Sooner or later the science will
be done properly. It should be
blindingly obvious that the following is true:
1
Doctors
are trained technicians who can collect and electronically record critical data
and monitor results. After all they are
called upon to do exactly this for clinical trials.
2
It can now
be done for all medicines and all other curatives been used. The patients can also be logically dragooned
into properly building his profile for medication. This provides a wealth of information which can
also be confirmed by additional blood test as warranted.
3
Thus all
medications can now be effectively tracked on an ongoing basis over decades
even. This obviously provides a
statistical gold mine were a wide range of filters can be used to eliminate false
signals caused by under or over reporting.
This all means that all so called
phase three trials are better done as trial releases with full monitoring by
both doctor and patient. This also
encourages trust and data sharing which is very important.
This also means that problems will
be quickly recognized, warnings issued and either limits soon established or
even suspension ordered.
Yes the patient population is
conducting the trial but it with eyes wide open and on the lookout for issues
to report. This also all happens in real
timed.
Someone close to me has had
experience with the Vioxx disaster where phase III was completed and a full
release made. I consider it likely that
the phase III numbers got cooked there and that is what an open trial period
eliminates. The numbers themselves are
too large, the number of doctors involved is too large and the patients are
looking for problems. Pass that sieve
and you are surely good to go.
Even better, all 3000 plus herbals
out there can also be monitored for simple statistical significance. That might be important. I would love to
crack open an herbal in which the benefit is spelled out and a level of
significance is supplied. A curative may
be at the third standard deviation while an improver may be at the second
standard deviation. Most placebos will
actually be used to establish the limits of a single standard deviation.
This pretty basic and we can be
sure that most herbals do fit into the second standard deviation. It needs to be known at least this
rigorously.
A Call To
Rein In Phase III Trials
February 28, 2014
Posted
by Derek
Here's a very
nice perspective on what gets funded in drug research and
why. Robert Kocher and Bryan Roberts bring their venture-capital viewpoint
(Venrock) to the readers of the NEJM:
It is not mysterious why projects get funded.
As venture-capital investors, we evaluate projects along four primary
dimensions: development costs, selling costs, differentiation of the drug
relative to current treatments, and incidence and prevalence of the targeted
disease (see table). For a project to be attractive, it needs to be favorably
reviewed on at least two of these dimensions. Many drugs designed for
orphan diseases and cancers are good investments of scarce capital, since they
tend to have relatively low development costs and selling costs and to be
strongly differentiated from the current treatment options. Conversely,
investors are less likely to fund drugs with much higher development and
selling costs (e.g., drugs for type 2 diabetes or psychiatric disorders) and
drugs that cannot be strongly differentiated from current treatment options —
often because low-cost generics are available to treat the targeted condition —
despite the condition's high incidence and prevalence (e.g., drugs for
hypertension or hypercholesterolemia).
Since improving the rate of discovery is a
rather knotty, multivariate problem, the authors turn to the economic back end
of the process. They make the case for the FDA to move more towards
conditional approvals, since no Phase III trial can be large enough (or
long-running enough) to pick up on all the "long tail" adverse events
that might be waiting out there. Current Phase III trials, they say, are
often overpowered for efficacy but are still underpowered for rare events, so
we're spending a lot of money rather inefficiently.
I think they've got a good point, but the FDA
already gets enough flak as it is. Changing things in this way, if done too
quickly (and frankly, if done too openly) would be seen by many as a
bean-counting technique to shift the risk onto the paying customers. Can't you
hear it now? But the world they describe would be a good one, if it's feasible:
We estimate that development costs for drugs
could be reduced by as much as 90%, and the time required by 50%, if the
threshold for initial approval were defined in terms of efficacy and
fundamental safety.
Cutting costs and time, while requiring
high-quality and transparent patient registries for independent safety
monitoring, would be a more informative and cost-effective approach. With the
widespread adoption of electronic health records and the introduction of many
low-cost data-analysis tools, it is now feasible to develop mandatory
postmarketing surveillance programs that make thousand-patient trials obsolete.
