Protection of persons in clinical research

1
Protection of persons in clinical research

• Daniel Sereni
• Paris, May 2007

2
TGN 1412 CD28-SUPER MAB

• Humanised Monoclonal
• Antibody
• B chronic leukemia, rheumatoid Arthritis
• London March 2006
• six healthy volunteers multiple organ failure

3
Protection of Persons during clinical research

• New York, 1963, in order to study the immunology
  of cancer a respected specialist in clinical
  research made an experiment in which 22 patients
  received live cancer cells injections without
  their knowledge.
• See NEJM, 351, 628-630, 2004.
• March 1996, a 19-year -old student , healthy
  volunteer died after receiving a fatal dose of
  lidocaine before a fibroscopy as part of the
  study.
• See NEJM, 346, 1425-1430, 2002

4
Declaration of Helsinki

• First adopted 1964, WMA
• 5 Basic principles
• Research must be scientifically and morally
  justified
• Conducted by qualified persons
• Importance of objective in proportion with
  inherent risk
• Preceded by careful assessment of risks
• Special caution if risk of alteration of the
  personality of the subject

5
Clinical research combined with professional
care Non therapeutic clinical research

• The clinical research should be justified by its
  therapeutic value for the patient
• Protection of life and health
• Respect of rights and integrity of the person
• Patients freely informed consent
• Case of legal or physical incapacity
• Right for discontinuation

6
Major Issues for Protection of Participants

• Trials approval and follow up
• Good clinical practice
• Quality of investigational work and monitoring
• standard of care / placebo
• Adverse events
• Toxicological issues
• Finance, Insurance and liability
• Confidentiality

7
Major Issues for Protection of Participants

• Real time information of investigators and
  patients
• Participation of patients to decisions
• Data Safety Monitoring Board
• Interim analysis and other statistical issues
• Disposition of the treatment after the end of the
  trial
• Children, patients in coma, prisoners,
• Stem cells, cloning, genetic screening
• Research into care at the end of life

8
Scientific quality of the research

• The sponsor and the investigator are responsible
• Sponsor institutional or private - industry-
• Investigator scientific credibility
• Authority ( drug agency) may deliver an
  authorisation to start a trial
• after evaluation of the protocol and - when
  justified- of the documents regarding the drug
  Investigators Brochure
• What is not scientifically valid cannot be
  ethical

9
ETHICS COMMITTEE

• Role of the Ethics Committee- Institutional
  Review Board
• Expertise on pre-clinical and clinical studies
• Evaluation of the Protocol
• Relevance of the research
• Qualification of the investigators
• verification that the sponsor is insured and
  liable
• Quality of information
• Evaluation of the risks for the participants
• Amount of financial compensation for participants
• Follow up of the research
• An approval by the Ethics committee is mandatory

10
placebo

• Is it ethical to conduct placebo-controlled
  trials in stable angina?
• A case example ( NEJM, 345,915-919,2001)
• Chronic stable angina has a placebo-response rate
  of 30 to 80
• Stable angina has a fluctuating course with
  spontaneous remissions
• Approved treatments are partly and variably
  effective
• Answer provided the patients with high risk of
  myocardial infarction are identified and
  excluded, short duration ( lt10 weeks ) placebo
  controlled trials are considered as ethical

11
Placebo

• Methodological advantages of placebo-controlled
  trials
• Proves efficacy
• Variability and unpredictability of effects
• Demonstration of side effects
• No harm for the patients receiving placebo
• Less patients exposed to the investigational
  drug to be compared to an equivalence trial
• Ethical criteria for the use of placebo when
  proven therapies exist
• Serious methodological reasons
• Careful selection of patients
• No permanent or adverse consequence
• No serious harm or inconvenience
• the case of Rheumatoid Arthritis
• the case of Crohn disease

12
Placebo

• Is it ethical to use placebo in trials for
• Crohn disease ?
• Rhumatoid Arthritis ?
• Ethical criteria for the use of placebo when
  proven therapies exist
• Serious methodological reasons
• Careful selection of patients
• No permanent or adverse consequence
• No serious harm or inconvenience

13
Adverse Events

• What is important?
• What is to be reported, and How?
• What information to give to the subjects?
• Important
• Serious adverse events
• Unexpected
• Tools
• Protocol
• Case Report Form
• monitoring
• Causality with a treatment or a procedure , or
  the protocol itself
• Committee for validation of adverse events
• Tables
• Ethics committees or authorities can intervene

14
Importance of preclinical studies

15
Toxicology problems revealed during clinical
development

• Bone tumours in rats with an anti osteoporosis
  agent
• Testicular hyperplasia in dogs with a derivative
  of sildefanil ( Viagra)
• QT enlargement in dogs with a new antiviral
• Bladder tumours in dogs with an antimitotic
• How to deal with such problems?
• Are there general guidelines?

