of Investigator-sponsored trial (IST) · PDF fileof Investigator-sponsored trial (IST) ... –A cover letter listing all the submitted documents ... blinded to group assignment. When

Prof. Juliana CHANDirector, CRMO

12th Feb 2015

1st Workshop for Clinical Trial Management of Investigator-sponsored trial (IST)

Grant application, Regulatory approvals, and Clinical Trial Insurance

9th December 2015

• Investigator-sponsored study (IST)/ Investigator-Initiated study (IIT)

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Principal Investigator (PI): the physician responsible for conduct of the clinical trial at the local site.

Sponsor: an individual, company, institution, or organization that takes responsibility for the initiation, management, and/or financing of clinical research.

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Manpower & Resource Allocation

Time management/ Planning

BudgetingTeam Work

Clinical Trial is a complicated project

• grant & budget• study design & protocol

write-up• informed consent form

design & informed consent process

• regulatory approval• insurance and indemnity• quality assurance &

quality control• data management • publications• ……

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• Trials should be conducted in compliance with theprotocol which has received IRB/EC approval (ICH-GCP1996, 2.6)

ICH-GCP Principles #6

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• “Joint CUHK-NTEC CREC was established…for overseeing research involving human subjects undertaken by and/or conducted in the premises owned, managed and/or controlled by CUHK and/or NTEC, and/or involving patients and/or staff thereof as human subjects in such clinical studies.

• Jurisdiction: The Joint CUHK-NTEC CREC is responsible for performing ethics and scientific review and oversight of clinical studies:– (a) undertaken by CUHK and/or NTEC (and/or the employees/ appointees/

students of CUHK and/or NTEC);

– (b) conducted wholly or partially in the premises owned, managed and/or controlled by CUHK and/or NTEC; and

– (c) involving the patients and/or employees/appointees/students of CUHK and/or NTEC as human subjects.

Regulatory ApprovalIRB Approval

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• http://www.crec.cuhk.edu.hk/

Regulatory ApprovalIRB Approval

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• Continuous Oversight – The IRB/REC will perform

continuous oversight of each approved clinical study, until its completion or early termination, by:

(a) regular continuing review;

(b) review of amendments and changes;

(c) review of new information;

(d) review of deviations and compliance incidents;

(e) review of safety reports; and

(f) final review.

• Clinical trials should be conducted in compliancewith the Declaration of Helsinki, ICH-GCP, andregulatory requirements (ICH-GCP 1996, 2.1)

– Regulation 36B of the Pharmacy and Poisons Regulations,HK

ICH-GCP Principles #1

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• Under Regulation 36B (the regulation) of the Pharmacy and Poisons Regulations, a Certificate for Clinical Trial/Medicinal Test (the certificate) is required for the purpose of conducting a clinical trial on human beings or a medicinal test on animals. The regulation only applies to pharmaceutical products.– A person must not conduct a clinical trial on

human beings/medicinal test on animals, or cause or permit such a trial/to be conducted, except in accordance with a Clinical trial/medicinal Test Certificate (CTC) issued to the person. Any person who contravenes the above commits an offence and is liable to a fine at level 2 (currently HK$ 5,000).

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Regulatory ApprovalDOH Approval

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Application for a CTC

Is the trial medicine registered in HK?

Any extensive class data or clinical

evidence for the trial medicine?

Is the trial commercially sponsored?

Potential risk of using the trial medicine higher

than standard care?Type C

(Standard)

YesNo

Type A(listed)

No

Yes

No

No

Type B(meeting)

Type B(meeting)

Yes

Yes

Type A: No higher than the risk of standard medical care Listed Scheme (No need to submit GMP, COA, IB)Type B: Somewhat higher than the risk of standard medical care Discussion in Registration CommitteeType C: Markedly higher than the risk of standard medical care Standard Scheme

Regulatory ApprovalDOH Approval

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• http://www.drugoffice.gov.hk/eps/do/en/pharmaceutical_trade/guidelines_forms/clinicalTrial.html

• Standard Scheme:– A completed application form and checklist

– A cover letter listing all the submitted documents

– A letter from PI confirming his involvement

– CV of PI

– CREC approval (may be submitted when available at a later date)

– Proposed patient information and patient consent form, in both English and Chinese, or in Chinese only

– Proposed protocol

– Information on the drug (e.g. investigator’s brochure, package insert, other information if applicable, etc.)

