Good morning.
The most important take home message for today is the obvious deficiencies in the support
study consensus process signal an urgent need to strengthen informed consent for human subjects
research, not weaken as some in the community are advocating.
It's remarkable and disturbing the pretext the on two fallacies first is support study
is a representative example of research involving intervention that are used at standard of
care treatment in the non-research context.
It is not as review of the protocol related documents will show.
Let me highlight just a few of the support studies many complex experimental interventions
that cannot be considered standard of care treatment in the non-research context.
We rely on a flip of a coin to make life and death medical conditions independent of clinical
status or need, not standard of care Subject of saturations within a narrow high or low
range combined with a maximum procedure using display either falsely low or falsely high
oxygen readings depending upon experimental group assignment was not standard of care.
The use of falsely reading pulse okay similar tears represents an extraordinary deviation
standard of care in non-research setting particularly since oxygen saturation levels play a role
in important clinical decisions related to the respiratory support whether incubating
or extubating a infant.
The stated purpose for altered pulse okay similar tears was to have a blinding procedure
to avoid bias.
The unstated more important purpose was to force medical teams caring for the infants
to consistently target the assigned experimental oxygen levels and achieve separation between
the two groups.
This matching was considered essential to minimize co-intervention and contamination
by bias of neonatal care providers.
Comment in a paper discussing rationale behind the design of the support boost to and cox
studies reflected awareness that medical teams caring for the study infants were given accurate
oxygen information they would not maintain oxygen levels within the range of stipulated
by the research protocol.
This is a clear acknowledgment the target range cohorts consistent with standard of
care intervention in non-research setting.
The study CPEP experiments included a group that did not receive standard of care.
The treatment i.e. experimental group received early CPEC with strict criteria designed to
force babies off ventilation versus control group which received similar standard of care
interventions including early intubation and surfactant life saving plus conventional ventilation
and criteria for intubation considered standard of care.
In a 2004 presentation describing the support study CPEP intervention the investigators
noted the following.
These CPEP intubation criteria are more severe than used in any trial and as far as we can
tell more severe than used in most network centers.
the CPEP group clearly did not represent standard of care treatment.
Finally there was a complex interaction between the oxygen experiment use of falsely reading
pulse OXIMETERS and criteria for deciding whether to intubate or extubate a infant as
shown here.
It is notable these criteria are based on false pulse OXImeter readings.
The investigators recognize these criteria were not consistent with standard of care
as stated the following in the protocol.
CPEP infants require intubation three times for criteria will have subsequent treatments
including subsequent extubations and re-intubations performed using standard of care.
This addition is to prevent such infants being exposed to further protocol driven intubations
and extubations.
Thus the support study clearly involved in interventions that deviated from standard
of care in the non-research context.
Every infant in the study received experimental interventions not standard of care.
The low oxygen CPEP group received the most extreme combination of experimental intervention,
management with miscalibrated pulse OXIMETERS CPEP and criteria for intubation designed
to force the infants off ventilation.
The second fallacy which is the pretext of this meeting is based is we have entered a
new area of human subjects research that involves studies comparing creams used as part of standard
of care or usual clinical care treatment in the non-research context.
And as a result investigators and IRB conducted and reviewed the support trial and similar
studies justifiably unsure how to apply the requirements of the human subject regulations
regarding informed consent.
This fallacy must be rejected.
Randomized clinical trials comparing interventions that have been used in treatment and non-research
context have been conducted for many decades and claims of ignorance regarding how to apply
the regulations to such research ring hollow.
The history of human experimentation over the century is filled with victims of unethical
research conducted without adequate informed consent.
Outrage of regulations reach a crescendo in the early 1970s, Congress finally pass a law
requiring HHS to ensure the protection of human subjects.
The resulting regulations were implemented nearly four decades ago.
Now in the wake of disclosures about the unethical conduct of support study there appear as possibility
that these disclosures will result in weakening of human subject protections particularly
with respect to implementation of the ethical principle with respect forepersons to informed
consent.
Soon after these findings regarding support came to public attention a group of individuals
within medical research establishment launched a well orchestrated attack in defense of support
study.
Leading this effort has been editors of New England journal of medicine, NIH director
and researchers and bioethicists with close ties to the support study at NIH.
Many critics of actions sought to blur the line between research and clinical care and
appear to view the process of obtaining informed consent as unnecessary impediment to conducting
clinical trials and advancing medical knowledge.
They want to change the rule to satisfy the research needs at expense of subjects rights
the fact this meeting is occurring reflect as tremendous influence that NIH which approved
the support study and spent nearly $20 million has wielded in an effort to undermine authority
and reverse findings.
Your seven minutes are up.
In conclusion efforts to weaken human subjects protections must not succeed.
