understanding clinical trials

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Understanding Clinical Trials Prof. David Baker [email protected]

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Page 1: Understanding clinical trials

Understanding Clinical TrialsProf. David Baker

[email protected]

Page 2: Understanding clinical trials

• DRUG DEVELOPMENT PROCESS

• INVENTION TO MARKETING

• CLINICAL TRIAL PHASE 0-IV

• UNDERSTANDING TRIAL DESIGN

• UNDERSTANDING OF TRIAL RESULTS

5,000-10,000

compounds

Investigational New Drug

Pre-Clinical

Drug Discovery

250 Compounds

Clinical Trials

5 Compounds

1Approved

Drug

New Drug Application

FDA/EMA Review

3

6

12

14-15

0

Phase IV

Phase III

Phase III

Phase I

Compound Success Rates

3

6

12

14-15

0

$230 Million

$70 Million

$60 Million

$170 Million

$200 Million

$45 Million

MS Drug 2010 $1.5 Billion

PharmaExpenditure

per compound(2004)

STRUCTURE

Clinical Trial are scientific investigations that examine and evaluate safety and efficacy of different therapies in human subjects (Experimental Unit, Intervention, Evaluation)

Page 3: Understanding clinical trials

Animal Models AreImportant in Drug

Development Pipeline

Phase I TrialsIn Healthy People

(Drug Safety)

Phase II Trialsin pwMS

(Drug Safety)

Phase III Trialsin pwMS

(Drug Efficacy)

Drug-The Game www.ms-res.org

Drug Approval

DRUG DEVELOPMENT

Page 4: Understanding clinical trials

DRUG DISCOVERY

Identifying a Drug Target. Most Drugs work by interacting with a TARGET MOLECULE (receptors/channels)AGONISTS Stimulate the TargetANTAGONISTS Block the Target

New drugs discovered by: Trial & ErrorSerendipityRational Drug Design

Ligand-based Drug/Indirect Drug Design.Knowledge of other molecules that bind to target and minimal structural characteristics needed to bind to targets are defined.

Structure-based Drug DesignRelies on 3-D knowledge of the three dimensional structure of the biological target

Page 5: Understanding clinical trials

DRUG DISCOVERY

Identifying a Drug Target. Most condition as due to defects in biochemical pathwaysIdentifying the target is the start of the drug discovery programme

Developing a Bioassay: A bioassay is devised to measure effects of a drug.

Screening drugs in the bioassay. Drug must clear this step

Establishing Effective and Toxic Doses: Provides clues for doses in humans

Investigational New Drug (IND) FilingSpasticity & Tremors

Develop

Page 6: Understanding clinical trials

• PRE-CLINICAL FAILURE• Model does not reflect human disease biology• Drug does not target biology relevant to human application• Lack of appreciation of human disease• Dogma & overstating effect • Model used in a way that does not reflect human indication• Drug doses are not used in at physiological doses• Drugs are not delivered in a way appropriate to how used in humans• Studies are not transparent & not reproducible (Ineffective Study Design)• CLINICAL FAILURE • Lack of clear understanding of human pathology• Drug is seldom investigated by scientists developing the Idea.• Over-interpretation of significance of pre-clinical studies• Drug is not used at a dose relevant to the pre-clinical studies• Population does not respond as predicted. (Ineffective Trial Design)• Dose-limiting side-effects• Study Underpowered, too short or unrealistic expectations• Measurement Instruments Inadequate Clinical Outcomes and Surrogate Markers• Wrong Group of pwMS studied (IneffectiveTrial Design)• Commercial Interests

Mechanism is all Important. Relevance of Slight Delay of a Few Days, Slight Diminution

Prophylactic/Therapy“Building Site Effect”

“Route & Timing”

“Placebo Effect”Less Circuitry so Less Compensation Capacity

Non-Responders

Immune (T/B cell) or Neurodegeneration

Professional Trialists

Reporting Issues

FAILURE TO TRANSLATE ANIMAL STUDIES TO MS

Page 7: Understanding clinical trials

$£€ PATENT

A patent is a set of exclusive rights granted by a state to an inventor for a limited time (Usually 20 years from the filing date) in exchange for public disclosure of an invention.

