an ethics committee experience with expctas s2p3 nagels, guy.pdf · • even when the risks are...

3/31/2009

1

An ethics committee An ethics committee experience with expCTAsexperience with expCTAs

Guy Nagels MD PhDGuy Nagels MD PhDECEC--IRB Hospital Network Antwerp, BelgiumIRB Hospital Network Antwerp, Belgium

Path to IRB approval

Ledford, Trial and error, NATURE|Vol 448|2 August 2007

Applicable law in Belgium

1) experiment: relevance and design

2) expected benefits and risks: judged correctly?

3) protocol: quality

4) investigator and coworkers: competence

5) product documentation

Belgian law on human experimentation, May 7th 2004 (amended)

3/31/2009

2

Applicable law in Belgium

6) experimental facilities

7) informed consent documents and procedure

8) compensation in cas of injury or death

9) insurance

10)payments to subjects and investigators

11)recruitment procedures

Belgian law on human experimentation, May 7th 2004 (amended)

Benefits phase 0 trials

• Drug development becomes:– More efficient through:

• Earlier development of target assays

• More informed phase I starting dosesMore informed phase I starting doses

– Less resource intensive: • Unsuccessful candidate agents are eliminated earlier in the process

Abdoler et al., Clin Cancer Res 2008;14(12) June 15, 2008

Why phase 0 trials ?

• There are potential social benefits• Preclinical studies often do not provide an accurate estimate of the pharmacokinetics and toxicity of candidate agents in humansTh f h I l i l• Therefore many phase I agents are ultimately abandoned

• Costs in time and resources raise the need for alternative methods of drug development

• Phase 0 trials may result in fewer individuals being exposed to nonviable drugs


3/31/2009

3

“ Biomedical research involving human subjects cannot legitimately be carried out unless the importance of the objective is in proportion to the inherent risk to the subject. ”

Helsinki declaration

“ Concern for the interests of the subject must always prevail over the interests of science and society. ”

Unfavorable risk/benefit ratio in 0/I studies on (oncology) patients

• Phase I trials in patients may provide psychological benefits

• This is unlikely in shorter phase 0 trials


What is the difference between phase I and phase 0 for the research subject ?

Preclinical data

GMP

FIM

.

3/31/2009

4

Phase 0 in patients

• Phase 0 concept may be difficult to explain to most patients in a general oncology clinic

• Participation might delay or exclude entry into a trial with potential therapeutic benefita trial with potential therapeutic benefit– Microdose => shorter washout ?

• All options should be discussed in IC– Including other trials

Kummar, Eur J Cancer, 2009; 45:741

“ Physicians should abstain from engaging in research projects involving human subjects unless they are satisfied that the hazards

Helsinki declaration

are satisfied that the hazards involved are believed to be predictable.”

• “Indeed, even the best experts in the field would not have foreseen the most seriousforeseen the most serious adverse events in the TeGenero case.” (Rittner, Legal Medicine, 2009)

3/31/2009

5

“ canariesin a mine shaft ”

Hanauer, Nature Clin Pract Gastroenterol & Hepatol, 2008; 5: 533

Risk communication

Stobbart et al, BMJ, 2007; 334: 566


• Quality of life and performance status in onclology patients in phase I trials do not seem to be affected, when compared to palliative support care

• Some report a burden of repetitive procedures

• Time commitment in phase 0 is smaller => smaller chance of negative influence on these parameters


3/31/2009

6

Let’s see... Possible side effects... Dizziness, cramps, nausea... SUPERPOWERS !!

Hey, sign one up !!

Communicating risk to subjectsR isk fo r hair lo ss in o nco lo gy tria l

(n=25)

60

80

100

Rector, IRB: ethics & human research, july-august 2008

0

20

40

common possible unlikely rare

Communicating risk to subjects

"rarely" means to students:

drymouth

0 5 10 15 20

impairedvision


3/31/2009

7

Communicating risk to subjects

• Should we use numbers in stead of probabilistic words ?

• 46% of respondents in a mail survey could not convert 1% to 10 in 1000convert 1% to 10 in 1000

• Respondents in another study judged a risk of death from disease of 1.286 out of 10.000 riskier than 12.86 %



• However, risk levels may be lower in phase 0 trials, allthough data on this topic is not yet available– Phase I:– Phase I:

• 0.5 toxic death rate

• 14% at least 1 grade 4 toxic event

– Phase 0:• No dose escalation

• Toxicity is not an endpoint


3/31/2009

8

When is clinical research ethically justified ?

• When the risks are minimized

• When the potential benefits to subjects have been enhanced

h h i l b fi bj d• When the potential benefits to subjects and society justify the risks and burdens to subjects

• Net risks for subjects should not be excessive

• (33)Abdoler et al., Clin Cancer Res 2008;14(12) June 15, 2008

When is clinical research ethically justified ?

“In phase 0 trials, however, investigators are not h l i bj h bj h l ihelping subjects; rather, subjects are helping investigators answer a scientific question.”


TeGenero trial

• ICU availability ‐ in order to protect the individual

.

3/31/2009

9

Recommendations of theExpert Scientific Group

• The clinical environment for first‐in‐man studies– Where there is a predictable risk, plans should be made to have all necessary supporting measuresmade to have all necessary supporting measures or antidotes available and potential access to intensive treatment unit (ITU) facilities should be arranged.

– The study should be in an appropriately staffed and equipped environment.

