[Federal Register Volume 84, Number 245 (Friday, December 20, 2019)]
[Notices]
[Pages 70196-70197]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2019-27524]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

[Docket No. FDA-2019-D-4964]


Demonstrating Substantial Evidence of Effectiveness for Human 
Drug and Biological Products; Draft Guidance for Industry; Availability

AGENCY: Food and Drug Administration, HHS.

ACTION: Notice of availability.

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SUMMARY: The Food and Drug Administration (FDA or Agency) is announcing 
the availability of a draft guidance for industry entitled 
``Demonstrating Substantial Evidence of Effectiveness for Human Drug 
and Biological Products.'' This guidance complements and expands on the 
1998 guidance entitled ``Providing Clinical Evidence of Effectiveness 
for Human Drug and Biological Products'' (the 1998 guidance). Although 
FDA's evidentiary standard for effectiveness has not changed since 
1998, the evolution of drug development and science has led to changes 
in the types of drug development programs submitted to the Agency. 
Specifically, there are more programs studying serious diseases lacking 
effective treatment, more programs in rare diseases, and more programs 
for therapies targeted at disease subsets. There is a need for more 
Agency guidance on the flexibility in the amount and type of evidence 
needed to meet the substantial evidence standard in these 
circumstances.

DATES: Submit either electronic or written comments on the draft 
guidance by February 18, 2020 to ensure that the Agency considers your 
comment on this draft guidance before it begins work on the final 
version of the guidance.

ADDRESSES: You may submit comments on any guidance at any time as 
follows:

Electronic Submissions

    Submit electronic comments in the following way:
     Federal eRulemaking Portal: https://www.regulations.gov. 
Follow the instructions for submitting comments. Comments submitted 
electronically, including attachments, to https://www.regulations.gov 
will be posted to the docket unchanged. Because your comment will be 
made public, you are solely responsible for ensuring that your comment 
does not include any confidential information that you or a third party 
may not wish to be posted, such as medical information, your or anyone 
else's Social Security number, or confidential business information, 
such as a manufacturing process. Please note that if you include your 
name, contact information, or other information that identifies you in 
the body of your comments, that information will be posted on https://www.regulations.gov.
     If you want to submit a comment with confidential 
information that you do not wish to be made available to the public, 
submit the comment as a written/paper submission and in the manner 
detailed (see ``Written/Paper Submissions'' and ``Instructions'').

Written/Paper Submissions

    Submit written/paper submissions as follows:
     Mail/Hand Delivery/Courier (for written/paper 
submissions): Dockets Management Staff (HFA-305), Food and Drug 
Administration, 5630 Fishers Lane, Rm. 1061, Rockville, MD 20852.
     For written/paper comments submitted to the Dockets 
Management Staff, FDA will post your comment, as well as any 
attachments, except for information submitted, marked and identified, 
as confidential, if submitted as detailed in ``Instructions.''
    Instructions: All submissions received must include the Docket No. 
FDA-2019-D-4964 for ``Demonstrating Substantial Evidence of 
Effectiveness for Human Drug and Biological Products.'' Received 
comments will be placed in the docket and, except for those submitted 
as ``Confidential Submissions,'' publicly viewable at https://www.regulations.gov or at the Dockets Management Staff between 9 a.m. 
and 4 p.m., Monday through Friday.
     Confidential Submissions--To submit a comment with 
confidential information that you do not wish to be made publicly 
available, submit your comments only as a written/paper submission. You 
should submit two copies total. One copy will include the information 
you claim to be confidential with a heading or cover note that states 
``THIS DOCUMENT CONTAINS CONFIDENTIAL INFORMATION.'' The Agency will 
review this copy, including the claimed confidential information, in 
its consideration of comments. The second copy, which will have the 
claimed confidential information redacted/blacked out, will be 
available for public viewing and posted on https://www.regulations.gov. 
Submit both copies to the Dockets Management Staff. If you do not wish 
your name and contact information to be made publicly available, you 
can provide this information on the cover sheet and not in the body of 
your comments and you must identify this information as 
``confidential.'' Any information marked as ``confidential'' will not 
be disclosed except in accordance with 21 CFR 10.20 and other 
applicable disclosure law. For more information about FDA's posting of 
comments to public dockets, see 80 FR 56469, September 18, 2015, or 
access the information at: https://www.gpo.gov/fdsys/pkg/FR-2015-09-18/pdf/2015-23389.pdf.
    Docket: For access to the docket to read background documents or 
the electronic and written/paper comments received, go to https://www.regulations.gov and insert the docket number, found in brackets in 
the heading of this document, into the ``Search'' box and follow the 
prompts and/or go to the Dockets Management Staff, 5630 Fishers Lane, 
Rm. 1061, Rockville, MD 20852.
    You may submit comments on any guidance at any time (see 21 CFR 
10.115(g)(5)).
    Submit written requests for single copies of the draft guidance to 
the Office of Communication, Outreach and Development, Center for 
Biologics Evaluation and Research, Food and Drug Administration, 10903 
New Hampshire Ave., Bldg. 71, Rm. 3128, Silver Spring, MD 20993-0002 or

[[Page 70197]]

Division of Drug Information, Center for Drug Evaluation and Research, 
Food and Drug Administration, 10001 New Hampshire Ave., Hillandale 
Building, 4th Floor, Silver Spring, MD 20993-0002. Send one self-
addressed adhesive label to assist that office in processing your 
requests. See the SUPPLEMENTARY INFORMATION section for electronic 
access to the draft guidance document.

