Principles and Practice of Pharmaceutical Medicine

21.15 Establishing differences

among medicines

It is often important to establish that a company’s
medicine for which it desires an orphan drug des-
ignation differs from another medicine. There are a
number of principles that will help a company
establish a difference.

1. Different chemical structures. If it is unequivo-
   cally shown that two structures differ and it
   makes a biological or clinical difference,
   both will be given orphan drug designation.
   However, if the chemical difference is minor
   (e.g. one amino acid difference in a protein or
   the terminal carbohydrate portion of a large
   molecule) and no clinical differences can be
   shown, they will usually be viewed as the
   same product.


2. Differences in clinical effects. This is often a
   very difficult criterion to demonstrate, but if it
   can be shown, a difference would be estab-
   lished.


3. Contribution to patient care. If a marketed
   dosage form of a medicine cannot help certain
   patients with a problem, or not help them ade-
   quately compared to a different dosage form
   (e.g. parenteral), then the parenteral form would
   be eligible for orphan drug designation.


4. New production methods to purify a drug. If
   such methods lead to a difference in safety or
   efficacy, this would qualify for orphan drug
   designation. A real example is a new Factor IX.


5. New excipients. Differences in excipients that
   lead to a difference in clinical safety or efficacy
   would qualify for orphan drug designation.

Rear-Admiral Marlene Haffner MD MPH FRCP,
Director of the FDA’s Office of Orphan Products
Development, has summarized this issue best by
saying ‘For a difference to be a difference it must
make a difference’ (personal communication). A
lower cost of a second form of a medicine, or of the

same dosage form, is not a criterion to establish a

difference between two drugs, even if the original

is considered extremely expensive and a new

breakthrough allows the new product to be sold at

a markedly reduced price.

21.16 What is an orphan drug

indication?

It is obvious that arthritis, epilepsy, depression,

asthma and other similar diseases are not rare and

drugs to treat them do not qualify for orphan drug

designation. But would a medically plausible

subset of each disease qualify as an orphan indi-

cation if there were fewer than 200 000 patients

with, for example, a severe form of the disease?

The FDA’s principle in addressing this common

question is to ask the question: ‘Could (and

would) patients with less severe forms of the

disease use the new treatment?’ If so, then the

FDA says that the indication is not a true orphan

and usually denies the application for orphan

designation.

A rare variant of depression, asthma or other

common disease might qualify as an orphan indi-

cation if it is deemed to be a medically plausible

separate indication. In this situation, it is possible

that the company may receive the designation,

but the reviewing division of the FDA may

impose much higher standards for regulatory

approval of an orphan drug for marketing if

they believe it will be widely used in medical

practice. For example, a drug to treat a rare rheu-

matological disorder that could also be useful in

rheumatoid arthritis would likely have to provide

much more data to obtain approval than if the

drug were limited to treating a very small patient

population. On the contrary, a toxic medicine that

could only be used to treat severe cases of patients

with a common disease (because of benefit to risk

considerations) could receive orphan designation

and regulatory approval for marketing as an

orphan drug, with relatively little data. This

assumes that there was a significant medical

benefit to using the medicine in patients with

severe forms of the disease.

21.16 WHAT IS AN ORPHAN DRUG INDICATION? 275