Clinical Trials for Registration of New Medicines

Becki BINEDELLHoang DANG

MBioEnt Medicines Workshop23Feb2015

DisclaimerThe information within this presentation is based on the presenter’s expertise and experience, and represents the views of the presenters for the purposes of a training workshop

Who are we?

Becki BinedellSr. Clinical Research Associate

Hoang DangClinical Research Associate

Our Agenda History of Good Clinical Practice Guidelines and Regulations Overview of Drug Development Why Clinical Trials?

– Purpose – Phases

Lifecycle of a typical Phase III study Clinical Trial Oversight Issues/Challenges

A history of unethical research Tuskegee (Alabama) Syphilis Study

– 1932 – 1972 WWII: Nazi war crimes in death camps 1960s: Thalidomide

– Prescribed as antiemetic to pregnant women– New borns phocomelia– 50% survival rate

A history of unethical research 1963: NY jewish chronic diseases hospital

injection of cancer cells into transplant patients

1964: NY Willowbrook School hepatitis injections in ‘retarded’ children

Clinical Trial Regulations Nuremberg Code

– End of WWII – set of research ethics principles for human experimentation set as a result of the Subsequent Nuremberg Trials

WMA: Declaration of Helsinki– Adopted in 1964, amended six times since.– 2008 Amendment now published– It is the duty of the physician in medical research

to protect the life, health, privacy and dignity of the human subject.

ICH-GCP ICH-GCP: harmonise the regulations and

guidelines required Who came together?

– Regulatory agency/industry representatives from Europe, Japan and US

Purpose:– Create unified standard / mutual acceptance of

clinical data for drugs, biologics and devices– Remove redundancy /duplication in development

and review process

Brief History: GCP 1995: WHO published Guidelines for Good

Clinical Practice (GCP) for trials on pharmaceutical products

1997: GCP became Topic E6 ICH Who is responsible:

– Sponsor, sites, CROs, ECs, Reg., Participants Encompasses:

– Trial design, conduct, recording, reporting– Ethics + quality

Purpose of Clinical Studies Positive (or negative) data can lead to a

recommendation to use (or not to use) a treatment. Studies can be:– Pragmatic

• determine the efficacy and safety of a medicine in human subjects

• support applications made by pharmaceutical companies to register new medicines for marketing

• guide clinicians as to the best medical practice

– Explanatory• evaluate the biological effects of treatment

IMP development overview

http://www.fda.gov/

Phase I

•20-80 pts; Healthy volunteers•Determine PK/PD and MTD (safety)

Phase II

•200-300 pts•Efficacy, short term side effects, common risks

Phase III

•Hundreds – thousands of pts•Efficacy, overall risk-benefit

Phase IV

•Thousands of pts•Ongoing safety of approved drug

Clinical Trial Phases

New Zealand Clinical Trials Must be reviewed and approved by:

Definitions and Roles Health and Disability Ethics Committee (HDEC)

– Reviews ethical issues relating to studies

Locality– Reviews locality-specific research governance issues

Standing Committee on Therapeutic Trials (SCOTT)– Reviews scientific validity of the study– Relays recommendations to MedSafe

Coordinating Investigator (CI)– Affiliated with NZ site– Lead PI

HDECs

Four Committees:

Northern ANorthern BCentralSouthern

Meeting held every week by one of the four HDECs No costs associated with HDEC review HDEC size of 8 members (5 for quorum)

Online Application Form Secure, password protected online system RED – Research Ethics DB System Any online user can submit the form Responsibility of the lead site Study documents will need to be uploaded before

submission– Coordinating Investigator authorisation must be

obtained

Timelines for approval

HDEC cut off date Decision dueDay 0 Day 15 Day 35

Day after Submission Decision dueDay 0 Day 15 Day 35

• Full review• Physical meeting

• Review of amendments, progress reports, protocol violations• Clock starts day after submission• No physical meeting

Full review cycle:

Expedited review cycle:

Maori review Maori Research Review Committees (MRRC) HDEC review does not constitute

consultation with Maori Up to localities to consult local iwi HDEC does not require evidence of MRRC

approval

Post-Approval items A “post-approval item” is an item submitted for HDEC (or SCOTT) review

through Online Forms in respect of an approved study. Examples of “post-approval items” include:– substantial amendments – annual progress reports– protocol deviations or violations– notifications of conclusion of study– final reports

