Baggrund til ekspertmødet 29/11-23

Side 1 | 1
Epidemiudvalget
Til: Udvalgets medlemmer
Dato: 30. oktober 2023
Baggrund til ekspertmødet 29/11-23
Epidemiudvalget holder onsdag den 29. november kl. 14-15 lukket ekspert-
møde om internationale erfaringer om senfølger efter covid-19 og bivirkninger
ved covid-19-vaccinationer m.v. samt om STRIVE-samarbejdet.
Under mødet er der deltagelse af Jens Lundgren, professor i infektionssyg-
domme, Rigshospitalet og Københavns Universitet, og Trine Myrup Mogen-
sen, overlæge i infektionssygdomme ved Aarhus Universitetshospital og
professor ved Institut for Biomedicin, Aarhus Universitet.
Forud for mødet omdeles til baggrund for udvalget:
Artikel fra health/au.dk 10/2-22: Millionbevilling: Aarhus skal være med til at
besvare de store corona-spørgsmål:
Millionbevilling: Aarhus skal være med til at besvare de store corona-
spørgsmål (au.dk)
Magasinet EUindblik, 1:2023, side 14-17: Caseinterview ”Tænk stort og tænk
samfundseffekt” med professor Trine Hyrup Mogensen:
EUindblik_Januar_2023 (ufm.dk)
Feedback fra det globale forskningskonsortium (STRIVE) på WHO-høring om
”global trial ecosystem”: Vedlagt.
Med venlig hilsen
Hanne Schmidt,
udvalgsassistent
Offentligt
EPI Alm.del - Bilag 1
Epidemiudvalget 2023-24


Feedback form for the public consultation for WHO guidance for global practices for clinical
trials
Please note we are providing this word file of the full list of questions to help you plan your
online submission – DO NOT make a submission using the word file, the submission should
be through the online form. Wherever possible, please coordinate one submission per
organization or per institution using the word file to collate input into consolidated
submissions through the online form.
Personal information:
Last name Matthews First name Gail
Organization/
Affiliation
STRIVE research consortium Country of residence or
organization/affiliation
Global network
E-mail (optional) gmatthews@kirby.unsw.edu.au
General comments:
Please provide general comments on addressing context-specific issues, considerations, and implications for adapting and
implementing the guidance, as well as identifying gaps in the evidence that should be addressed through future research. Please
also provide any comments about the strengths of the draft guidance. Feedback to specific content to enhance clarity, address
technical errors, and provide any missing information will be in the suggested amendments.
This feedback is provided on behalf of the STRIVE research consortium
(https://insight.ccbr.umn.edu/i18/). STRIVE (Strategies and Treatments for Respiratory Infections and
Viral Emergencies) is a global network of networks formed as a broad international research
collaboration in 2022 in the aftermath of the COVID pandemic. STRIVE is primarily funded by the
United States National Institutes of Health (NIH) and has developed a master protocol which currently
guides 2 multi-site clinical trials. STRIVE is an outgrowth of the Accelerating COVID-19 Therapeutic
Interventions and Vaccines (ACTIV) public-private partnership sponsored by NIH, with the
infrastructure provided by the ACTIV-3 initiative and sites from ACTIV-1, ACTIV-3, ACTIV-5 and
ACTT. STRIVE is aimed at improving the clinical outcomes of patients with acute severe infections
while being prepared to respond to infectious disease emergencies, through the rapid implementation of
clinical trials designed to inform practice guidelines, public health policy, and the delivery of health care.
With 200+ collaborating sites in 40+ countries on all six inhabited continents, and with substantial
expertise and experience in conducting RCT’s globally to address research questions of public health
relevance, STRIVE is an example of an international consortium that can inform considerations to
establish a well-functioning global trial ecosystem. Our feedback below reflects wide consultation among
the key STRIVE stakeholders.
