Attachment II - Page 25 
Federal Register / Vol. 49, No. 252 / Monday, December 31, 1934 / Notices 50879 
NDA holders who intend to market an 
approved drug under conditions other 
than those approved in the NDA must 
submit a supplemental NDA containing 
clinical evidence of the drug’s safety 
and effectiveness for the added 
indications. Extensive changes such as a 
changed formula, manufacturing 
process, or method of testing differing 
from the conditions of approval outlined 
in the NDA may also require additional 
clinical testing. 
Section 351 of the PHS Act defines a 
“biological product” as "any virus, 
therapeutic serum, toxin, antitoxin, 
vaccine, blood, blood component or 
derivative, allergenic product, or 
analogous product * * * applicable to 
the prevention, treatment, or cure of 
diseases or injuries of man * * V 
Biologies are regulated similarly to new 
drugs during the IND phase; approval for 
marketing is granted by license, which is 
only issued upon demonstration that 
both the manufacturing establishment 
and the product meet standards 
designed to ensure safety, purity, 
potency, and efficacy. All biologies are 
subject to general provisions in the 
regulations that assure potency, general 
safety, sterility, and purity. In addition, 
specific tests and standards are 
established for particular products. To 
obtain a license, the manufacturer must 
submit information demonstrating that 
the manufacturing facility and the 
product meet FDA standards, and the 
facility must pass a prelicensing 
inspection. Licensed products are 
subject to specific requirements for lot 
release by FDA. 
Manufacturers of new drugs and 
biologies must operate in conformance 
with current good manufacturing 
practice (CGMP) regulations, which 
address: adequately equipped 
manufacturing facilities; adequately 
trained personnel; stringent control over 
the manufacturing process; and 
appropriate finished product 
examination. CGMP’s are designed to 
protect the integrity and purity of the 
product. Approval of the product 
application is also approval of the 
sponsor’s process techniques. 
General Requirements for Animal Food 
Additives and Drugs 
Animal food additives and drugs are 
subject to similar mandatory 
requirements of the act as the like 
products for use in humans. Animal 
biologies, however, are regulated by the 
U.S. Department of Agriculture under 
the authority of the Virus-Serum-Toxin 
Act of 1913. Uncertainties as to whether 
a product fits the definition of a drug or 
biological drup are decided by a 
standing committee comprised of 
representatives from USDA and FDA. 
Application for approval must go 
through the Investigational New Animal 
Drug (INAD) and New Animal Drug 
Application (NADA) process similar to 
that required for human drugs, as 
discussed earlier. The regulations 
pertaining to INAD's do not require that 
the Agency approve clinical 
investigations, only that the food being 
marketed from treated food-producing 
animals be safe for human consumption. 
The data must be specific for each 
animal species for which the drug is 
intended. For NADA approval, it must 
be shown that those drugs which are 
intended for use in food-producing 
animals and used in accordance with 
approved label directions, do not 
accumulate as unsafe residues in the 
edible tissues of the animal at the time 
of slaughter. Moreover, the 
manufacturer must submit acceptable 
methods for recovery and detection of 
any drug residue in edible tissues. To 
further insure drug quality, animal 
drugs, including medicated feeds, must 
be manufactured in conformance with 
CGMP’s. 
Substances that are used in animal 
feeds, other than drugs, and that are 
produced by recombinant DNA 
technology, are considered to be food 
additives and require approval of a food 
additive petition (FAP). Other products 
of new biotechnology may also be 
considered to be food additives, 
requiring an FAP. Animal drugs or food 
additives produced by recombinant 
DNA technology must be the subject of 
approval even if the active substance is 
shown to be identical or similar to the 
active substance in approved products 
produced by conventional methods. 
General Requirements for Medical 
Devices 
Medical devices for human use are 
regulated by requirements of the act as 
amended by the Medical Device 
Amendments of 1970. In general terms, a 
device is defined in the act as any 
health care product that does not 
achieve any of its principal Intended 
purposes by chemical action in or on the 
body or by being metabolized. Devices 
include diagnostic aids such as reagents, 
antibiotic sensitivity discs, and test kits 
for in vitro diagnosis of disease. 
Veterinary medical devices are subject 
to the act but are not subject to 
pruclearance requirements. 
Regulations promulgated under the 
Medical Device Amendments control 
introduction of medical devices into 
commerce. In May 1976 when these 
device amendments were enacted, 
expert advisory committees 
recommended classifications for all 
medical devices of the types marketed 
at that time. The law segregates medical 
devices into three classes: 
Class I devices are subject to the 
minimum level of control; general 
controls include the CGMP's. 
Class II devices have been declared to 
require performance standards to assure 
their safety and/or effectiveness. They 
must also meet the controls of class I. 
Class III devices require formal FDA 
approval of a Premarket Approval 
Application (PMAA) for each make and 
model of the device to assure its safety 
and effectiveness. The controls of class I 
are also required. 
Before a manufacturer may Introduce 
into commerce any medical device not 
previously marketed, the manufacturer 
must formally declare that intent to FDA 
and proceed along one of two legal 
avenues. The manufacturer can file a 
premarket notification to FDA seeking a 
determination that the device is 
substantially equivalent to a 
preamendment device and proceed to 
market the device subject to whatever 
controls apply to the older versions of 
the device depending on its 
classification. This is the so-called 
"510(k)” process, which takes its name 
from a paragraph in the act. 
A new device — that is, one not 
substantially equivalent to a 
preenactment device — is automatically 
a class III device requiring FDA 
approval of a PMAA unless FDA 
reclassifies it into class I or class II. In 
the premarket approval process, the 
manufacturer must establish that the 
device is safe and effective. This is 
typically accomplished by scientific 
analysis by the Agency of product 
performance and data from clinical 
trials, submitted by the manufacturer in 
the PMAA. 
For a "significant risk device," as 
defined in FDA's regulations, the 
sponsor must submit an application to 
FDA for approval to conduct the 
investigation. This application is known 
as the Investigational Device Exemption 
(IDE). When the manufacturer believes 
there are sufficient data to establish the 
safety and effectiveness of its device, 
the manufacturer may file a premarket 
approval application, or PMAA. The law 
requires that FDA act on such an 
application within 180 days. 
Regulation of Specific Products 
Within the framework of FDA’s 
statutes and regulations, strategies have 
been developed for the evaluation of 
various kinds of "biotechnological" or 
"genetically engineered" products, as 
well as for other products. These 
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