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Section 3 (Chapters 3.1 & 3.5), Glossary and Revisions to Section 5 National Statement on Ethical Conduct in Human Research, 2007 submission

ID: 
21
Personal Details
First Name: 
Suzanne
Last Name: 
Elliott
Specific Comments
Comments: 
2. Chapter 3.1

A/ 3.3.1 ( f) - Where relevant, the research meets the requirements of any relevant regulations or guidelines ..... (such as those related to privacy and reporting requirements for disclosure of child abuse

** THIS SHOULD ALSO reflect the NS2007 ( 3.1.3 (d) with notification to the CPMP/ICH Note for Guidance on Good Clinical Practice etc.... I know it is reflected later in section 5. - but if this section on 3.1.1 SHOULD also reflect the clinical trial aspect in this section.

B/ 3.3.1 (g) .....reviewed by a formally constituted academic, scientic or professional review process.

Suggestion - should include regulatory review (ie Clinical trials reviewed by the EMEA or the FDA- constitute requirements of scientific validity of a Clinical trial study design for the purpose of drug registration. The current statement should also reflect Local/International Regulatory review. This carries significant relevance when reviewing clinical trials. 

eg. …..reviewed by a formally constituted academic, scientific, local or international regulatory or professional review process.

C/ 3.1.2 ( c) whether there is a realistic possibility that the innovative intervention being studied will be at least as beneficial overall as standard treatment, taking into account effectiveness, burdens, costs and risks

Statements such as these are more for research in patients with diseases. It does not take into consideration that the intervention is purely for regulatory purposes, that is required to be scientifically valid, follow a specific design, and get approved by the HREC. The example below demonstrates a clinical trial that I am not sure fulfils the above statement unless the interpretation is that it is at least as beneficial by being bioequivalent but there is NO benefit of Treatment in these healthy participants.

What about bioequivalence clinical trial studies or comparative PK studies of varying formulations in healthy participants in clinical trials. There is no benefit, as it is not a required intervention. There is no “ treatment” – How would this be considered with this statement.

D/ Page 8, Footnote 1: A notable change in Section 3 is the integration of some of the material in current Chapter 3.3: Interventions and therapies, including clinical and non-clinical trials, and innovations into the new Chapter 3.1 and the relocation of other material from Chapter 3.3 into Section 5. You may wish to consider whether the guidance related to interventional research, particularly clinical trials of unapproved therapeutic substances, devices or biologicals, is sufficient

I do not believe the incorporation of the Chapter 3.3 into various sections of the new Section 3.1 is intuitive and comprehensible or flowing for a reviewer to selectively consider the important elements that were concisely put together in Chapter 3.3. I think the random distribution of the various points from Chapter 3.3 are now all over the place after cross checking the wording against the current elements of Chapter 3.1.

E/ 3.1.2 (d) where patient care is combined with intent to contribute to knowledge, that any risks of participation should be justified by potential benefits to which the participants attach significance. The prospect of benefit from research participation should not be exaggerated, either to justify to an HREC a higher risk than that involved in the participant’s current treatment or to persuade a participant to accept that higher risk

I do believe there will be exceptions to this statement with some of the novel technologies and molecular developments in treatments. Some of the immunotherapy that was done in the 1990’s that would probably have met the last statement at the time, is now in real clinical trials with adoptive therapies of selective T cell therapy, and/or providing monoclonal antibodies against various specific immunotherapeutic markers. At the time in the 1990’s the benefit was really unknown, but potential was there. Agree it should not be exaggerated, but at the time, it was very hypothetical with the tools of that time. Because of that research, the novel therapies now being used 1-2 decades later are proving to be very therapeutic.

 

F/ 3.1.2 ( e) whether the research is without likely benefit to participants, or whether the benefits or risks cannot be accurately estimated in advance. For such research to be ethically acceptable, the known risk to participants must be lower than for research in which there are likely benefits

 

This 3.1.2 (e) new statement has removed the “ Chapter 3.3.7  “ In ‘first time in humans research projects, risks are uncertain, and recruitment….….. “statement” .

The later part of that statement is particularly relevant to early phase Clinical trials (Phase 1). Healthy participants in clinical trials have no benefit to the treatment that they are being exposed to. Risks to the participants can only be predicted by the animal toxicology and any knowledge of the class of drug, if not novel. So the risk to a healthy participant in a clinical trial is not lower than the benefits. It can only be minimised and fully informed. An example is human challenge studies. Totally acceptable internationally in USA, UK, Germany, Netherlands and Africa and Australia. Participants are exposed to controlled manufactured and monitored specific malaria, and then fully monitored for development of the microscopic disease and then treated with novel anti-malarial drugs. Ask the question proposed in 3.1.2 (e), and the answer is probably “no” but the benefits to the research is immense. There are known risks to participants and these are carefully considered and monitored and fully explained. This research has been considered ethically acceptable by  local and international HREC’s and regulatory agencies.

