EPI, Alm.del - 2023-24 - Bilag 1: Baggrund til ekspertmødet 29/11-23

Epidemiudvalget 2023-24
EPI Alm.del Bilag 1
Offentligt

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

Organization/

Affiliation

E-mail (optional)

Matthews

STRIVE research consortium

[email protected]

First name

Country of residence

organization/affiliation

Gail

Global network

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also provide any comments about the strengths of the draft guidance.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

EPI, Alm.del - 2023-24 - Bilag 1: Baggrund til ekspertmødet 29/11-23

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.

EPI, Alm.del - 2023-24 - Bilag 1: Baggrund til ekspertmødet 29/11-23

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

EPI, Alm.del - 2023-24 - Bilag 1: Baggrund til ekspertmødet 29/11-23

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.

EPI, Alm.del - 2023-24 - Bilag 1: Baggrund til ekspertmødet 29/11-23

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

EPI, Alm.del - 2023-24 - Bilag 1: Baggrund til ekspertmødet 29/11-23

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

EPI, Alm.del - 2023-24 - Bilag 1: Baggrund til ekspertmødet 29/11-23

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

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

Amendments

Please

provide

the

rationale

for

the

suggested amendments

138

Add bullet point

–

rural and remote settings in HIC

Under-represented populations also include those in HIC who do not typically

have access to major research centres

Amendment 3

EPI, Alm.del - 2023-24 - Bilag 1: Baggrund til ekspertmødet 29/11-23

Please indicate the line

number the suggested

amendment starts

Amendments

197

Please

provide

rationale

for

the

suggested 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

the

Document does not currently include reference to this issue

Amendment 4

Please indicate the line

number the suggested

amendment starts

Amendments

259 (1.4.3)

Please

provide

rationale

for

suggested 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

the

Currently this section lacks detail and could benefit from more clearly

the

articulating components

Amendment 5

Please indicate the line

number the suggested

amendment starts

Amendments

Please

provide

rationale

for

suggested amendments

268 (1.4.4)

Add statement:

Reporting of diversity and inclusion parameters relating to

trial populations is essential to ensure trial representativeness

the

Ensuring reporting is made mandatory will allow monitoring of diversity and

the

inclusion and trial representation

Amendment 6

Please indicate the line

number the suggested

amendment starts

Amendments

342 (Section 2.1)

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

EPI, Alm.del - 2023-24 - Bilag 1: Baggrund til ekspertmødet 29/11-23

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

Amendments

Please

provide

rationale

for

suggested amendments

337

Expand sentence

“should

not be unnecessarily restrictive,

and where possible

harmonised across multiple studies

the

Highlights importance of harmonisation to allow cross study comparison and

the

generalisability

Amendment 8

Please indicate the line

number the suggested

amendment starts

Amendments

377

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.”

Clarity

Please

provide

the

rationale

for

the

suggested amendments

Amendment 9

Please indicate the line

number the suggested

amendment starts

Amendments

381

Please

provide

rationale

for

the

suggested 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.

the

Clarity

Amendment 10

Please indicate the line

number the suggested

amendment starts

Amendments

Please

provide

rationale

for

the

suggested amendments

428

Add words

“…of the intervention,

thus compromising the ability to interpret

the results of the trial.

the

Emphasis

EPI, Alm.del - 2023-24 - Bilag 1: Baggrund til ekspertmødet 29/11-23

Amendment 11

Please indicate the line

number the suggested

amendment starts

Amendments

446

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.

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

Please

provide

the

rationale

for

the

suggested amendments

Amendment 12

Please indicate the line

number the suggested

amendment starts

Amendments

487

Add sentence:

Outcomes defined based on objective parameters help

attenuate the potential biases of adjudication.

Emphasis

Please

provide

the

rationale

for

the

suggested amendments

Amendment 13

Please indicate the line

number the suggested

amendment starts

Amendments

510

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

priori.

EPI, Alm.del - 2023-24 - Bilag 1: Baggrund til ekspertmødet 29/11-23

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

Amendments

576

Add following sentence:

In situations in which the DMC recommends ceasing

enrolment into the trial, follow-up should continue on persons previously

enrolled.

Clarity

Please

provide

the

rationale

for

the

suggested amendments

Amendment 15

Please indicate the line

number the suggested

amendment starts

Amendments

576

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.

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

Please

provide

the

rationale

for

the

suggested amendments

Amendment 16

Please indicate the line

number the suggested

amendment starts

Amendments

821

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.

Highlights aspects to improve trials feasibility and importance of forward

planning

Please

provide

the

rationale

for

the

suggested amendments

Amendment 17

Please indicate the line

number the suggested

amendment starts

824

EPI, Alm.del - 2023-24 - Bilag 1: Baggrund til ekspertmødet 29/11-23

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

Monitoring of sites involved in trials (and most especially in pandemic situations

rationale

for

the

which present an extra set of challenges)

is the bane of everyone’s lives.

suggested amendments

Important to emphasise capacity strengthening and remote monitoring.

Amendment 18

Please indicate the line

number the suggested

amendment starts

Amendments

870

Please

provide

rationale

for

the

suggested 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

the

This is not currently specified

Amendment 19

Please indicate the line

number the suggested

amendment starts

Amendments

1049

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

Although there are advances in streamlining these processes across countries,

rationale

for

the

current models are still far from ideal and greater engagement and funding from

suggested amendments

governments is required

Amendment 20

Please indicate the line

number the suggested

amendment starts

Amendments

1082

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

This document should highlight to third parties the importance of timely review

rationale

for

the

and passage of documents. Currently regulatory bodies have returned to pre-

suggested amendments

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

EPI, Alm.del - 2023-24 - Bilag 1: Baggrund til ekspertmødet 29/11-23

Amendment 21

Please indicate the line

number the suggested

amendment starts

Amendments

1640

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

Amendments

1432

Add the following words:

Please

provide

rationale

for

suggested amendments

“Consider the use of innovative adaptive study designs,

novel point of care

diagnostics

and digital technologies…..”

the

Novel diagnostics esp at POC may play critical part in simplifying clinical trials

the

infrastructure

Amendment 23

Please indicate the line

number the suggested

amendment starts

Amendments

1361

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

It is essential to advocate for international parties to work together to find

rationale

for

the

solutions to these complex issues. Failure to do so will inevitably lead us to

suggested amendments

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.