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The following message was posted to: PharmPK
I think Roger puts his elegant finger right on a vital issue when he
asks what we all think about following guidelines without reasoning. I
have been concerned about this for many years because when safety is
at stake it can be especially important. My main example of that would
be the Tegenero disaster because I think it could have been greatly
mitigated if the investigator team had not thought they were safe
because they had "ticked all the boxes". Knowing that they were a
leading group when it comes to regulatory and guideline compliance
they had lulled themselves into a false sense of security so they gave
a relatively large dose, immunologically speaking, for such a novel
compound and to a whole group of 6 subjects.
A real problem is the difficulty of being seen to question or
criticize guidelines. I can give a small, true example when I was
actually reported for doing that by an opinionated nurse who was quite
a rigid follower of procedure. We were dosing a novel micro-inhaler
and the very first subject seemed to fumble it unexpectedly despite
previous training and the tiny crystal of drug disappeared, possibly
into the atmosphere. I thought out loud and asked the team "What do we
do now? Perhaps we should give a second dose properly." (It was a
well-known drug and we were going on to double and re-double the dose
in the study anyway). My worry was that poor or nil absorption due to
the fumble might be interpreted as a formulation failure with serious
consequences for the project. If the first dose had been absorbed so
we doubled the AUC it would be obvious by matching it to the AUC of
the volunteer's next dose. In fact the client's representative was
present and he was happy to leave it at one dose and so the decision
was not mine to take.
The nurse angrily called it a near disaster when in fact it was
entirely logical and safe. I felt that it was a great pity that she
could not ask me what my reasoning might be. In the end I probably
would have stayed at one dose myself, but by logic, not
guideline-following. By that I mean that on balance I probably would
have accepted the risk of sacrificing an expensive volunteer dose with
considerable weakening of the value of his later dose data, hoping
that he had absorbed the drug. There was also the counter-risk of
doubling the lowest dose AUC for this subject so we would not be able
to use his within-subject data for linearity calculations. Nonetheless
I do think I was right to reason it through and to try to involve
everyone present.
So I not only agree with Roger's emphasis on reasons and reasoning but
would suggest that we try to share it with others during our
experiments, be they in the lab or the clinic. That way we all
maximize our learning and locating the scientific boundaries of
individual guidelines. An atmosphere of questioning them is actually
more robust and safer than one that does not.
Andrew Sutton
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Andrew:
This seems to be apples and pineapples. Roger's discussion relates to
quantitation following fairly well established (if philosophically
unchallenged) procedures. Your instance was in the execution of a
Clinical
Trial where review boards oversee and approve protocols, primarily to
insure
the integrity not only of the study but of the patient as well. Your
reflexive action to double the dose may have been well appreciated in
discovery but not in a disciplined clinical setting. An individual who
puts sponsor safety ahead of patient safety in practice as well as in
clinical trials is an individual in need of another profession. Not
having
seen the trial protocol, but assuming there was a proper one, the
nurse's
response was undoubtedly correct and you are indebted both to her and
to the
sponsor.
Drugs can also disappear because of formation of a CIC, an antibody
established by exposure to a related drug or other epitope with
convergence
(HAMA). Or by induction of enzyme systems. If the dose is doubled in
these
instances because the 'drug was not seen" patient- and sponsor risk
escalates, the latter being more tolerable than the former.
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Thanks for your comments although some of them make me wonder if you
understood that I really was writing about the fringe occasions where
the guidelines don't reach and you have to think about the best course
of action to salvage the most ethically and scientifically of the
project. Your own phrase "fairly well established" seems to imply that
they do exist and I think the Tegenero case was one of them. I'm
curious that you of all people reacted so reflexly to the point of
mentioning unfit physicians because it illustrates the difficulty we
have in thinking, and I mean thinking openly, about guidelines. As
Niels Bohr once said..."No, no, no. You're not thinking, you're just
being logical."
As you have raised the safety issue I have to repeat that it was a
well known compound, fentanyl in fact, that anaesthetists often give
in much higher doses intravenously than we were going to use
sublingually. We were going to double and redouble the dose in this
subject anyway. I knew from previous work that bioavailability from a
vapourized inhaler system (so probably more efficient than this one
due to using a much bigger surface area) was about half IV indicating
a suitable margin of safety. Being anaesthetically qualified I also
know that rarely a person can be hypersensitive to fentanyl but in
that case they would have reacted as overdosed at any level, which is
why we had the antidote immediately available. Therefore, safety was
not the issue. I did fail to mention for brevity's sake that I was
also concerned not to waste the volunteer's efforts, venepuncture etc.
I do of course agree with review boards, as you point out, but I would
note that in this particular discussion that a review board had agreed
to the Tegenero protocol so it was an example of how guidelines do
fail from time to time.
So when events occur on the fringes of routine or easily defined, and
I thought Roger was writing about that issue otherwise he would not
have invoked REASON, will you just sacrifice the work you are doing
because a procedure isn't in place? Sometimes I think that the more
complicated, expensive and time consuming research becomes the more
the issue of waste itself approaches a moral if not an ethical conundrum
Best regards
Andrew
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My apologies-I was far too harsh. They are though two far different
issues.
In protocols, especially clinical protocols, all sorts of
contingencies need
to be addressed. They are monolithic admittedly but they must be.
There is
some flexibility by amending them or by capturing variances in a
protocol
deviation. With the proper rationale and justification almost
anything can
be handled. In your case the justification would be that "it was
observed
that the preparation was not inhaled or was lost before inhalation". A
further justification was that the dose was to be escalated in
subsequent
exposures. Of course the simplest approach would be just to continue-
without
re-dosing and making a note to follow with the results. Possibly also
to
re-dose at a later time with the missed dose. The latter is probably
the
cleanest from a documentation view. You could also amend the protocol
to
permit retesting at the same dose if similar problems arise.
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Thanks Ed. Apology accepted.
It was a line of thinking that Roger's piece brought immediately to my
mind since I do see quite a reasonable parallel. I then thought that a
forum is one of the few places where it can be explored effectively...
so here goes for another round.
The parallel that I see is that many people don't apply reason to a
situation because they either don't know how to or they see it as
straying from a guideline or a protocol for which others will condemn
them out of hand. Like Roger I think there is a hidden price to pay
if experienced and safe scientists are forced into blind compliance
with the necessarily preconceived ideas that were written in the
protocol... so unable to cope with an ill-defined grey area or an
unexpected phenomenon. So I very much agree with your comments on
flexibility. Of couree I'm also both sorry and glad that you did have
a temporarily harsh reaction because it proved my point
I agree with all your comments on the study situation. It was a quite
a challenge because I had to think instantly. For example I did think
about re-dosing this fumbled dose on a fourth occasion as you suggest,
but on the spur of the moment rejected that as being not only a
protocol violation too far but giving the subject a reward of an
increased honorarium (which I judged at the moment to be unavoidable)
for a making a mistake, which wasn't itself so much of a problem for
that one genuine occasion as setting a somewhat alarming precedent
that other volunteers might want to follow deliberately...
Best regards
Andrew
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Andrew the difference being that ideally the protocol is as
circumspect as
possible. Needless to say stuff happens, and not all possibilities
can be
foreseen. In non clinical trials these exigencies can be addressed by
amendments or deviations, with supporting justifications. The clinical
trial carries the additional weight of informed consent. You may write a
deviation with justification but the informed consent will no longer be
valid since the contingency was not discussed and that is the hurdle.
If you list possible contingencies in the protocol and the subjects are
aware and consent to them it's done.
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