Please use this space to elaborate on any responses from above.
More and more scientists.researchers in a variety of fields are buying in/supporting adaptive designs.
There are so many different ways to adapt a trial and several different settings that it makes it difficult to respond to some of these questions without further explanation about the setting. Thanks for having us.
Need better education of all - patients, researchers, reg grps - in ada[t/ design. Currently there are lots of misconceptions about this design.
Carrying a message from the group I am involved with: Not all adaptive designs are synonymous with Baysian statistics
These are difficult questions to answer without context. Not all adaptations are the same; some approaches may be valid for early phase trials but not confirmatory trials. The idea of adaptation seems at odds with the notion of a "confirmatory" clinical t
good design adaptive designs have great potential. lots of crummy design can still occur and call itself adaptive. excluding those, adaptive design is likely to be very beneficial to all and efficient. There is the disadvantage to teh resesearcher of p
Adaptive design means different things to different people. Phase 3 adaptive trials have already been funded by NIH in a limited sense.
responses all depend on the quality of the adaptive design and control of type I error
I believe the FDA will accept adaptive designs, but only if the investigators have done a thorough job of validating the proposed design. In my opinion, much of the negative remarks made about the FDA are by researchers who do a poor job of justifying th
The adaptive design must be appropriate for the specific trial and must be technically sound. Blanket statements about adaptive designs don't make sense- they aren't always the correct solution.
They all depend on the design, clinical areas, etc.
I think review panels and the FDA are making a good effort to understand when adaptive designs are appropriate and are anxious to accept them when they are valid. I think they have the potential to greatly improve the efficiency of the development proces
Adaptive clinical trial designs (whether frequentist or bayesian) are efficient only if designed and conducted by a group of highly experienced clinical and statistical investigators. The logistics of conducting such trials are not trivial.

1) NIH grant review panels will understand Phase II adaptive clinical trial designs.
They are increasingly exposed to adaptive designs.
They are straight forward and simple. There has been enough press about them to understand. Some misconceptions.
Many reviewers may not have been trained in or familiar with the methods
Although these types of trials are becoming more common, several researchers (particularly in the academic setting) have little experience designing and conducting phase II adaptive designs. Experience allows for better understanding of these designs.
I think it depends on the reviewers. Certainly some reviewers will not understand the technical/methodlogical detqails.
Statisticians on the panels will understand, but clinicians will not. They will ask the statisticians for their opinion and defer.
this meeting will make the design understandable
will require extensive discussion and explanation
1. Review panels not selected with ACTD, Phase II experience. 2.Phase II is often seamless in ACTD not a broadly understood/accepted concept
new concept - doesn't always fit into standard application - usually requires continued grants which are not under review
general CSR study sections don't have the necessary expertise
Statistician will others not as easily. I think buy in to concept is more the issue than understanding.

2) NIH grant review panels will accept as valid Phase II adaptive clinical trial designs.
they will understand them and the data for sure
These approaches a gaining acceptance, especially for liaison phase (phase I/phase II) trials.
They may be more likely to accept these designs even if they don't necessarily understand; mainly because they are innovative and other efficiencies.
Reviewers may be more likely to accept phase II designs as valid (over phase III) because this is not a confirmatory trial. Some may accept it as valid even if don't completely understand the methodology.
If they don't know, they're less likely to accept
interest in using these novel methodologies
still relatively new and not many studies validating their use
attitude: additional paradigms, as belief system, are there to be justified, not there to create/encourage disvobery process.
reviewers with experience can be put on panel
I think people just starting to dare to submit in recent years - soon it will be familiar and common place

3) NIH grant review panels will understand Phase III adaptive clinical trial designs.
The bar is higher in phases III. There greater concern about Type I error.
They are more complex beause of type I error, but they will ignore that and accept the data and design.
Most statisticians on NIH study sections have no experience or training in this area and have incorrect preconceptions.
They may be more likely to accept these designs even if they don't necessarily understand; mainly because they are innovative and other efficiencies.
Not likely that NIH- _______ grants have collected history of any Phase III trials. Needed: survey of NIH sponsored adaptive design trials. Not easy to do given NIH/gov policies on information distribution.
outcomes are standard with fellow FDA lead
NINDS clinical study sections should (not all phase III's are in those sections)
This is a T-2 translational type problem People need funding hesitate to submit an analysis that might be anything "too novel", "safe" to do the tried and true (less good way)

