GUIDANCE FOR SPONSORS, INDUSTRY, RESEARCHERS,
 

INVESTIGATORS, AND FOOD AND
 

DRUG ADMINISTRATION STAFF
 

Certifications To Accompany Drug, Biological Product, and Device
 

Applications/Submissions: Compliance with Section 402(j) of
 

The Public Health Service Act,
 

Added By Title VIII of The Food and Drug Administration
 

Amendments Act of 2007
 

Additional copies are available from:
 

Office of Policy, Office ofthe Commissioner
 

Food and Drug Administration
 

White Oak Building 1, Room 4305
 

10903 New Hampshire Avenue
 

Silver Spring, MD, 20993
 

301-796-4830.
 

.h.nQ:llwww.fda.govIoc/initiativesladvance/fdaaa.html
 

u.s. Department of Health and Human Services
 

Food and Drug Administration
 

Office of Policy, Office of the Commissioner
 

January 2009
 
Contains Nonbinding Recommendations 

Guidance for Sponsors, Industry, Researchers,
 

Investigators, and Food and Drug Administration Staff
 

Certifications To Accompany Drug, Biological Product, and Device
 

Applications/Submissions: Compliance with Section 402(j) of
 

The Public Health Service Act,
 

Added By Title VIII of The Food and Drug
 

Administration Amendments Act of 2007
 

This guidance document represents the Food and Drug Administration's current thinking on this 

topic. It does not create or confer any rights for or on any person and does not operate to bind 

FDA or the public. You may use an alternative approach if the approach satisfies the 

requirements ofthe applicable statutes and regulations. If you want to discuss an alternative 

approach, please contact the appropriate FDA staff. 

I. Introduction 

This guidance describes the Food and Drug Administration's (FDA or Agency) current thinking 

regarding the types of applications and submissions that sponsors, industry, researchers, and 

investigators submit to the Agency with accompanying certifications under section 4020)(5)(8) 

of the Public Health Service Act (PHS Act), 42 U.S.C. § 282(j)(5)(8). New section 402(j) of the 

PHS Act was added by Title VIII ofthe Food and Drug Administration Amendments Act of 

2007 (FDAAA) (Public Law 110-85). 

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FDA's guidance documents, including this guidance, do not establish legally enforceable rights 

or responsibilities. Instead, guidances describe the Agency's current thinking on a topic and 

should be viewed only as recommendations, unless specific regulatory or statutory requirements 

are cited. The use of the word should in Agency guidances means that something is suggested or 

recommended, but not required. 

II. Background 

Title VIII of FDAAA, Public Law 110-85, amended the PHS Act by adding new section 4020), 

42 U.S.C. § 282(j). The new provisions require that additional information be submitted to the 

clinical trials data bank (www.ClinicalTrials.gov) previously established by the National 

Institutes of Health (NIH)/National Library of Medicine (NLM), including expanded information 

on clinical trials and information regarding the results of clinical trials. 

One new provision, 42 U.S.C. § 282(j)(5)(B), section 402(j)(5)(B) of the PHS Act, requires that 

a certification accompany certain human drug, biological product, and device applications and 

submissions to FDA. The new provision reads as follows: 

(B) CERTIFICATION TO ACCOMPANY DRUG, BIOLOGICAL 

PRODUCT, AND DEVICE SUBMISSIONS.-At the time of submission 

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Contains Nonbinding Recommendations 

of an application under section 505 of the Federal Food, Drug, and Cosmetic Act, 

section 515 of such Act, section 520(m) of such Act, or section 351 of this Act, 

or submission of a report under section 51 O(k) of such Act, such application or 

submission shall be accompanied by a certification that all applicable 

requirements of this subsection have been met. Where available, such certification 

shall include the appropriate National Clinical Trial control numbers. 

The certification requirement went into effect on December 26,2007. To assist sponsors, 

industry, researchers, and investigators in complying with the requirement, FDA created a 

certification form to be used to satisfy the certification requirement. This form is FDA Form 

3674, OMB Control No. 0910-0616. The form can be obtained at 

www.fda.gov/opacom/morechoices/fdaforms/default.html. 

III. Purpose and Agency Recommendations 

FDA has received numerous inquiries asking whether various kinds of information and 

documents that sponsors, industry, researchers, and investigators submit to the Agency must be 

accompanied by the certification. FDA also has had experience with the submission of 

certifications since the form was implemented. This guidance provides FDA's current thinking, 

for purposes of implementing Title VIII of FDAAA, 1 regarding specific types of applications and 

1 In particular, the Agency's discussion of "applications" and "submissions" in this guidance is not necessarily 

applicable to any other provision oflaw. 

