Building Tuberculosis Clinical Research Capacity in China – NIH /China Collaborations

OutlineOutline

NIH TB clinical research activities NIH TB clinical research activities CTCTC (China TB Clinical Trial CTCTC (China TB Clinical Trial Consortium) and the role of NIHConsortium) and the role of NIHPerspective of EBA studies in China Perspective of EBA studies in China

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NIAID TB/HIV Clinical Research Agenda

June 17, 2012Baltimore, MD, USA

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STUDY NUMBER

BRIEF DESCRIPTION

Biomarkers

A5302 Evaluation of TB biomarkers of treatment response in upcoming ACTG (A5289/A5290) and TBTC (Study 31) clinical trials

Diagnostics

A5253 Sensitivity and specificity of TB diagnostics

A5255 FASTER: Rapid TB DST study

A5295 Evaluation of Xpert MTG/RIF Assay

DMID Grant Interferon‐Gamma Release Assays in TB‐HIV co‐infected children

DMID Grant Eiken TB LAMP test for POC TB diagnosis in Uganda

Summary of NIAID Studies for TB ‐ 1

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STUDY NUMBER

BRIEF DESCRIPTION

HIV/TB

A5274 REMEMBER: Empiric TB treatment + ART to reduce early mortality following ART initiation

A5284 RIF + GS‐9350 (Cobicistat) PK interaction

A5290 Comparison of LPV/r‐based ARV ± RAL with RBT and double dose LPV/r with RIF‐based TB RX

LTBI

A5259 Rifapentine‐INH x 3 mos vs SOC for LTBI (TBTC Study 26)

A5279 Ultra‐short course RPT/INH for LTBI

A5300 TMC‐207 for preventive therapy for MDR/XDR contacts

DMID 07‐0083

INH Preclearance before BCG Revaccination

Summary of NIAID Studies for TB – 2

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STUDY NUMBER

BRIEF DESCRIPTION

MDR

A5300 TMC‐207 for preventive therapy for MDR/XDR contacts

A5312 The Early Bactericidal Activity of High‐Dose Isoniazid among Adult Patients with inhA‐related  INH‐Resistant Tuberculosis

Nardell Inhaled Colistin to Decrease XDR TB Infectivity ‐ Harvard CFAR

Optimizing Standard Treatment Regimen

A5307 Essentiality of INH After Two Doses: Randomized 14‐day EBA Comparison of Standard RHZE with Only 2d INH + RZE or Substituting Moxifloxacin for INH (RMZE) During Days 3 and 14

A5311 Phase I Clinical Trial of the Pharmacokinetics of High‐dose Daily Rifapentine, Given as a Single Dose or in Divided Doses to Healthy Volunteers

Summary of NIAID Studies for TB – 3

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STUDY NUMBER

BRIEF DESCRIPTION

Optimizing Standard Treatment Regimen – continued

DMID Grant Evaluation of increasing doses of rifampin (10‐15‐20 mg/day) for safety and improving treatment outcomes

Pediatrics

P1073 Study of IRIS in children ≤ 5 years of age

P1078 Safety and Efficacy of Antepartum vs. Postpartum INH Preventive Therapy in HIV‐infected Women and Infants

IMPAACT CS TMC‐207 with OBT for treatment of MDR TB in children

Other

TBRU EBA Feasibility Study with Standard EHRZ Chemotherapy in Kampala/Mulago

Summary of NIAID Studies for TB – 4

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STUDY NUMBER

BRIEF DESCRIPTION

New Drug Development

A5267 PK interaction study of TMC‐207 and EFV

A5306 Safety, tolerability, and PKI study of PA‐824 together with Efavirenz or Ritonavir‐Boosted Lopinavir or Rifampin

DMID 11‐0006

Multiple Dose Extended EBA of Oxazolidinone AZD5847

DMID Grant PK interactions of one‐dose TMC‐207 with steady‐state rifabutin or rifampin

New Combo Development

A5289 TMC‐207 substitution of standard drugs for TB treatment

A5304/REMox

Two Moxifloxacin containing treatment shortening regimens compared with the standard regimen

Summary of NIAID Studies for TB – 5

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Current NIH sponsored HIV/TB international clinical research sites

Most of the NIH / NIAID sponsored / Most of the NIH / NIAID sponsored / funded early phase TB drug studies are funded early phase TB drug studies are

conducted in the USA, however conducted in the USA, however --

-----Data from healthy volunteers in the USA or any other country may not always be extrapolated to other populations given the current understanding of the metabolism of the TB drugs.

-----Data from healthy volunteers in the USA or any other country may not always be extrapolated to other populations given the current understanding of the metabolism of the TB drugs.