4) NIH grant review panels will accept as valid Phase III adaptive clinical trial designs.
They will ignore the design and acdept the data.
General, vague, ill-informed concerns about multiple testing and multiplicities.
Same reason as for phase II adaptive designs.
Because of the confirmatory nature of p hase III trials review panel may be less likely to accept adaptive as valid.
If they don't know they are less likely to accept.
"understand" and "accept" have common character among reviewers. Scattered knowledge of adaptive designs, not coordinated/collaborative foundation/education in non-industry trials.
Not certain now but will in future if we keep submitting
They need more education about this type of trial design

5) The FDA will understand adaptive clinical trial designs relative to regulatory approval.
They are garnering experience by the day.
They have spent a lot of time learning about these designs. Theya re the experts. Experience!
The FDA isn't __________. Statisticians at CDRU are likely to. Physicians and engineers less so. Few statisticians at CDER and mores. CBER may be less likely to. Again to due prior exposure/training.
It depends on the FDA branch and group of statisticians.
The FDA has guidance documents on adaptive designs and the statisticians on the regulatory panels should understand.
Ditto Caveat - I am referring to stats at FDA at lower, non research level
this meeting will make sure designs are uderstandable
DA has dedicated inerest in ACTD, i.e. a focus - BUT current senior staff at FDAhave "power" in narrow environment. Referee rather than player mentality
depends on risk methodology is still being developed
More exposure to them and clinical research expertise they approve small trials more readily

6) The FDA will accept as valid adaptive clinical trial designs relative to regulatory approval.
Depends on the care taken in tyhpe I error and the conduct relative to the plaqnned design.
History of acceptance. The Gitcal Path ____________ encourages ___ to accept well designed adaptive trials.
Will depend on particular, individual FDA statistician and quality of trial design.
I don't have enough knowledge about the FDA to respond to this question.
team of later reviewers by post-hoc statisticians in the event of adverse outcomes with _____/device
I am confident but still not enough knowledge
likely to have difficulty because regs are not adaptive
FDA not ready to accept - although has infact accepted ACTD, esp in industry - paradoxical limbo status for adaptive trials.

7) Researchers will understand adaptive clinical trial designs.
Some misconceptions, but general understanding.
They are natural to understand. We can often times have more personal interaction and direct Q&A than with NIH reviewers at FDA.
This will vary quite a bit across researchers.
Adaptive trials can be complex. I think researchers will either accept or reject the results but maybe won't understand the design.
The researchers are more committed to understanding their own design.
Those involved in the studies will if they are involved in the research
well-versed in reasons behind the need for adaptive designs
assuming interest in there career security is not impacted (in senior researchers) have relevant statistical background

8) Researchers will accept as valid adaptive clinical trial designs.
Many will accept what statistician tell them are valid.
The data is all that matters in the end.
Will depend highly on clarity of explanation and presentation in publications.
I believe researchers are split on this (validity). It also depends on the trial phase.
If one journal does not want to publish results, possible to submit to another
those not involved with the research might be skeptical
Researchers with clinical experience may more likely accept as valid ACTD. Exposure to patients in emergency care is a strong factor in acceptance.
going to be transition to standard field

9) Journal peer reviewers will understand adaptive clinical trial designs.
The least likely so far to understand. Not a lot of experience.
Lack of print exposure/familiarity/training. Also preconceived biases by statistical reviewers. Oftentimes we (statisticians) aren't given much room to describe to design in detail in a clinical journal.
Will depend on luck of getting a knowledgeable reviewer.
It may take 2 separate manuscripts, one strictly on the design and one on the triaql results.
Editors/reviewers are interested in probability new and novel study design concepts
the job of writers is to makie the trial design understandable
Based on current portion of clinical trials reviewers

10) Journal peer reviewers will accept as valid adaptive clinical trial designs.
Most reviewers, if non-statisticians, will accept as valids
It depends on how the trial is executed and whether the investigqtions can adequately explain the design.
if explained well and with statistical backup
likely to accept if understand. Similr characteristics as NIH reviewers - same population
Depends on whether their stats reviewer understands and accepts adaptive trials

