October 2003
Issues To Consider When Seeking Ethical Approval For Phase II and III Clinical Trials
The scientific and documentary requirements for ethics approval are incorporated into Good Clinical Practice (GCP) through the International Conference on Harmonisation (ICH) process (refer to the ICH E6 guideline for details). Compliance with ICH GCP has been a regulatory expectation since 1996. Within Europe, compliance will become a legal requirement in May 2004 when the EU Clinical Trial Directive (2001/20/EC) is implemented.
In my experience, the best approach to obtaining ethics approval is to interrogate each individual scenario from three angles:
Compliance with regulatory and medical guidance
A huge range of regulatory and medical guidance has been published. It is important to check that your proposed protocol complies with both the regulatory and medical guidance that prevails in the location(s) where you are seeking to perform the clinical trial. If this is not the case then a straightforward ethical approval is unlikely to be achieved. Study designs should be compared against the following:
ICH guidance. This is primarily methodological in nature.
Regional / national guidance (e.g. CPMP in Europe, FDA in US). Most regulatory therapeutic guidance is in this category.
Medical guidelines. In some cases these apply on a regional or global basis (e.g. the GINA guidelines covering asthma studies are applied globally). In other cases, guidance may only be recognised nationally (e.g. British Hypertension Society guidelines for anti-hypertensive studies in UK).
Regulatory compliance is important since failure to comply risks rejection of the data at the marketing authorisation stage.
Compliance with medical practice guidelines is important because ethics committees will assume that any local medical guidance is in the best interests of their patients and should therefore be followed.
Experience suggests that greater weight is given to local guidance on medical practice than to regulatory guidance. This is entirely logical since ethics committees are primarily interested in patient well-being rather than regulatory science.
In addition, don't forget to confirm that sufficient non-clinical work has been performed to support the level and duration of human dosing proposed. The ICH M3 guideline (Non-clinical safety studies for the conduct of human clinical trials for pharmaceuticals) is very helpful here.
You should not give up hope if you find that your protocol does not meet the precise details outlined in published guidance. Verbatim compliance is sometimes technically impossible and frequently scientifically undesirable. It is more realistic to ensure that patients are treated within the spirit of the guidance. The key is to clearly explain why your protocol diverges from the guidance and justify the proposed alternative study design.
Common sense
In general, clinical trials are ethical (and therefore likely to be approved by ethics committees) if they are reasonable at the common sense level. It is worth testing each scenario by applying the following statements:
The risk to each individual patient is not excessive.
Scientific knowledge about the test drug will be advanced by performing this trial.
I would feel comfortable if a relative of mine were to take part in this trial.
If you can answer "true" to each question, then the signs are good. If not, you have identified a problem and you should expect resistance from ethics committees.
Countries surveyed
Argentina Germany Romania
Belgium Hungary South Africa
Canada Italy Spain
Czech Republic The Netherlands UK
France Poland US
Documentation and administrative procedures
The basic documentation requirements for ethics committees are set out in ICH GCP, but for this article I wanted to look at the practical realities of the ethics process rather than reviewing the content of published guidelines. A brief questionnaire was therefore circulated to senior phase II & III clinical research professionals in 15 countries. The aim of the questionnaire was to establish the highest priorities when seeking ethical approval for a phase II or III clinical trial. The questionnaire and the resulting data are summarised in the panel. The countries surveyed span four continents although the main focus is on Europe.
1. What do you consider to be the top 3 priorities when assembling a package in support of a phase II / III clinical trial for submission to an ethics committee / IRB in your country?
Item Total
Completeness of ethics package 7
Informed consent 7
Administrative details of submission process 5
Insurance 5
Protocol 4
Investigator brochure 2
Anticipate questions from ethics committee 1
Application form 1
Fees for ethics committee review 1
Obtaining all the documents that patients will see 1
Patient information sheet 1
Quick response to questions 1
Responses to question 1 clearly identify five priorities when assembling an ethics submission (informed consent form, completeness of the overall ethics submission package, insurance, administrative details and the protocol). These five items polled 28 of the 36 votes cast (78%) with only one other item (the investigator brochure) polling more than one vote.