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Toxicology

• more questions..
• Is it a class effect?
• Have human toxicity of the kind been reported?
• One specie or several?
• Dose / effect relationship?
• At what dose? What would be the estimated
• corresponding dose in humans? Would that dose be
  in the therapeutic range?
• Is possible toxicity acceptable compared to the
  potential therapeutic benefit?

17
Data Safety Monitoring Board

• What is it?
• What is the purpose?
• How does it work?
• Independent committee of experts
• Assessment of
• Quality of data
• Security of persons
• Absence of major efficacy or safety difference
  that would compromise the continuation of the
  trial
• Highly recommended in phase II,III comparative
  trials
• Independence
• Scheduled meetings
• Access to the complete database
• May make the decision to unblind or to stop a
  study

18
Funding and financing clinical research

• A sufficient funding is a condition of volunteers
  /patients security in clinical research
• Identified source
• A good budget is mandatory
• Investigators honoraria must not be
  disproportionate
• Independence
• transparency
• Compensation or Payment of Volunteers is
  authorised but limited depending on
• Type of study
• Amount   it is not a way to make a living 

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Healthy Volunteers

• Men preferably
• Not supposed to make a living of participation to
  clinical research
• With total freedom
• prisoners?
• people without resources or access to care
• Risk of certain type of compounds cytotoxicity,
  mutagenesis, genotoxicity
• Security depends on
• competencies,
• quality of care
• strict use of good Clinical Practice

20
TGN 1412 CD28-SUPER MAB

• London March 2006
• six healthy volunteers multiple organ failure
• administered at 0.1mg/kg
• 500 lower than NOEL in animals

21
 FIRST IN MAN  clinical trialsEMEA Guidelines
2007

• No expected benefit
• Safety is the paramount consideration
• Requirements animal models
• Pharmacodynamics
• Pharmacokinetics
• Toxicology
• Calculation of the first dose in man
• No Observed Adverse Effect Level ( NOAEL)
• Minimal Anticipated Biological Effect Level
• (MABEL) for  at high risk  drugs

22
 FIRST IN MAN  clinical trialsEMEA Guidelines
2007

• General organisation
• Expert investigators
• Adequate information system between sites
• Long trem monitoring
• Protocol design
• Main purpose is to assess tolerance
• Healthy volunteers or patients
• Sequential dose administration
• Start with single doses
• Importance of the dose escalation scheme
• Number of subjects per cohort
• Collection and review of data between cohorts
• Stopping rules

23
Research in developing countries

•  A new colonialism?-conducting clinical trials
  in India , NEJM 35216, April 21, 2005
• Advantages
• Rapidity
• Lower costs
• What possible dangers / risks for the subjects
  can you imagine?

24
Research in developing countries

• Answers
• Less restrictive regulations
• Research of no interest for the local population
• Insufficient structures, controls and
  competencies
• No or poor chance to get the treatment after the
  trial if beneficial ( affordable?)
• Difficulty in obtaining well informed consent
• Unethical study
• Difficulty in maintaining patients liberty when
  they are proposed disproportionate compensation
  or the hope of receiving an unaffordable
  treatment

25
Difficulties in obtaining correct protection of
subjects in developing countries

• To test an antiviral for preventing HIV infection
  in high risk populations in African and Asian
  countries,
• Prostitutes
• IV drug users
• see the lancet, vol 365, 26 March, 2005
• What is the problem?
•  At the conclusion of the study,every patient
  entered into the study should be assured of
  access to the best proven prophylactic,
  diagnostic , and therapeutic methods identified
  in the study , 2000 Declaration of Helsinki
• Treatment or prophylactic measures will be
  provided by the sponsor after the trial which has
  been approved by national and international
  authorities

26
Information and reporting

• To the participants
• Duty of the investigator
• Positive and negative results, side effects
• See the Lancet, 365, march 2005   offering
  participants results of a clinical trial sharing
  results of a negative study 
• Letter from the sponsor
• Can he/she benefit from the new treatment or
  procedure and when?
• To the medical community
• Reporting and publishing all results
• Editorial policy of Journals can protect
  participants registration of all trials, ethics
  committees advice, declaration of conflicts of
  interest

27
Non Therapeutic clinical research is not
necessarily harmless for the patient

• Advantage of optimised care and follow up
• Motivation of doctors may be extremely strong
• Complete information about the standard of care
  and its availability
• Risk of procedures included in a protocol but not
  mandatory in usual care( invasive )
• Psychological effects
• One of my patients   So, I am a guinea pig! 
  
• Inconveniences may be disproportionate with
  potential individual benefit phamacokinetics