11) Clinicians will understand adaptive clinical trial designs.
The least likely of all these, because they rarely do trials and don't care.
Not yet - there is still a great deal of education surrounding the design and conduct of adaptive designs
Statistical details are more complicated
Assuming you mean general clinicians not statistic/research trained
Its more intuitive than non adaptive trial design

12) Clinicians will accept as valid adaptive clinical trial designs.
I've had lots of experience dealing with clinicians and adaptive designs.
Again, the data is all that matters to them and that will be clear.
Relatively little concern about lack of understanding.
It probably depends on the design (that is actually b eing adapted) and the trial results.
Clinicians may be okay with accepting the validity without understanding statistical details. Clinicians tend to be very excited about adaptive designs.
They make like innovation; may possibly mistakenly equate adapt des w/ smaller N, faster trial.
those that go to the trouble of learning about them will increasingly accept them
will need education but have little time available to look in depth
probably do not distinguish between adaptive and conventional design.

13) Adaptive clinical trial designs pose ethical advantages from the patients’perspective.
when done will they treat patients in and out of the trial better?
doses/treatments that offer no efficacy (or are unlikely to) or have safety concerns are less likely to remain as a possibilty. Also they are more ethical for patients outside the trial because they can get products to react faster.
Better assurance that their participation will contribute important information
It depends on the design, but for example response adaptive it may be more advantageous to have higher probability of being randomized to active arm.
flexibility is needed as all patients are different
Whether or not an adaptive trial really offers ethical advantages (random) patients will perceive "a new and different" approach aimed at time issues and increased communications is progressive
faster, better, more efficient, less chance of going to worse group as trial goes on
Patients are shunted to the more promising area as a difference develops for first time patients may actualize benefit from being a subject
response adaptive randomization gives patients a better chance of being randomized

14) Adaptive clinical trial designs pose ethical disadvantages from the patients’perspective.
If enrolled in first part of trial, more likely to be randomized when little is known
only if they reject treatments too early
not likely to be different from perceptions of conventional trials
I can only see it would ______ the process unblinded

15) Adaptive clinical trial designs pose ethical advantages from the researchers’perspective.
Gives ability to address many questions in a single trial.
Can create designs that learn more and treat better. There isn't the burden of sacrificing patients for research.
The researcher, while maintaining the blend of his or her equi_______, can be confident the patient is more likely getting a safe and effective treatment than with equal _____________ even if the MD remains blinded. He can also be more sure "bad" doses w
Better justification for erollent and treatment of each subject
We have an ethical obligation to design best possible trial.
Ethical issues not primary and often never are addressed.
allows research to adapt to current trends
fewer patients needed to answer question
Conservation of resources, pt protection more patients exposed to the evolving better answer

16) Adaptive clinical trial designs pose ethical disadvantages from the researchers’perspective.
Potential greater concerns about unblinding if appropriate firewalls aren't in place.
trials funded for 5 years trial ends early for no change of finding results can't keep research staff

17) Adaptive clinical trial designs pose ethical advantages from the societal perspective.
They are more efficient in terms of patients and resources. The "non-adaptive" approach is leading the US into bankrupcy becaquse of health care costs.
More likely to get the right answer on treatments and less likely to "waste" subjects.
Yes. Fewer patients are "used" to identify ineffective therapies freeing them up for trials of potentially effective therapies. Also effective therapies. Also effective therapies can get to market faster. Plus were more likely to have a better dose ma
Better, more efficient, and more rapid development of effectiove treatments. And more rapid abandonment of losers
If we can design "smarter" trials, that would be an advantage to all.
Ethical issues should in fact play greater role - above key and current patient protection regs
don't think public opinion will understand difference
More trial done, questions answered at less societal cost I think

18) Adaptive clinical trial designs pose ethical disadvantages from the societal perspective.
Only if treatments on inappropriately rejected too early
No trial, rejecting gold standards is by definition ethically certain. Outcomes and use of outcomes can vary

19) Adaptive clinical trial designs increase the overall efficiency of research.
this is what they are constructed to do. Can be huge savings, worst case is no savings not negative savings.
On average well designed adaptive designs offer demonstratable advantages in sample size.
It all depends on the phase of the trial and what is being adapted. In addition,it depends on how one defines efficiency. I think a comparison of a trial run under different desins is needed to answer this question.
It is hard to say because efficiency can be measured in many ways, total sample size, total subjects on active, time from bench to bedside, etc. Not all metrics may agree.
conceptually yes, needs to be tested. Cost is still an issue.
except the inefficiencies of high trial turnover start up efforts etc.

