapted from Krueger G et al. Arch Dermatol 2001; 137: 280–4. Mostfrequently experiencedsymptoms

11. Epidemiology • Common skin disorder • Prevalence variable: ~ 0.3–2.5%1 • Prevalence equal in males and females2 • Estimated incidence: ~ 60 per 100,000 per year3 1. Plunkett A et al. Australas J Dermatol 1998; 39: 225–232. 2. Barker J. Clin Exp Dermatol 2001;26(4):321-5. 3. Bell LM et al. Arch Dermatol 1991; 127: 1184–7.

12. Age of Onset • Mean age: ~ 23–37 years1 • Current theory: 2 distinct peaks with possible genetic associations1 • Early onset (16–22 years)2 • More severe and extensive • More likely to have affected first-degree family member • Late onset (57–60 years)2 • Milder form • Affected first-degree family members nearly absent

13. Genetic Influence • Evidence suggests strong genetic association • Studies of monozygotic twins show concordance for psoriasis (e.g. 64% in a Danish Study)1 • Multiple susceptibility loci have been identified2 • Disease expression • likely result of genetic and environmental factors2 1.Brandup F et al. Acta Dermato-Vernerol 1982; 62L: 229–36. 2. Barker J. Clin Exp Dermatol 2001; 26(4): 321–5.

14. Common Trigger Factors for Psoriasis • Infections (e.g. streptococcal, viral) • Skin trauma (Koebner phenomenon) • Psychological stress • Drugs (e.g. lithium, beta blockers) • Sunburn • Metabolic factors (e.g. calcium deficiency) • Hormonal factors (e.g. pregnancy) 1. Dermatology Expert Group. Therapeutic guidelines: dermatology. Version 3. Melbourne: Therapeutic Guidelines Limited, 2009. 14

15. Psoriasis is a T-cell Mediated Autoimmune Disease • Current hypothesis: • Unknown skin antigens stimulate immune response • Antigen-specific memory T-cells are primary mediators • Leads to impaired differentiation and hyperproliferation of keratinocytes 1. Lee M et al. Australas J Dermatol 2006; 47: 151–9. 15

16. 16

18. CURRENT TREATMENTS Tahsinul Anam

19. • Lubrication • Removal of scales • Slow down lesion proliferation • Pruritus management • Prevent complications • Lessen patient stress • Season and climate

20. Step 1 Anthralin Calcipotriene Coal Tar Tazarotene Intralesional Steroid Topical Steroid Climatotherapy Moisturizers Keratolytics Step 2 PUVA PUVA + Step 1 agent Acitretin Step 3 Methotrexate Cyclosporine Rotational: 12-24 months of each step 3 agent Supplementary Tx Step 4 Enbrel/Remicade/Amevive/Raptiva

21. Topical Therapies for Psoriasis • Corticosteroids: • mid-high potency for most areas • low potency for face and intertriginous areas • Calcipotriene (Dovonex®): • works best in combination with topical corticosteroids • Tazorotene (Tazorac®): • works best in combination with topical corticosteroids • Tacrolimus (Protopic®): • for face and intertriginous areas • Ointments, creams, gels, foams, sprays, shampoos, and medicated tape all available

22. Older Systemic Therapies for Psoriasis • Phototherapy: UVB, narrow-band UVB, PUVA, Excimer laser • Methotrexate • Acitretin (Soriatane®) • Cyclosporine

23. • Alefacept (Amevive®): • LFA3-tip, targets CD2+ T cells • Etanercept (Enbrel®): • soluble TNF- receptor • Adalimumab (Humira®): • human anti-TNF- mAb • Infliximab (Remicade®): • chimeric anti-TNF- mAb • Golimumab (Simponi®): • human anti-TNF- mAb • Ustekinumab (Stelara®): • human anti-IL-12/IL-23 mAb Biologic Treatments for Psoriasis

24. TRENDS IN CURRENT CLINICAL TRIALS Mona Ahadzadegan Ahani

25. • The primary goal of current research in plaque psoriasis: • Increased efficacy & tolerability • Fewer AE • Combination, rotational, or sequential treatment strategies • Resistance to existing therapies: • More therapeutic options • New formulations • New target and mode of action