A substantial amendment is defined as an amendment that is likely to affect to a significant degree any of the following:– the safety or physical or mental integrity of participants– the scientific value of the study– the conduct or management of the study– the quality or safety of any medicine or item used in the study

SCOTT Standing Committee on Therapeutic Trials

Applications made through Online Forms

Site Self-Certification only required for studies where participants are staying overnight or longer during dosing periods

No need to provide SCOTT approval to HDEC (and vice versa)

MedSafe required 6-monthly reports from the Sponsor

Overview of New Zealand and Australia Ethics and Regulatory Environment

CountryPreparation

of Documents

Regulatory Approval Ethics Committee Approvals

Import License

/ Initiatio

n

Parallel or Sequential

Total Timeline

Per legislation Currently achievable

Per legislation

Currently achievable

Per legislation

Currently achievable

Australia 2 weeks

CTN - 10 working days

CTX - 30 (chemical,

pharmaceutical, biological)-

50 working days (medical

devices)

CTN 8-10 working

daysCTX -

variable

60 days 45 days 3 weeks

CTN-Sequential

CTX-Parallel

91- 141 working

days3 months

New Zealand 8 days within 45 days 14 days 1-2 months 21 days NA Parallel 1-2

months1.5

months

…how do we ensure trial patients are safe and confidence in the data?

With what should I be compliant?

ICH/GCP

Local Regulations•FDA•EU Directive•Country

specific guidelines

Protocol•Related

documents

Becki BinedellSr. Clinical Research Associate

Phase III study lifecycleDesign: Randomized, double-blind, placebo-controlled

Aim:To investigate the efficacy, safety and tolerability of

IMP vs. placebo as part of a treatment regimen including peginterferon and ribavirin

Target Population: Genotype 1 hepatitis C-infected subjects

Study overview Number of countries = 24 Number of sites = 180 Number of randomised subjects = 1350

• screening of approximately 1800 subjects in order to achieve 1350 subjects enrolled (25% screening failure rate expected)

CLINICAL FOOTPRINTArgentina - 3 Canada - 8 Mexico - 4 Russia - 13

Australia - 7 France -10 Netherlands - 3 Slovakia - 4

Austria - 3 Germany - 13 New Zealand - 4 Spain - 5

Belgium - 7 Great Britain – 9 Poland - 7 Turkey - 4

Brazil - 9 Israel – 7 Portugal - 6 Ukraine - 4

Bulgaria - 4 Italy - 8 Romania - 3 USA - 35

Investigator costs# of sites Site Set-up costs (fixed) # of subjectsPer Subject costs (variable)

Argentina 3 $12,000 $36,000 30 $9,900 $297,000Australia 7 $12,000 $84,000 70 $9,900 $693,000Austria 3 $12,000 $36,000 30 $9,900 $297,000Belgium 7 $12,000 $84,000 70 $9,900 $693,000Brazil 9 $12,000 $108,000 90 $9,900 $891,000Bulgaria 4 $12,000 $48,000 40 $9,900 $396,000Canada 8 $12,000 $96,000 80 $9,900 $792,000France 10 $12,000 $120,000 100 $9,900 $990,000Germany 13 $12,000 $156,000 130 $9,900 $1,287,000Great Britain 9 $12,000 $108,000 90 $9,900 $891,000Israel 7 $12,000 $84,000 70 $9,900 $693,000Italy 8 $12,000 $96,000 80 $9,900 $792,000Mexico 4 $12,000 $48,000 40 $9,900 $396,000Netherlands 3 $12,000 $36,000 30 $9,900 $297,000New Zealand 4 $12,000 $48,000 40 $9,900 $396,000Poland 7 $12,000 $84,000 70 $9,900 $693,000Portugal 6 $12,000 $72,000 60 $9,900 $594,000Romania 3 $12,000 $36,000 30 $9,900 $297,000Russia 13 $12,000 $156,000 130 $9,900 $1,287,000Slovakia 4 $12,000 $48,000 40 $9,900 $396,000Spain 5 $12,000 $60,000 50 $9,900 $495,000Turkey 4 $12,000 $48,000 40 $9,900 $396,000Ukraine 4 $12,000 $48,000 40 $9,900 $396,000USA 35 $12,000 $420,000 350 $9,900 $3,465,000