Prevent Others from commercially exploiting the Invention

Patents are “prosecuted” by Patent Examiner and rejected or Granted

Invisible for 18 months from filing.When published it becomes Prior Art and enters the Public Domain

A granted patent application must include one or more Claims that define the Invention

Patents should demonstrate: Novelty, Usefulness Non-obviousness by someone skilled in the Art

European Patent Office: https://www.epo.org/searching/free/espacenet.html

Patents are filed and Paid Country by Country and need to be translated Patents are subject to Renewal Fees to keep the patent in force(USA Fees due 3½, 7½ and 11½ years after grant of the patent, UK yearly after year 4).

Page 8: Understanding clinical trials

GENERICS

After Patent Protection is lost Competitors Make Generics

A generic drug is a (small molecule) drug defined as "a drug product that is comparable to a brand/reference listed drug product in dosage form, strength, quality and performance characteristics, and intended use.

Generic Biopharmaceuticals are known as biosimilars

Biosimilars are typically more expensive to make than small molecules and so price does not drop too much.

Brand Product Generic Betaseron Extavia (about $3,500 p.a. cheaper) Copaxone (one & day) Glatopia

Gilenya Patent Expires US 2019

Page 9: Understanding clinical trials

PHASE 0 PRE-CLINICAL

Cellular Assay Potency: Selectivity (Screen against broad spectrum of targets)

Activity in in vitro Assays

Phys-Chem Solubility Stability

Stability Cytochrome P450-Inhibition/Microsome Stability, Drug transporters

In vitro Toxicology Ames-test, hERG, Nav1.5

BBB Permeability Caco2, P glycoprotein assay

Pharmacokinetics Rodent (mouse/Rat), & metabolite studiesPK/PD Disease Model Mechanism of Action Studies

Pharmacokinetics Second Species

Chemistry Scale up Production, Formulation feasibility, stability

Toxicity In vitro in vivo in rodents In vivo in second species (pig, dog, non-human primate)

Safety In vitro & vivo Cardiovascular & CNS safety, Genotoxicology, ReprotoxCarcenogenicity

WORKS IN pwMS

PHASE I

PHASE III

PHASE II

PHAS

E 0

SAFE IN HUMANSSAFE IN ANIMALS

SAFE (& HIN

T OF W

ORIN

G) IN

pwM

S

Page 10: Understanding clinical trials

ADME STUDIES

Liberation: Release of the drug from the pharmaceutical formulation

Absorption: Process of Drug Entering the Blood Circulation Bioavailability that influence routes of administration

Distribution: Dispersion or dissemination of substance throughout the fluids and tissues of the body and Blood Brain Barrier Permeability

Metabolism: Biotransformation or Inactivation. Drug-metabolism by cytochrome p450 enzymes

Excretion: Removal of the compounds and their metabolites from the Body Kidneys (products excreted in urine) Gut (Biliary or Faeces excretion)

Lungs (gases

PHASE 0 PRE-CLINICAL

TOXICOLOGY STUDIES

INVESTIGATIONAL NEW DRUG (IND) Filing to get permission to text drug in humans

Page 11: Understanding clinical trials

International Conference on Harmonisation (ICH) of Technical Requirements for Registration of Pharmaceuticals for Human Use

Brings together Drug Regulatory Authorities of pharmaceutical industry of Europe, Japan & USA

• Prevents duplication of Trials in humans• Streamlines the regulatory Assessment process for new Drug Applications• Reducing the development times for drug development

GuidelinesQuality Guidelines: Pharmaceutical QC based on Good Manufacturing Practice

Safety Guidelines: Safety Guidelines to uncover potential Risks

Efficacy Guidelines concerning Design conduct , safety and reporting of clinical trials Good clinical Practice

Multidisciplinary Guidelines cross cutting topics e.g. medical terminology

Trial Is conducted in compliance with a protocol that has received prior ethical Review

CLINICAL TRIALS

Page 12: Understanding clinical trials

PHASE 0 TRIAL Phase 0 trials can be the first-in-human trials in human subjects.

Microdosing: Single sublethal doses administered to a small group (e.g.10-15) healthy

• Pharmacokinetics in humans instead of relying on animal data Low doses unlikely to lead to side effects

Time course of drug plasma concentrations over 96 hours following oral administrations every 24 hours (τ). Absorption half-life 1 h, elimination half-life =12h. Note that in steady state and in linear phamacokinetics AUCτ=AUC∞. Steady state is reached after about 5 × 12 = 60 hours.

