Perhaps the biggest challenge facing regulators is justifying the rigor and integrity of the evidence you compile to grant
a license to market a drug. This is a decision of monumental importance; it can save the lives of many thousands of patients—or
condemn some to early deaths. It can provide billions in revenues to drug makers—or bankrupt them. And it can either facilitate
or constrain interest in new areas of research. Is the criticism and "background noise" around the legitimacy of clinical
data politicizing your position as a responsible regulator?
TL: The issue is that the technology that has allowed us to generate increasingly vast amounts of information has not been accompanied
by an increase in the ability to interpret it, with perfect judgment as to what it means for providers, patients, and society.
Two decades ago we had much less information and were not expected to evaluate risks during the post-authorization phase,
when a drug is being used in the community. Today, this is the expectation from the start. In addition, the science has changed;
the compounds we review are much more complex. And there is a built-in dilemma in striking a balance between risk and benefit—from
a practical standpoint, people prefer to know more about risk because of the implications for health and survival.
I also believe industry marketing practices have skewed perceptions around risk. It frankly makes it harder to fulfill our
task in certifying that a product is safe. Consider it this way: In a randomized clinical trial (RCT), the protocols are carefully
established with us and the patient profiles are well defined, so you tend to have less "noise" in the assessment of results.
Then when the drug is out and being used correctly according to the label, you tend to find more side effects and a higher
level of risk. But what really skews the outcome—and creates the conditions for a product withdrawal—is where irrational use
and off-label prescribing occurs in clinical reality. Risk exposure soars precisely because the company's product is not being
used as was intended by the regulator. A study conducted here in the UK on the GSK drug Avandia included subjects who were
known to be at risk for cardiovascular events. They never should have been prescribed the medicine, but the commercial pressure
to show a gain in this area was too much of a temptation. What resulted was just more evidence of risk—the negatives were
accentuated to the detriment of benefit. Then it is left to us, the regulator, to explain why we approved the product in the
first place. Do you see what is lost in the translation?
What should the R&D industry do to minimize this prospect?
TL: The best tactic is improving the patient response rate of medicines—to achieve the desired therapeutic effect. Our sense
is that at present the response rate for medicines we approve is low. As a patient thinking of whether to take a medicine,
I have to ask, "Will I be one of the 20 percent of patients that derive a benefit or one of the 80 percent that don't—and
still bear all the risk too?" The goal of industry has to be to clearly identify those who respond, because then you have
a very positive risk versus benefit profile that will in turn drive access to the market. The Agency is seeking to encourage
this with our new pathway for the approval of biomarkers, which includes a fee reduction for consortia that produce new candidates.
There is a downside here, in that a targeted, personalized-medicine approach tends to reduce the potential takeup and size
of the market for a new medicine.
TL: True. But I believe this is a better approach for industry because it documents the gains and societal value of innovation.
We need better evidence to show that what the industry is producing is actually innovative. I support the notion that innovation
can be demonstrated incrementally over time, in products that were initially approved for one indication, but find new life
in another. You cannot judge innovation just at the time of approval. This is why we as regulators carry an obligation in
the post-authorization phase—in our risk management plans—to assess benefit as well as risk. Often the emphasis is heaviest
on the latter.