26. • Topical agents - for minimal disease • First-line therapy: phototherapy • The most effective UVB phototherapy: NBUVB phototherapy • Example: Efficacy of methotrexate and NBUVB combination was investigated • Improve psoriasis in significantly less time, with lower cumulative UVB UVB therapy: production of non-melanoma skin cancer

27. • Second-line therapy: Traditional, non-biologic systemic agents (MTX, CSA) • Long-term toxicity • Treatment resistant • Safety concerns related to their long-term use • Methotrexate: • The gold-standard comparator for new interventions such as biologics • Despite being highly effective: • fail to respond to methotrexate monotherapy • risk of liver toxicity

28. Topical agents for minimal disease Phototherapy (First-line therapy) Traditional systemic agents (Second-line therapy) Biologics (Third-line therapy) The most effective UVB phototherapy: NBUVB phototherapy High risk of AEs & SAEs, resistance to the agents For failure, intolerance or co-morbidities with traditional systemic agents

29. • Third-line therapy: Biologics • For failure, intolerance or co-morbidities with traditional systemic agents • Choice of biologic • Not clear which one is the best first choice • Often lose response over 1 year • Add phototherapy or MTX • Switch to another biologic

30. Advantages More effective than conventional treatments Few drug interactions Avoid absorption issues Novel MOA & focused target Disadvantages Increased common & rare infections (TB) Must stop drug during infection/surgery Cannot be used together (with other biologics) Tolerance/Antibody formation IV or SQ admin Cost Long term side effects ?? Biologics

31. Etanercep • first TNF inhibitor • Serious infections Adalimumab • third TNF inhibitor after etanercept • Serious infections (TB), cases of lymphoma Ustekinumab • Blocks two cytokines, IL-12 and IL-23 • Target different points in the cascade of immune-system signalling molecules • Rsk of SAE: major cardiovascular events Secukinumab

32. Secukinumab (AIN457): • A fully human anti IL-17A • An investigational biologic treatment for moderate-to-severe psoriasis • Has shown early promise in a phase II trial, currently being further investigated in a phase III trial • Anti IL-17s : (new class of drugs) • A new therapeutic target in psoriasis • Preliminary clinical results: blocking IL-17 reduces disease severity • Animal models: blocking IL-17 reduces psoriasis- like pathology • PASI 100

33. Secukinumab (AIN457): • A randomized, double-blind, phase II, placebo-controlled, parallel by Novartis • July 2009 - Dec 2010 • Objective: To evaluate the safety and efficacy of three induction regimens of secukinumab • Result: The investigational anti‐IL‐17 monoclonal secukinumab showed significant efficacy and tolerability in up to 81% of patients

34. “September 27, 2012 - Novartis announced today new Phase II data showing AIN457 (secukinumab) may significantly improve moderate-to-severe plaque psoriasis on the hands, feet and nails...” “Given what we've seen in phase II, where all these therapies were well tolerated and continued to be effective, it is very unlikely that there will be something in phase III to prevent regulatory approval,” – Dr. Kim Papp

35. • Challenge: The selection of safer and more effective agents to treat plaque psoriasis, particularly when it comes to biologics • At the moment, psoriasis therapy is dominated by: • Amgen/Pfizer's etanercept • Abbott Laboratories' adalimumab • Ustekinumab from Janssen Biotech • Novartis’ secukinumab may offer new therapeutic options for plaque psoriasis in the near future.

36. Secukinumab Trial Design and Issues Nishreen Leila

37. Immune Modulators • TGN1412: humanized mAb against CD28 Tcell receptors developed by TeGenero • Phase I trial conducted in UK on March 13 2006 • Resulted in the hospitalization of all 6 subjects within a few hours of taking the drug • Drug induced cytokine storm caused near fatal organ failure

38. Starting Dose for Phase I trials involving Immune Modulators • Starting dose determination • Extreme caution in determining the dose for a first in man trial • Use “minimal anticipated biological effect level” MABEL instead of “no observed adverse effect level” NOAEL • Preclinical studies in an appropriate animal model and invitro studies are critical • Explains the longer( 30 day) CTA approval time