Many agree deficiencies in support study consent forms are obvious and what's correct in findings.
As an nature editorial said last week no matter the thorniness of issues raised research is
research and whatever context and duty to protect human subjects must remain paramount.
In closing as Dr. Menikoff said about the support study, this should never happen again.
Unfortunately even now it is happening again.
Thank you.
Let me turn to federal panelists, FDA.
Let me just ask about the -- this was a factorial study and one factor was what oxygenation
level patients would be sent to, the major area OHRP criticized.
Apart from what physicians were supposed to do in the event of people having difficulty
do you think there was a problem with comparing the high oxygen level and low oxygenation
level as a perfectly reasonable thing to explore if there was uncertainty about it and what
do you think people should have been toll about that part of the study?
Q. There's a lot to say in response to that question.
What we had essentially was two experimental groups getting care with respect to oxygen
therapies replaced randomly, subjects on either side of the extremes of usual range of oxygen
therapy, irrespective of clinical factors that may be taken into account doing that
and we combine that with pulse OXImeters that blinded the entire medical team to the care
of these infants in terms of what oxygen they were on and that combination procedures clearly
exposed these infants to serious risk.
What should have been disclosed to the parents were those serious risks including the risk
of death, the risk of eye injury and blindness, depending upon individual factors and what
group the babies were in.
There should have been a clearer disclosure how the research was altering the care of
infants compare to care they would have received had they not been in the trial.
In general the consent forms failed in many regards across all the centers.
NIH.
Thank you.
At the time the study was initiated you argue that the parents should have been informed
that in the two arms two oxygen arms of the trial parents should have been informed of
differences an increase risk of death.
What were those in your evaluation of the literature and what should parents have been
told about increase risk in those two arms increase risk of death?
An noting that of course these baby were extremely vulnerable within extremely high mortality
rates, something in the order of 25 to 33%.
We agree, yes, these were critically ill babies with high baseline mortality rate doing things
to alter care for the purpose of experiment could have altered various outcomes including
death, brain injury, eye disease.
We know from earlier studies dating back decades that oxygen is life saving.
If these babies have undeveloped lungs if you don't give them oxygen the death rate
will be much higher than the 20% you noted.
We also know if you give 100% oxygen all the time to infants that they will have a higher
rate of eye disease retinopathy prematurity.
There are offsetting risks, death on the one hand, if you don't give enough oxygen, eye
disease if too much for too long.
That was generally known.
This research was trying to see if we could find medium sweet points where we could lower
the risk of eye disease without affecting the death rate.
But that indeed was unknown, they were trying to answer that and it was highly conceivable
that given not enough oxygen to low group would increase death rate for some infants
and high oxygen group receive more oxygen than received if they had not been in trial
and that included eye disease.
Those risks were reasonably foreseeable and should have been disclosed to the parents.
OHRP.
i would Like to thank Dr. Carome, no questions.
You're welcome.
Can I ask another?
One minute.
So the consent form actually at least what referred to the possibility that higher oxygen
could cause ophthalmic disease.
I would have to agree what the downside was, was part of the primary end point.
Is that your principle criticism?
It would be one of many that we have.
You are correct.
A couple of consent forms noted in the risk section there's a risk of eye disease, some
in the background discussion noted whether eye disease might -- the rate of that might
be altered with respect to oxygen levels.
Many benefit sections of consent forms noted lower likelihood of developing eye disease.
If that's the case, that was not an unreasonable thing to disclose, the counter to that is
there were risks depending which we end up having more eye disease.
Thank you.
Beyond what Dr. Carome said, standard of care research is a misnomer for an experiment testing
comparative risks of a subunit of a broad range of itself standard of care is conducting
an experiment.
With subunit risks certainly differing from those of the broad range, otherwise why would
there have been any point in doing the experiment, subunits themselves cannot be standard of
care.
Main source of conflict precipitating this meeting are contrasting views whether interventions
in support and similar studies are more like experiments or more like existing standards
of care.
Another way looking at this dichotomy between foreseeable risk of experiment and standard
of care or to continue the dichotomy between obligation of researchers as researchers and
obligations of clinics taking care of patients.
In a letter signed by a number of people who will be presenting this meeting, researchers
involved in the study, researchers not involved, ethicists to the New England journal they
confirmed the stance on this conflict.
Saying these two saturation targets were consistent with standard of care, conclusion -- they
stated the conclusion of OHRP the studies experimental evaluation of these otherwise
routinely used oxygen saturation levels, in other words the implication is each of these
two ranges were routinely used which I doubt seriously is the case.
Spatially used.
Exposed subjects to additional risk is not supported by the evidence.