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submissions submitted to FDA under section 505, 515, 520(m), or 5l0(k) of the Federal Food, 

Drug, and Cosmetic Act (the Act), or under section 351 of the PHS Act, and accompanying 

certifications described in section 402(j)(5)(B), 42 U.S.C § 282(j)(5)(B). 

The purpose of Title VIII is to provide a means for ensuring that the public has access to 

information about certain clinical trials. Specifically, Title VIII is intended to provide a 

mechanism for the public to learn about certain clinical trials that are being conducted, as well as 

the results of those trials. In determining its current thinking on specific applications and 

submissions submitted under the statutory sections cited above and submission of accompanying 

certifications, FDA has focused on the role the certification plays in helping achieve the purposes 

of Title VIII of FDAAA. 

One purpose of the certification is to require the submitter to confirm that it has complied with 

all applicable requirements of Title VIII, including the requirement to register applicable clinical 

trials.2 Failure to submit a certification, knowingly submitting a false certification, failure to 

submit required clinical trial information, and submission of clinical trial information that is false 

or misleading are all newly added prohibited acts under section 30l(jj) ofthe Act (21 U.S.c. § 

33 1(jj)). Requiring a certification to accompany certain applications and submissions submitted 

to FDA is, therefore, one way of encouraging compliance with the provisions of the law. 

2 "Applicable clinical trial" is defined at section 402U)(l)(A)(i) ofthe PHS Act (42 U.S.C. § 282G)(1)(A)(i)). For 

additional information, visit http://prsinfo.clinicaltrials.gov. 

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The certification also facilitates FDA's exercise of its responsibilities under the new law. For 

example, as stated previously, FDAAA created four new prohibited acts relating to compliance 

with the requirements of Title VIII, including compliance with the requirement to submit a 

certification. The certification requirement is critical to the Agency's ability to determine 

whether the law has been complied with and whether an enforcement action is appropriate. In 

addition, section 402G)(3)(F) of the PHS Act (42 U.S.c. § 282(j)(3)(F)) requires FDA to notify 

the Director ofNIH of certain actions taken on applications and reports that were accompanied 

by a certification. That notification alerts NIH to the fact that the responsible party must submit 

the results ofthe trials within a certain period oftime, thereby enabling NIH to exercise its 

responsibilities under Title VIII. The information provided in the certification form also will 

help FDA assist NIH in "linking" information posted on FDA's website regarding certain FDA 

regulatory actions to specific applicable clinical trials included in the registry and results 

databases. This linking, using the information in the certification form, particularly the NCT 

(National Clinical Trial) number(s) required in the form, eventually will allow FDA to help the 

public more easily correlate various reports, medical reviews, advisories, health alerts, advisory 

committee actions, and other materials with specific applicable clinical trials registered with 

ClinicalTrials.gov and identified by the NCT number. 

New drug applications (NDAs), supplemental NDAs, biologics license applications (BLAs), 

supplemental BLAs, abbreviated new drug applications (ANDAs), premarket approval 

applications (PMAs), PMA "panel track" supplements, humanitarian device exemptions (HOEs), 

and resubmissions of these, are all "applications" under their respective sections of the Act or the 

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PHS Act. Similarly, 51 O(k)s are "submissions of a report" under that section of the Act. Thus, 

all of these specified applications and submissions fall within the plain language of the statutory 

provision. Additionally, they all represent the initiation of the regulatory review process 

through which clinical investigations supporting approval of a previously unapproved medical 

product are submitted to FDA for marketing approval of that product. Because amendments to 

pending applications, pending supplemental applications, or pending submissions of 51 O(k)s are 

not independently "applications" or "submissions of a report under 51 O(k)," such amendments 

need not be accompanied by a certification. 

We believe that the statutory requirement to submit a certification also applies to investigational 

new drug applications (INDs) and the submissions of new protocols to INDs. INDs are 

authorized under § 505(i) of the Act (see also 21 C.F.R. § 312.3 (defining "IND" as "an 

investigational new drug application")). We also have concluded that a certification must 

accompany the submission of a new clinical protocol to an IND as described in 21 CFR § 

312.30(a). There are a number of different types of submissions to an IND that are referred to as 

"amendments" under FDA's regulations, but these types of submissions are varied as to their 

purpose and the role they play in the regulatory process. One type of submission is that of a new 

protocol submitted to a pending IND. A new clinical protocol that is submitted to a pending 

IND, for a study not already included in an existing protocol, is the investigational stage analog 

to an efficacy supplement to an NDA or BLA for a new indication not already covered by the 

existing application. New protocols are referred to as amendments to ThTDs, and are submitted to 

existing INDs, as a matter of regulatory process; FDA could have required that new protocols 

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filed with the Agency be submitted to a new IND, but for administrative ease chose to have them 

submitted to the existing IND. In contrast, other types of amendments to pending INDs are more 

analogous to amendments to NDAs, BLAs, and PMAs; as such, consistent with our 

interpretation of the statute with regard to amendments to NDAs, BLAs, and PMAs, 

certifications need not be submitted with IND amendments other than submission of a new 

protocol to an existing IND. 