FOR FURTHER INFORMATION CONTACT: Stephen Ripley, Center for Biologics 
Evaluation and Research, Food and Drug Administration, 10903 New 
Hampshire Ave., Bldg. 71, Rm. 7301, Silver Spring, MD 20993-0002, 240-
402-7911 or Ei Thu Lwin, Center for Drug Evaluation and Research, Food 
and Drug Administration, 10903 New Hampshire Ave., Bldg. 22, Rm. 6236, 
Silver Spring, MD 20993-0002, 301-796-0728.

SUPPLEMENTARY INFORMATION:

I. Background

    FDA is announcing the availability of a draft guidance for industry 
entitled ``Demonstrating Substantial Evidence of Effectiveness for 
Human Drug and Biological Products.'' This guidance complements and 
expands on the 1998 guidance. The 1998 guidance was issued in response 
to the Food and Drug Administration Modernization Act of 1997 (FDAMA) 
(Pub. L. 105-115), which stated that the substantial evidence 
requirement for effectiveness, which had generally been interpreted as 
calling for two adequate and well-controlled trials, could also be met 
by a single trial plus confirmatory evidence. The 1998 guidance, 
therefore, provided many examples of the types of evidence that could 
be considered confirmatory evidence, with a specific focus on adequate 
and well-controlled trials of the test agent in related populations or 
indications, as well as a number of illustrations of a single adequate 
and well-controlled trial supported by convincing evidence of the 
drug's mechanism of action in treating a disease or condition.
    FDAMA, thus, introduced a specific new area of flexibility in the 
evidence needed to support effectiveness, but there are many other 
characteristics of the evidence supporting effectiveness that can vary 
(notably, trial designs, trial endpoints, statistical methodology), and 
evidence that varies in such ways potentially can provide substantial 
evidence of effectiveness but because of these characteristics may 
provide greater or lesser certainty. These characteristics also deserve 
consideration and were not discussed in the 1998 guidance. FDA's use of 
these various designs, endpoints, and analyses which can differ in the 
strength of evidence they provide, reflects the Agency's longstanding 
flexibility when considering the types of data and evidence that can 
meet the substantial evidence requirement.
    Although FDA's evidentiary standard for effectiveness has not 
changed since 1998, the evolution of drug development and science has 
led to changes in the types of drug development programs submitted to 
the Agency. Specifically, there are more programs studying serious 
diseases lacking effective treatment, more programs in rare diseases, 
and more programs for therapies targeted at disease subsets. There is a 
need for more Agency guidance on the flexibility in the amount and type 
of evidence needed to meet the substantial evidence standard in these 
circumstances. The approaches discussed in this guidance can yield 
evidence that meets the statutory standard for substantial evidence and 
reflect the evolving landscape of drug development.
    This guidance discusses the quality of evidence to establish 
effectiveness, including trial designs and trial endpoints. It also 
discusses the quantity of evidence needed in a given development 
program, i.e., two adequate and well-controlled trials, one adequate 
and well-controlled trial plus confirmatory evidence, or reliance on a 
previous finding of effectiveness of an approved drug when 
scientifically justified and legally permissible (i.e., no new 
effectiveness or pharmacodynamic data would be needed). The guidance 
also expands upon the discussions included in the 1998 guidance on the 
types of mechanistic and pharmacologic evidence and non-clinical 
evidence that can constitute confirmatory evidence.
    Although randomized superiority trials with a placebo- or active-
control design generally provide the strongest evidence of 
effectiveness, this guidance discusses the circumstances under which 
trials not using a placebo control, superiority design, or 
randomization may be acceptable. In addition, this guidance also 
discusses situations in which human efficacy trials are not ethical or 
feasible, and the animal rule may be applied. In all cases, FDA must 
reach the conclusion that there is substantial evidence of 
effectiveness to approve a drug; however, the degree of certainty 
supporting such a conclusion may differ, depending on clinical 
circumstances (e.g., severity and rarity of the disease and unmet 
medical need).
    This draft guidance is being issued consistent with FDA's good 
guidance practices regulation (21 CFR 10.115). The draft guidance, when 
finalized, will represent the current thinking of FDA on 
``Demonstrating Substantial Evidence of Effectiveness for Human Drug 
and Biological Products.'' It does not establish any rights for any 
person and is not binding on FDA or the public. You can use an 
alternative approach if it satisfies the requirements of the applicable 
statutes and regulations.

II. Paperwork Reduction Act of 1995

    This draft guidance refers to previously approved collections of 
information found in FDA regulations. These collections of information 
are subject to review by the Office of Management and Budget (OMB) 
under the Paperwork Reduction Act of 1995 (44 U.S.C. 3501-3520). The 
collections of information in 21 CFR part 312 for submission of an 
investigational new drug application have been approved under OMB 
control number 0910-0014. The collections of information in 21 CFR 
314.50 for submission of an NDA have been approved under OMB control 
number 0910-0001. The collections of information in 21 CFR part 601 for 
submission of a BLA have been approved under OMB control number 0910-
0338.

III. Electronic Access

    Persons with access to the internet may obtain the draft guidance 
at either https://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm, https://www.fda.gov/vaccines-blood-biologics/guidance-compliance-regulatory-information-biologics, or https://www.regulations.gov.

    Dated: December 16, 2019.
Lowell J. Schiller,
Principal Associate Commissioner for Policy.
[FR Doc. 2019-27524 Filed 12-19-19; 8:45 am]
BILLING CODE 4164-01-P