Some general comments to the draft guidance from WHO:
The document is well-structured and concise. It covers some of the relevant topics required for a much-
needed strengthening of the global clinical trials ecosystem, and the specific guidance is largely
consistent with STRIVE’s perspective on global trials. The WHO is to be complimented for serving a
convening role. Nonetheless, we think that the WHO’s unique role could be used to further coordinate
and advocate for work across governments in support of global clinical trials designed to address global
health emergencies.
Some areas could be strengthened:
The definition of the “global clinical trial ecosystem” is critical to the overall message but is
underdeveloped. An ecosystem is defined by its relevant actors and the systems in place that mediate
their interaction. From our perspective, the critical actors are governments, funders, regulators, ethics
Offentligt
EPI Alm.del - Bilag 1
Epidemiudvalget 2023-24
committees, pharmaceutical companies, academic trialists, trial participants, patient advocates, and
patients. This guidance document could benefit from describing which aspects of these systems are
barriers to preserving human health in the context of an international health emergency.
The WHO has a unique role with regard to defining the conditions of an international health emergency
and is therefore uniquely positioned to describe how interactions in the ecosystem should be modified in
the context of such an emergency. We observed that the systems for mediating interactions between
agencies in the ecosystem were modified during the COVID-19 pandemic, however there is uncertainty
as to the extent to which this will occur in the future, and this remains a current barrier to plans for trials
during health emergencies. Securing agreements to make such modifications predictable would greatly
facilitate planning for and potentially reduce harm from future such emergencies.
The target audience for recommendations on agreed processes is a combination of governments,
regulators, and ethics committees. As such, this guidance document could be strengthened by focusing
its message on these components of the ecosystem. However, this recommendation should not be
construed as recommending reducing the amount of relatively technical material central to proper trial
design (e.g., randomization and concurrent controls). Indeed, we applaud WHO for communicating
critical aspects of trial design that may be unfamiliar to these actors in this guidance document.
In summary, this document is an important first step towards harmonizing expectations for the design
and conduct of international trials in health emergencies. The next steps involve working with
governments to coordinate funding and ethical and regulatory review of trials, as well as other aspects
of trial conduct, such as international shipment of investigational agents. This will likely involve
numerous meetings with members of the ecosystem from enough countries to ensure access to the
relevant patient populations. These meetings could benefit from the participation of STRIVE and similar
networks.
We now remark on a number of more specific areas:
Section 1.3.4 calls for increased involvement of pregnant and lactating women in trials. We agree with
this point, in particular in situations where novel interventions are relevant to study in this population
because of increased vulnerability to adverse serious outcomes (e.g., influenza and COVID-19).
However, what is not recognized in the document is that a key reason for lack of data in this area is that
regulatory authorities have very strict views on allowing pregnant and lactating women into trials. For
example, pregnant women were not allowed to participate in trials assessing human antibodies to treat
COVID-19 before teratogenic tests had been completed. During an infectious emergency, there is often
the need to study novel agents, and not allowing pregnant women into such trials clearly leaves them at
a disadvantage, is inconsistent with the autonomy of these women, and is ultimately inconsistent with
the consent process. We call for discussions including experts and the child-bearing community on how
to handle this dilemma in situations of infectious emergencies.
Section 1.4.1 points to the need of being able to identify a relevant research question. We agree the
principles mentioned but request further clarity on how to reach consensus on this among the key
stakeholders – principally, governments and funders.
We strongly agree with the sentiment mentioned in section 1.4.2 to ensure that oversight of trials by
authorities should be proportional and focused on key aspects of conduct of the trial (i.e., consent, and
appropriate reporting of data related to the key research question). Emphasis should be placed on those
components of research activity that are critical to trial integrity, safety and outcome, as opposed to time
spent on activities that have little bearing. This emphasis should be stronger developed within the
document.
Section 1.4.3 is short, lacks detailed content and appears almost as an afterthought. How to strengthen
the global trial ecosystem is obviously the central component of the report.
We agree with the recognition of ICH guidelines when conducting trials aimed for review by regulatory
authorities.
