Principles and Practice of Pharmaceutical Medicine

will have much less pressure to approve the

more common indication when the NDA is sub-

mitted and approved for the orphan indication

because of the availability of another form of the

product. This means that during this period, the

company will not be able to promote the drug for

the common indication. Thus, it is usually pre-

ferable to try to obtain regulatory approval for

the more commercially important indication

first. There are some important exceptions to

this rule. For example, start-up companies

have limited funds and may seek approval for

the rare indication first out of necessity.

Another consideration regarding this issue is that a
company seeking an orphan approval and hoping
for off-label use for a more common disease may
find a strong regulatory backlash when the compa-
ny’s strategy becomes apparent. There are real
cases where a company submitted an NDA for a
rare disease and then shortly thereafter submitted
an IND for a more common disease. The FDA
realized the company’s ploy and significantly
raised the standards for approving the rare disease
indication.

21.10 Benefits of orphan drugs

from a development

perspective

The most obvious benefit for a company is that the
number of clinical trials and the quantity of clinical
data required for marketing approval will be
usually less for an orphan drug. This is primarily
based on the limited number of patients available
for clinical trials. Even though the numbers are
fewer, the data must be convincing and the stan-
dards of trial design are often unchanged. The
standards of clinical trial design may be modified
for extremely rare diseases where a company may
be limited to obtaining a number of individual case
studies.
A possible benefit in some drug development
programs is that less toxicology data may be
required. A regulatory requirement for less toxi-
cology data is based both on the difficulty of

obtaining the data as well as the benefit risk ratio

for getting the product to market rapidly.

A more rapid regulatory review may be antici-

pated for products of high medical value. This

results from the medical need of society for the

drug, the smaller application (dossier) compared to

other drugs with substantially more data and the

high priority of the application. In most circum-

stances, there will be a waiver of administrative

fees charged (e.g. user fees) for orphan drugs to be

reviewed.

Standards of manufacturing and quality control

for orphan drugs are identical to those of non-

orphan drugs. In some situations, a few differences

are that fewer validation batches may be required

and the duration of stability tests may be addressed

while the drug is being evaluated by the regulatory

authority, or in exceptional cases, after the product

is on the market. Thus, the time to develop the

chemistry and the technical package of data for

the regulatory submission may or may not differ

from that needed if the drug was for a common

disease.

Orphan drugs do not have medical value simply

because they are orphan drugs. Most drugs that

could be used for rare diseases do not have great

medical value in terms of safety, efficacy or prac-

tical reasons (e.g. number of doses required per

day, unpleasant taste, cost).

The opportunity costs of developing an orphan

drug must always be considered. In considering

whether or not to undertake this activity, most

large companies have indirectly said that they

will not develop orphan drugs because they have

implemented financial hurdles (xmillion dollars in

sales per year) that extremely few orphans could

meet. As a result, companies usually have specific

reasons for developing orphan drugs.

An approved indication is not always necessary

in order for a marketed drug to capture a rare

disease market for which it is also found to be

active. Patients may use a marketed drug to treat

a disease in some countries before it is approved by

the regulatory authorities for that use. This is often

understood and accepted by the regulatory author-

ity. For example, the FDA did not approve acyclo-

vir for Herpes encephalitis for over five years after

the NDA was submitted because they said it was

21.10 BENEFITS OF ORPHAN DRUGS FROM A DEVELOPMENT PERSPECTIVE 271