50744 Federal Register / Vol. 74, No. 189 / Thursday, October 1, 2009 / Proposed Rules 

proposed rule. Under the current 

regulations, existing leaseholders are 

excepted from the introduced species 

prohibition if they have active lease 

agreements at the time of 

implementation of the regulation (the 

regulation took effect on March 9, 2009). 

Under the proposed rule for the 

GFNMS, this exemption will no longer 

contain a geographic restriction of 

Tomales Bay, and will no longer restrict 

new permits from being issued through 

the State (as opposed to through the 

ONMS). This prohibition would not put 

any current operations out of business, 

because they will not need to change 

anything about their current procedures 

to continue in their operations. A 

beneficial effect from this proposed 

action may result for existing and future 

lease holders, such as reduced 

administrative burden for issuance or 

renewal of a lease permit. Comments 

received on the economic impacts of 

this proposed rule will be summarized 

and responded to in the final rule. 

F. Paperwork Reduction Act 

This proposed rule does not contain 

information collections that are subject 

to the requirements of the Paperwork 

Reduction Act. Notwithstanding any 

other provision of the law, no person is 

required to respond to, nor shall any 

person be subject to a penalty for failure 

to comply with, a collection of 

information subject to the requirements 

of the PRA, unless that collection of 

information displays a currently valid 

OMB Control Number. 

V. Request for Comments 

NOAA requests comments on this 

proposed rule for 45 days after 

publication of this notice. 

List of Subjects in 15 CFR Part 922 

Administrative practice and 

procedure, Environmental protection, 

Fish, Harbors, Marine pollution, Marine 

resources, Natural resources, Penalties, 

Recreation and recreation areas, 

Research, Water pollution control, 

Water resources, Wildlife. 

Dated: September 24, 2009. 

William Corso, 

Deputy Assistant Administrator for Ocean 

Services and Coastal Zone Management. 

Accordingly, for the reasons set forth 

above, 15 CFR part 922 is amended as 

follows: 

PART 922—NATIONAL MARINE 

SANCTUARY PROGRAM 

REGULATIONS 

1. The authority citation for Part 922 

continues to read as follows: 

Authority: 16 U.S.C. 1431 et seq. 

Subpart H—Gulf of the Farallones 

National Marine Sanctuary 

2. Section 922.82(a)(10) is amended to 

read as follows: 

§ 922.82 Prohibited or otherwise regulated 

activities. 

(a) * * * 

(10) Introducing or otherwise 

releasing from within or into the 

Sanctuary an introduced species, 

except: 

(i) Striped bass (Morone saxatilis) 

released during catch and release 

fishing activity; or 

(ii) Species cultivated by a 

mariculture activity within the area of 

the sanctuary lying within the seaward 

boundary of the State of California and 

authorized by a valid lease, permit, 

license or other authorization issued by 

the State. 

* * * * * 

Subpart M—Monterey Bay National 

Marine Sanctuary 

3. Section 922.132(a)(12) is amended 

to read as follows: 

§ 922.132 Prohibited or otherwise 

regulated activities. 

(a) * * * 

(12) Introducing or otherwise 

releasing from within or into the area of 

the Sanctuary lying beyond the seaward 

boundary of the State of California an 

introduced species, except striped bass 

(Morone saxatilis) released during catch 

and release fishing activity. 

* * * * * 

[FR Doc. E9–23576 Filed 9–30–09; 8:45 am] 

BILLING CODE 3510–NK–P 

DEPARTMENT OF HEALTH AND 

HUMAN SERVICES 

Food and Drug Administration 

21 CFR Part 4 

[Docket No. FDA–2008–N–0424] 

RIN 0910–AF82 

Postmarketing Safety Reporting for 

Combination Products 

AGENCY: Food and Drug Administration, 

HHS. 

ACTION: Proposed rule. 