– Sample COA of the drug (no need to submit drug sample)

– GMP Certificate

Regulatory ApprovalDOH Approval

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• The CTC will be used as supporting document for applying Import Licence

• All certificate holders are required to:– Submit all local drug-related safety reports according to specific timeline

– Submit yearly progress report

– Submit final study report

– Renew CTC every 5 years

• According to ICH GCP

– 5.8.1. If required by the applicable regulatory requirement(s), the sponsor should provide insurance or should indemnify (legal and financial coverage) the investigator/the institution against claims arising from the trial, except for claims that arise from malpractice and/or negligence.

• Clinical Trial Insurance has been arranged by Faculty to offer protection to researchers who are involved in clinical trials recruiting human subjects.

Clinical Trial Insurance

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• Currently broker: Newline Asia Services Pte. Ltd.

– No-fault compensation

– Limit of indemnity: $10,000,000 (any one claim and series of claims arising out of one event)

– Deductible:$50,000 each claim

– The policy excludes:

• Trials involving research subjects who are pregnant at the time of the trials unless with prior approval.

• Trials involving research subjects who are under the age of 3 years at the time of the trials unless with prior approval.

Clinical Trial Insurance

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• Investigators should assess the risk level of their trials and decide whether or not to join the scheme.

• Currently apply via CRMO

Clinical Trial Insurance

Grant application What why and how

Juliana Chan Professor of Medicine and Therapeutics

Director, CRMO9th Dec 2015

Grantsmanship is like telling a story

• What is the problem? – Hypothesis (research question) and objectives

• Why do you want to do this?– Background or rationale (your observations and others’)

• How do you do this?– Methods and analysis

• For whom do you do this?– Impacts and implications

• Where and with whom do you do this?– Settings, tools, teams, infrastructures

• Can you deliver?– Access to study subjects, institutional support, track record

My personal observations as a panel member of RGC, ITC, HMRF • Increasing number of proposals of high quality • VERY COMPETITIVE with success rate of 20-30% • RGC

– 2-4 overseas external reviewers (selected by panel member)– 2 readers (panel members, majority overseas experts)– Unlikely to be funded if graded <4.5

• ITC – Detailed review by biotech officer with majority eliminated– 50% success rate of shortlisted for interview by panel members

• HMRF– Similar to RGC with external reviewers selected by grant officers – 2 readers (majority are local experts)

Success and failure• Failure

– Too ambitious, lack of preliminary data or contingency plan– Lack novelty or application or market– Poor presentation, lack clarity in expression and execution– Difficult to read– Lack IP protection – Lack track records

• Success– Well argued rationale – Unmet clinical needs – Built on existing strengths– Good credentials – Scalable and transferrable – Niche area, energizing and enjoyable to read

Success and failure

• ITC, Collaborative Research, TRS, AoE– Big questions and challenges – Deliverables: technologies, products, prototypes – Possibility of commercialization other than just

publications– Novel technology from scientists – Little access to clinicians for translation– Few teams/institutes possess all know-how and capacity to

deliver these complex projects– PI needs to build multidisciplinary team and inter-

institutional collaborations

Evidence based medicine (EBM) based on Bradford Hill’s criteria for causality

• Different methods to generate a body of evidence:– Strength of association– Consistency– Specificity– Temporal relationship– Biological gradient– Biological plausibility– Coherence– Experiments– Analogy

• EBM aims to– protect health– prevent disease – reduce disabilities and death rates– Improves quality of life

AgeSex

Genetics/genomes (e.g. Family history)