Dowsing & Kendall, Journal of Clinical Pharmacy and Therapeutics (2007) 32, 203–207

Phase 0 trials

• staggered approach ‐ should be long enough

.

Adaptive trial design

• Outcome‐adaptive decision rule:

• Treatment decisions for new subjects are based on the outcomes of subjects treated previously

• Phase I dose finding trial is an example• Phase I dose finding trial is an example

• Phase II trial with a rule saying that if there are three or fewer responses in the first 19 patients then the trial must be stopped; otherwise 30 additional patients should be treated.

Thall, Stat Methods Med Res 2002; 11; 429

3/31/2009

10

Phase 0 informed consent, what do subjects have to understand ?

• They are being asked to contribute to an effort to collect information that might help others in the future.

• Participation offers no prospect of personal medical benefitmedical benefit.

• Even when the risks are low, there is typically a high degree of uncertainty.

• Participation is entirely voluntary.• Their enrollment decision will not affect their individual care.


Trust in early phase research: therapeutic optimismand protective pessimism

• IRB members and patients were presented with a protocol description and a questionaire.

• Three questions were asked:• Three questions were asked:– Direct benefit question

– Risk question

– Societal benefit question:

Kim et al., Med Health Care and Philos 2008

Direct benefit question:

• A potential subject has read the informed consent form, and during a discussion with the principal investigator (PI) of the genethe principal investigator (PI) of the gene transfer trial, he or she asks:


3/31/2009

11

Direct benefit question:‘‘I know this is research, and I know your primary aim is to test the safety of gene transfer for PD. But it would help me if you could give me the percent likelihood that I would really improve if I participate i thi t d Wh t i th h th t Iin this study. What is the chance that I could improve to the point that medications would allow me to function almost normally except for mild side effects?’’


Risk question:

• The same potential subject now asks the PI: ‘‘You told me several possible bad things that could happen if I participate.

ld h l if ld iIt would help me if you told me, in your opinion, what is the percent chance that I would actually suffer one or more adverse events if I participate?’’


Risk question:

• What is the lowest percent chance of an adverse event occurring that you feel comfortable allowing the PI to tell the bj ? (0 00%) %subject? (0–100%) _______%


3/31/2009

12

Societal benefit question:

• The same subject now asks the PI: ‘‘I know this study is only to test the safety of the procedures for gene transfer. I k i il i diknow you are not primarily intending to benefit me in this Phase I study. But it would help me to know the likelihood that this study could eventually lead to a cure for Parkinson’s Disease in 10 years?’’


Societal benefit question:

• What is the highest percent chance of such discovery of a cure for PD in 10 years that you feel comfortable allowing h ll h bj ? (0 00%)the PI to tell the subject? (0–100%) ______%


Trust in early phase research: therapeutic optimismand protective pessimism


3/31/2009

13

Phase 0: payment ?

• .

Incentives:

Money “shadow economy”

Free room and board

Access to approved drug ?

Paying Research Participants

• Variable reimbursement practice• Reason:

– Covers time and out‐of‐pocket expenses– Incentive for participationIncentive for participation

• Model– Market model– Wage payment model– Reimbursement model

• Often no written guidelines existFry, J Med Ethics, 2005; 31: 542

North Park Hospital tragedy TeGenero TGN1412 study

Suntharalingam et al., N Engl J Med 2006;355:1018-28.

3/31/2009

14

Ethical Assessment of the TeGenero TGN1412 Trial

• Ethical review suggests that the following ethical criteria were fulfilled:

• Social value: It was socially desirable to evaluate an immune modulating experimental g pagent, which might have been beneficial in leukemia and autoimmune disease. This necessitated an initial safety evaluation in human volunteers before conducting efficacy studies.

Emanuel & Miller, The American Journal of Bioethics, 7(2): 76–81, 2007


• Safety:• Extensive safety tests had been performed in tissue culture

and in three different animal species: – rabbits– cynomolgus monkeys– rhesus monkeys.

• Both monkeys are identical to humans for the epitope under investigation.

• Repeated dosing during 4 weeks did not elicit substantial pro‐inflammatory cytokine release

• The MHRA in Britain assessed all the animal data before authorizing human trials.



• Favorable risk/benefit ratio:– The healthy volunteers had no prospect of direct medical benefit.

• Were the risks minimized and justified by the j ypotential value of the knowledge to be gained from the research ?– Agent was tested in cynomolgus and rhesus monkeys

– Starting dose was 1/500 of the maximal dose tried in monkeys.


3/31/2009

15


• Independent review:– The regulatory authorities in Britain (MHRA)

– Paul‐Ehrlich‐Institut Langen, Germany

Independent research ethics board (REB)– Independent research ethics board (REB)



• Informed consent: Detailed pip states:– Study purpose is to asses safety of a drug

– No therapeutic benefit

First time in man study– First time in man study

– Possibility of anaphylaxis or allergic reactions

– Life‐threatening reactions are possible



• What was not done:– Administering sequentially rather than simultaneously;

– Administering to humans no more quickly than to animals;

– Stopping the study when the first subjects complain of serious discomfort;

– Administering steroids immediately, as the protocol required;

– Informing ICU physicians immediately after the study’s risks had materialized.

Spielman, American Journal of Bioethics, 2007; 7: 93

3/31/2009

16

an ethics committee experience with expctas s2p3 nagels, guy.pdf · • even when the risks are...

Documents