39. SecukinumabRandomized,DoubleBlind, Placebo-controlled,PhaseII Regimen-findingStudy 404 patients randomized Randomization 1 1:2:2:1 Randomization 2 1:1 Responders:PASI 75

40. Randomized Withdrawal Design : “Enriched Enrolment” • Patients who respond positively in the induction phase are re-randomized to active or placebo arm • To study long term effects of treatment and length of treatment • Experimental treatment is limited to patients who respond • Shortened time on placebo arm • Disadvantages: • Carryover effect • Longer study duration

41. Ongoing Phase III Secukinumab Trials • Treatment of nail and palmoplantar psoriasis • Comparison of IV vs SC administration of drug • Prefilled syringes and auto-injectors for drug administration • Long term safety • Comparison to etanercept • Two pivotal extension studies recruiting 740 and 1220 patients respectively: long term efficacy and safety. Patients recruited for this study will be responders from previous phase III studies.

42. Placebo Controlled Trials • Psoriasis trials are placebo controlled • Good trial design • Chronic nature of the disease • Account for the Placebo Effect

43. Placebo Effect: Conditioning • Immune system and CNS are linked • Increased stress levels linked to psoriasis flare ups • Release of neurotransmitters in response to a placebo may positively alter the immune system • Common to see 15-20% improvement of PASI score on placebo

44. EnrollmentCriteria in a PsoriasisBiologic Trial: Moderateto Severe Psoriasis • Body Surface Area • Intensity of local signs and symptoms • Response to previous treatments

45. Placebo Effect: Eligibility Creep • What is best for my patient? • Tendency for patients to meet eligibility criteria when they are close to the eligibility criteria by scoring them on the higher end of scale • Patient is enrolled in the trial and randomized to placebo arm • Patient is now scored as usual: this score is now lower than the score used to enroll • “Placebo effect” artifact introduced by the investigator

46. Eligibility Creep: Characteristics • Significant improvement observed between baseline and first visit with little improvement after • Seen in trials that have subjective outcome measures that are also used as eligibility criteria

47. Other Issues in Trial Design • Absence of head to head comparator trials • More beneficial for patients • Required for physicians to make good decisions based on strong scientific evidence • Subjectivity in eligibility determination may result in the exclusion of patients from participating in a trial

48. EFFICACY & ENDPOINTS Nicole Ricker

49. Psoriasis Assessment Tools • What is being measured: Psoriatic lesions on the surface of the skin (redness, thickness, and scaliness) • How: Various assessment tools (e.g. the Psoriasis Area Severity Index) generate a numerical score that represent severity of psoriasis • When: clinical trials and clinical practice • Why: Measure change in psoriasis severity to assess medical need (clinical practice) and efficacy of treatment (clinical trial) • Requirement: STANDARDIZATION!

50. PASI (Psoriasis Area and Severity Index) The affected area and lesion characteristics are entered in a formula that results in a score from 0 to 72. The PASI is most often used in clinical trials PGA (Physician’s Global Assessment) The PGA is a 5, 6, or 7-point ordinal rating ranging from ‘‘clear’’ to ‘‘very severe psoriasis’’ PaGA (Patient’s Global Assessment) The PaGA is an ordinal rating ranging from ‘‘clear’’ to ‘‘very severe psoriasis’’ assessed by the patient SAPASI (Self-Administered PASI) The SAPASI is a structured PASI-like instrument designed for patient self- assessments of severity PASS (Psoriasis Assessment Severity Score) The affected area and plaque characteristics are entered in a formula that results in a score from 0 to 140. Infiltration is given more weight than erythema and scaling. LS-PGA (Lattice System Physician’s Global Assessment) The LS-PGA integrates ranges of involved BSA and the overall plaque morphology in which infiltration is given more weight SPASI (Simplified PASI) The SPASI equals the sum of the average redness, thickness, and scaling of all the psoriasis lesions multiplied by the percentage of body surface area involved PEASI (Psoriasis Exact Area and Severity Index) The PLASI is derived from the PASI but uses actual BSA percentages instead of an area score PLASI (Psoriasis Long-based Area and Severity Index) The PLASI is derived from the PASI but uses six BSA groupings with finer partitioning for smaller extents of BSA