20) Adaptive clinical trial produce scientifically valid results.
Properly designed clinical trial are scientific by design.
We can demonstrate type 1 error ____ and higher power. Therefore the PPU is higher than a similarly sized fixed/_______ trial.
This is time when designed, simulated, and executed properly
I need more information regarding methodologies
Evaluating data before/throughout trial not relying on statistical evaluation only seems to me to be very valid

21) Adaptive clinical trials will improve patient care faster than traditional trials.
Answer sooner. Kills duds faster opening up research for
Not sure of the speed, but the worst case is no change, the best is huge changes.
Maybe. For example, if you comgine a phase I and II or II and III then maybe under the right conditions you can shorten the time to finding an answer. But in general I think it is rare.
It is hard to say because efficiency can be measured in many ways, total sample size, total subjects on active, time from bench to bedside, etc. Not all metrics may agree.
Certainly are of possible purposes or bi-product
obvious yes if process works. Cuts research time

Please provide any comments regarding NIH and FDA responses to adaptive clinical trial designs.
There is a need to understand the confirmatory vs. exploratory purpose of these designs and not make sweeping generalizations, but rather target the approach to the problem
Research criteria may not be the same as regulatory consideration
FDA has accepted well understood adaptations for years. SOme of the more imaginative adaptive designs may have problems, so I am not sure I get the gist of these questions.
There are adaptiuve and adaptive. Some are well-understaood , ignoresm one survey somne mnay not be (clearly). I see little problem for phase 2 studies. PH 2. more likely to be troublesome.
My impression is that the FDA will not accept any type of analysis that could leave open the possibility that the result occurred because of chance or unforseen circumstances. Adaptive trials are necessarily complex. The FDA desires simple designs so tha they can unequivocally support the primary outcome measure AND so that practitioners can eaily understand the results. While the FDA may understand the designs, they may not accep it as valid.
While many clinicians will not understand these designs, the clinical trials study section (at least at NINDS) has statisiticians that are very capable of understanding them Whther or not they will accept them as the best way to do a trial is another mattr. Same for FDA.
Forms of these designs have been used for many years. "accept" the designs? I think NIH demands them.
A study would have to be improved by an adaptive design (cheaper or easier to interpret) in order for NIH or FDA to prefer that design over frequentist approach.
The term "adaptive clinical trial designs" encompasses a very broad spectrum. The NIH and FDA already accept adaptive designs based on prespecified blinded analysis of interim results, as well as prespecified group sequential designs (which designs do, ofcourse, adapt to interim estimates of treatment effect). Many researchers consider adaptive modification of maximal sample size based on unblinded interim results. This does not truly provide much in the way of an advantage, and I see no reason for ths type of "adaptation" to prevail over the more standard group sequential designs (whether they be eventually analyzed in a frequentist or Bayesian manner). Other researchers have considered adaptive modification of randomization ratios across treatmen arms or within strata defined by eligibility criteria. (Such can in some sense be viewed as including adaptive dropping of treatment arms or subgroups.) In my experience, the FDA has already accepted adaptive selection of subgroups and doses based on intrim estimates of treatment effects when those rules were prespecified in an easily understood manner. I hope the NIH, in particular, will adopt phase II strategies that use adaptive design strategies to better control the type I and type II errors as teatment investigations proceed from phase II to phase III. As a general rule, the setting and conditions under which phase III studies are conducted do not exactly mirror those of the antecedent phase II studies, in part due to a certain amount of "data-dedging" of the phase II data. Bayes' rule tells us that the predictive value of the positive can be parameterized by the type I and type II errors, and uncontrolled "data-dredging" tends to inflate the type I error much more than decreases the type II errr. Many of the adaptive strategies allow a formalism for 1) describing the prespecification of adaptive rules when such is being used, and 2) controlling the type I and type II errors even when the adaptive r
within NIH it may depend on the review study section
With respect to FDA's acceptance of adaptive clinical trial designers it depends on the basic trial design. If the trial is an open label, uncontrolled trial (regardless of the adaptive design), the FDA will need significant interaction and discussion wih researchers/companies.
R6#6. FDA will accept as valid A.CTDS if appropriately designed.
My understanding is that the FDA is likely much farther along to understanding adaptive clinical trial designs.