Large data sets would also inoculate drug makers against spurious claims such
as the false association of pancreatitis with the glucagon-like peptide 1
(GLP-1) and dipeptidyl peptidase 4 (DPP-4) inhibitors. At the same time, it
is essential to empower the FDA to quickly remove or restrict the use of drugs
when safety signals emerge from the improved data and safety monitoring.
This moves beyond clinical science and into
politics, which (as the cliché has it) is the art of the possible. Even if we
agree that this move is desirable, is it possible, or not?
Too much distrust out
there to allow for this policy change.
From a layman
perspective, this will look like nothing more than a money grab:
1. Pharmas will save 90% of costs, but will not discount the drugs accordingly.
1. Pharmas will save 90% of costs, but will not discount the drugs accordingly.
2. More new molecules will be put on the market, and will create revenues for the pharmas, just to be pulled out later.
3. Shorter development time will mean more time under patent protection - more profits before generic competition kicks in.
4. More risk will be transferred to the patients.
The shadow of
thalidomide is long....
Late last year the
MHRA Expert Group on Innovation in the Regulation of Healthcare called more
flexible licensing of medicines that address unmet needs - and Early Access to
Medicines Scheme that would allow patients to access certain medicines at end
Phase II.http://www.mhra.gov.uk/Opendocuments/OpenPDFdocuments/CON336728
Late last year the
MHRA Expert Group on Innovation in the Regulation of Healthcare called more
flexible licensing of medicines that address unmet needs - and Early Access to
Medicines Scheme that would allow patients to access certain medicines at end
Phase II.http://www.mhra.gov.uk/Opendocuments/OpenPDFdocuments/CON336728
OH MY GOODNESS. SPOKEN
AS A TRUE VC WHOSE PRIMARY GOAL IS TO MAKE MONEY. WHO WOULD HAVE TO PAY FOR THE
EVENYUAL LAWSUITS? IT WON'T BE THE VC INVESTOR, FOR SURE, WHO WILL HAVE SOLD
THEIR POSITION, MOVED ON.
AND WHAT ABOUT FDA'S
ROLE TO LOOK AT SAFETY?
REMINDS ME OF
DEREGULATION IN THE FINANCIAL SECTOR. THE REASONS FOR THE ORIGINAL
IMPLEMENTATION DO NOT JUST "EVAPORATE".
BAD IDEA OF
"PROGRESS"
One issue is that
physicians often do not share results/labs with each other. Whether that is a
patient going from a general practitioner to a specialist or changing general
practitioners (or just simply seeing another because their current physician
has a two week wait list). Anecdotally, I've seen this many times personally
(and the physicians had EMR systems to make it easy), and I'm sure the readers
here have also seen this.
Because of the lack of concern from physicians (or just laziness) information does not disseminate as quickly as it should. If it did, we would see better resolution in post marketing studies. We need to see better data from these studies if we are going to make a case for putting the drug on the market sooner. The FDA is not simply going to trust a company to keep an eye out. If this is the case, does this mean that pharma will be requesting all patients on this new drug to sign away access to their medical records? If that is the case I'm sure liability language would also be included (just as it would in a trial). Maybe it will save pharma from a few large lawsuits? If so, might that imply a lax environment for their reporting standards?
Additionally, we are
talking about shifting costs away from pharma and towards insurance providers
who will be resistant. A Kaiser like model would be needed on the insurance
side.
I really don't see physicians or insurance providers putting in effort that will only help patients and not help their wallets.
From above, a good example
of poor transfer of information in Vioxx.
Both # 1 and #5 are
absolutely right. This is just money guys looking out for #1 in the most
self-serving way possible. Maybe if George Merck was asking to try this
approach and pharma companies were still viewed as “The Merchants of Lifeâ€
it could be considered. However, multi-tens of billions of dollars in fines and
litigation losses, over compensated ruinous executives, plus drug pricing only
a big money hog could love have so tarnished the industry’s image that no
sane regulator is going to get into bed with these sleaze-buckets. They need to
try again. I have an idea. Let’s put the MDs and scientists back in charge
with the mission of putting the patients way ahead of the company, stockholders
and management. Yeah pharma might become a backwater sleepy industry again, but
I would certainly invest in it for the long term.