Please provide general comments for Section A: Key scientific and ethical considerations for good clinical trials.
This section would benefit from defining the principal aims of a trial. Many aspects of trial design,
regulatory oversight and reporting of findings will depend on these aims. For example, some trials aim
to inform regulatory authorities’ decision on whether to licence a novel drug. Others aim to evaluate
drugs already approved for routine use for other conditions. Yet other trials may address strategic
questions for how to optimize the use of a drug known to be effective for a given condition (e.g., should
be early or later in course of the disease).. The latter two categories may or may not involve a regulatory
evaluation. For example, the label for dexamethasone does not include COVID-19, but the drug is often
used for these patients.
Section 2.1.3 - adequate sample size. For clarity: “random errors must be small by comparison with the
clinically meaningful effect sizes. Also, the clinically meaningful effect size may be smaller than the
expected effect size, the sample size of the trial allows to have adequate power to detect.” Also
“Adjusting for pre-randomization covariates that are predictive of the outcome can also be an effective
strategy for reducing the magnitude of random errors.”
Section 2.1.4 - blinding and use of placebo/control. We agree with the principles stated here. Of note,
some have stated the opinion that appropriate controls are not ethically acceptable – if the condition
under study has a high fatality rate. For example, during the Ebola and Mpox epidemics, but also during
the COVID-19 pandemic, this view was articulated, and trials designed accordingly. Trials of novel
compounds were done (and some are still ongoing) without having a contemporarily identified control
group. If no appropriate control group is included as part of trial design, possible benefit, or harm, from
the intervention can’t be assessed. Our view – consistent with the text of the draft document – is that it
is both ethically acceptable and actually strongly encouraged to design trials evaluating novel
interventions with a placebo/control group (e.g., randomize to active or placebo on top of whatever
interventions that are considered as standard-of-care for that condition). Such trials clearly must be
monitored during their conduct by a DMC in order to identify safety and efficacy signals. This is also
true for conditions without any standard-of-care interventions other than supportive care. Adhering to
these principles will accelerate the possibilities of identifying standard-of-care interventions, and hence
further advance better care. Conversely, lack of adherence to these principles will do the opposite.
Section 2.15 – adherence to allocated intervention. The statements made (that lack of adherence/cross
over within a trial reduces the chance of detecting a possible benefit from an intervention) are true if the
goal of the study is to detect the pharmacological effect of an intervention. We recommend increasing
the sample size if adherence is an issue since the impact of lack of adherence is to reduce the magnitude
of the effect size. However, from a pragmatic point of view, lack of adherence to allocated treatment arm
may be informative for ultimate decision making.
Section 2.1.6 – lost-to-follow-up. We agree with the statements made but think it would be relevant to
emphasize that in a situation in which the stated principles are not adhered to, the ability to interpret the
results of the trial is compromised.
Section 2.1.7 – outcome in trial. Although the stated principles are reasonable, we suggest to further
expand on this section. We suggest that the key principle is that trials aimed to improve public health
should study outcomes that actually are important and relevant to improve public health. We recognise
the dilemma – trials powered to assess whether a prioritized intervention being studied actually affect a
serious clinical outcome typically requires a much larger sample size than a trial using a laboratory
defined outcome. If a laboratory outcome is to be used, demonstrating surrogacy of that outcome is
critical and established criteria are available for such demonstration.
While relying on precedent to define a good outcome may make planning and regulatory review more
straightforward, it may have the consequence of discouraging innovation, and it leaves the qualities of a
good outcome unspecified/vague. It would be more helpful if the qualities of a good outcome were
enumerated, i.e., clinically relevant / interpretable, patient-centric, objective, and statistically
efficient/feasible. These qualities are at odds at times, and it can be difficult to find an outcome that
satisfies all qualities. In this case one often needs to make a hard, pragmatic decisions. WHO should
encourage regulators to embrace this thinking rather than relying exclusively on precedent.
