Photography: Comstock Illustration: Paul A. Belci
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Recent safety issues associated with several blockbuster drugs, such as the Cox-2 inhibitors and antidepressants, have raised
tremendous public and governmental concern regarding the safety of drugs and devices on the market. This publicity is naturally
creating a more cautious and reactionary environment around the approval of new drugs by the Food and Drug Administration
(FDA). This reaction, unfortunately, comes at the very time when it had been hoped that the approval process would be more
streamlined and that promising, innovative therapies would be approved more quickly.
While the problem of slower approval cycles seems likely to worsen rather than improve, a solution is already at hand. New
technologies and methodologies being applied in Phase IV safety studies and registries create an opportunity to change the
paradigm to a proactive and systematic postapproval approach to detecting, estimating, and controlling risk as early as possible
after approval. This approach is necessary because it is often not reasonable or possible to have all relevant safety information
available prior to approval.
A proactive approach to postapproval risk management and safety monitoring has two important components. First, the public
should be educated on the limitations of pre-approval testing and the current postmarketing surveillance process of FDA's
MedWatch, as well as programs from other initiatives and independent groups. Second, pharmaceutical companies should create
and advocate safety registries as well as targeted safety studies and controlled distribution systems for situations where
risk is not fully known at the time of approval (e.g., for potential blockbusters) or where risk is known but primarily confined
to populations that can be readily identified.
Figure 1. Safety registry with controlled distribution program.
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By proactively addressing safety issues through programs that improve on the industry's ability to monitor, detect, and act
on adverse events in a broad patient population, pharmaceutical companies can make a stronger case for more rapid approvals
and allay concerns for future blockbusters.
Limitations of the current approach Two related limitations of pre-approval trials, which are difficult to overcome prior to approval, demonstrate why the anticipated
reaction of slowing the approval process may be counterproductive.
First, pre-approval studies can only include a tiny fraction of the aggregate number of patients who will eventually be exposed
to a drug or device. Second, pre-approval studies are often not fully representative of the population who will eventually
receive the product for both scientific and ethical reasons. Taken together, these two limitations virtually guarantee that
there will be subpopulations of patients in whom safety has not actually been assessed in the pre-approval phase.
With blockbuster drugs and devices, millions of patients are treated with the product and it becomes more likely than not
that some patients, whose genetic constitution or co-morbid health status places them at greater risk than those included
in the pivotal trials, will be "exposed." It is a matter of numbers.
Clozapine and Controlled Distribution
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While the relative risk in these population subsets may be very low, events will still occur. The general public needs to
be educated that it is not possible to predict all potential safety issues prior to approval. Therefore, in order to enable
promising therapies to be approved with reasonable amounts of pre-approval data, a new emphasis is required on effective,
early detection systems.