Page 13: Understanding clinical trials

PHASE I TRIAL

Phase I trials are usually the first stage of testing in human subjects.

Normally, a small group (e.g.20–100) healthy volunteers will be recruited.

• Safety (Pharmacovigilance) • Tolerability,• Pharmacokinetics (PK. What the Body Does to the Drug. ADME)• Pharmacodynamics (PD. What the Drug does to the Body. E.g. blocking target)

Dose Ranging (Dose Escalation)Phase I trials: 0ften include healthy volunteers.

Sometimes in people with Disease

Volunteers are paid an inconvenience fee for their time spent in the volunteer centre. Pay depends on length of participation.

Phase 1a Single Ascending Dose (SAD) (Maximum Tolerated Dose)Phase 1b Multiple Ascending Dose (MAD)Food Effect. Influence of Feeding

Page 14: Understanding clinical trials

PHASE II TRIAL

Once Dose or Range of Doses Identified

Phase II trials are the first stage of testing in human subjects with Disease (pwMS). Normally, a larger group (e.g.100–300/group) people with Disease recruited.

• Safety (Pharmacovigilance)/Toxicity • Tolerability,• Efficacy

• Pharmacokinetics/Pharmacodynamics sometimes

Size informed by Past Studies

Phase IIa Designed to assess dosing requirements Phase IIb Designed to study efficacy at the prescribed doses.

WORKS IN MSers

PHASE I

PHASE III

PHASE II

PHAS

E 0

SAFE IN HUMANSSAFE IN ANIMALS SAFE (&

HIN

T OF W

OR

ING

) IN M

Sers

Page 15: Understanding clinical trials

PHASE III TRIAL Phase III (Pivotal) trials are the final stage of testing in human subjects with Disease (pwMS) prior to licensing. They are designed to show effectiveness in clinical practise

Normally, a large group (e.g.300–1000/group) people with Disease recruited. They are often randomised, multi-centre studies

• Safety/Tolerability• Efficacy• Pharmacokinetics/Pharmacodynamics/Pharmacogenomics done sometimes

Size informed by Phase II Studies

Phase IIIb Extension Study of Phase III. People continue taking drug whilst licencing in progress, placebo arm switch to active drug.Extra safety/Efficacy Data.

TWO phase III Trials Required to Replicate the efficacy/safety data.Regulators like to see evidence of a dose-response

NEW DRUG APPLICATION (NDA) to Regulators where Sponsors suggest new pharmaceutical for sale and marketing.

Page 16: Understanding clinical trials

REGULATORY AUTHORITIESMHRA: Medicines and Healthcare Products Regulatory AgencyEMA: European Medicines AgencyFDA: Food & Drug Administration in USA

NICE National Institute of Health and Clinical Excellence

National Institute of Health and Clinical Excellence

COST EFFECTIVENESS ASSESSMENTS

Page 17: Understanding clinical trials

Quality-adjusted life-year (QALY) is a measure of disease burden including the quality and quantity of Life. The QALY is based on the number of years of life that would be added by the intervention Suggested Limit for Cost effectiveness is about £30,000/QALY

SATIVEX: £49,300/QALY in UK (Lu et al 2012) FAMPYRA: £160,000/QALY in UK

REGULATORY AUTHORITIES

Page 18: Understanding clinical trials

ANTI-INFLAMMATORY DRUGS FOR MS

INDUCTION

Lemtrada

ESCALATION

First Line

AvonexBetaseronExtaviaRebifCopaxoneAubagio

Tecfidera

Second Line

Gilenya

Tysabri IncreasingEfficacy/

Side-Effect RiskRRMS = Considered Cost-EffectiveMost PPMS/SPMS = Considered Non Cost-Effective

CHOICE

NoEvidence of

Disease Activity

REGULATORY AUTHORITIES

UK First LineUSA Third Line

Page 19: Understanding clinical trials

NO-EVIDENCE OF DISEASE ACTIVITY

NEDA-4NO BRAIN ATROPHY

NEDA-5/6NO NEUROFILAMENTS INCSF (NERVE BREAK DOWN)

NO COGNITIVE DYSFUNCTION

NoEvidence of

Disease Activity

THERAPEUTIC TARGETS

NEDANO RELAPSES

NO GADOLIUM ENHANCINGLESIONS

NO PROGRESSION OF DISABILITY

Page 20: Understanding clinical trials

PHASE IV STUDIES Phase IV trials are known as Post-Marketing Surveillance after the drug is approved to be sold and is used in medical practise.