There might be some
value for the health care system to shift focus from costly clinical trials to
better patient monitoring post-marketing, but I find it very hard to believe
that 90% of a drug's development costs could be eliminated without losing
essential safety and efficacy data.
Can't this risk simply
be covered by a regulatory policy and caveat emptor?
We have to risk
peoples lives/well being either way, whether through volunteers in trials or
volunteers in the marketplace.
If it was a
requirement for new medications that have gone through a streamlined phase 3
trial to be clearly labelled as new to the market with potentially rare unknown
adverse effects, who's really losing out?
We know by stage 3
anyway that we aren't going to be killing legions of people. We permit plenty
of other risky activities in the marketplace, from motorbike driving(36 times
more dangerous than cars) to tobacco and alcohol sales (that kill far more than
a drug that's got to stage 3 trials is liable to do for no meaningful benefit).
Is the boogie man of a
few harmful reactions in thousands really worth considerable delays and
economic restrictions in new drugs coming to market? The potential benefit of
reducing the cost/length of trials is massive, and the potential downside
really extremely small if you take emotion and fear out of the equation.
In exchange for the
money saved in trials we could easily require more extensive market follow up
studies to help balance out the reduced trial data.
I don't see why in
this one area of drugs that actually provide some utility we take a zero tolerance
risk approach whilst allowing plenty of risk in recreational activities.
Every (potential)
change has to start with a proposal and that's what the folks at Venrock have
done. Self serving--sure, but also potentially benefits everyone. I'm in
agreement with #10 Samsonite that conditional approval is not inherently a bad
idea, especially for a drug with limited or mixed efficacy signals in a Phase
III trials. I'm thinking of rare diseases or cancers where the patient
population is small to begin with, or an Alzheimer/Parkinson's/etc drug that
showed some activity in a trial subpopulation. A conditional approval would
allow for more rapid follow-up in broader or more select populations without
having to go back and re-doing the trial design.
Moves the FDA from
being the crossing guard before a drug gets onto the highway to more along the
lines of being the State Police car on the side of the road watching for
deviants. Lots of questions whether that's a good thing for society (pluses
& minuses in both directions), lots more questions whether society would
accept such a change, and lots more on how to make it actually work.
But the discussion has
to start somewhere.
10: The riskiest
activities we do have pretty well-known risks, and ones that have not been
misrepresented. At least some, if not most, of the risky activities have risks
within our control (in a car, don't speed, look around - smoking, duh...).
Medicines' risks are
difficult enough to assess when likely side effects and profiles are known for
doctors and patients even when they understand what the patient's needs are,
and are probably more difficult for people who don't work with drugs for a
living or in a related field. The risks are mostly random, rather than
controllable (for example, other than by not drinking grapefruit juice, there
isn't much of a way to avoid the rhabdomyolysis side effect for statins other
than not take them). Lately, pharma has not been the world's most trusted
industry - people (in lots of cases) don't trust that companies haven't hidden
risks from them. People also probably inversely correlate cost to risk, but
drugs don't work that way, and people feel unhappy accepting lots of risks from
expensive things. I think the risk aversion is probably related to people's
willingness to accept large risks voluntarily but to be highly intolerant of
risks taken involuntarily (particularly those taken for someone else's
benefit).
The costs for such a
change in policy will come in the relative near term, while the benefits (more
drugs and eventually more generics, which will probably lower costs some) will
come later (after the first wave of drugs goes off patent). Given the bolus of
older people likely to need medical care, I can see that being a problem as
well.
While I tend to agree
with the idea of conditional approval, this idea has the classic style of VCs
or McK types who oversell the positives without discussing (or perhaps seeing?
maybe entrepreneur's phenotype)the potential downsides.
Re cost savings,
registry is not cheap and collecting high quality data on efficacy and adverse
events can't be done with social media apps, so no way one is saving 90% of
development costs with reduced power in Phase 3.