SUMMARY: The Food and Drug 

Administration (FDA) proposes to 

amend the combination product 

regulations to set forth postmarketing 

safety reporting requirements for 

combination products. Specifically, the 

rule will clarify the postmarketing safety 

reporting requirements that apply when 

regulated articles (drugs, devices, and 

biological products) are combined to 

create a combination product. The 

proposed rule is intended to promote 

and protect the public health by 

clarifying requirements for 

postmarketing safety reporting for 

combination products, and is part of 

FDA’s ongoing effort to ensure the 

consistency and appropriateness of the 

regulatory requirements for combination 

products. 

DATES: Submit written or electronic 

comments on the proposed rule by 

December 30, 2009. Submit comments 

on information collection issues under 

the Paperwork Reduction Act of 1995 by 

November 2, 2009, (see the ‘‘Paperwork 

Reduction Act of 1995’’ section of this 

document). 

ADDRESSES: You may submit comments, 

identified by Docket No. FDA–2008–N– 

0424 and/or RIN number 0910–AF82, by 

any of the following methods, except 

that comments on information 

collection issues under the Paperwork 

Reduction Act of 1995 must be 

submitted to the Office of Regulatory 

Affairs, Office of Management and 

Budget (OMB) (see the ‘‘Paperwork 

Reduction Act of 1995’’ section of this 

document). 

Electronic Submissions 

Submit electronic comments in the 

following ways: 

• Federal eRulemaking Portal: http:// 

www.regulations.gov. Follow the 

instructions for submitting comments. 

Written Submissions 

Submit written submissions in the 

following ways: 

• FAX: 301–827–6870. 

• Mail/Hand delivery/Courier (for 

paper, disk, or CD–ROM submissions): 

Division of Dockets Management (HFA– 

305), Food and Drug Administration, 

5630 Fishers Lane, rm. 1061, Rockville, 

MD 20852. 

To ensure more timely processing of 

comments, FDA is no longer accepting 

comments submitted to the agency by email. FDA encourages you to continue 

to submit electronic comments by using 

the Federal eRulemaking Portal, as 

described previously, in the ADDRESSES

portion of this document under 

Electronic Submissions. 

Instructions: All submissions received 

must include the agency name and 

docket number and Regulatory 

Information Number (RIN) for this 

rulemaking. All comments received may 

be posted without change to http:// 

www.regulations.gov, including any 

personal information provided. For 


jlentini on DSKJ8SOYB1PROD with PROPOSALS
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1Combinations of two investigational products as 

defined at § 3.2(e)(4) are outside the scope of this 

proposed rule. Those types of combination products 

are investigational only and have not yet been 

approved for marketing. This proposed rule applies 

to all combination products for which 

postmarketing safety reports are required. 

2As described in the Department of Health and 

Human Services (HHS) Unified Agenda (72 FR 

22490, April 30, 2007), FDA also plans to propose 

regulations on current good manufacturing practice 

for combination products. FDA proposes to codify 

those requirements in part 4, subpart A, and to 

codify the postmarketing safety reporting 

requirements for combination products in part 4, 

subpart B. 

additional information on submitting 

comments, see the ‘‘Request for 

Comments’’ heading of the 

SUPPLEMENTARY INFORMATION section of 

this document. 

Docket: For access to the docket to 

read background documents or 

comments received, go to http:// 

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 Division of Dockets 

Management, 5630 Fishers Lane, rm. 

1061, Rockville, MD 20852. 

FOR FURTHER INFORMATION CONTACT: 

Leigh Hayes, Office of Combination 

Products (HFG–3), Food and Drug 

Administration, 15800 Crabbs Branch 

Way, suite 200, Rockville, MD 20855, 

301–427–1934. 

