However, when anything new is discovered
about a drug in phase IV, then, by definition, it
will not be in the product label. Furthermore,
sometimes, when such a signal is observed, a
retrospective trawl through the preclinical and
clinical databases can often uncover consistent
information whose significance had not been ear-
lier realized. In this case, a ‘gap’ exists between
what is known about a drug and what information
has been provided to prescribers.
The gap may exist for a very short period of
time because of a prompt change in product
labeling, and the company will have done every-
thing that is appropriate as fast as it possibly
could. In some cases, the ‘gap’ might exist
due to a very rarely occurring adverse event of
questionable direct association with the
product, which does not warrant inclusion into
the label.
However, on other occasions the ‘gap’ will need
to be urgently addressed. The range of actions
that might be needed, in increasingly alarming
order, are
design/implement purpose-built phase IV study
change in label at next routine printing
more urgent change in labeling
issuance of ‘Dear Prescriber/Doctor/healthcare
professional’ letter
institution of restrictive access program
product withdrawal.
The phase IV development program will almost
always generate information that is relevant in
choosing from among these alternative actions.
The corporate lawyers will always be depending
on the phase IV clinicians to determine the appro-
priate course of action due to their knowledge of
the post-marketing trial program, results and how
that information has been communicated to the
medical community.10.2 Conclusion
Phase IV clinical trials, in all their many forms, are
the natural extension from the constrained environ-
mentofphaseIIandIIIdrugdevelopment,aswellas
a pivotal, interfacing position between the market-
ing, research, regulatory and legal departments.
Indeed, such distinctions can be seamless, espe-
cially when there is no change in development
team post-approval, or when phase IV is actually
begun before approval. The variety of questions that
phase IV teams must answer are many and varied.
This can be a liberating, stimulatingand educational
assignment for thosewho have hithertoworkedonly
in early-phase product development.References and further
readingCharlton BG. 1966. ‘Megatrials are based on a meth-
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Friedman LM, Furberg CD, DeMets DL. 1985.Funda-
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Hammer CE. 1990.Drug Development. CRC Press:
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Hampton JR. 1996. ‘Alternatives to mega-trials in
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Guidance E2E: Pharmacovigilance planning. Draft
version 4.1, November 11, 2003.
Makuch RW, Johnson MF. 1986. ‘Some issues in the
design and interpretation of ‘negative’ clinical
studies’.Arch. Intern. Med. 146 : 986–989.
Makuch RW, Johnson MF. 1989. ‘Issues in planning
and interpreting active control equivalence studies’.
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Spilker B. 1991.Guide to Clinical Trials. Raven:
New York.REFERENCES AND FURTHER READING 125