Second question
relates to marketing limitations post-approval while essential data are
collected. Limited? What are the claims granted? How is liability assessed? Do
subscriptions come with informed consent like for trail participants?
Finally, will not the
evils of pharma be magnified? Will marketers mobilize "patient advocacy"
groups to be vocal upon review of post-marketing registry data? Did not the
Genentech Avastin conditional approval give some insight into how personal
opinions on how a drug "worked", delivered passionately by dying
patients, obscure rational discussion of risk benefit across a population?
I'm not at all sure
why the fact that these are VC's that are writing this makes a difference.
These are essentially the same types of calculations that every Pharma and
Biotech, or just about every other venture for that matter, does.
Basically, what is the
size of investment, what are the risks, and what is the potential return on
that investment?
And that investment
can be time, money, effort, or opportunity costs.
The lowering of the
size of an investment would obviously make risk more palatable, for any given
return which in theory could lead to more breakthrough therapies. At the cost
of more adverse effects certainly.
So the real question
we should be asking is not a cynical "Oh sure, who's getting rich off that
idea?" but rather an enquiring "Will this help more people than what
we currently do?"
I honestly don't know,
but I do agree with them that PhIII studies are generally overpowered for
efficacy and underpowered for safety, so how do you change that if that's a
problem?
"shift the risk
onto the paying customers"
Isn't this what right
wing nutjobs want? Shouldn't the all-knowing free market be left to decide
which drugs are safe and which aren't? Nope, I don't see any problems with
Uncle Bob in Springfield being able to choose a drug without adequate studies
being done. I mean, if it's toxic people wouldn't buy it.....
Trump/Palin in
2016!!!!
I don't see any
problem at all with this model - provided that the greater risk to patients is
compensated by a significantly reduced price agreed upfront! So if pharma want
lower risk they must be prepared to take a lower return. But having the option
to choose between low risk-low return and high risk-high returns adds economic
value overall.
@16,
well said
What about the idea of
dynamic clinical trials that was floated by the FDA some time ago. Were not
they supposed to make clinical trials less expensive and less long?
I think these comments
must be coming from academics. If one of the posters had $1M to invest, where
would you invest it? Would you put it into a high risk drug with a risky
long-term development that requires huge Ph3 data (like a diabetes drug) or one
that has a better chance to succeed like an orphan? It's all theory until it's
your money on the table.
I'm not a clinician
but:
Shouldn't drugs tested
in a superiority trial be higher cost than drugs in a non-inferiority trial?
Superiority requires more patients than comparability. Did they get it backward
or am I missing something?
@12
I agree from a
political perspective there's little incentive to make this policy change,
however there's little political incentive to make any positive policy change
so I'll talk about the argument on its own merits.
It's important to make
a distinction between something unknown and something that exists between
bounds of probability.
The risks of a drug
that's made it to phase 3 clinical trials are not as you have suggested
"random". In fact by phase 3 we have narrowed down the short
term/acute side effects to fairly accurate numbers. The long term side effects
also exist within probability bounds. We might discover some long term health
risk that weren't anticipated, but it will be a matter of shaving years off
peoples QALYs, not striking thousands dead in their prime. The potential
magnitude of effect for things that have made it to phase 3 simply aren't that
great or they would have showed up in earlier trials.
If people are
intolerant of unknown risks, surely these people can just not take these
medications that would be clearly labelled as still under investigation? The
idea that any medicine is definitively safe after being put through trials is
bogus anyway. There's no rubber stamp of safety in science, our knowledge
continually develops and it sends an erroneous message to the public about the
nature of risk and health to put trial data on a pedestal given all its
limitations. Scientific understanding has shifted on a great many mass market
drugs, from beta blockers to aspirin. Health is so conditional its impossible
to say that drug is and will always be safe for everyone. What we can say is we
know its not going to kill/seriously damage over X% of the people who take it
and we understand enough about the mechanism of action to say whether its
likely to be carcinogenic, teratogenic, neurotoxic etc.
