[Federal Register Volume 60, Number 147 (Tuesday, August 1, 1995)]
[Pages 39180-39181]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 95-18877]


[Docket No. 95N-0230]

Statement Regarding the Demonstrations of Effectiveness of Human 
Drug Products and Devices

AGENCY: Food and Drug Administration, HHS.

ACTION: Notice.


SUMMARY: The Food and Drug Administration (FDA) is announcing its 
position regarding demonstrations of product effectiveness in new drug 
applications (NDA's) and premarket approval applications (PMA's). In 
evaluating NDA's and PMA's, FDA weighs the product's demonstrated 
effectiveness against its risks and considers other factors such as the 
seriousness and outcome of the disease being treated and the adequacy 
of existing treatments. The agency does not require new human drug 
products or medical devices to be more effective than existing 
therapies nor does it necessarily require the product to be compared to 
other products. However, for products intended to treat life-
threatening diseases, diseases with irreversible morbidity, and 
contagious diseases that pose serious health risks to others, it is 
essential for public health protection that a new therapy be as 
effective as existing, approved therapies.

DATES: Written comments by October 30, 1995.

ADDRESSES: Submit written comments to the Dockets Management Branch 
(HFA-305), Food and Drug Administration, rm. 1-23, 12420 Parklawn Dr., 
Rockville, MD 20857.

Philip L. Chao, Office of Policy (HF-23), Food and Drug Administration, 
5600 Fishers Lane, Rockville, MD 20857, 301-443-2831.

SUPPLEMENTARY INFORMATION: On March 4, 1995, President Clinton 
announced plans for reforming the Federal regulatory system as part of 
his ``Reinventing Government'' initiative. Part of this reform is aimed 
at reviewing regulatory processes to determine which requirements could 
be reduced or eliminated without lowering health and safety standards.
    Pursuant to the President's ``Reinventing Government'' initiative, 
FDA made several recommendations with respect to the regulation of 
human drug products and medical devices. One recommendation was the 
issuance of a public statement clarifying certain aspects of the 
standards for the effectiveness of human drug products and medical 
    The Federal Food, Drug, and Cosmetic Act (the act) requires NDA's 
and PMA's to contain full reports of information demonstrating that the 
drug or device is safe and effective under conditions of use in the 
product's proposed labeling. (See sections 505(b) and 515(c) of the act 
(21 U.S.C. 355(b) and 360e(c)).) The agency must deny approval of a NDA 
or a PMA if it finds that the application does not demonstrate that the 
product is safe and effective for the uses indicated in the product's 
proposed labeling. (See sections 505 (c) and (d) and 515(d) of the 
    Pharmaceutical and device manufacturers have sometimes claimed that 
the agency requires new human drug products and especially class III 
devices (devices for which insufficient information exists to assure 
that general controls and special controls provide reasonable assurance 
of safety and effectiveness; in general, these are the higher risk 
devices) to be more effective for their intended uses than comparable 
therapies that are already approved for marketing. These firms assert 
that FDA's requirements for demonstrating effectiveness present 
unreasonable difficulties in developing new therapies and bringing 
those new therapies to market.
    This notice is intended to address the concerns about a comparative 
effectiveness standard that have been raised. In evaluating the safety 
of a new drug or medical device, FDA weighs the product's demonstrated 
effectiveness against its risks to determine whether the benefits 
outweigh the risks. This weighing process also takes into account 
information such as the seriousness and outcome of the disease, the 
presence and adequacy of existing treatments, and adverse reaction and 
other safety data.
    In evaluating effectiveness, FDA reviews new drug products and 
devices on their merits. FDA does not require new drug products or 
devices to be more effective than approved therapies for the same 
disease or condition. In general, both new drug products and class III 
devices must be shown to be effective through evidence consisting of 
clinical investigations that provide a basis on which it can be 
concluded that the new drug product or class III device will be safe 
and have the effect that it is represented to have.
    For most new drug products and new class III devices intended to 
treat serious 

[[Page 39181]]
illness or provide symptomatic relief, a showing of effectiveness is 
usually based on a clinical trial comparing the product to a placebo. 
Such a showing does not necessarily involve a comparison to another 
active treatment or a product that is known to be effective.
    In certain circumstances, however, it may be important to consider 
whether a new product is less effective than available alternative 
therapies, when less effectiveness could present a danger to the 
patient or to the public. For example, it is essential for public 
health protection that a new therapy be as effective as alternatives 
that are already approved for marketing when: (1) The disease to be 
treated is life-threatening or capable of causing irreversible 
morbidity (e.g., stroke or heart attack); or (2) the disease to be 
treated is a contagious illness that poses serious consequences to the 
health of others (e.g., sexually transmitted diseases).
    It should be noted that new products are often developed for 
particular subpopulations who either do not respond to or are not able 
to tolerate an existing approved therapy. FDA will generally approve 
for use in such a subpopulation a product that is shown to have 
effectiveness in this group, regardless of whether the product can be 
shown to be as effective in the broad target population as the 
alternative therapy. This is because, in effect, there is no available 
alternative therapy for the subpopulation. For example, a number of 
patients cannot tolerate a widely used therapy for an acquired immune 
deficiency syndrome (AIDS)-related pneumonia. FDA approved atovaquone 
for use in these patients even though the drug had been shown to be 
less effective than the standard therapy when tested in a broad 
    An additional issue related to product effectiveness concerns the 
assertion, by some industry officials, that the act not be interpreted 
as requiring multiple clinical studies when one ``pivotal'' study could 
    FDA believes good science dictates that a showing of effectiveness 
must be methodologically sound and provide a high level of confidence 
in the validity of the result. For human drug products, this ordinarily 
is achieved by independently replicating the result in a second study, 
to constitute an adequate demonstration of effectiveness for a new 
product. While a second study may well be needed to replicate results 
demonstrated in a first study, in some instances, it is possible to 
replicate results within one large, well-designed, multi-center study. 
FDA emphasizes that this approach can be successful only when results 
are strong. The agency has, in the past, approved new human drug 
products on the basis of a single, multi-center study. Examples include 
dornase alfa for the treatment of cystic fibrosis, timolol for 
treatment of people after a heart attack, and zidovudine for AIDS. A 
statistically marginal result, even in a very large study, cannot 
provide convincing evidence without replication.
    For medical devices, where the mechanism of action is a result of 
product design and substantially verified by in vitro performance 
testing, the agency has routinely relied on single studies evaluated 
for internal and across-center consistency to provide this high level 
of confidence in the result.

    Dated: July 27, 1995.
William B. Schultz,
Deputy Commissioner for Policy.
[FR Doc. 95-18877 Filed 7-31-95; 8:45 am]