Selection of the relevant primary endpoint in trials among hospitalized patients during the COVID-19
pandemic provides a good example. Ordinal scales at days 7 or 14 were advocated initially but dropped
because they did not capture the total disease course, including rehospitalizations and deaths after day
14. Subsequently, favoured endpoints were composite primary endpoints that either encapsulated clinical
disease progression (death or possible progression to COVID-ARDS), or time to recovery. Prevention
of death is an obvious relevant and ascertainable outcome in populations at high risk. However, in lower
risk populations, the ideal intervention should both prevent disease progression and accelerate recovery;
only focusing on a progression endpoint typically makes sample sizes to achieve adequate power
extraordinarily large. Novel endpoints were subsequently developed for such situations. However, not
all regulators have accepted these novel endpoints, rather many have insisted to focus on 'death' being
the gold standard endpoint for COVID-19. As the pandemic/epidemic evolved and deaths became less
frequent, even in high-risk populations, trials with mortality endpoints became futile.
Section 2.1.9 – ascertainment of outcome. We agree with statements made but would suggest
emphasizing that outcomes defined based on objective parameters only attenuate/preclude the potential
biases of adjudication.
Section 2.1.10 – statistical analyses. We suggest emphasizing the following: there can be strong rationale
for allowing modified ITT (mITT) analyses, namely when the modifications improve the potential for
treatment differences without risking selection biases. For example, when there is delay between
randomization and the initiation of the intervention, it may be quite reasonable to exclude persons who
clinically deteriorate and cannot initiate the intervention or exclude those who withdraw consent during
this short gap, or persons for whom the study drug is never delivered in a remote trial due to a courier
mistake. Such exclusions are reasonable if there is not plausible way the exclusion mechanism is
associated with the allocation, such as the use of blinding of treatment assignment. This guidance is too
dogmatic about using ITT. There are situations where mITT is advantageous and does not compromise
the internal validity of the clinical trial, but the rationale for exclusions needs to be clearly described and
follow-up for excluded participants should continue when feasible with ITT as a sensitivity analysis. A
fully developed statistical analysis plan determined by the trial steering committee should define these
analyses a priori.
The document emphasizes caution in the interpretation of analyses of subgroups. We agree with that, but
also finds it of relevance to do so in relation to secondary outcomes, as there are multiple comparisons
at play, and these outcomes may have (much) lower power than the primary outcome.
Section 2.1.12 – interim monitoring of trials. In situations in which the DMC recommends ceasing
enrolment, it would be helpful to be more specific that enrolment into the trial may cease, but follow-up
would continue on persons previously enrolled.
The plan for interim monitoring should also be nimble and allow for modifications to the timing and
content of reviews, e.g., by using an error-spending approach to efficacy monitoring. Such flexibility is
sometimes discouraged by regulators and much of the pharmaceutical industry operates under the
assumption of fixed monitoring times. This rigidity of approach should be modified.
Situations may arise where the DMC and one or more regulatory bodies come to different sets of
conclusions. This section should outline such a scenario and describe how such situations are best
resolved. Whereas the DMC has access to the totality of intermediate data within the trial, regulatory
authorities often only have access to reported serious adverse events (sometimes across multiple trials).
In particular, in trials assessing interventions in high-risk populations, balancing possible safety signals
against progression of underlying disease(s) does require a broad perspective. We advise that the WHO
recommend that in such circumstances, the DMC and regulatory authority(ies) have conversations on
best path forward of the trial, while ensuring that the trial’s integrity is best preserved.
Section 2.2-2.6 – good trial practise that respects participants rights and wellbeing, are collaborative,
are feasible, manage quality effectively and efficiently.
There should be much more emphasis on capacity building for RECs, and DMCs, and community
engagement. In the pandemic the various PPI groups, for example, the one created at one of the largest
Clinical Trials Units in the UK to help with the pandemic work, could not work at the pace required to
have any meaningful input.