Normally, data is collected from people using the drug

• Safety/Tolerability (pharmacovigilance). Identify low prevalence/long-term side-effects

• Conditions in trials may differ from those in clinical practise

• Trial Duration is limited (2 years)

• Drug Interactions

Page 21: Understanding clinical trials

CLINICAL PRACTISE

Page 22: Understanding clinical trials

LICENSED PRODUCT FOR

CANCER NEW USE IN MS

REPURPOSING

REPURPOSING FOR RRMS –LICENCED OPTIONS AVAILABLE(AZATHIOPRINE AS GOOD AS BETA INTERFERONS)

REPURPOSING FOR PPMS/SPMS-NO LICENCED OPTIONS AVAILABLE

patent

Page 23: Understanding clinical trials

THE PHARMA WAY REPURPOSING

Page 24: Understanding clinical trials

THE PHARMA WAY REPURPOSINGTHEIR OWN DRUGS

Page 25: Understanding clinical trials

SCIENCE INNOVATION: IDENTIFY TARGETSLEAD TO PATENTS & COMMERCIAL DEVELOPMENT

CLINICAL INNOVATION: IDENTIFY TARGETS FOR PHARMA EXPLOTATIONIDENTIFTY TARGETS FOR PHARMA REPURPOSINGLEAD TO PATENTS & COMMERCIAL DEVELOPMENT

IDENTIFY METHODS TO DETECT EFFICACYRAPID PHASE II DESIGNROBUST TRIAL DESIGN SUPPORT THE CASE FOR A CHANGE IN REGULATION

THE ACADEMIC WAYREPURPOSING

REGULATORS: BARRIERS CREATED FOR PHARMA-HARD TO ACHIEVE FOR ACADEMICSFUNDERS: FINANCING TWO PHASE III DEVELOPMENT PLANS & REGULATORS DIFFICULTGOVERNMENT: NOT CREATING INCENTIVES/STRUCTURES

Page 26: Understanding clinical trials

Maximum Funding for Academic Trial = £2-4,000,000

New DMT due to Academic Led Trials UnlikelyDMT cost for Comparator (current cost £12,000 per person) v Test e.g. Trial of 500 people = £6,000,000

Speak to EMA =£>30,000 MHRA = £>3,000 (hour consultation)Holding Licence = >£100,000

Trial Monitoring & Regulatory Submission. Pharma may pay >£50,000,000In EU should not prescribe off-label if there is Licenced alternative

OFF-LABEL prescription for untreated conditions possible

THE ACADEMIC WAYREPURPOSING

Page 27: Understanding clinical trials

DESIGN OF TRIAL

PATIENT POPULATION: Ensure that participants are similar to reduce variability of ResultsInclusion CriteriaExclusion Criteria

CONTROL: Treatment is Against Placebo or Active comparatorSuperiority Trial (Active Test Drug is better than placebo or Active Comparator)Non-Inferiority Trial (Active Test Drugs is no worse than highly active Comparator)

OBJECTIVES/ENDPOINTS: Defined Primary Endpoints/Secondary Endpoints.If Primary Endpoints are not Achieved Trial is a Failure

If Primary Endpoints are not Achieved by Secondary Endpoints Achieved Trial is a Failureand New trial will need to be done with the Secondary endpoints of the first trial now thePrimary endpoints in the second trials

BIAS ELIMINATION: Randomisation & Blinding of pwMS and monitoring Neurologist

SAMPLE SIZE Big enough to show effect small enough to limit exposure of humans to drugThat could be dangerous

Page 28: Understanding clinical trials

ENDPOINTS IN MS TRIALSCLINICAL• ANNUALISED RELAPSE RATE (ARR): NUMBER OF RELAPSES DIVIDED BY THE TRIAL DURATION ARR =1 = 1 relapse a year ARR = 0.1 = 1 Relapse every ten years• DISABILITY PROGRESSION (TIME TO EDSS INCREASE)