51. Types of Assessments • Psoriasis Area and Severity Index (PASI): The affected area and lesion characteristics are entered in a formula that results in a score from 0 to 72. The PASI is most often used in clinical trials • Physician Global Assessment (PGA): The PGA is a 5, 6, or 7-point ordinal rating ranging from ‘‘clear’’ to ‘‘very severe psoriasis’’ • Quality of Life Measures • Biopsies and Photographs Advantages Disadvantages PASI •Widely used in clinical trials • Large scale (0-72) •Not widely used in clinical practice •Does Not discriminate when body- surface-area is low PGA •Widely used in clinical trials •Similar to the assessments physicians actually perform in clinical practice •Easy to understand •Requires definition of each score •Does not discriminate small changes (uses a 7 point scale)

52. Assessment Selection • Consider population, trial design, and psoriasis type • Consider historical findings and previous successful study designs • Consider the implications of the type of measure used • Use a combination

54. Plaque Characteristics http://www.dermnetnz.org/scaly/pasi.html

55. Endpoints in Clinical Trials • Purpose of endpoint: to demonstrate that more patients achieve clinically meaningful success with the drug treatment than with placebo • ‘Clinically Meaningful Success’ can be hard to define • A large improvement and a small improvement can be ‘clinically meaningful’ • Combine with other measures (QofL, PGA, EEG etc.) • Standard: at least 75% improvement in disease OR 75% improvement in the PASI score

56. Secukinumab Trial: Evaluating Efficacy Primary Outcome Measure: Efficacy of secukinumab in subjects with moderate to severe chronic plaque-type psoriasis • Cumulative rate of subjects with Loss of Psoriasis Area and Severity Index (PASI) 75 response (75% improvement on PASI scale) Secondary Outcome Measures (Safety) • Change in Psoriasis Area and Severity Index (PASI) • Investigator Global Assessment (IGA) 2011 score • Time to Psoriasis Area and Severity Index (PASI) 75 response • Hemoglobin count, hematocrit count, red blood cell count, white blood cell count • Electrocardiogram (ECG) test results - measured in degrees • Adverse events – measured in % of patients with any adverse events • Change in quality of life – measured by change in questionnaire scores

57. SAFETY PARAMETERS & ADVERSE REACTIONS Rachel Armstrong

58. Safety Parameters in Biologics Trials • AEs and SAEs • Haematology • Blood and urine analysis • Vital signs • ECG Assessments Overall, relatively simple assessments to perform...

59. Key Challenges: Safety Profile • Lack of long-term data • Accurate long-term safety profile requires AE collection over longer time frame with broader patient population • Critical for ensuring overall patient safety • Plaque psoriasis is a lifelong disease • Long term administration of medication seems to be key to helping patients manage symptoms

60. Key Challenges: Adverse Events • Collection of AEs • Conflicting evidence • Phase I and II trials with relatively few patients • Inadequate ascertainment / classification of AEs • Inconsistencies in reported Aes • AEs reported as secondary outcomes and not pre- specified • Trials are powered for detection of significant difference between groups for beneficial effect • Estimates for adverse effects may lack precision

61. Adverse Events: Treatment-Related Infection • Primary drug action: • Inhibition of the IL-17 pathway • This pathway plays a role in protective immunity • Infection rates: • Must be monitored in both groups when conducting a trial • Future Steps: • Until the generation of more safety data, patients with a history of viral infection (HIV, Hepatitis) should be excluded from trials

62. Adverse Events: MACEs • Patient Risk: • Psoriasis patients are at increased risk of cardiovascular disease • MACEs: • Analyses of other biologics (e.g. briakinumab) have raised concerns about increased risk of Major Adverse Cardiovascular Events • Future Steps: • All future studies should incorporate safety parameters to account for this risk, such as ECG recordings

63. Adverse Events: Malignancy • Patient Risk: • Association between biologics and malignancies such as skin cancer • Risk of malignancy might be further increased if patient has used phototherapy • Next Steps: • Need for patient counselling and regular check- ups to reduce chance of malignancy • Safety parameters for future secukinumab studies should be designed to assess the incidence of cancer

