20.5 Regulatory considerations
of drug interactionsThis chapter has concentrated on drug interaction
studies during the development of new drugs.
Just as important is that the development of a
drug does not stop after marketing authorization
has been obtained because new information on a
marketed drug can emerge at any stage of its
lifespan. Marketing Authorization (MA) or New
Drug Application (NDA) holders are obligated to
monitor this emerging information for its rele-
vance to prescribers and patients. This includes
any new information on the potential for drug
interactions.
When drug interaction information emerges late
in the productlife cycle, it is almost always a matter
of clinical importance. This information must be
made available to prescribers and patients, and can
be communicated by inclusion into the product
labeling, or, more quickly for issues of serious
hazard, as a ‘Dear Healthcare Professional’ letter.
All such newinformation tobe included in thelabel
is subject to regulatory scrutiny and approval, and
the initiating entity can be the MA or NDA holder
or regulatory authorities themselves. However, the
pharmaceutical physician should be aware of the
important differences between regional regulatory
systems.
In the United States, pharmaceutical companies
have the option of including important new safety
information (such as a relevant drug interaction) in
the label and sending a notification with the new
label text to the FDA. The changed label will come
into effect at the time of sending the notification to
the agency. This ‘Changes being effected’ notifica-
tion is justified on the grounds of an immediate
improvement in notifying product hazards.
Usually, the relevant FDA medical reviewer will
communicate with the NDA holder and state
whether the label change was accepted or whether
he/she considers the change subject to prior
approval. The latter allows the FDA reviewer
more time and the option to adapt the proposed
label text. In any case, this is a quick and effective
way to ensure communication to all relevant par-
ties in a minimum amount of time.
In the European Union matters are slightly more
complex. Whether products have been approved
using the central or mutual recognition procedures,
the MA will have harmonized the product labeling
across all EU Member States. European regulations
require that all changes to product labeling must
have prior approval. Thus, important new drug inter-
action findings will require the submission of a
typeIIvariationtotheMAanda(albeitabbreviated)
Common Technical Document. The Summary of
Product Characteristics and Patient Information
Leaflet must all be changed accordingly, and
approval by the regulatory authority(ies) will inevi-
tably take several months. For very significant clin-
icalhazards, amorerapidanddirectcommunication
of such important new information from the MA
holder to prescribers and patients will be needed.Prospectus
As in many areas of drug development, the amount
of information about drug metabolism in children
is limited: more work on the ontogeny of drug
metabolism systems will be needed in the future.
Regulatory authorities are actively encouraging
this with certain incentives both in Europe and
the United States, which generally find support
not only from academic societies of pediatric med-
icine but also from MA and NDA holders them-
selves. Studies of drug interactions will form a part
of this pediatric metabolic research, and should be
able to exploit these regulatory initiatives.
Furthermore, as more information is wrung from
the human genome, it is likely that many drug
interactions that we currently view as idiosyncratic
will acquire mechanistic explanations. This form
of personalized medicine, with the capability to
predict a pharmacokinetic or pharmacodynamic
interaction by knowing the patient’s phenotype in
advance, will be a powerful therapeutic tactic in
the interests of patient safety and optimization of
therapy.20.5 REGULATORY CONSIDERATIONS OF DRUG INTERACTIONS 263