180 Total Set-Up Cost$2,160,00

0 1800 Total Subject Cost $17,820,000

Study Management Costs

Project Management and Support $2,400,000Data Management (Vendor) $2,150,000Pharmacovigilance $7,132,000Central Laboratory (Vendor) $6,800,000Cognitive Function (Vendor) $3,200,000ECG (Vendor) $22,000Medical Monitor $55,000IMP supply - formulation/release $643,000Rando/drug distribution (Vendor) $890,000Miscellaneous $192,000

$23,484,000

Clinical Study Costs Cost depends on many factors:

– Is the IP already approved for use?– Number of countries– Number of sites– Drug manufacture– Staff salaries– Vendor costs (CRO, lab, etc.)– Study materials and shipping– Monitoring and site travel– Training meetings– Payments to study participants*

These costs are incurred over several years

Study Management Team Global Project Manager (1) Local Project Managers (4)

Clinical Research Associates (22) Clinical Trial Assistants (3)

• Trial Physicians (PIs, SubIs)• Medical Monitor• Vendor Managers

Direct Contacts and Vendors

STUDY SITE WDC

Central ECG

Data Mgt

IndependentVirology Monitoring

Central Lab

Timelines Important dates for study start:– First subject screened: 18 Sep 10– Target to end screening: end of July 2011

Important dates for study conduct:– First subject treated: end May 2011– Last subject treated: August 2011– Last subject last visit: end Jan 2013– First Interim DB Lock: Mar 2013

Total duration of trial per subject: maximum of 78 weeks

•Screening period:– maximum of 6 weeks

•Treatment period:– 48 weeks

•Follow-Up period:– 24 weeks

Timelines

Patient Recruitment Dilemma

Recruiting in approx 10 months requires fast enrolment

versus

Geographical well-distributed patient population by allowing sufficient time for all sites worldwide

to enroll according to expected start-up timelines

“Competitive Recruitment”

“Controlled Recruitment”

STUDY MILESTONESFeasibility

Country do-abilitySite feasibility

Site SelectionRegulatory and Ethics SubmissionsInvestigator MeetingSite InitiationRoutine MonitoringDatabase LockSite Close Out /study archivingClinical Study Report / FDA submissionFDA Inspection

CLINICAL STUDY MONITORING

CRAs required to monitor sites as part of ICH-GCP requirementsCRA functions:

Ensure rights and the well-being of trial subjects all patients on the study should be eligible and have signed ICF.

On site monitoring / Central monitoringSource Data Verification

The reported trial data are accurate, complete, and verifiable from source documents

Ensures compliance with ICH-GCP, the protocol

The Challenges Pharma/Biotech Industry Face

Pharma industry is shifting clinical trial to where:– Large number of patients/qualified investigators– Good data quality– Cost effective and cost efficient– Significant market potential

Regulatory hurdles have increased– FDA has issued 96 “non-approvable” letters since 2004– NDA rejections have increased by 5-fold– NME approvals down 33% in 2007, lowest number in 27 years

R&D productivity is down– R&D spending has soared but the number of new drugs approved by the FDA is

down

Result:– Reduce Clinical Footprint– Pharma Collboration (eg. Transcelerate)

Emerging Markets

Emerging Market Challenges

Linda Martin, DIA2013

IMP Development Costs

Costs to develop one new drug

• Limited patent window to recoup costs• patent filed on a drug lasts for 20 years

• companies file even before clinical trials• by the time the drug hits the marketplace,

the patent may only have between 8 to 10 years left.

Dramatic change in Study Design

2002 2012Total number of endpoints 7 13Total number of procedures 106 167Total number of eligibility criteria 31 50Total number of countries 11 34Total number of investigative sites 124 196Total number of subjects randomised 597 729Mean number of case report form pages 55 171Total number of data points collected N/A 929,203Average length of clinical trial 460 780

Tufts CSDD, *Medidata

Costs R&D spending from the 12 leading pharmaceutical companies

from 1997 to 2011:– $802 billion to gain approval for just 139 drugs: a

staggering $5.8 billion per drug.