Place of residenceEducation Socioeconomic statuspersonality

Social habitsLifestylesBehaviors Psychological health

BP Glucose LipidsObesity

Renal disease

Cardiovasculardisease

HospitalizationsDisabilities

DeathQuality of life

Other diseases

Disease duration

INTERVENTIONS(e.g. drugs)

ADHERENCEACCESSIBITILITYAFFORDABILITY SUSTAINABILITY

Complexity, causes and consequencesPerinataldevelopment

HEALTH CARE SYSTEM

Types of research• Basic Science

– Discovery (genome, epigenome, proteome, metabolome)– Structure and function – Mechanism (proteins, drugs, TCM)– Cell and animal based studies– Biomarkers, pathways and targets

• Clinical Science– Descriptive (epidemiological surveys and cohorts)

• fact finding and hypothesis generating– Analytical (statistics and data mining)– Experimental (invasive or non-invasive intervention)– Clinical trials

• preclinical, phase 1, phase 2a, b, phase 3, phase 4, outcome trials

Types of research • Data Science

– Big data and integrated analysis • multiomic analysis, data mining, machine learning, modelling, artificial

intelligence…)– Pharmaco-epidemiological analysis– Drug utilization studies– Outcome research in real world setting

• Improvement Science– Care processes– Care organization – Health economics – Policy and health care financing – Making EBM happen in real life!

Grant writing

• Summary: 1-2 page • Full proposal: 7-8 pages• Conceptual framework• Diagrams • Flow charts• Consort diagram • Checklist for RCT

Grant writing

• Rationale– your work and others

• Controversies and consensus • Key Questions • Objectives• Setting

– community, clinic-based• Subjects

– inclusion/exclusion criteria

Grant writing• Study design

– Cross-sectional, prospective, case-control – Placebo, active comparator, single/multiple dose– Randomization (single or multiple centres)

• Intervention– succinct and clear (e.g. dose, regimen, route)– people can follow the protocol step by step

• Precision of measurements (e.g. CV of lab assays)• Outcome measures

– Efficacy and safety– Quality of life – Cost effectiveness

Grant writing• Data analysis

– Intention to treat– Per protocol analysis– Pre-define subgroup analysis – Post hoc analysis – hypothesis generating– Adjustment for bias, confounders, attritions – sensitivity analysis

• Sample size estimation– Expected meaningful changes and variance– type 1 and type 2 error– Homogeneity and large effect size: small sample size– Heterogeneity and small effect size: large sample size – Pilot study – Interactive effects

• Expected outcomes and impacts• Budget, justification and timeline• Read again and again before submission!

Consort checklist for randomised clinical trial (RCT)

TITLE & ABSTRACT 1 How participants were allocated to interventions (e.g., "random allocation", "randomized", or "randomly assigned").

INTRODUCTIONBackground

2 Scientific background and explanation of rationale.

METHODSParticipants

3 Eligibility criteria for participants and the settings and locations where the data were collected.

Interventions 4 Precise details of the interventions intended for each group and how and when they were actually administered.

Objectives 5 Specific objectives and hypotheses.

Outcomes 6 Clearly defined primary and secondary outcome measuresand, when applicable, any methods used to enhance the quality of measurements (e.g., multiple observations, training of assessors).

Consort Statement, Annals Int Med 2001C0604 Clinical SOPs

Consort checklist for RCTSample size 7 How sample size was determined and, when applicable,

explanation of any interim analyses and stopping rules.

Randomization --Sequence generation

8 Method used to generate the random allocation sequence, including details of any restrictions (e.g., blocking, stratification)

Randomization --Allocation

concealment

9 Method used to implement the random allocation sequence (e.g., numbered containers or central telephone), clarifying whether the sequence was concealed until interventions were assigned.

Randomization --Implementation

10 Who generated the allocation sequence, who enrolled participants, and who assigned participants to their groups.

Blinding (masking) 11 Whether or not participants, those administering the interventions, and those assessing the outcomes were blinded to group assignment. When relevant, how the success of blinding was evaluated.