FDA intends to exercise enforcement discretion with regard to submission of certifications with 

four categories of applications and submissions: 1) a supplement to an approved NDA, BLA, or 

PMA other than an efficacy supplement (for NDAs and BLAs) or a panel track supplement (for 

PMAs), 2) a supplement to an approved ANDA, 3) INDs that fall within the types ofINDs 

described in section 561 of the Act (21 U.S.C. § 360bbb), and 4) submission ofa 510(k) ifthat 

submission does not refer to, relate to, or include information on or from a clinical trial. FDA 

believes that, in contrast to the types of applications and submissions discussed above, the 

majority of supplements to approved NDAs, BLAs, and PMAs do not refer to, relate to, or 

include information on or from a clinical trial. Furthermore, even to the extent that, for example, 

a labeling supplement to an approved NDA may refer to, relate to, or include information on or 

from one or more clinical trials, those clinical trials in all likelihood were conducted under an 

IND, and therefore the sponsor would already have submitted a certification regarding those 

trials during the investigational phase. It would be repetitive and would serve little or no purpose 

to have a sponsor repeatedly certify to having complied with the requirements of Title VIII of 

FDAAA with regard to the same clinical trial. 

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With regard to supplements to approved ANDAs, even when such supplements are intended to 

add an additional indication (such as when existing patents or exclusivities have expired), such 

supplements would not ordinarily refer to, relate to, or include information on or from any 

clinical trial other than those which were referenced or referred to in the original ANDA 

submission. Thus, as with non-efficacy supplements to approved NDAs and BLAs, and panel 

track supplements to approved PMAs, certification with a supplemental ANDA would be 

repetitive, and would serve little or no purpose with regard to ensuring that the requirements of 

Title VIII had been met. 

With regard to INDs that fall within the types ofINDs described in section 561 of the Act (21 

U.S.c. § 360bbb), none of the clinical trials conducted under such INDs will meet the definition 

of applicable drug clinical trial in section 402(j)(I)(A)(iii) of the PHS Act (42 U.S.C. 

§ 282(j)(1)(A)(iii)), and thus none of those trials will be subject to the registration and reporting 

requirements as set forth in Title VIII of FDAAA. One of the criteria for being an applicable 

drug clinical trial is that the trial at issue is a "controlled clinical investigation." Trials conducted 

under INDs that fall within the types ofINDs described in section 561 of the Act are not 

controlled. Because none of the clinical trials conducted under an IND of the type described in 

section 561 of the Act would be subject to the requirements ofTitle VIII of FDAAA, 

certification with regard to such clinical trials when submitting an IND for such a clinical trial 

would serve little or no purpose with regard to ensuring that the requirements of Title VIII had 

been met. 

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Finally, with regard to 51 O(k)s, the majority of 51 O(k) submissions do not refer to, relate to, or 

include information on or from a clinical trial. Accordingly, FDA believes that certification with 

regard to 51 O(k) submissions that do not refer to, relate to, or include information on or from a 

clinical trial would serve little or no purpose with regard to ensuring that the requirements of 

Title VIII had been met. 

Because FDA believes that the statutory purposes of Title VIII would not be furthered by the 

submission of certifications with these four categories of applications and submissions, the 

Agency intends to exercise enforcement discretion regarding certification with these applications 

and submissions. 

Based on these considerations and as described above, FDA recommends that a certification 

accompany the following types of applications and submissions: 

Applications/Submissions (including Resubmissions) 

IND 

New Clinical Protocol Submitted to an IND 

NDA 

Efficacy Supplement to an Approved NDA 

BLA 

Efficacy Supplement to an Approved BLA 

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ANOA 

PMA 

PMA Panel Track Supplement 

HOE 

5l0(k) that refers to, relates to, or includes information on a clinical trial 

IV. Paperwork Reduction Act of 1995 

This guidance refers to previously approved collections of information. 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 ofinfonnation 

have been approved under OMB Control No. 0910-0616. 

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