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Large patient population: 1 million new Large patient population: 1 million new PTB cases/yearPTB cases/yearLow cost: 1/3 or 2/3 in comparison to Low cost: 1/3 or 2/3 in comparison to Western Countries Western Countries Excellent infrastructure Excellent infrastructure Increased disease awareness and the Increased disease awareness and the enthusiasm for collaborations enthusiasm for collaborations

Strong government support Strong government support

Advantages Conducting Clinical Advantages Conducting Clinical Trials in China Trials in China

Building Tuberculosis Clinical Research Capacity in China

NIAID is establishing a NIAID is establishing a collaboration/partnership collaboration/partnership with the Chinese Ministry of with the Chinese Ministry of Health (MOH) / TB Health (MOH) / TB Society to build a sustainable Society to build a sustainable Chinese research Chinese research network/consortium that network/consortium that would conductwould conduct multicentermulticenterclinical TB studies.clinical TB studies. April 11 2011, Beijing

TB Clinical Trials in ChinaTB Clinical Trials in China

Drug Period Sponsor Study sites

OPC-67683 2008- OtsukaPharmaceutical Co. Ltd

Beijing,Shanghai,Shenzhen

TMC-207 2010- Johnson & Johnson Pharmaceutical Ltd

Beijing, Shanghai, Shenzhen,Nanjing

Moxifloxacin 2011- TB-Alliance Beijing, Tianjin, Shanghai

Clofazimine 2010- Beijing Chest hospital

Beijing,Chongqing

None of the EBA Studies Have None of the EBA Studies Have Been Conducted in China Been Conducted in China

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History of Delay of AntiHistory of Delay of Anti--TB drug TB drug Use Use in China in China

Drugs Year of discovery Used in China Years delayed Terizidone(TB1) 1946 1950 6

Isoniazid(INH) 1952 1953 41

Streptomycin(S) 1944 1953 9

P-aminosalicylicacid(PAS)

1946 1955 11

Pyrazinamide(PZA) 1952 1957 5

Kanamycin(Km) 1957 1966 9

Rifampicin(RFP) 1965 1973 8

Ethambutol(EMB) 1959 1975 16

Capreomycin(Cm) 1961 1976 15

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Advantages of Conducting Early Advantages of Conducting Early Phase Clinical Trials in China Phase Clinical Trials in China

Data accuracy and reliability

85% of the healthy volunteers are recycled patients in the USA

5% of the phase I healthy volunteers are returning subjects in China

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Qualified hospitals by SFDA for Qualified hospitals by SFDA for clinical trials:384clinical trials:384

Eligible Hospitals for TB Drug Eligible Hospitals for TB Drug Registration TrialsRegistration Trials

Hospital Qualified Subject Beds TB beds

Beijing Chest Hospital TB, Cancer 533 250

Shanghai Chest Hospital TB , Cancer and Respiratory diseases

800 250

Shenzhen Donghu Hospital TB, HIV and Liver disease 600 100

No 1 Hospital of Chongqing Medical University

Respiratory diseases et al 2000 50

Shangdong Chest Hospital TB 452 300

Tian Jin Hai He Hospital TB 270 150

Total 4655 1100

Organizational Structure of Organizational Structure of CTCTCCTCTC

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Chairs / scientific committees / consultants Chairs / scientific committees / consultants (national and international) / data center / (national and international) / data center / administrative offices / ethics committee administrative offices / ethics committee

Central laboratories / pharmacies / QC Central laboratories / pharmacies / QC centerscenters

Research centers: Beijing / Shanghai (2) / Research centers: Beijing / Shanghai (2) / Tianjin / Guangzhou / Shenzhen / Chongqing Tianjin / Guangzhou / Shenzhen / Chongqing / Shandon / Chengdu / Shenyang / Changsha / Shandon / Chengdu / Shenyang / Changsha / Wuhan / Wuhan

CTCTC Mission CTCTC Mission Conduct GCP/GLP compliant multicenter clinical trials for evaluation and approval of new TB drugs/combinations and vaccines with a range of collaborators.Serve as the center of excellence and training to build clinical research capacity within China. Harmonize approaches, policies, and standard operating pressures (SOP) for clinical sites, pharmacies, labs, operational support , and data management/statistical centers.Exchange information and define the optimal methodologies and procedures for efficient regulatory approval of clinical trial application and new drug registrations.

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NIH / China Collaborations Technical assistance / consultations GCP / GLP TrainingsPolicies and procedures Establishing a data center and a Establishing a data center and a coordinating center coordinating center Building websites, in both Chinese and Building websites, in both Chinese and English English Scientific projects / programs

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Feasibility of EBA studies Feasibility of EBA studies in China in China

1.1. Chest hospitals in midChest hospitals in mid--sized cities are sized cities are optimal sites: such as Chengdu, Jinan, optimal sites: such as Chengdu, Jinan, and Nanjing.and Nanjing.

2.2. PK / PD assays can be outsourced by the PK / PD assays can be outsourced by the remote universities.remote universities.

3.3. Office space, Office space, bacteriological laboratory, and the relevant equipment are available.

4.4. Trained Trained microbiologists are urgently are urgently needed.needed.

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Conclusion Remarks Conclusion Remarks The future is promising, The future is promising, but many challenges but many challenges exist exist Partnerships are the key Partnerships are the key to success to success

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““Demystifying PZADemystifying PZA””September 5September 5‐‐6, 2012, Bethesda, MD6, 2012, Bethesda, MD

Areas of Emphasis Areas of Emphasis Mechanisms of action Mechanisms of action Drug resistanceDrug resistanceToxicityToxicityThe role of PZA in The role of PZA in combination therapycombination therapy

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