 

G/ 3.1.3 For a Clinical trial research, researchers must register the project in a publicly accessible register before the recruitment of the first participant.

This has changed from NS 2007 3.3.12 from SHOULD to MUST

“Before beginning the clinical phase of research, researchers should register clinical trials in a publicly accessible register.

I understand that this is a requirement for publications and also for transparency to the public  of research. From a regulatory perspective, the USA FDA, do NOT require Phase I clinical trials to be registered, and nor does the EMEA both before Phase 2. I agree  that for transparency this is important.

However I want to stress again the issue of Bioequivalence/Biosimilar clinical trials where a generic company wants to produce a “me-too”drug. This from a public perspective is great for cost savings to the country. However, if a Generic Drug manufacturer has to publically disclose these clinical trials which are purely done for regulatory purposes, this will likely result in legal ramifications from the innovator drug manufacturer. These are Not treatment trials, but again have specific design for regulatory purposes that need to be reviewed by an HREC. It is unlikely that a Generic Drug Manfacturer would be happy to MUST register in a PUBLICLY ACCESSIBLE REGISTER for their studies. This really should be considered when changing this single word in this statement.

 

H/ 3.1.5  In their assessment of research quality, reviewers must recognise that thematic and other forms of generalisability may be more relevant than statistical generalisability.

What does this string of words actually mean?

 

I/3.1.7 Where the total project cannot be described in advance because it will be realised in successive stages whose detail and design will be informed by preceding stages, researchers should provide an indicative description of the stages that are foreseen and how it is intended to seek approval for each of these

I think this is a good statement, especially with the new ADAPTIVE CLINICAL TRIALS that are being submitted, considered, approved and also internationally accepted.  Adaptive design requires careful consideration of the successive stages, and how these are progressed, monitored, reviewed and advanced. I believe this statement captures this. The only comment I have is more with the “ to seek approval for each of these.” I believe that a protocol can be written with eg. consideration of a Dose Escalation Review process, - how it is done, on what data, by who – Safety Evaluation Committee etc. If the HREC approves the protocol, then the “PROCESS” of dose escalation is approved, and not sure that each stage needs approval for progression. This may require a case by case consideration.

J/ 3.1.20  Researchers should consider how the potential participants will experience the recruitment process.

I am not sure what would be expected to be stated by the researcher to satisfy an HREC review of this. I believe it is open to a significant level of different interpretations by multiple HREC’s.

 

K/ 3.1.22 Reviewers should consider the degree to which any payment in money or incentives of any kind, whether to researchers or participants, could result in pressure on individuals to consent to participate (see paragraphs 2.2.10, and 2.2.11). This is especially important with respect to research that involves more than a low risk of harm.

It would be useful to reference the NHMRC guidance on payments of participants in clinical trials.

 

L/3.1.55 Where clinical research involves the use of materials of biological origin, records should be preserved for long enough to enable participants to be traced in the event that evidence emerges of late or long-term health-related effects

Many clinical trials may contain use of materials of biological origin. The data must be stored legislatively for 15 years in clinical trials. Only specific forms of biological origin (ie GMO) may have further criteria as described. However, archived data can be destroyed after 15 years. I am not sure that the generalisability of the “ biological origin” is satisfactorily defined here. I do recognise though that “should” is used. Of note the original GTRAP had this type of statement in for long term information to be kept in trials with a GMO product. GTRAP no longer exists, and this statement is relevant, but wonder if too broad.

 

M/ 3.1.60 In the absence of justifiable ethical reasons (such as respect for cultural ownership or risks to the privacy of research participants) and to promote access to the benefits of research, researchers should collect and store data generated by research projects in such a way that they can be used in future research projects. Where a researcher believes there are valid reasons for not making data accessible, this must be justified

This may have implications for commercial clinical trials where the data is specifically bound by confidentiality and cannot be shared.

General Comments
Comments: 

I believe the merging of the Chapter 3.3 Clinical trials into the new section 3.1 has dissolved many of the flow and considerations necessary by both researchers and reviewers. Although I have cross referenced most of the statements of the original NS 2007 Chapter 3.3 into the new document, there are significant components missing, because of the generalisation of this chapter. We need to recognised that internationally there is a Chapter 3.0 in the  International GCP document that for Australia is removed by the TGA as this is replaced by the National Statement. Most of those elements are still within the section 5, but by removing the critical section of Chapter 3.3 and dispersing it amongst various elements, some of importance of those sections will be lost and open to further differences of interpretation of clincial trial review.

Page reviewed: 10 July, 2018