64. Safety Parameters & Adverse Events Re-Cap... • Safety Parameters • Infection rates • MACEs • Malignancy • Future Considerations… • Larger, post-marketing studies will be required • Additional safety parameters must be included to ensure patient safety • Protocols should pre-specify AEs based on pharmacological mechanisms and data from earlier studies • Systematic review should be conducted to build a complete safety data set

65. INCLUSION & EXCLUSION CRITERIA Neeti Galwankar

66. • Phase I: Healthy volunteers and patients to study the PK/PD • degree of psoriases on the PASI scale not significant • Phase II: moderate to severe psoriases on PASI scale(Very thick lesions located in ‘difficult-to-treat’ regions, such as the palms and soles) • Phase III: Similar to phase II. • Few targeted specific psoriatic populations (eg. Nail, palmoplantar etc).

67. Inclusion Criteria 1. PASI score ≥ 12 at baseline (moderate to severe psoriases) 2. Body surface area ≥ 10% 3. Patients whose disease was inadequately controlled by topical treatments, phototherapy, or previous systemic therapy. 4. Male patients and female patients of childbearing age are eligible if they are willing to use an effective method of contraception during the study and for 4 months after the last dose of study drug. 5. Age 18-65 yrs

68. Exclusion Criteria 1. Psoriasis other than chronic plaque-type 2. Ongoing use of prohibited psoriasis treatments such as conventional systemic therapy (e.g. methotrexate, cyclosporine) 3. Biologic systemic therapy (eg, adalimumab, efalizumab, etanercept), topical or systemic corticosteroids, ultraviolet light therapy, or other investigational drugs, within specified time periods prior to study entry • Rationale: Contraindication 4. Live vaccination within 6 weeks before first study drug administration; and known immunosuppression, active infection, or history of active tuberculosis • Rationale: patient susceptible to infection 5. Patients with a history of congestive heart failure • Rationale: Some biologics have been associated with cardiovascular events. Eg: Briakinumab • confound the results of the study(determine if the side effects are due to the original disease or due to the drug)

69. Patient RecruitmentIssues Arising from Inclusion/ExclusionCriteria 1. Most patients lie in mild – moderate. So, finding patients in moderate- severe category difficult 1. Clinical variants excluded(eg. Gutate psoraises) 1. High rate of a number of co-morbidities. • Challenging to evaluate impact on co-morbidities • Prevents the evaluation of drug-drug interactions • Phase IV trials to understand co-morbidities

70. STATISTICAL CONSIDERATIONS Neeti Galwankar

71. • Placebo effect-size of the target population and during data analysis • Dropout rate- parallel design is to cross over the non- responding patient to the other arm to see if that makes a difference in response • Compromised blinding- Due to the visual nature of the disease. Solution is to have separate individuals treating the patient and assessing disease progression • Variations in disease severity over time- sequential evaluation of disease response using standardized criteria

72. ETHICAL CONSIDERATIONS Lavanya Uruthiramoorthy

73. • Patient Autonomy • Informed Consent • Language barriers • Coercive influences • Beneficence • Conflict of interest • Bias in the data presented • Competing studies • Non-maleficence • Use of placebos • Distributive Justice • Patient treatment after study completion

74. SELECTION OF INVESTIGATORS & SITES Lavanya Uruthiramoorthy

75. Selection Criteria  Timeliness  Investigator interest, motivation & reputation  Available resources  Patient referral  Previous experience & performance in studies  Previous audits  Recruitment history  Acceptable facilities and resources  Access to the appropriate patient population  Trained & qualified staff  Low staff turnover  Budgetary factors  Sponsor relationship

76. Feasibility Questionnaires • Patient population • Staffing • Research Ethics Board information • Proper equipment • Competing studies

77. Site Assessment Visit • Investigators’ interest • Time availability • Methods of recruitment • Staff involvement • Equipment • Suitability of location • Storage facilities

78. Site & Investigator Exclusion • Low recruitment rates • Too many queries • Poor quality of data • Insufficient/inexperienced staff • Inadequate facilities/equipment • Presence of competing studies • Lack of PI involvement • Infrequent IRB/REB meetings

79. Suggestions • Early in the planning of the trial • Review relevant medical/scientific literature • Conduct thorough Feasibility Questionnaires and Site Assessment Visits • Consider opinions of all stakeholders