Please provide any comments regarding researcher, peer-reviewer and clinician responses to adaptiv...
these are broad audiences, spanning medicial disciplines and cultures that are different
It will vary by the area of medicine. Oncology and other areas where it takes years to complete phase 2 and/or phase 3 studies have been more amenable. So journals will vary by the comfort zone of their editorial board members with the topic. Clinicians w
Detailed understanding of study design by clinicnias and journal reviewers is quite variable but the less controversial will be acceptable. Phase 2 "exploratory" are far easier to accept.
Journal reviewers are less likely to understand adaptive designs than are researchers.
If published in major peer reviewed journals, clinicians will accept them. Unlikely that will understand them. In terms of the review, here it is a matter of luck. At study section you are almost guaranteed that the statistician will understand it (even i
Think that clinicians are the most unlikely to understand adaptive designs, but if the trial publication appears in a high profile journal, they will be more likely to accept the results as valid despite not fully understanding the methodology. Peer revi
Outside of review panels, the level of knowledge will drop.
I note that the level to which each of these groups need to "understand" the designs is different. And, most importantly, not every "adaptive design" will be understood by everyone. Indeed, it is my experience that many advocates of adaptive designs do no
Same comment as in above box, if study is open label and without concurrent control. Above box reads: If this is an open-label, without concurrent control study (of an unproven technology) the FDA will need a lot of convincing and interacting with the

Please provide any comments regarding ethical aspects of adaptive clinical trial designs.
I suspect getting an answer more rapidly has some advantages.....without defining what it means to be adaptive it is hard to say if society will or will not benefit. SOme suggest treatment effect sizes are exaggerated when the study stops early.
IF they're rigorous they can shorten trials, lead to success (where app, all good for everyone. If they increase errors all lose.
I have not thought and read much about ethical aspects of adaptive design.
Adaptive design ensures that the more efffective a treatment appears, the more people get it. However, if not much difference between treatments may need a larger sample. So is very advantageous when one treatment clearly superior (thin RCT of placebo vs
Ethics of the trial is based on the soundness of the science of the trial design; if the trial is designed so that a valid result is obtained, there appear to be significant ethical advantages to adaptive designs, particularly in terms of reducing sample
One concern would be if the resulting trial is less easily digested by the readers and reviewers, then the subjects were exposed to risk for knowledge that does not change practice as much.
It is unclear to me the exact distinction you want to make between the "patients' perspective" and the "societal perscpective". I see three possible patients' perspectives: patients currently on the RCT, patients who will eventually be on the RCT, and pat
All of these questions depend on the basic trial design as well as the specific adaptive nature of the particular trial design.
These designs will potentially allow placebo controls on issues that have equipoise.

Please provide any comments regarding efficiency, validity, and translation into practice of adapt...
THe efficiency of the research will come when these approaches are more standardized. RIght now, we are learning as we go along.
Properly designed adaptive clinical trials could improve effeciency , validiaty and translation of clinical trials.
seemy comments to prior panel. They will produce valid results. BUT, is primary outcomes are different enough, then you may lose power to study secondary outcomes (as too few assigned to arm that "loses" on primary outcome) and there are times when the se
Depends how they are done. Could improve or hinder clinical practice.
Again, each of these opinions are based on an assumption that the adaptive trial has adequate power to detect an important clinical difference. Given that, adaptive trials appear to be able to (potentially) reduce the sample size, shorten the duration of
There is some advantage in efficiency in terms of requiring fewer subjects. This advantage must offset any perception that the analysis or design is convoluted and hard to follow. A larger, simpler trial that is more compelling and understandable might
Here I answer the questions according to my beliefs about whether the adaptive designs will be used in a scientifically valid manner. In my previous answers I stated that adaptive designs could be useful when used properly. I just think that the hyper
I agree with each of the above from a theoretical standpoint.