Section 2.2.6, includes extensive discussion of timeliness, but this needs definition. We would suggest
emphasizing that use of a central trial database, real-time data collection, and clearly laid out statistical
analysis plan at the onset of the trial, are the optimal means to ensure swift trial oversight by the DMC
and in case of unblinding of the results, rapid communication of findings made. The STRIVE
consortium has a great deal of experience with this approach with rapid publication of findings at the
conclusion of the trial.
In this section, there is no mentioning of access post-trial in LMICs settings to IMPs proven to be
‘successful’ in trials conducted in those locations. Is that intentional?
Finally, there are many opportunities to improve clinical site monitoring. The focus needs to be on
verification of critical elements of informed consent, eligibility, and ascertainment of the primary
outcome. This is especially true in the context of an international health emergency.
Please provide general comments for Section B: Guidance on strengthening the clinical trial ecosystem.
Section 3.1.1 - what is the definition of a ‘well-functioning’ clinical research institution, and who
decides on whether this is true or not for a given institution?
Section 3.1.2 - in this section WHO states quite clearly that WHO can’t support countries to develop
clinical trial infrastructure. But what the document does not describe is which agencies are identified as
having funding responsibilities. A global trial ecosystem will only function if there is dedicated
funding to develop it.
Section 3.2.1 – it is stated that “WHO has a key role in developing global health research priorities”.
While this may be an accurate description of WHO’s perception, it does not fully recognize the
interests of all ecosystem members. The track-record indicates that WHO should not lead the conduct
of trials but leave this to professionally led consortia developed for this purpose. Conversely, WHO’s
role is to convene stakeholders to reach a consensus on what those priorities are. Having ‘dry runs’ of
how to reach quick consensus is encouraged if this process is to work quickly and efficiently in
situations of an emergency.
Of note, there is no mention of the importance of access to healthcare, and how this needs to be
strengthened in order to facilitate clinical research.
Section 3.2.2. The ambition of having a cooperative REC/regulatory approval system would be the
ideal scenario. Most recently, the International Coalition of Medicines Regulatory Authorities has
served a convening role in relation to immunobridging for authorization of COVID-19 vaccines. Also,
the EU launched the CTIS platform for this purpose. However, the workload required to submit a trial
for regulatory review using this platform is extensive, as each member state may have specific
requirements for their review. Agreement among governments to harmonize is the obvious key.
It is also recognised that approval process in some countries outside the USA and EU is accelerated for
trials already approved by the US FDA or the EU EMA. The issue here is obviously that the launch of
trials outside of the US and EU are delayed; a clearly unintended consequence of doing submissions in
series (i.e., first in US and/or EU and then elsewhere) as opposed to in parallel across the globe. More
international coordination could greatly accelerate the initiation of trials in the countries in which the
health emergency started, thereby reducing the global impact of such emergencies.
It should also be recognized in the document that regulatory approval time has slowed considerably
post pandemic. There is no recognition of this in the document, and consequently no suggestion of
what to do to remedy the situation. In STRIVE, we are developing a contingency plan for how to
optimize timely launch and conduct trials with a global reach within this consortium of 40+ countries.
Please provide general comments for Section C: Addressing under-represented subpopulations.
We agree with the principles of attempting to ensure that as diverse populations as possible are
included in trials. This will optimize the generalizability of the findings obtained. But equally
important, this will ensure that diverse countries are involved with generating trial data and
consequently in how trials are designed and conducted, and findings interpreted. This involvement will
be a central part of improving global public health. And this certainly includes populations living in
LMICs.
In relation to pregnant women – we kindly refer to general comments above and will not repeat them
here.
Please provide general comments for ANNEX 1: Provisions for rapid funding and approval of good randomized evidence
generation in emergencies.
STRIVE is created to respond to the emergencies described in this appendix. The rationale for forming
STRIVE was – as also outlined in this document – that few global trial infrastructures existed prior to
the pandemic and as a result, research efforts during the pandemic were uncoordinated.
