What Would a Rational
System for New Anti-Cancer Drug Development Look Like?
By
Leonard Zwelling
Some of my best friends are clinical investigators and many
of them work at the very edge of the clinical-laboratory interface, phase 1
drug development. This is the area of human subjects research that deals with
the earliest clinical trials, often first-in-man experiments using novel agents.
To do this well requires incredible clinical judgment, skill, smarts and
courage.
These
folks are really under attack from all directions right now and it is mainly
because the system in which they are forced to operate simply does not work. As
someone who once devised such a system that my co-developers and I thought
worked reasonably well for its time (the late 1990s), I think I have some ideas
that might help my friends a bit.
Problem one, what’s the problem? The problem simply stated
is that there are a lot of people with intractable forms of cancer who are in
desperate need of new therapies. Let’s just agree to leave aside the discussion of
the relative contribution of genetics, life-style choices, and chance to
carcinogenesis. These people are sick now and are seeking the help of
oncologists. They ought to be at the center of any new system. Not the IRB, nor
the regulators, nor the lawyers, nor the drug companies nor even the doctors,
should be the focus of our new system. And certainly not money except to make
sure it cannot produce undue influence on any part of the system (i.e.,
conflicts-of-interest).
That being said, it also must be realized that these people with
cancer cease being “only patients” the moment they enter a clinical trial. They
are and should be special. They are human subjects now and need even more
protection than do patients being treated with FDA-approved anti-cancer
therapies. Anyone with a fatal disease is in a particularly vulnerable
population and extra protections must be afforded to them, like the right to
quit any trial at any time for any reason. Children in particular have been
given a foolhardy designation as being particularly vulnerable to the side
effects of new cancer agents and are often denied access to new drugs that
might save their lives while waiting for the adult trials with new agents to be
completed. This is nonsense. The kids
are likely to be fitter than some old dude like me with regard to their ability
to withstand untoward side effects, yet benefit from tumor regression. After
all, the earliest successes of combination chemotherapy were in children with
acute lymphocytic leukemia over 50 years ago.
IRBs need to be far more tolerant of allowing doctors to
exercise judgment when registering patients for trials. The degree of rigidity
for inclusion or exclusion of a patient in any given trial has gone way
overboard. There are certainly exclusion criteria that must be written into any
protocol precluding the entry of a patient in a trial who is at increased risk
if given a drug with unknown toxicities. But this does not require daily EKGs,
nor should it disallow a patient with stage 4-lung cancer from entry into a
phase 1 trial if the patient also happens to have a slow-growing skin cancer.
(Yes, this occurs. You would be surprised). Also, IRBs should allow this flexibility
to be written into the protocols and approve these studies rather than bounce
them back as unready for new patient accrual. Who is supposed to be helping whom
here?
This
mess also occurs because the drug companies control who goes on the trial and
who does not and the companies live in constant fear that an ineligible patient
with a fabulous clinical response will be excluded from consideration during
the FDA’s review of their trial’s results because the patient was not perfectly
eligible albeit currently alive! Once the trial is approved by the IRB and the
FDA and is under an IND, the drug companies should assume the role of financial
sponsor and data integrity oversight, not be the research cops. That’s the
IRB’s job and if there are too many protocols at an institution for the IRB to
do its job, allow teams of investigators to make the choices of which trials are
prioritized most highly, not the IRB, which is loaded with lawyers and lay
people, as it should be by law, but these people are ill-equipped to determine
the preference of one trial over another. The only reason to limit the
portfolio of trials available to cancer patients should be the investment the
institution is willing to make in infrastructure to support our new system.
What is in the portfolio should not be determined by the trial paying the most
per patient accrued to the institution. And on that subject, ALL FUNDS to
support clinical research must come through the institution, not the
investigator, and should be based on actual cost and should always be backed by
a clearly constructed contract. However, the investigator has sole check
writing privileges on these institutional funds. No stock or options for anyone
at the institution doing the research. No skimming from the direct costs by
deans and vice presidents. Period!
And that brings me to the worst culprit of all, the FDA. The
agency’s job is to get safe and effective drugs to needy patients AS FAST AS
POSSIBLE. If the agency would allow drugs showing promise in phase 2 studies to
instantly go onto the market as long as post-marketing studies are carefully
performed, a lot more patients (human subjects) might benefit and remember they
are the center of this new universe we are creating.
The FDA should be FULLY funded by the Congress and cease
charging the drug companies the users’ fees that partially support the
operation of the approval agency using funds from the very companies the agency
is supposed to regulate. This is a complete conflict-of-interest and should
stop yesterday. Ditto any conflicts-of-interest among the members of the panels
of academics advising the FDA. No exceptions. If you take money from pharma
with which you can make a boat payment (it’s OK if your institution takes the
money to support your research), you cannot serve on a federal panel. Period.
Finally, the training program that any cancer clinical
investigator must go through must be heavy on the regulatory aspects of human
subjects research as well as on the cancer medicine that all oncologists need
to know. Sorry, history has shown us that without these regulations (in fact,
even with them) bad stuff happens and unless we are extra careful, Tuskegee or
cases like Jesse Gelsinger’s at the University of Pennsylvania can arise again.
Finally, Congress needs to appropriate a ton more money for
clinical research than it currently does to allow academic investigators to
stop having to feed at the trough of the drug companies who exert too much
control and insufficient amounts of judgment of concern for patient welfare.
There is a real sense of urgency here. While prevention,
genomics and perhaps life style changes may save the next generation from the
scourge of cancer (unlikely in the extreme), the need is immediate for those
with the disease now. The investigators are frustrated and getting more so,
because before they were investigators they were doctors and dedicated their
lives to help sick people. The FDA, the IRBs, the cancer centers themselves
with their over-dependence on lawyers and administrators, the drug companies
and the Congress are all in their way. This can change tomorrow, but Congress
has to act—or even understand that it has to act.
My experience on Capitol Hill suggests that the members of
Congress tend to be clueless on this need—until one of their family members
gets cancer.
Only then does the sense of urgency set in.