Despite this general agreement, there was still considerable diversity in the responses when taking all three answers into account. Responses from France, Spain and the Czech Republic all identified the informed consent form, the insurance and the protocol as being the top priorities. Argentina and Canada specified the completeness of the overall package and the administrative details of the submission process without nominating a third priority. The remaining 10 countries each produced a unique response comprising two of the top five priorities plus one other.
2. What are the 3 most common issues raised by ethics committees / IRBs when they review submissions for phase II / III clinical trials in your country?
Item Total
Protocol 10
Informed consent 9
Insurance 6
Financial arrangements 2
Free medication and post-study patient care 1
Genomic testing 1
Incomplete documentation 1
Investigator brochure 1
Patient information sheet 1
Safety profile 1
Site certification for phase II 1
Responses to question 2 indicate that the protocol (use of placebo, choice of comparator and its dosage, requirement for diagnostic interventions etc), informed consent and insurance are by far the most common issues raised by ethics committees. These polled 25 of the 35 votes cast (71%). Only one other item (financial arrangements) received more than a single vote.
Once again, however, diversity is very much in evidence. Responses from Germany, The Netherlands and Spain all specified the protocol, informed consent and insurance as being the most frequent source of questions, but the remaining 12 countries each submitted a unique response.
The US response was particularly interesting, as it identifies issues around genomic testing as being the second most common source of concern. As the prevalence of pharmacogenetic testing increases, we can probably expect ethics committees to raise more and more questions in this area, which is currently not at all well-served by internationally recognised guidance.
3. Please rank the following documents according to their relative importance in the eyes of ethics committees / IRBs in your country (most important first):
Investigator brochure
Informed consent form
Other written information for patients
Patient recruitment advertisement
Financial statement
Insurance statement
Signed agreement between the parties involved in the trial
Investigator CV
In question 3, respondents were asked to force-rank in order of importance nine of the documents usually required in ethics packages. Points were allocated according to ranking (9 points for the most important, 1 point for the least important). One response ranked three items in equal first position; all three items were allocated 8 points. Responses from four countries did not rank all of the documents; unranked documents were allocated zero points.
Document Total
Informed consent 122
Protocol 113
Investigator brochure 89
Other patient information 87
Insurance 82
Investigator CV 52
Patient recruitment advertisement 39
Signed agreement 33
Financial statement 29
The forced-ranking approach clearly identifies informed consent as the most critical item (122 points) with the protocol coming a close second (113 points). The investigator brochure, other written information for patients and insurance formed a second tier with scores of 89, 87 and 82 points respectively. These five documents were well ahead of the remainder; the next highest score being the investigator CV with 52 points.
In general, the rankings from each country for a given document were fairly consistent. The notable exceptions were:
"Other patient information" which included two zeros and five scores of 8.
Insurance, which included all possible scores except zero and 4.
Patient recruitment advertisement, which included five zeros and two scores of 7.
In practice, most phase II and III clinical trials involve multiple sites in multiple countries. Very often the protocol and investigator brochure will be prepared centrally and supplied to local clinical operations teams for incorporation into ethics submissions. How can the results discussed above be used to maximise the prospects for smooth and timely ethics approvals? Obviously, some aspects apply in all areas and the responsibility should lie with the central drug development team. Other issues are local and can be much more efficiently handled on a decentralised basis.
Table 1.
Function Key priorities
Central drug development team Compliance of protocol with regulatory and medical guidance in each country in which the trial will be performed.
High quality investigator brochure.
"Common sense" test.
Local clinical operations staff Informed consent form.
Other information for patients.
Study insurance.
Completeness of the ethics package.
Knowledge of the submission process for the ethics committee concerned.
Knowledge of particular issues of importance to the ethics committee concerned.
By way of conclusion, Table 1 suggests key priorities for the central and local teams based on the information discussed above.
For further information please contact:
Steve Pinder,
Director of Regulatory Affairs, MDS Pharma Services