Good Clinical Practice: A Question & Answer Reference Guide - May 2014 - 27

GCP Regulations, Standards, and Guidelines for Clinical Research
concluded that the FDA would view this as a promotional activity. In response, the agency established "that
providing a drug for study would not, in and of itself, be viewed as a promotional activity if the manufacturer or
distributor provides the product for a physician-initiated, bona fide clinical investigation. [FDA also] explained that
it is the responsibility of the investigator to determine whether or not an IND is necessary."
1.34 Q. Has the FDA provided specific examples of the applicability of the IND submission exemption to
specific types of studies involving marketed drugs in the United States, such as the degree to which a drug
to be used in a study may differ from the approved version?
A. Although the FDA does not generally believe it is "desirable" to indicate specific situations in which an IND is
not required, it offered several examples of such situations in its October 2010 draft guidance titled, "Investigational
New Drug Applications (INDs)-Determining Whether Human Research Studies Can Be Conducted Without an
IND," in its 1987 IND regulations, and in the January 2004 guidance titled, "IND Exemptions for Studies of
Lawfully Marketed Cancer Drug or Biological Products" (first published in September 2003).
In discussing the criteria for exemption, the FDA's October 2010 draft guidance specifically addresses the degree
to which a drug or use to be studied in a new trial may differ from the approved drug/use and still be eligible for
exemption:
* To what degree can a sponsor change the marketed drug product or conditions of use and still be exempt from
the IND regulations? "Sponsors or sponsor-investigators can make low-risk modifications to the lawfully
marketed dosage form to, for example, blind a study," the draft guidance states. "In making modifications to
the marketed dosage form, sponsors and sponsor investigators should consider the potential risk implications
of the modifications based on the type and complexity of the dosage form. For example, minor variations to
solid oral dosage forms, such as changing the color, scoring, or capsule size of the marketed dosage form for
blinding purposes, would generally be low risk provided the changes did not involve major manufacturing or
formulation changes. Similarly, using capsules to over encapsulate the marketed dosage form would generally
be low risk provided the capsule meets appropriate standards. Changes to more complex oral dosage forms
and injectable and other non-oral dosage forms would usually carry greater risk. Products that are very
sensitive to conditions in their environment (e.g., protein products) also carry greater risk because changes
to the formulation, dosage form, manufacturing, or primary packaging may significantly increase risk for
such products. Given the range of possible modifications to a marketed dosage form, FDA cannot provide
comprehensive guidance on the degree of risk presented by all such modifications."
* Is the risk associated with the product significantly increased (or the acceptability of the risk significantly
decreased)? "Historically, assessing whether a particular use of a drug in a clinical investigation significantly
increases the risk, or decreases the acceptability of the risk, compared to its approved use or uses, has been the
most difficult issue in determining whether an IND is needed for a clinical investigation of a marketed drug,"
the September 2013 guidance notes. It adds that, in assessing the "risk implications" of any conditions of use
in the study that deviate from the approved labeling, investigators/sponsors should give particular attention to
route of administration ("a change in the route of administration can introduce a significant new risk"), dose
(increases or decreases in dose, frequency, or duration of administration can significantly increase the risk in a
study using a marketed drug), and patient population (the acceptability of known and unknown risks can vary
considerably across different populations).
The guidance also addressed the applicability of the IND exemption to specific trials, including those involving
cold isotopes, endogenous compounds, live organisms, dietary supplements, and radioactive drugs for certain
research uses.
In the January 2004 cancer guidance, the agency also addresses several case examples about which it was asked
directly in response to the proposed regulation:
* "In general, the use in a clinical investigation of a drug in capsule form that is lawfully marketed in tablet
form should not, in itself, raise safety concerns necessitating submission of an IND. Of course, there may be
exceptions. For example, the agency can foresee circumstances in which reformulation to capsule form of a
drug product might so affect its bioavailability as to raise safety concerns warranting submission of an IND.
There might also be significant problems involved in grinding up and encapsulating enteric-coated or film-

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Good Clinical Practice: A Question & Answer Reference Guide - May 2014

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