As described above, STRIVE is developing a contingency plan that outlines the tasks for designing,
and conducting trials, and what aspects are potential bottlenecks for rapid conduct. It is clear that some
of the bottlenecks are intrinsic to the consortium (i.e., tasks we are in control of completing), whereas
others require involvement of a third party for their completion (e.g., regulatory or ethics authorities in
participating countries, shipment of study drug to trial site pharmacy, seeking approval from institution
leadership where the 200+ sites are located across the world, etc). We expect that this detailed and
specific outline will facilitate a discussion within the consortium but also with each of the relevant third
parties – as well as doing dry runs of completion of relevant tasks - in order to optimize STRIVE’s
ability to implement trials quickly and seamlessly. This work could greatly benefit from WHO efforts
at international coordination, thereby rapidly implementing trials, finding safe and effective treatments,
and ending pandemics more rapidly.
Our trial oversight committee (called the Executive Committee) is important to anchor the key
stakeholders that support STRIVE. However, equally important is to have a priori agreement with
funders, the pharmaceutical and diagnostic industry, on decision making in case of an emergency.
Please provide general comments for ANNEX 2: Recommendations for Member States, research funders and researchers.
Suggested amendments (maximum 30 amendments):
Amendment 1
Please indicate the line
number the suggested
amendment starts
54
Amendments Suggest add words in bold
Although a universal definition was not established and remains undefined
Also suggest to add:
Efforts to clearly define the parameters of a global clinical trial ecosystem
should continue with the aim of ensuring all stakeholders have a clear
understanding of remit.
Please provide the
rationale for the
suggested amendments
The definition of global trials eco-system remains unclear. Consequently, various
stakeholders’ input are listed as generic and this central concept to the document
remains ill defined. Efforts should be made to agree on a definition of the concept
outlined in resolution 75:8 to ensure that all stakeholders involved have the same
understanding when talking about this.
Amendment 2
Please indicate the line
number the suggested
amendment starts
138
Amendments Add bullet point – rural and remote settings in HIC
Please provide the
rationale for the
suggested amendments
Under-represented populations also include those in HIC who do not typically
have access to major research centres
Amendment 3
Please indicate the line
number the suggested
amendment starts
197
Amendments Add sentence: A well-functioning global clinical trial eco-system which
includes and involves funders and Industry can help to ensure that equity in
access, including access of post-trial IMP in LMIC, is achieved
Please provide the
rationale for the
suggested amendments
Document does not currently include reference to this issue
Amendment 4
Please indicate the line
number the suggested
amendment starts
259 (1.4.3)
Amendments Section 1.4.3 Suggest to expand this section with a definition of global clinical
trial ecosystem and bullet point list of critical elements required - including not
least the role of regulatory authorities in streamlining the implementation of
global clinical trials in an emergency
Please provide the
rationale for the
suggested amendments
Currently this section lacks detail and could benefit from more clearly
articulating components
Amendment 5
Please indicate the line
number the suggested
amendment starts
268 (1.4.4)
Amendments Add statement: Reporting of diversity and inclusion parameters relating to
trial populations is essential to ensure trial representativeness
Please provide the
rationale for the
suggested amendments
Ensuring reporting is made mandatory will allow monitoring of diversity and
inclusion and trial representation
Amendment 6
Please indicate the line
number the suggested
amendment starts
342 (Section 2.1)
Amendments Suggest to add ‘Defining principal aims of trial’ as one of the key features of a
good clinical trial
Key messages: Appropriate definition of the key aims of a clinical trial will
help guide many aspects of the trial design including appropriate eligibility
criteria, choice of outcome, degree of regulatory oversight required and
reporting of the findings.
