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2013 Educational Material

TB ELIMINATION: DREAM OR REALITY?

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SCHOOL COURSE

2013 Educational Material

Designing clinical trials for new drugs General principles

Prof. Dr Giovanni Sotgiu1, Dr Masoud Dara2

1Clinical Epidemiology and Medical Statistics Unit, Department of Biomedical Sciences - University of Sassari – Research, Medical Education and Professional Development Unit,

AOU Sassari, Italy 2World Health Organization, Regional Office for Europe,

Copenhagen, Denmark gsotgiu@uniss.it, MDD@euro.who.int

Aims

To explain the rationale behind the introduction of new anti-tuberculosis drugs.

To describe the characteristics of clinical trial phases in the tuberculosis field (i.e., phase I, II, and III).

Summary Tuberculosis represents an important clinical and public health threat [1]. Since 1960s’ tuberculosis cases have been treated with a combination of antibiotics active against Mycobacterium tuberculosis strains [2,3]. Unfortunately, several shortcomings in the clinical and public health management of the disease have favoured the emergence and spread of drug-resistant strains worldwide [1,4]. Currently, there are limited therapeutic options to treat the so called multi- and extensively-drug resistant tuberculosis [1,4]. New drugs are needed to prescribe efficacious regimens [1]. However, regulatory agencies (such as Food and Drug Administration and European Medicine Agency) require that specific efficacy, safety, and tolerability criteria are fitted before the introduction of a new drug in the market. Observational and experimental epidemiology can prove the efficacy and safety profile of an anti-tuberculosis drug, but international agencies require only clinical trials for the final approval owing to their scientific strength . After the clinical success of a drug in the pre-clinical studies, clinical trials (that is I, II, and III) can be approved in human beings. In the first clinical phase it is evaluated the safety of a drug in human beings and its pharmacokinetic features. In the second phase it is studied the efficacy of the drug and the correct dosage. The pre-registration phase, i.e. the third, evaluates the efficacy, safety, and tolerability of the experimental drug in a large sample of patients [5].

References 1. World Health Organization. Global tuberculosis report 2012. WHO/HTM/TB/2012.6. Geneva:

WHO, 2012. 2. Toman K, et al. World Health Organization. Toman’s tuberculosis: case detection, treatment,

and monitoring: questions and answers. Geneva: World Health Organization; 2004. 3. World Health Organization. The treatment of tuberculosis guidelines. Document

WHO/HTM/TB/2009.420. Geneva, World Health Organization. 2010. 4. Falzon D, et al. WHO guidelines for the programmatic management of drug-resistant

tuberculosis: 2011 update. Eur. Respir. J. 2011;38(3):516–28. 5. http://cptrinitiative.org/wp-content/uploads/2012/01/Minutes-TB-Clinical-Trials-Consultants-

Meeting.pdf

97

Designing clinical trials for new drugs

General principles

Giovanni Sotgiu1, Masoud Dara2

1Clinical Epidemiology and Medical Statistics Unit, Department of Biomedical Sciences - University of Sassari – Research, Medical Education and Professional Development Unit, AOU Sassari, Italy

2World Health Organization, Regional Office for Europe, Copenhagen, Denmark

Faculty disclosure

• We declare that we have no competing interests.

• We have not received any financial aids or grants from companies involved in the R&D of new anti-tuberculosis drugs.

Introduction

AIMS

• Reasons explaining new clinical trials: TB burden.

• TB and clinical trials: alerts.

• Conclusions

98

CLINICAL RESEARCH

Carstensen, 1948 : first randomization for Streptomycin + PAS.

Epidemiological study of the disease

Burden and social impact in the population

Disease model

Causal relationship

⇓ Need of a new therapy

Pharmacological rationale

Feasibility of the research study

Epidemiological background

Estimated number of cases

Estimated number of deaths

0.99 million*

(range, 0.84–1.1 million)8.7 million

(range, 8.3–9.0 million)

0.63 million**

(range, 0.46–0.79 million)

All forms of TB(men and women)

Multidrug-resistant TB

HIV-associated TB 1.1 million (12.6%)(range, 1.0–1.2 million)

0.43 million(range, 0.4–0.46 million)

The global burden of TB in 2011

*excluding deaths among HIV+ people** prevalent cases*** 2010

~ 0.15million ***

All forms of TB(in women)

2.9 million (33%)(range, 2.6–3.2 million)

0.3 million*(range, 0.25–0.35 million)

WHO; Global tuberculosis report, 2012

99

Most TB cases are still in Asia

South-East Asia

34%

Africa30%

Western Pacific21%

EMR7%

Europe4%

Americas3%

55% cases in Asia WHO; Global tuberculosis report, 2011

Exposure SubclinicalInfection

InfectiousTuberculosis

Non-infectiousTuberculosis

Death

Prevalence of infectious casesDuration of illnessIntensity, frequency and duration of contact

Largely exogenousParticles/volume x exposure timeProduction of infectious dropletsClearance of airExtent of exposure

Largely endogenousInnate resistancePerformance of cell-mediated immunityRe-infectionStrain virulence

Form and site of TBAgePatient’s susceptibilityDelay in diagnosis

R F

R F R F

R F

Natural history of an infectious disease

Epidemiological studies

Observational

Experimental

Descriptive

Analytical

Longitudinal(incidence)

Prospective(cohort)

Retrospective(case-control)

Clinical trials

Field trials

Cross-sectional - Prevalence

100

Final decision?

