Of Tight Rations and Titrations
Guernsey McPearson
Everybody is blaming it on the credit squeeze but I think it
has more to do with the parlous state of our pipeline. Either way the number of
initiatives seems to be burgeoning at Pannostrum. The
other day I was sent to attend a ROAD (Reviving Old Abandoned Developments)
meeting with Harvey Puffer. Our remit was to scan through old asthma projects
to see if there was anything worth reviving.
We stated with the usual pleasantries. “Great news about Sir
Lancelot, Guernsey,” opined Harvey.
He was referring to the news announced only the day before that Sir Lancelot
had been elected to the Ancient and Royal Society of Engineers and Scientists.
“How acronymically apt,” I said, “Time
to cash in all our Pannostrum options.”
“How so?” said Harvey.
“Well, the last prominent captain of industry they elected
was Stu the Screw, from the Bank of Avalon”, (I was
referring to Sir Stuart Tightwad, former chairman of that profligate
institution), “and haven’t they just had to be bailed out by the government to
the tune of zillions?”
Harvey looked
worried. “Surely something like that couldn’t happen to us?”
“Cheer up, Harvey”
I said, “at least we are one of the few enterprises in this country that
actually produces things and it’s nice to know that Sir Lancelot’s pension will
be safe. Now to business, I think that the old Harmattan project might be worth
looking at.”
“You can’t be serious, Guernsey? That
project was stopped because of tolerability problems. There was a definite
increase in headaches, sore throats and even a suggestion of some problems with
incontinence.”
“Yes. But these came from one very large study, PHAT” (I was
referring to the Placebo-controlled Harmattan in Asthma Trial), “which had a
design flaw.”
Harvey was
shocked. “PHAT had a design flaw! Guernsey, the trial
was conceived, promoted and led throughout by Professor Alan Veola. You couldn’t have had more expertise involved. We
had 3000 patients followed intensively over one year. A feature of the trial
was also that they attended frequent clinic visits to measure lung
responsiveness using methacholine challenges. The results were published in the
Journal of Appalachian Medicine,” Harvey
continued, a tone of awe in his voice. ‘I was a co-author,’ he added.
“Quite,” I said, “repeated methacholine challenges. What are
the side-effects of methacholine?”
Whenever you ask Harvey
anything like that it’s like pressing a button.
A look of beatific happiness comes over his face and in a trance he
rattles off the answers just as if he had turned up for a medical viva. “Headache, itching, lightheadedness,
throat irritation. Stress incontinence can be precipitated.......Oh. I
see what you mean...but that’s not possible. You see this was a controlled
trial”, he added, “you must make the head to head comparison. These side
effects were much more common in the Harmattan group.”
“It involved titration, Harvey”
Harvey looked
baffled. “No. The doses were fixed. You are quite wrong about that.”
“Not the treatments, Harvey,
the methacholine. It involved titration, since you establish the concentration
of methacholine that produces a 20% drop in FEV1 (forced expiratory
volume in one second). How did Harmattan do in terms of efficacy?”
“Oh the efficacy was brilliant. It was better in anything
you measured. Why the PC20, for example was about 16 times what it was for
placebo.”
“So this means that the patients on the Harmattan arm were
actually getting much more methacholine.”
“Of course”, said Harvey,
as if talking to some particularly obtuse junior doctor. “That’s how the thing
works. I thought you were supposed to know all about asthma trials.”
“So how do we know that when we see an excess of headaches
in the treatment group this is not the effect of methacholine rather than the
effect of Harmattan?”
Harvey looked
taken aback.
“Has the penny dropped I said? Perhaps it’s just the stress
incontinence.”
“I’ll have to think about that one. He said. I’ll get back
to you.”
He was as good as his word. Some days later, I came across
him in the corridor.
“I consulted an expert on that PHAT study question’, he
said. ‘Your theory was interesting but wrong.”
“Oh. How so?”
“Well, it turns out that methacholine challenges are always
done that way. Yes, you can take it to the bank that the PHAT results were not
misleading.”
“Would that bank be the Bank of Avalon?” I asked.