Why this is important: Clinical trials cover a wide range of situations and
questions. Some of these may relate to licensing of novel investigational
agents whilst others may evaluate strategic questions using already licensed
produce. Requirements for study procedures including reporting, data
collection and regulatory involvement are linked to the overall study aims
which must be clearly determined at the onset
Please provide the
rationale for the
suggested amendments
Appropriate definition of aims of trial not currently mentioned
Amendment 7
Please indicate the line
number the suggested
amendment starts
337
Amendments Expand sentence “should not be unnecessarily restrictive, and where possible
harmonised across multiple studies
Please provide the
rationale for the
suggested amendments
Highlights importance of harmonisation to allow cross study comparison and
generalisability
Amendment 8
Please indicate the line
number the suggested
amendment starts
377
Amendments Adapt sentence: “random errors must be small by comparison with the clinically
meaningful effect sizes. Also, the clinically meaningful effect size may be
smaller than the expected effect size that the sample size of the trial allows
to have adequate power to detect.”
Please provide the
rationale for the
suggested amendments
Clarity
Amendment 9
Please indicate the line
number the suggested
amendment starts
381
Amendments Add sentence “Adjusting for pre-randomization covariates that are
predictive of the outcome can also be an effective strategy for reducing the
impact of random errors.
Please provide the
rationale for the
suggested amendments
Clarity
Amendment 10
Please indicate the line
number the suggested
amendment starts
428
Amendments Add words “…of the intervention, thus compromising the ability to interpret
the results of the trial.
Please provide the
rationale for the
suggested amendments
Emphasis
Amendment 11
Please indicate the line
number the suggested
amendment starts
446
Amendments Suggest to add:
However, it should also be recognised that relying exclusively on precedent
in choice of outcome may limit innovation in defining the most important
outcomes that can improve public health. Instead, the qualities of a good
outcome which include being clinically relevant / interpretable, patient-
centric, objective, and statistically efficient/feasible should all be taken into
consideration and the most appropriate outcome chosen and justified.
Please provide the
rationale for the
suggested amendments
Inflexibility in only using precedent to define what is a good outcome may result
in impractical studies with sample sizes that are not feasible to achieve.
Regulatory bodies should be encouraged to view the evolving ecosystem of a
pandemic with flexibility
Amendment 12
Please indicate the line
number the suggested
amendment starts
487
Amendments Add sentence: Outcomes defined based on objective parameters help
attenuate the potential biases of adjudication.
Please provide the
rationale for the
suggested amendments
Emphasis
Amendment 13
Please indicate the line
number the suggested
amendment starts
510
Amendments Add following paragraph:
Strong rationale can be made for allowing modified ITT (mITT) analyses,
namely when the modifications improve the potential for treatment
differences without risking selection biases. For example, when there is
down-time between randomization and the initiation of the intervention, it
may be quite reasonable to exclude persons who clinically deteriorate and
cannot initiate the intervention or exclude those who withdraw consent
during this short gap, or persons for whom the study drug is never delivered
in a remote trial due to a courier mistake. Such exclusions are reasonable if
there is no plausible way the exclusion mechanism is associated with the
allocation. The rationale for exclusions needs to be clearly described and
follow-up for excluded participants should continue when feasible with ITT
as a sensitivity analysis. A fully developed statistical analysis plan
determined by the trial steering committee should define these analyses a
priori.
Please provide the
rationale for the
suggested amendments
This guidance is too dogmatic about using ITT. There are situations where mITT
is advantageous and does not compromise the internal validity of the clinical trial,
Amendment 14
Please indicate the line
number the suggested
amendment starts
576
Amendments Add following sentence: In situations in which the DMC recommends ceasing
enrolment into the trial, follow-up should continue on persons previously
enrolled.
Please provide the
rationale for the
suggested amendments
Clarity
Amendment 15
Please indicate the line
number the suggested
amendment starts
576
Amendments Add following sentence:
In the event that a trial DMC and regulatory authority(ies) have differing
opinions on the implications of data being reviewed respectively by both
bodies, a collaborative approach is suggested, whereby conversations on best
path forward for the trial take place, while ensuring that the trials integrity
is best preserved.