Consort Statement, Annals Int Med 2001C0604 Clinical SOPs

Consort checklist for RCT

Statistical methods

12 Statistical methods used to compare groups for primary outcome(s); Methods for additional analyses, such as subgroup analyses and adjusted analyses.

RESULTSParticipant flow

13 Flow of participants through each stage (a diagram is strongly recommended). Specifically, for each group report the numbers of participants randomly assigned, receiving intended treatment, completing the study protocol, and analyzed for the primary outcome. Describe protocol deviations from study as planned, together with reasons.

Recruitment 14 Dates defining the periods of recruitment and follow-up.

Baseline data 15 Baseline demographic and clinical characteristics of each group.

Numbers analyzed 16 Number of participants (denominator) in each group included in each analysis and whether the analysis was by "intention-to-treat". State the results in absolute numbers when feasible (e.g., 10/20, not 50%).

Consort Statement, Annals Int Med 2001C0604 Clinical SOPs

Consort checklist for RCTOutcomes and

estimation17 For each primary and secondary outcome, a summary of

results for each group, and the estimated effect size and its precision (e.g., 95% confidence interval).

Ancillary analyses 18 Address multiplicity by reporting any other analyses performed, including subgroup analyses and adjusted analyses, indicating those pre-specified and those exploratory.

Adverse events 19 All important adverse events or side effects in each intervention group.

DISCUSSIONInterpretation

20 Interpretation of the results, taking into account study hypotheses, sources of potential bias or imprecision and the dangers associated with multiplicity of analyses and outcomes.

Generalizability 21 Generalizability (external validity) of the trial findings.

Overall evidence 22 General interpretation of the results in the context of current evidence.

Consort Statement, Annals Int Med 2001C0604 Clinical SOPs

Diabetes research as an example

RegistryQuality Assurance

Risk prediction

Clinicaltrials

CohortsDatabases Biobanks

Genetic markersPersonalized CareWeb-based portal

Phenotypic heterogeneity

ProtocolsTeam

Monitoring

Suboptimalcare

Genotype-phenotype-intervention-outcome Risk Assessment, Education and Care Centre

Bio-IT platformHealth care policy and financing

My personal experiences• Croucher Foundation

– Clinic-based survey to establish cohorts (Insights: phenotypic heterogeneity)

• Pharmaceutical company grant – A RCT comparing ACEi and CCB in HT and DM (Insights: benefits of structured

care )

• Research Grant Committee– Epidemiological surveys for extended phenotyping (Cohorts/databases)– Genetic research (biobanks)– Central Allocation and Theme Based Research Scheme (genetic analysis)

• Innovation and Technology Grant– Biomarkers discovery for personalized care

• Health Care and Research Fund – Structured Care and quality improvement

My personal experiences • Investigator-initiated studies supported by industry

– Registry and risk equations– Web-based JADE Program– Quality Improvement Program– Comparative effectiveness study – Islet/incretin biology

• JCICM – Mechanistic studies of TCM • External grants

– NIH – Consortium in genetics/genome research in diabetes – EFSD – Depression and diabetes– AAFP Foundation – peer support and diabetes

• Central Policy Grant– Cost effectiveness of Private public partnership through community based DM Centres

• ITC (TSSSU) and social enterprise grants – promotes translation• CUHK, donors and foundations through private-public partnerships • Fellows, postgraduate students, post docs and supporting staff

Knowledge Era

• Information ≠ Knowledge– Information : facts and figures – Knowledge: inter-relationships amongst information

• Novelty ≠ Innovation– Novelty: interesting– Innovation: utility (technology – products/service)

• Problem solving to keep us happy, healthy and productive

• Intellectual property – Novel, not obvious, utility

Knowledge Industry

Discovery

Dissemination

Transfer

People

Products

Services

Academic-industrial-government-foundation collaboration

An idea starts with clinical observation s & should end with a solution