MAGNETIC RESONANCE IMAGING

• T1-GADOLINIUM ENHANCING LESIONS = ACTIVE BLOOD BRAIN BARRIER BREAKDOWN• T1 BLACK HOLES = MEASURE OF NERVE DAMAGE & GLIOSIS• T2 LESION VOLUME = MEASURE OF LESION LOAD• BRAIN ATROPHY = VOLUME OF THE BRAIN = NERVE LOSS + OEDEMA + GLIOSIS• SPINAL CORD ATROPHY = VOLUME OF THE SC = NERVE LOSS + OEDEMA + GLIOSIS

• MTR =MAGNETIZATION TRANSE RATI0 = (LOOSE) MEASURE MYELIN LOSS• N-ACYTEL ASPARTATE (NAA) = (LOOSE) MEASURE OF NERVE LOSS

QUALITY OF LIFE (QoL) QUESTIONAIRES• MULTIPLE SCLEROSIS IMPACT SCALE (MSIS-29)

Page 29: Understanding clinical trials

DESIGN OF TRIAL

TITRATION (INCREASING DOSE) DESIGNS

CROSS-OVER DESIGN: Each person acts as their own control (Reduces number of people)

PARALLEL GROUP: Each person gets only one treatment control verses Test

Randomization

Test

Control

Test Control

TestControl Was

h-O

ut

CROSS-OVER DESIGN PARALLEL GROUP

Page 30: Understanding clinical trials

SAMPLE SIZE CALCULATION

SAMPLE SIZE Big enough to show effect small enough to limit exposure of humans to drugthat could be dangerous

Sample size = Capacity to predict the correct result (Power) with a probability of the result being significant for a certain effect size of the treatment.

POWER or Sensitivity is the probability that the test correctly rejects the null hypothesis (that there is no difference between groups) when the alternative hypothesis (There is a difference between groups) is true.

As the power increases, there are decreasing chances of a Type II Error (False Negative) and Type I (False positives) Errors. In trials an 80% power is often used although this is increased to 90% in some phase III trials

PROBABILITY. (e.g. P=0.05. There is a one in twenty chance of getting this result by chance so if the level is set a P=0.001, it would be a one in a thousand chances)

EFFECT SIZE. How much is effect is the drug going to have a 10% reduction or a 60% reduction the smaller the effect the larger sample size

Page 31: Understanding clinical trials

BIAS REDUCTIONRANDOMIZATION

Process by which people are allocated to an interventionafter assessment eligibility

• It eliminates selection bias• It eliminates confounding issues by adjusting co-variants (gets same demographics in test and control groups) • Facilitates Blinding of investigators, participants, and assessors

BLINDING/MASKINGIndividuals withheld the knowledge of the treatments

OPEN LABEL No BlindingSINGLE BLIND pwMS unaware of their TreatmentDOUBLE BLIND Neuro & pwMS unaware of their treatmentTRIPLE BLIND Neuro & pwMS and Assessor unaware of treatment

Page 32: Understanding clinical trials

1. TITLE & ABSTRACT2. BACKGROUND & OBJECTIVES3. TRIAL DESIGN4. PARTICIPANTS (Eligibility)5. TREATMENT6. OUTCOME MEASURES7. SAMPLE SIZE CALCULATION8. RANDOMIZATION METHOD9. ALLOCATION OF RANDOMISATION10. IMPELEMENTATION OF RANDOMISATION11. BLINDING12. STATISTICS13. PARTICIPANT FLOW RESULTS14. RESULTS-RECRUITMENT15. RESULTS-BASELINE DEMOGRAPHICS16. RESULTS-NUMBERS- HOWMANY PEOPLEIN EACH GROUP17. RESULTS-OUTCOMES18. RESULTS ADDITIONAL ANALYSIS19. RESULTS-SIDE EFFECTS20. DISCUSSION-LIMITATIONS21. DISCUSSION- GENERALISABILITY (VALIDITY)22. DISCUSSION- INTERPRETATION23. REGISTRATION (www.clinicaltrials.gov)24. SOURCE OFPROTOCOL25. FUNDING

CONSORT GUIDELINES FOR REPORTING DESIGN OF TRIAL

Checklists of Reporting Items

Improve Transparency and Replication

Ensure critical appraisal and interpretation

http://www.consort-statement.org/

Page 33: Understanding clinical trials

DEMOGRAPHICS: Comparing Like for Like (Sex, Age, History)