Please provide the
rationale for the
suggested amendments
Situations may arise where the DMC and one or more regulatory bodies come to
different sets of conclusions, in this case a harmonised approach is supported
Amendment 16
Please indicate the line
number the suggested
amendment starts
821
Amendments Add following sentences:
The use of a central trial database, real-time data collection, and a clearly
laid out statistical analysis plan at the onset of the trial, are optimal means
to ensure swift trial oversight by the DMC and in case of unblinding of the
results rapid communication of findings made.
Please provide the
rationale for the
suggested amendments
Highlights aspects to improve trials feasibility and importance of forward
planning
Amendment 17
Please indicate the line
number the suggested
amendment starts
824
Amendments Add sentence: The burden of unnecessary monitoring on sites and trial staff
should not be under-estimated, particularly during a pandemic. Remote
monitoring should be considered where appropriate as well as trial staff
training, free access to online resources and capacity building during
periods of relative quiescence
Please provide the
rationale for the
suggested amendments
Monitoring of sites involved in trials (and most especially in pandemic situations
which present an extra set of challenges) is the bane of everyone’s lives.
Important to emphasise capacity strengthening and remote monitoring.
Amendment 18
Please indicate the line
number the suggested
amendment starts
870
Amendments Provide sentence on what WHO considers to be a well-functioning clinical
research institution. If it is those core competencies set out in Fig 1 then this
should be specified
Please provide the
rationale for the
suggested amendments
This is not currently specified
Amendment 19
Please indicate the line
number the suggested
amendment starts
1049
Amendments Expand sentence: ‘Such models need to be developed further, as workload
required to submit trials using these platforms are extensive, particularly
when each member state has specific requirements for their review.
Further investment in infrastructure at the national, regional and global
levels is required
Please provide the
rationale for the
suggested amendments
Although there are advances in streamlining these processes across countries,
current models are still far from ideal and greater engagement and funding from
governments is required
Amendment 20
Please indicate the line
number the suggested
amendment starts
1082
Amendments Add sentence: ‘Established and evolving global clinical research networks
are critical to the conduct and generation of high-quality clinical research.
However, they are only part of the global trial ecosystem, and their
efficient functioning relies on other parties, including regulatory agencies,
to facilitate timely and efficient passage of clinical trials through the
system. All stakeholders should strive to work together on a global level to
ensure procedures are in place so that quick consensus can be achieved in
state of emergency”
Please provide the
rationale for the
suggested amendments
This document should highlight to third parties the importance of timely review
and passage of documents. Currently regulatory bodies have returned to pre-
pandemic state and there is no clear remedy to this. WHO can play a major part
in convening working parties and advocating for the importance of this concept
Amendment 21
Please indicate the line
number the suggested
amendment starts
1640
Amendments Add the following dot point:
Representatives from the child-bearing community should be embedded in
decision making on how to conduct research in women of child-bearing age
Please provide the
rationale for the
suggested amendments
Emphasis on community involvement
Amendment 22
Please indicate the line
number the suggested
amendment starts
1432
Amendments Add the following words:
“Consider the use of innovative adaptive study designs, novel point of care
diagnostics and digital technologies…..”
Please provide the
rationale for the
suggested amendments
Novel diagnostics esp at POC may play critical part in simplifying clinical trials
infrastructure
Amendment 23
Please indicate the line
number the suggested
amendment starts
1361
Amendments Add the following sentences
“In addition to improving rapid decision making at the national level,
efforts must be made to encourage international dialogue and agreement,
particularly in the areas of regulatory approval and ethical reviews.
Enhancement of these processes across borders are essential to facilitate
the conduct of global clinical trials, particularly in times of emergency. In
between emergency periods and as part of preparedness, planning should
be ongoing to ensure that processes are worked through, and solutions
reached, prior to future states of crisis”
Please provide the
rationale for the
suggested amendments
It is essential to advocate for international parties to work together to find
solutions to these complex issues. Failure to do so will inevitably lead us to
similar situations as were observed in the COVID-19 pandemic and prevent true
global equity in clinical trial conduct and access.
Please copy the above form if you wish to suggest more amendments.
Thank you for your participation in the public consultation.