This again was from Dr. Coal, paper referred to by Dr. Carome, designing the study we do
it because importance in outcomes such as importance to mortality and real concerns
of oxygen intentions.
I think one of the things that most illuminates to me part of the answers to the question
is Dr. Temple and Dr. Hudson, what should you have told them?
The answer instead of being looking back at what you should have told them, you can look
at a consent form that did tell them these things.
None U.S. consent forms mention the risk with regard to use of lower oxygen levels, in contrast,
2005 version of consent form in New Zealand boost study by OHRP and sent out a letter
to the investigators two and a half months ago, this is what that consent form said to
the patients considered participation.
Too low oxygen in the blood, long periods increase the risk the baby will not survive
or contribute to poor growth.
And damage brain cells and lead to developmental problems.
The aim purpose of the study to state in the informed consent the aim of the study is to
determine within the range of oxygen saturation currently being used 85 to 95, whether targeting
the lower end of this range, 85 to 89 compared to upper end of the range 91 to 95 is safe
and effective in reducing serious vision and lung problems without increasing mortality
or neuro-developmental dissent.
This is something used in New Zealand, I doubt whether baby there is had any different resistance
to low oxygen or high oxygen as they do here.
But they thought it important and attend of the part, they said had U.S. investigators
included something like that, we would not have criticized for omissions with respect
to issue of dangers of low oxygen.
The underlying principle behind arguments imposing informed consent in such experiments
that is necessary and mechanism this can be accomplished is inadequate informed consent
to blur the line between research and standard of care to facilitate more consent and participation.
The origins of this are not recent, 20 years ago.
In a letter in the British medical journal by noted British neonatologist Dr. Mode she
said though it might be argued parents have a right to know about all aspects of baby
care, this means many instances distressed parents were forced to make decisions not
normally asked to make.
In other words given information about the experiment versus what they would otherwise
get and makes it difficult and no doubt it's difficult but it is argued by us that they
do have a right to know.
Back 30 years ago the issue of therapeutic misconception arose when participants in studies
found unaware of participating in study and receiving personalized care in the clinical
setting.
Research participants failure to recognize how personal care obligation of physicians
to make medical decisions maybe compromised by research procedures.
more recently this concept was studied in 25 different experiments on 225 people that
agreed to participate and a third express inaccurate beliefs regarding degree of individualization
of their treatment as a result they may have failed to clearly appreciate the risk benefit
ratio of research project which they're asked to consent.
Blurring the distinction between standard of care -- oops.
And experiments such as support is fostered by inappropriate inaccurate portrayals of
experiment in the consent forms.
To look at the consent form we examine 22 -- 15 of 22 literally referring to each of
the separate arms to which someone maybe randomized says it's standard of care.
Further in terms of the risk, 20 of the 22 consent forms failed to identify retinopathy
prematurity or brain injuries as a result of -- as a risk of research and none mentioned
risk of death for the oxygen experiment as I mentioned earlier.
This is paper a couple of years ago people who do research --
Time is up.
Please wrap up.
I will summarize the final slide then.
Other remedies to the serious problem of misinformed consent or therapeutic misunderstanding must
include enhancing surveillance an authority to enforce regulations not weakening the surveillance
authority or the regulations.
To weaken these the authority regulations protecting human subjects would be to sacrifice
critical informed consent dependent autonomy of patients decisions whether they participate
in research by deferring to researchers autonomy to conduct trial.
Thank you.
Panelists OHRP.
FDA.
One of the thoughts I had as I was reading this material is that one way to conceivably
inform patients would be very explicit about what the end points of the study were.
Which was not in the consent form.
I know it's hard to translate these things sometimes.
Do you think that an appropriately worded statement well, we're looking at eye disease
and we're looking at pulmonary disease and death and that's what we're going to look
for and we don't know which, blah, blah, blah.
Would that do the job?
I think what I read from the New Zealand consent form really does that in terms of the oxygen
part of the experiment.
So the purpose of the experiment is to see whether we can as Dr. Carome referred to,
find somewhere within what is the range of 85 to 95, that maybe better.
Among other thing it is experiment should have had a control group that was actually
the real standard of care.
But yes, if they had said the purpose of the experiments to see whether we can reduce the
risk of eye damage at higher group and reduce the risk of death in the lower group by looking
at these two groups, obviously people depending on which group they're randomized to may have
different results in terms of death or eye disease.
Yes.
Going in that direction would have been much more informative obviously back in 2005 people
in New Zealand got it with respect to oxygen so it wasn't something that was unknown unimaginable
based on non-foreseeable risk.
New Zealand they thought perceivable risk they felt obligated to inform parents about
the foreseeable risk.
NIH.
No questions, thank you.
No other questions from the panel.
Okay.
Thank you very much.