Evidence based medicine

Good clinical practice

Regulatory Agencies:

EMA

FDA

Drug development

0

2

4

6

8

10

12

14

16

18

1983-1987 1988-1992 1993-1997 1998-2002

Tot

al #

New

Ant

ibac

teri

al A

gent

s

*R2 = 0.99

*p = 0.007 by linear regression

New antibacterials

Edwards J; ICAAC, 2003

Potential reasons for pharmaceutical company shiftsaway from anti-infective development

Shift in demographics of population to elderly;

Need for treatment of chronic diseases;

Antibiotics become auto-obsolete;

Thought leaders advocating conservative use;

Increasing standards for efficacy and safety evaluation;

Increasingly complex patients in clinical trials;

Significantly increased costs in clinical trials;

Attractive to develop agents used for life of patient.

Edwards J; ICAAC, 2003

101

Features of a new drug

n Yesterday: efficacious and safe

n Today: efficacious and safe (improved profile) + :

Social impact:

Original (action and/or formulation) me too drugs

Affordable

Drug development

Advantages

Patient?

Physician?

Healthcare system and society?

Pharmaceutical companies (orphan drugs)?

Drug development

Robert Koch (1843 – 1910)

Discovery of M. Tuberculosis (1882)

102

First sanatorium Germany, 1857 First Dispensary,

Scotland, 1897

Koch, Mtb,1882

Drugs, 1945-1962

MMR,1950

DOTS, 1999

Sanatoria

screening

BCG vaccination

drug therapy

Socio-economic improvement

Surplus of beds (staff)

Inefficient and costly casefinding

Erratic use of drugs

Insufficient funding, HIV

INTERVENTIONS OVER TIME: SHORTCOMINGS

"Why making things simple when they can be made complicated?" XDR-TB is born…

1st-line agents

•INH

•RIF

•PZA

•EMB

Injectable agents

•SM

•KM

•AMK

•CM

Fluoroquinolones

•Cipro

•Oflox

•Levo

•Moxi

•Gati

2nd-line Oral agents

"3rd-line" agents•ETA/PTA

•PASA

•CYS

Not routinely recommended, efficacy unknown,

amoxacillin/clavulanic acid,

clarithromycin,

clofazamine,

linezolid

XDR= MDR + any FQ + ≥1 Injectable (KM or AMK or CM)

WHO; Global tuberculosis report, 2012

103

DRUG-SUSCEPTIBLE TB

Standard regimen does not perform well in key patient subgroups,particularly HIV+ and those with extensive cavitary pulmonary disease

Korenromp EL; Clin Infect Dis, 2003Chang KC; Am J Respir Crit Care Med, 2004

DRUG-SUSCEPTIBLE TB

Duration of treatment: months? operational problems for NTP.

Adherence and supervision.

Adverse events.

Pharmacological interactions.

DRUG-RESISTANT TB

20%–30% with MDR-TB experience treatment failure.

Treatment duration: ~18–24 months.

Adverse events poor adherence.

104

CHILDHOOD TB

Difficult to diagnose.

MDR-TB is difficult to treat.

0.5 million cases and 64,000 deaths in 2011.

The pooled estimate for treatment success was high (81.67%), with 5.9% of deaths; 39.1% experienced AEs.

Ettehad D; Lancet Infect Dis, 2012Migliori GB; Lancet Infect Dis, 2012

WHO; Global tuberculosis report, 2012

PRE-CLINICAL STUDIES

Pre-clinical safety.

Inferentiality of experimental findings in human beings.

Phase 1 studies

105

PHASE 1 STUDIES

Safety, tolerability, and pharmacokinetics (evaluation of dosages).

Activity in the first 1–2 wks of TB treatment effect on sputum bacterial load (EBA).

Activity:

- during the first 2 days correlates with the ability to prevent drug resistance.

- during days 2–14 correlates with sterilizing activity.

Early bactericidal activity (EBA 0–2)

Rate of fall in sputum cfu (log10 units) during the first 2 days of study drug

EBA = (log10 cfu/ml S0 - log10 cfu/ml S2)/2

S0: initial cfu (mean of the cfu from the two pretreatment sputum samples)

S2: day 2 colony count

Extended early bactericidal activity (EBA 2–7)

Rate of fall in sputum cfu between days 2 and 7 (b2–7) estimated by the slope of the linear regression obtained from fitting the six sputum cfu values corresponding to days 2 to 7, with the sign of the slope reversed.

PHASE 1 STUDIES

Activity during days 2–14 may correlate with sterilizing activity

Jindani A; Am J Respir Crit Care Med, 2003

PHASE 1 STUDIES

106

PHASE 1 STUDIES

Activity during days 2–14 may correlate with sterilizing activity

Johnson JL; Int J Tuberc Lung Dis, 2006

Phase 2 studies

PHASE 2 STUDIES

Sputum culture status after 2 months of therapy.

Differences in 2-month cultures are associated with the sterilizing activity of regimens.

A sample size of 100-200 individuals is required.

Dose-finding studies

107

PHASE 2 STUDIES

Changes in quantitative culture results over the first 2 months of therapy

Rustomjee R; Int J Tuberc Lung Dis, 2008

PHASE 2 STUDIES

Time to detection of growth in broth culture systems

R2: 0.92

Joloba ML; Int J Tuberc Lung Dis, 2000

Phase 3 studies

108

PHASE 3 STUDIES

Treatment failure and recurrent TB.

Efficacy, safety and tolerability.

Safety in specific subgroups (elderly, children, pts with co-morbidity, etc.)

Sample size: 500–1,000 patients per arm.

Conclusion

Methodology is crucial.

Sample should be representative.

More focus on sub-groups.

Economic analyses.

109