There's a degree of
randomness in all risk. There's plenty of surgeries where you have a random
chance of dying. We don't say no one can have the surgery because you can't
control the chance you might die, in fact patients are provided with very
little detailed information on risks before a surgery and even surgeries with
known high mortality rates are permitted under the right circumstances.
The argument of it
being an unknown (therefore unacceptable) risk simply doesn't make sense to me
if we're already allowing people to take known serious risks for no good
reason. By releasing a drug to market we'll find out much sooner what the exact
long term risks will be. we can always pull drugs from the market if they turn
out to be unexpectedly harmful, as we have in the past and will do in future.
"We estimate that
development costs for drugs could be reduced by as much as 90%, and the time
required by 50%, if the threshold for initial approval were defined in terms of
efficacy and fundamental safety."
If we take what the authors state, namely that 40% of the cost of development is Phase 3 trials, then 60% of the cost is spent even before Phase 3 is entered, and the maximum that could be saved even by doing no Phase 3 studies is 40%. Thus the authors' conclusion that "as much as 90%" of teh development cost could be saved is disingenuous at best - they might as well have said "up to 100%" and it would have been essentially as true, i.e. not true in any reasonable sense.
As for time saving, Phase 3 trials are not quick, though in my experience sponsors try to move them as fast as they can - because they think they have a winner and the sooner they get it approved the better. But a lot of development time - if we define "development" as being from the start of the program to NDA approval, and I think that's how the authors intend it, since they talk about "from bench to bedside" - is spent in hit to lead to preclinical to Phase 1 to Phase 2 before we can even talk about saving of time by reducing the size of Phase 3.
For this, and for a number of the reasons mentioned by earlier commentors, I call BS on this article.
@19,
Not sure of others,
but I have worked on 8 drugs, 3 remain in trials, two were approved.
If I had a million to
invest, I would know that I could only get through a well done non-clin
package, so would base my investment on the quality of the product candidate
and its discrimination from the competition at that stage. The non-clin data
would be designed to highlight the desirable advantage that the molecule had
over the 100s to thousands found on the shelves of pharma.
To your point re huge
Ph3 data, I would not invest in a program where the purchaser would need a
10,000 patient phase 3 to show gain a label advantage.
Orphan designation
might mean the overall clinical dollars required would be lower since
enrollment would be terribly long for rare diseases. It also offers market
exclusivity advantages. It does not, however, offer any greater odds of success.
Pharmacology and the complexity of human disease still rule supreme.
I wasn't arguing that
unknown risks were necessarily untakeable, but that the significant risks
people are normally willing to assume generally differ in significant ways from
the risks with drugs. Other than the risks that Cellbio has brought up, I don't
think making approval easier in this way and more contingent would necessarily
be bad. I think that people's perception of risk and of pharma (and perhaps of
VC investors, who would receive a lot of the benefits under this plan with few
of the costs - patients, insurance companies, and pharma would bear most of
them) make this hard.
Maybe i'm a cynic but
does but "lower bar for getting medicines to patients" mean
"increase type I error and soften endpoints"?
The vision sounds
fine, but I suspect putting a specific protocol/stat plan together would be a
bit more controversial.
No. 16 wins the
thread.
The most common
failure in phase 3 is lack of efficacy, either compared to placebo or standard
of care. Not sure how under-powering trials will help. Sure, adding subjects to
enable accurate measure of smallish differences may not be a solution for
approval or product launch into competitive spaces, but smaller trials will
likely be a mess with the variation seen in trials.
The more I think about
it, the more this proposal seems lacking to me. As for reduced price, does this
remain steady, or can the company up the price when post-marketing studies
clarify pharmacoeconomics. And since marketing claims are tied to what you
roved in the clinic, how exactly to you state health and economic benefits in
this model? In other words, price is lower because benefit is uncertain?
The most sense I could
make of this is to allow more rapid approval with a period of reduced price off
of a retail price that comes into effect with proof of risk/benefit. But again,
the only case of this I know of (are there others) did not go smoothly once
data clearly showed the R/B ratio was not confirmed.
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