One frustrating problem over the years has been the relatively restricted nature of interventions available to Drug Regulatory Authorities in the event that a licensed medicine turns out to have unsuspected toxicity.
RESPONSES TO RISKS
One
frustrating problem over the years has been the relatively restricted nature of
interventions available to Drug Regulatory Authorities in the event that a
licensed medicine turns out to have unsuspected toxicity. These are
suspension, revocation or modification to the summary of product
characteristics. In these situations the perceived need to take action in
rela-tion to the risk from the product is often greater than the apparent risk
itself warrants. There is an under-standable tendency to emphasise risk and
forget about benefit. An example of this would be the manner in which the
recent controversy about the risks of the third-generation oral contraceptive
pills and throm-boembolic disease. As well as being of great intrinsic
interest, this example emphasises that not all risks relate to new or nearly
new drugs. Pharmacovigi-lance needs to remain alert to the potential problems
of drugs at all stages in their development and use. Another example of a
relatively old drug running into problems in the past was nomifensine, an
effective antidepressant in which evidence came to light about the risks of
acute haemolysis under unusual circum-stances of use. Given the relatively
long-established position of the medicine itself, the company involved found it
easier to withdraw it from sale than risk litiga-tion by continuing use with
adequate warnings. Was this the right decision? What happened to the long-term
recipients who were receiving benefits from this drug? Did they transfer to an
older antidepressant, or to a newer one (for which we had no compara-ble
information), or discontinue treatment? What were the outcomes in relation to
recurrence of depression, suicides and adverse effects to replacement
therapies? Unfortunately, we do not know the answers to these questions.
Clearly, the company involved in manufac-turing nomifensine was not going to
fund such a study.
A
more recent example has been the change in drug use patterns that has followed
the various safety restrictions and withdrawals in the antipsychotic drugs
class. As thioridazine fell from favour due to a combination of demonstrated
safety concerns and lack of efficacy in dementia sufferers, so patients were
treated with newer (and more expensive) atypical antipsychotics. In due course,
drugs from this class prescribed to sufficient numbers of patients showed
statistically significant problems with excess cardiac and cerebrovascular
events. Now many of those are disallowed. The result? We are using even newer drugs
that have not been used in adequate amounts to allow any sort of quantification
of risk, or we are using old drugs
with very significant tolerability and safety problems, for example
chlorpromazine and haloperidol. Has public health been well served by this
sequence? A study to assess the balance of risks and benefits over time would
need to include not only life-threatening events, but also quality-of-life
issues, functional ability and economic aspects too.
The
COX-2 story has been covered elsewhere in this book. Regulatory authorities
were catapulted into the limelight because of the company deci-sion to withdraw
rofecoxib from the marketplace, in turn precipitated by emerging results of an
increased risk of myocardial infarction from a (unfinished) randomised placebo
controlled trial. What were the main lessons for pharmacovigilance from this
still-evolving sequence of events? A number of points are worth mentioning.
First, drugs are usually licensed on surrogate endpoints, so we must keep an
open mind about all-cause outcomes to ensure that the risk–benefit balance
remains positive. In this case, despite the fact that core efficacy was no
different from comparators, use of a drug was driven by the rationale that
certain side effects might be avoided. This channelling of use was bound to
affect the over-all risk–benefit ratio. Secondly, we must be alert to the
signals of science. A large outcome study with this drug had shown a very weak
signal of cardiovascular events but no notice was taken, while pathophysio-logical
plausibility had already been published and discussed. Thirdly, we are reminded
that all methods of assessing post-marketing safety have their place. Numerous
observational studies on COX-2 drugs had indicated a possible hazard, while it
was the ‘gold standard’ RCT (albeit unfinished, with all the prob-lems
attendant on that aspect) that brought matters to a head. Finally, the perils
of direct to consumer and ‘blockbuster’ marketing are plain to see. Excessive
marketing zeal is likely to have exacerbated the chan-nelling phenomenon and
may also have stimulated exposure of those who would have been deemed at risk
from, and would otherwise have remained unex-posed to, other older drugs.
The
issue of regulatory response to signals or demonstrated hazards is one of
public health, and thus requires public funding. With the continuing
development of multipurpose databases and other data resources, we should be
better at managing such events in future. The need for post-withdrawal
surveil-lance studies in large databases is likely to persist so that some of
these questions can be answered. Sensible collaboration among pharmaceutical
compa-nies, academic researchers and regulatory authorities is surely to be
encouraged.
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