Top 5 Pharma# of Employees Total R&D Spend (USD)

Johnson & Johnson 119,000 $7,500,000,000Pfizer 82,000 $8,000,000,000GlaxoSmithKline 99,000 $7,500,000,000Roche 80,000 $10,000,000,000Novartis 99,000 $8,000,000,000

www.manhattan-institute.org (from 2010 Annual Report)

Top Recruitment Barriers Poor and infeasible protocols Conflicting studies Poor planning and execution Lack of subject incentive to seek alternative

treatments Low public awareness and trust Volunteer concern about safety and

convenience

Health Select Committee ‘Inquiry into improving NZ’s environment to

support innovation through clinical trials’

– Chaired by MP Dr Paul Hutchison

– Govt decisions announced Sept 2011

– 54 recommendations• Simplify and streamline the ethical review process• To ensure regulatory framework is as good as or better than

comparable countries

– 12 months to act

Inquiry into improving NZ’s environment to support innovation through clinical trials (2011): http://www.parliament.nz/resource/0000162010– Ethics systems: slow and bureaucratic– No coordination between DHBs– Friction between Pharmac and pharma

companies– Lack of investment in science, R&D– Lack of modern technical infrastructure

Risk-Based Monitoring Risk-Based Monitoring

– An adaptive approach to clinical trial monitoring that directs monitoring focus and activities to the evolving areas of greatest need which have the most potential to impact subject safety and data quality.

FDA recommends that risk must be:– Identified before the start of the

study, focused on safety and data reliability

– Tailored to the conduct of the protocol to eliminate or mitigate those risks

– Utilize monitoring as an adjunct to other data management tools used to identify early trends and need for re-assessing risks

Why conduct studies in NZ? Diverse patient population Ethnic sub-population English speaking health sector High ethics and well respected physicians Streamlined Ethics and Regulatory process Data Integrity Research Infrastructure

Q+A time

Extra slides

Phase 0 First human models Primary goal is to gather preclinical:

– Pharmacodynamic data (what the drug does to the body)

– Pharmacokinetic data (what the body does to the drugs)

Dose– Small, Sub-therapeutic

Typical Subject #– ~10

Obtains no safety of efficacy data Often skipped for Phase I

Phase I “First in Human” studies Primary endpoints: safety, toxicities, PK/PD,

MTD for Phase II (independent of the study population and secondary parameters)

Healthy volunteers or certain types of patients

Intense study design Exciting, high stress, tight timelines

Phase II IIa (exploratory non-pivotal)

– Primary endpoint: establish efficacy, PD or biological activity

– Usually placebo controlled IIb (definite dose range finding study) in

pts.– Can be used as pivotal studies (rare) – if drug

intended to treat life-threatening or severely debilitating illnesses eg cancer.

Restrictive protocols but easier study design

Phase III IIIa: pivotal study – need statistical

significance/ evidence of efficacy and safety.– Confirmation of safety and efficacy– What claims can be made for post-marketing.

IIIb: support publications rather than registration or label changes– Results not intended to be submitted in

submission dossier IMP helping patients

Phase IV Study starts after approval Intent: support publications Large population group to monitor safety

(pharmacovigilance). Protocol is a lot more relaxed.

What is a Sponsor?An individual, company, institution, or organization which takes responsibility for

– the initiation, – management, and / or – financing

of a clinical trial

Sponsor Responsibilities“The sponsor is responsible for implementing and maintaining quality assurance and quality control systems with written SOPs to ensure that trials are conducted and data generated, documented and reported in compliance with the protocol, GCP and the applicable regulatory requirements.”

ICHGCP5.1.1

ICH/GCP: Investigators responsibilities

Principal Investigator & Qualifications

Compliance with the Protocol

Communication with the IRB/IEC

Informed Consent Process

Source Data and Documents

Safety Reporting

Principal Investigator, Site Staff & Qualifications

Qualified by Education, Training & Experience

Knowledgeable about IP, Trial & related Doc’s

Adequate Resources

PI: SUPERVISE Trial Conduct

Document Delegation of Responsibilities

Document Collection of Data

Communication with the IEC

Approval protocols, ICF, amendments,

IB’s, recruitement materials...

Unique identifiers for documents

Timely information about deviations; safety

issues, trial closure...

Informed Consent Process

Informed Consent EC reviewed and approved prior to use

– Use correct version

Consent from subjects to participate must be without coercion and with full information of study requirements, treatment and side effects

Written consent is documented with signatures of the patient (subject) and the person conducting the consent process (investigator)

Patients must be informed of new information as it becomes available

Stages of a clinical trial Trial set up

– Submissions of all required docs to Reg. + EC Site Initiation

– train site staff Routine Monitoring from CRAs

– Ensure compliance with ICH-GCP and local requirements

Trial completion– Site close outs– Clinical Study Report