SAMPLE SIZE Power to Detect ChangeToo Small- Miss Important EventsToo Large-Extra Cost/Risk to People in Study

BIAS REDUCTION:•RANDOMIZATION: Methods to Achieve this. Was it achieved?•BLINDING (Single Blind/Double Blind)

METHODS OF Is the correct analysis used?ASSESSMENT

OUTCOMES: Are they fit for purpose?Are the Outcomes Responsive?Control Response (Placebo Effect)

COMPLIENCE Drugs don’t work if people do not take them

SIDE-EFFECTS Tolerability

*

*

*

CONSORT GUIDELINES FOR REPORTING DESIGN OF TRIAL

Page 34: Understanding clinical trials

Assessment for Eligibility

Randomization

Allocated to Intervention

Received Intervention

Follow Up

Analysed

Did Not Receive

Lost to Follow Up

Not Analysed

Allocated to Intervention

Received Intervention

Follow Up

Analysed

Did Not Receive

Lost to Follow Up

Not Analysed

Excluded

TEST CONTROL

CONSORT GUIDELINES FOR REPORTING DESIGN OF TRIAL

Page 35: Understanding clinical trials

TRIAL REGISTRATIONwww.clinicaltrials.gov (US-based Repository of Clinical Trials)NCTxxxxxxxx

https://www.clinicaltrialsregister.eu/ctr-search/search (EU Trial Register)EudraCT Number = Year- xxxxxx-xx

• REGISTRATION SHOULD OCCUR PRIOR TO BEGINNING STUDY

TRIAL DESIGNTRIAL ENDPOINTSTRIAL SITES

All Changes are Logged28,229/89,204 (31.7%) registered studies had their primary outcome changed.10,623/40,615 (26.2%) had their primary outcome changed after the study completion date. Ramagopalan SV et al. F1000Res. 2014; 3: 77.

Changes to Primary Outcomes after trial Completion Data were associated with a statistically significant primary outcome report. Ramagopalan SV et al. F1000Res. 2015; 4: 80.

• LIMIT DUPLICATION• CREATE EXSISTENCE OF A TRIAL (IMPORTANT FOR NEGATIVE STUDIES)• MINIMISE USE OF ANIMAL TESTING WITHOUT COMPROMISING SAFETY

Data Dredging for significant results = P hacking

Page 36: Understanding clinical trials

EVIDENCE-BASED MEDICINE/EVIDENCE BASED PRACTISE

Class 1(A). Evidence from a well designed randomised controlled trial of appropriate size. Systematic review of trials. e.g. Cochrane Collaboration Reviews (www.cochrane.org/)

Class 2(B).  Evidence from a well designed intervention study without randomisation.  A common research design is the before-and-after study.

Class 3(C).  Evidence from a well designed non-experimental study  e.g. cohort, case-control or cross-sectional studies. (Also include studies using purely qualitative methods) E.G. (cost-effectiveness studies).

Class 4(D). Opinions of respected authorities, based on clinical evidence, descriptive studies or reports of expert consensus committees

CLASS OF EVIDENCE

Page 37: Understanding clinical trials

DATA HANDLING

Mean = Average (Rarely used in Trials)Standard Deviation = Approximation of Variability 1.96SD contains 95% of sampleStandard Error (Square Root of SD) place were mean will occur in 95% of studies

Median = Middle NumberRange = Top – Bottom resultQuartile= 0, 25, 50, 75,100%Percentile = 1-100th divisionConfidence Interval 95% CI = 95% that mean will be with in limits

ANALYSISProportions: Chi-SquareTwo Groups: t test, Mann Whitney UMany Groups: ANOVA, kursall and Wallace

Is data Normally Distributed are the Variances EqualIf not use non-parametic stats

DATA ANALYSIS

Page 38: Understanding clinical trials

BIOLOGICALLY SIGNIFICANTA difference between groups that has a real impact on biology

STATISICALY SIGNIFICANTMathematical Measure of a difference between groups. Does this occur at a level greater than may be expected by chance.

