Download Clinical Trials in Oncology

GCP and
Clinical Trials
Cecilia Graffman
Clinical Research Unit - Oncology
Dept. of Hematology, Oncology and Radiation Physics
What is GCP?
International ethical and
scientific standard for planning,
conducting,
documenting and reporting clinical trials
(1996)
Clinical trials – a background
The different phases of clinical trials
GCP – Good Clinical Practice
Examples of translational research from
oncology
FROM MOLECULE TO MARKET
0
Identification
Preclinical research
Clinical decision
Clinical trials
12
Patent
ends
20
Time
(years)
Authority approval
Marketing and research
DEVELOPMENT OF NEW DRUGS

Number of substances developed from preclinical to
clinical research: 5 of 5000

Number of substances in clinical trials developed to
approved medications: 1 of 5 (2015 – 12%)

Average developmental cost for an approved medication:
> 6 billion SEK

Number of medications which recover developmental
costs: 1 av 12
FÖRESKRIFTER: VARFÖR?
Important milestones
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1906 First Food & Drug Legislation i USA
1931 FDA
1962 Safety documentation FDA
1964 Declaration of Helsinki (Europe/USA)
1996 Läkemedelsverkets Författningssamling
Swedish MPA
1996 International Conference of Harmonization –
Good Clinical Practice (ICH-GCP)
FÖRESKRIFTER: VEM? r
RULUES AND REGULATIONS
 Specific for each country, in Sweden
”Läkemedelsverket” Medical Product Agency -MPA
(Läkemedelslagen 1992 och LVFS) and ethical
approval (law 2003)
 Europe, The European Agency for the Evaluation of
Medicinal Products (EMEA). EU-directive 2003
 USA, Food and Drug Administration (FDA)
Clinical Trial Phases
Clinical trials are conducted in a series of
steps, called phases – each phase is designed
to answer specific research questions
Pre-clinical phase
- in vitro (cell lines)
- animal studies (effects and side effects)
Clinical Phase
Phase I - IV
Phase I
• The testing of a new drug or treatment in a
small group of patients for the first time.
Aim – to evaluate the safety, determine a
safe dosage and identify side effects.
Phase I
• Identify maximum tolerated dose; MTD
• Define toxicity, side-effects
• Small cohorts; 3-6 patients/doselevel
Principles for dose-escalation
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3-6 patients per dose level
Observation time before next dose-escalation
New patients at every dose-level
If toxicity – 6 patients
MTD-1The highest dose of a drug or treatment that does not
cause unacceptable side effects
• Recommended dose for phase II – incidence of DLT < 33%
Phase II
• The drug or treatment is given to a larger group
of patients to see if it is effective and also to
further evaluate its safety.
Phase II
• Primary aim – evaluate response
• Secondary aim – toxicity profile, reason for
phase III
• Same diagnosis
• Larger cohort – 10-50 patients/treatment
group
• Randomized Phase II
Phase III
• The drug or treatment is given to a large gropup of patients to
confirm that it is effective, compare new treatment with standard
treatment and collect further information on its safety
• Ground for registration of new treatment?
• Strict inclusion criteria
• Large cohorts ( 100´s to 1000´s of patients per treatment group)
• Randomized, multicentre
Phase IV
Purpose; to monitor effect and safety after
registration in various populations and the side
effects associated with long-term use.
Very large cohorts (1000´s) representing the
“general patient population”’
Endpoint in clinical trialsPrimary obejective
• In clinical trials, an event or outcome that
can be measured objectively to determine
whether the intervention being studied is
beneficial. Some examples of endpoints are
survival, improvements in quality of life,
relief of symptoms, disease free interval,
disappearance of the tumor.
Effect endpoints
 Response
 Overall survival (OS)
 Disease free survival (DFS, RFS, DFI)
 Time to progression (TTP)
 Duration of response
 Quality of life (QoL)
 Health economy
Clinical trials – Ethical approval
Lagen om etikprövning av forskning som avser
människor 2003:460
The law regulating research involving humans
Why a law?
Sweden has signed the EU convention regarding
human rights and biomedicine. In order for Sweden
to ratify this convention, legal regulation of the
ethical process was required (2001/20/EG)
Ethics legislation
• Research involving live or diseased persons,
biological material from human beeings,
and reseaech involving sensitive personal
information, ”personuppgifter”.
Important points
Humans participating in research need to be protected
against the risk of harm; physical, mental and integrity
High demands on the quality of the research project
It must be documented that the patients have
understood the informed consent and accepted
participation
The general public must be allowed insight into the
process
Regulations regarding research on biological material
Regional Ethics committee
• 6 regions (Lund, Göteborg, Linköping, Stockholm,
Uppsala and Umeå)
• Section for medical research
• Section for research regarding natural science,
”humanistic” and pedagogic research
• I chairman (lawyer) 10 researchers, 5 lay people
Regional Ethics committee
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Decision within 60 days
Approved
Returned for completion
Denied
-> Central ethics committee
16 000 SEK for clinical pharmaceutical research
2000 SEK for amendments
One “huvudman” /principal 5 000 SEK
More than one “huvudman”/principal 16 000 SEK
Central Ethics committee
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”academy of science” – Vetenskapsrådet
Chairman – lawyer
4 researchers and 2 laypeople
Appointed by the government
LVFS 2011:19
• Swedish MPA ”Läkemedelsverket”
regulation regarding clinical trials of
pharmaceuticals for human use
• From May 1st 2004 (revized 2011)
• www.mpa.se
Common EU applications
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Application
Reporting during the trial
Regulations regarding reporting sideeffects
Common database for clinical trials
(EUDRACT)
• Each trial has a specific EudraCT number
• Application done electronically
• Only one application per trial in resp.
country
• MPA must answer within 60 days
• Only one chance to complete
• 45 000 SEK
Good Clinical Practice; GCP
ICH-GCP 1.5.96
GCP
What is GCP = International ethical and