80. PATIENT RECRUITMENT STRATEGIES Manuel Reyes Caballero

81. Patient Recruitment Strategies • Key of a successful trial • Delays in patient recruitments • Higher cost of companies • Slower time to market the product • Loss of revenue • Weakens statistical power • No statistical significance

82. • Difficulty of recruiting subjects is low when inclusion criteria are narrow. • Aspects to consider for psoriasis recruitment: • Biological drugs • Psoriasis population percentage • Seasonal changes • Cost of psoriasis treatments • Quality of life • Retention of patients • Incentives

83. Biological Drugs • No cure for chronic plaque psoriasis • Biological drugs target aspects of the immune system • Effects in the immune system exclude many patients • The record on existing safety data in biological agents is limited • Risk of side effect is very low

84. Psoriasis Population Percentage • Psoriasis is the most prevalent autoimmune disease in the United States • Psoriasis affects ~2.2 % of the population • ~2 to 3 % of the total population have psoriasis • Psoriasis studies target usually enrollment between 15-30 patients • Psoriasis studies recruit 2 to 3 patients each month during the fall/winter time while about 1 patient each month during summer time

85. Seasonal Changes • UV rays causes damage in DNA and alter the immune system • In India in the summer months 43% improvement of psoriasis vs 7% improvement in the winter months • Photosensitive psoriasis (PP), in whom the condition is predominantly photodistributed is severe in the summer months

86. Cost of Psoriasis • Psoriasis drugs are very expensive • Most health insurance do not cover psoriasis drugs • Cost of total direct and indirect healthcare of psoriasis = $11.25 billion annually • On average 60% of psoriasis patients missed 26 days of work/year because of their illness

87. Quality of Life • 60% of people with psoriasis reported their disease to be a large problem in their everyday life • Psoriasis has a great impact in females and young people

88. Retention of Patients • Most studies are double blinded, crossover design • Study = 2 arms, placebo and treatment • Placebo = no cure = loss of interest

89. COMPLIANCE Manuel Reyes Caballero

90. Compliance • The follow up of recommendations by a doctor related to patients behavior + patient's adherence to prescribed drugs • Poor compliance = failure of the study or reducing the statistical power of the study • If 30% of patients in a clinical trial had inadequate compliance • Need 2x as many patients • There is a relatively high compliance in psoriasis studies • Factors that can result in poor compliance: • Vacation of patients to warm places with high radiation of UV light • Patient diet

91. INFORMED CONSENT Olayinka Abidemi Awofodu

92. • Follows the guidelines laid out in the Declaration of Helsinki and ICH-GCP • Biologic treatments have more systemic adverse events • It is included and explained/pointed out clearly to the patients/ clinical investigation subjects • Challenge: • The ability of the physician to explicitly describe the biologic to a patient • Procedures should be explained in a coherent, easy to understand manner, within grade 6-8 language level • Consent by the patient should be given freely and only after the physician is confident that the patient has understood all the involved risks and benefits. • Language barrier • A representative may be considered

93. BUDGET CONSIDERATIONS Olayinka Abidemi Awofodu

94. Budget Considerations • 3 major factors limit the process of biologic development: 1. Cost 2. Safety, 3. Time. • Complicated task: • all aspect of this study requires using skilled staff, professional services and specialized equipment • The Fair Market Value • Cost associated with patient recruitment • Planned on a fee-for-service basis with detailed per-patient costs

95. REPORTING & PUBLICATIONS STRATEGIES Olayinka Abidemi Awofodu

96. • Issue: • Non-publication of negative trials and non-reporting of negative outcomes, coupled with redundant publication of positive findings. • ICMJE requires registration of trial methodology but does not require registration of trial results • A globally unified system • to provide a better meta-analysis of the reports/data generated from the trials • better understanding of the disease, and therapeutic trends • Critique peer review must be employed • discrepancies between the registered trial and published results

97. CONCLUSION

98. QUESTIONS?

A Clinical and Technical Assessment of Biologics for Moderate-to-Severe Plaque Psoriasis: Key Issues in Planning, Implementation and Reporting

A Clinical and Technical Assessment of Biologics for Moderate-to-Severe Plaque Psoriasis: Key Issues in Planning, Implementation and Reporting

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