PROBABILITY VALUESLikelihood of obtaining a statistical result by chance, assuming there is no Difference in the results (null hypothesis) being investigated

P=0.05 is 1 in twenty chance of event occurringP=0.01 is 1 in one hundred chance of event occurring by chanceP=0.001 is 1 in one thousand chance of event occurring by change

Less Likely due to chance

DATA ANALYSIS

Page 39: Understanding clinical trials

PRESENTATION OF DATA

PIE CHARTSThese show the proportions of response, seldom used in trials, but may occur in Marketing material

A (50%)

B (25%)

(4%) D

(21%) C

Page 40: Understanding clinical trials

BAR CHARTSThese show the magnitude of the response/outcome

PRESENTATION OF DATA

Treatment A Treatment B

Cou

nt

Bar Chart

0

Measurement (Units)

Freq

uenc

y (%

)

Histogram

10 20 30 40 50

Page 41: Understanding clinical trials

WATERFALL PLOTThis graph represents each patient individually (e.g. looking at response rate status of each patient whether progression stabilization of improvement

PRESENTATION OF DATA

Page 42: Understanding clinical trials

LINE GRAPHS These show the analysis over a period of time (serial analysis)

PRESENTATION OF DATA

Page 43: Understanding clinical trials

KAPLAN-MEIER SURVIVAL CURVEThe curve represents the proportion of the study population that are free of the event (Progression, Time to relapse etc ) as successive times. i.e Time to an event

Commonly used to represent overall efficacy.

The larger the difference in the curves the larger the difference

PRESENTATION OF DATA

Page 44: Understanding clinical trials

HAZARD RATIOThe Hazard Ratio is the Relative Risk of the Event (e.g. Disease progression) happening in one arm of a trial compared to another over the time of the trialarm difference between groups that has a real impact on biology

Hazard Ratio = 1 means there is no differenceHazard Ratio = 2 means there is twice/double the risk Hazard Ratio = 0.5 means there is half the risk. Reduced risk by 50%

This methodology uses all available information, including people who didn’t complete the study

DATA ANALYSIS

Page 45: Understanding clinical trials

CONFIDENCE INTERVAL (CI)The CI Percentage indicates the certainty that a result will fall into a range of results noted by lower and upper limits

HR 0.55 (95% CI 0.40-0.77) The risk of converting to clinically definiteMS is reduced by 45% with estimates ranging from 60% reduction to 23% reduction and 95% certainty that the result would lie between 23% and 60% risk Reduction

The narrower the range the more precise the result.

The CI are used as an indication how a study would be reflected in the general population

DATA ANALYSIS

Page 46: Understanding clinical trials

PRESENTATION OF DATASCATTER GRAPH (Relationships)Individual data points are plotted showing two variables (e.g. height verses weight) to show relationships

Random Positive relationship Negative relationship

UnrelatedUnrelated Subset

Page 47: Understanding clinical trials

PRESENTATION OF DATASCATTER GRAPH (Relationships)

Page 48: Understanding clinical trials

PRESENTATION OF DATAREGRESSION (Relationships)

Spearman's rank correlation coefficient  is a non-parametric measure of stastical dependence between two  variables. It assesses how well the relationship between two variables can be described.

R= +1 perfect Correlation or R = −1 perfect inverse correlation.

R-squared is a statistical measure of how close the data are to the fitted linear regression line. It is the percentage of the response variable variation that is explained by a linear model. Or: R-squared = Explained variation / Total variation (It s between 0 and 100% or 0 to 1:)

90% explained40% explained

Page 49: Understanding clinical trials

PRESENTATION OF DATABOX & WHISKER PLOTRather than show all the distribution of individual data. The data is presented as a box with the whisker indicating deviation.

Page 50: Understanding clinical trials

FOREST PLOTFollowing meta-analysis of a number of different trials some showing benefit some not showing for treatment or for analysis of subgroups within a trial that may respond differently. A Forest plot is a way to compare different groups of data.

PRESENTATION OF DATA

Size of square is proportional to the importance of that data set and the horizontal lines are the confidence intervals

Page 51: Understanding clinical trials

ABSOLUTE RISK REDUCTION (ARR)The Difference between the number of events (e.g. pwMS who progressed)in the test verses the control group. e.g. Placebo progressed = 15% Test Drug = 10% progressedARR of the Test drug = 15%-10% = 5%

RELATIVE RISK REDUCTION (RRR). The RRR looks at the same differenceBetween groups given different treatments but expresses the change in riskAs a proportion, rather than an absolute difference

e.g. RRR of Progression by Test drug = 15-10/divided by progression of control15-10/15 = 5/15 = 33%

DATA ANALYSIS

Page 52: Understanding clinical trials

NUMBER NEEDED TO TREAT (NNT)The NNT is a statistic that tells one the actual number of pwMS that would need to be treated with a given therapy for a one patient to get a particular endpoint benefit. Determines whether Large number or small number of pwMS benefit. The Lower the NTT the more effective the treatment.