scientific standard for planning, conducting,
documenting and reporting clinical trials
(1996)
Signed by EU, USA, Japan, Australia,
Norway and Canada
Principles for GCP
The Declaration of Helsinki
The declaration of Helsinki
World Medical Association, WMA – Ethical principles
regarding medical research involving humans
Updated at the WMA:s 64th meeting in Fortaleza, Brazil,
October 2013
The world medical association has developed the Declaration
of Helsinki as a statement of ethical principles for medical
research involving human subjects, including research on
identifiable human material and data
The Declaration of Helsinki
”The health of my patient will be my first
consideration” and the International Code of Medical
Ethics) declares that ”A physician shall act in the
patient´s best interest when providing medical care”
The Declaration of Helsinki
Medical research is subject to ethical standards that promote and ensure
the respect for all human subjects and protect their health and rights.
While the primary purpose of medical research is to generate new
knowledge, this goal can never take precedence over the rights and
interests of individual research subjects.
It is the duty of physicians who are involved in medical research to protect
the life, health, dignity, integrity, right to self-determination, privacy and
confidentiality of personal information of research subjects.
Informed consent!
• Sponsor; an individual, company, institution or
organization which takes responsibility for the initiation,
management, and/or financing of a clinical trial
• Investigator, National coordinator, co investigator
GCP ”book”;
• Institutional review board IRB – Independent Ethics
committee IEC
• Investigator; qualifications and responsibilities
• Sponsor, responsibility
• Protocol; Content
• IB - Investigators brochure
• Essential documents and documentation
• Informed consent
Principles of GCP
The rights of the patient is central
Sound pre-clinical and clinical data of the investigational
product
High scientific quality-the trial must be described in a
detailed protocol
Principles of GCP forts.
Approval from IRB/IEC
The investigator must be qualified physician or dentist and all
comprehensive medical decision must be done by the
investigator
Patients who consent to participate must get adequate training
of study procedures
Informed consent must always be obtained before any study
procedure can take place
Principles of GCP forts.
All information regarding the trial must be documented,
handled and archived in such a way as to allow for correct
reporting, interpretation and verification
All information about the patients must be confidential
All investigational products must be manufactured according
to Good manufacturing practice, GMP
Principles of GCP forts.
There must be systems to ensure high quality in all
phases of the study; Monitoring and Standard
Operating Procedures
Principles of GCP forts.
The Declaration of Helsinki;;
• Voluntary
• Right to say no without this affecting future
treatment
• Right to discontinue at any time throughout
the trial without giving any cause
Investigator
Fully Qualified physician/dentist
Responsibilities; IEC, medical care, conduct
according to the protocol, safety reporting and
final report
Sponsor
Study design, the conduct of the study, data
management, documentation, archiving, MPA,
handling of investigational product, monitoring
Safety reporting;
AE, SAE, SUSARS
Guarantee patient safety
Fulfil demands from the authorities
Generate data for research and for the safety profile
of the investigational product
AE Adverse Event
Any untoward medical occurrence/undesirable
experience occurring in a patient participating in a
clinical trial
Does not have to be related to the investigational
drug
Must be documented in patient records and CRF
SAE Serious Adverse Event
An event is serious if it results in any of the following;
Death
Life-threatening
Hospitalization
Disability or permanent damage
Congenital Anomaly/Birth defect
SAE Serious Adverse Event forts.
Must be documented in the patient record and reported
to sponsor within 24 hours if sponsor is pharmaceutical
industry
In investigator initiated studies AND if related to
investigational product it has to be reported to the MPA
within 15 days, if life threatening within 7 days
Special SAE form
All SAE must be followed until restored
SUSARs
• Suspected
• Unexpected
• Serious
• Adverse
• Reactions
Report to EU-database
Electronic reporting
Responsibility of Sponsor
Documentation
Patient record – source data
Case Report Forms – CRFs (eCRF/paper CRF) all
information required by the protocol must be documented in
CRFs
Registration
Pre-treatment
On treatment
Off treatment
Follow up
Investigational product
Must be handled by the pharmacy; documentation
regarding all procedures from receiving the IP,
labelling, distribution and destruction.
Monitoring
Controlling data in the CRFs with source data
All clinical trials must be monitored to ensure high
scientific quality
Investigator initiated trials
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Protocol
Independent ethics committee
Swedish Medical Products Agency
Biobank
Local committees; Radiation committee, Radiology
committee
• CRF
• Monitoring
• Study coordinator if multi centre
Some examples;
CTC- Circulating Tumor Cells
Lisa Rydén. Anna-Maria Larsson
• To estimate whether measurement of CTC in women with
metastatic breast cancer give prognostic information as
well as can be used to evaluate tumor response.
• Gene and Protein expression
RASTEN
Lars Ek, Mattias Belting
• Randomised phase III study with standard treament +/enoxaparine in patients with Small Cell Lung Cancer
• Experimental studies have indicated that the coagulation system
stimulates the growth, invasion, angiogenesis and dissemination of
tumors.
• Clinical studies have indicated prolonged survival with the addition of
anticoagulants.
• Translational studies; Blood and tumor tissue- gene expression
analysis to identify prognostic and predicitve factors.
Phys Can
Anna Johnsson
• Effects of physical exercise and behavioral
strategies to prevent and minimize
cancerrealted fatigue and to improve quality
of lie in patients with cancer.
• Breast cancer ; 213 patients asked to participate, 100
declined. 85 Included and of those have 24 interupted
TACK!