ODDS RATIO. A measure of treatment effectiveness. The OR is the odds of an event happening in the treatment group expressed as a proportion of the odds of the event happening in the control group.

OR close to 1 the smaller the difference in the treatment effectIf greater (or lesser) than 1, then the treatment is greater (or less) than the control treatment.

DATA ANALYSIS

Page 53: Understanding clinical trials

INTENTION TO TREAT (ITT) ANALYSISITT analysis of the results of a trial is based on the initial treatment assignment and not on the treatment eventually received. ITT analysis is intended to avoid various misleading artefacts that can arise such as crossover loss of subjects, that may break random assignment to the groups.

ITT analysis provides information about the potential effects of treatment policy rather than on the potential effects of specific treatment.

ITT is also simpler than other forms of study design and analysis because it does not require observation of Compliance status for units assigned to different treatments or incorporation of compliance into the analysis.

Medical investigators often have difficulties in accepting ITT analysis because of clinical trial issues like missing data

DATA ANALYSIS

Page 54: Understanding clinical trials

Time

Chan

ge in

Bra

in V

olum

ePlacebo

Test

DATA ANALYSIS

MRI Outcome not fit for purpose: Trial FailedTrial Not Long Enough: Trial Failed

50% of people were not taking drug: Trial Failed

Page 55: Understanding clinical trials

Time

Chan

ge in

Bra

in V

olum

e

Placebo

TestRebaseline

DATA ANALYSIS

Rebaseline to allow for Pseudo atrophy

Page 56: Understanding clinical trials

DATA ANALYSIS

Regression to the mean is the phenomenon that if a variable is extreme on its first measurement, it will tend to be closer to the average on its second measurement—and if it is extreme on its second measurement, it will tend to have been closer to the average on its first.

In MS trials people are more likely to volunteer for trials if they are not doingas well and natural history of disease will mean the flair resolves and they getbetter

Page 57: Understanding clinical trials

ADVERSE REACTIONS

Grade 1 Asymptomatic (no) or mild symptoms; for this grade of AE, treatment is not indicated.

Grade 2 Moderate; for this grade of AE minimal, local or non-invasive intervention may be indicated, for example, this might involve treating the symptom (e.g. nausea and vomiting caused by a treatment

managed/prevented by giving the patient drugs to stop sickness, rather than stopping the drug).

Grade 3 Severe but not immediately life-threatening; for such AEs hospitalization and investigation/ management are often indicated.

Grade 4 Usually life-threatening consequences; for these AEs urgent intervention is indicated.

Grade 5 Death related to AE.

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NERVE LOSS

PROGRESSIVE MSRELAPSING-REMITTING MS

DISABILITY

Frequent inflammation, demyelination,axonal transections, plasticity and remyelination

Inflammation, Persistent Demyelination & Gliosis

Infrequent inflammation, Gliosis, Chronic Neurodegeneration

CLINICAL THRESHOLD

INFLAMMATION

Symptoms

Clinical Effects are Due to Altered Nerve Conduction

CLINICAL COURSE

Immune MediatedBeta-interferons, Aubagio, Alemtuzumab, Cladribine,Bone Marrow Transplantation,

Natalizumab, Rituximab are ACTIVE

NeurodegenerationBeta-interferon, Alemtuzumab,

Cladribine, RituximabBone Marrow Transplantation,

Fingolimod, Natalizumabare INACTIVE to stop Worsening

TREATMENT OF MS FUTURE TRIALS

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TREATMENT PYRAMID

STOP

SAVE

REPAIR

RESTORE

FUTURE TRIALS

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CONCLUSIONS

DRUG DEVELOPMENT PROCESS IS COSTLY AND SLOW

Clinical Trials are mechanism to develop safe and effective treatments

Understanding the clinical trials allows you to Interpret the results

Knowledge allows you to see the flaws that may affect the interpretation

Knowledge allows you to put the details in context of other studies