SUPPLEMENTARY INFORMATION: 

I. Introduction 

II. Description of the Proposed Rule 

A. Background 

B. General Principles 

C. Specific Examples 

D. Additional Considerations 

E. Role of Lead Center 

F. Recordkeeping Requirements 

G. Separate Applications and/or 

Reporters 

H. Applicability of Proposed Rule to 

User Facilities and Importers and 

Distributors as Defined in 21 CFR 

Part 803 

I. Stakeholders’ Comments on 

Postmarketing Safety Reporting 

Applicable to Combination 

Products 

III. Legal Authority 

IV. Environmental Impact 

V. Paperwork Reduction Act Analysis 

VI. Federalism 

VII. Analysis of Impacts 

A. Introduction 

B. The Rationale Behind This 

Proposed Rule 

C. Impact of Proposed Rule 

VIII. Request for Comments 

IX. Proposed Effective Date 

I. Introduction 

As set forth in part 3 (21 CFR part 3), 

a combination product is a product 

comprised of a combination of a drug 

and a device; a device and a biological; 

a biological and a drug; or a drug, a 

device, and a biological. A combination 

product includes the following: (1) A 

product comprised of two or more 

regulated components, i.e., drug/device, 

biologic/device, drug/biologic, or drug/ 

device/biologic, that are physically, 

chemically, or otherwise combined or 

mixed and produced as a single entity; 

(2) Two or more separate products 

packaged together in a single package or 

as a unit and comprised of drug and 

device products, device and biological 

products, or biological and drug 

products; (3) A drug, device, or 

biological product packaged separately 

that, according to its investigational 

plan or proposed labeling, is intended 

for use only with an approved 

individually specified drug, device, or 

biological product where both are 

required to achieve the intended use, 

indication, or effect and where upon 

approval of the proposed product the 

labeling of the approved product would 

need to be changed; e.g., to reflect a 

change in intended use, dosage form, 

strength, route of administration, or 

significant change in dose; or (4) Any 

investigational drug, device, or 

biological product packaged separately 

that, according to its proposed labeling, 

is for use only with another individually 

specified investigational drug, device, or 

biological product where both are 

required to achieve the intended use, 

indication, or effect.1 This rule does not 

address postmarketing reporting 

associated with approved products that 

are used in combination with 

investigational products. 

In the past decade, significant 

advances have been made in the 

development of combination products. 

In recognition of these advances, the 

Medical Device User Fee and 

Modernization Act of 2002 (MDUFMA) 

modified section 503(g) of the Federal 

Food, Drug, and Cosmetic Act (the 

FD&C Act) (21 U.S.C. 353(g)) to require 

the establishment of an Office (Office of 

Combination Products (OCP)) within 

FDA’s Office of the Commissioner. The 

responsibilities of OCP include ensuring 

the prompt assignment of combination 

products to agency components, the 

timely and effective premarket review of 

such products, and the consistent and 

appropriate postmarket regulation of 

like products subject to the same 

statutory requirements to the extent 

permitted by law (21 U.S.C. 353(g)(4)). 

To date, the agency has not issued 

regulations on postmarketing safety 

reporting specifically for combination 

products. Instead, the agency has 

applied provisions from the applicable 

postmarketing safety reporting 

regulations for drugs, devices, and 

biological products. These requirements 

for drugs, devices, and biological 

products share many similarities and 

have a common underlying purpose, 

namely to protect the public health by 

ensuring a product’s continued safety 

and effectiveness. However, each set of 

regulations has certain reporting 

standards and timeframes with unique 

requirements based upon the 

characteristics of the products for which 

the regulations were designed (i.e., for 

drugs, devices and biological products). 

External stakeholders have expressed 

concern about the lack of concrete 

information regarding the postmarketing 

safety reporting regulatory requirements 

for combination products (see section 

II.I of this document for further 

discussion). Generally, reporters have 

followed the safety reporting regulations 

associated with the type of marketing 

application used to approve or clear 

their combination product. For example, 

if a new drug application (NDA) was 

used to approve a drug/device 

combination product, reporters 

generally submit postmarketing safety 

reports in accordance with part 314 (21 

CFR part 314). However, if the device 

component of the combination product 

malfunctions, the reporter currently has 

no clear regulatory procedure to follow 

under part 314 when reporting this 

problem. This lack of regulatory clarity 

could lead to reporting that does not 

sufficiently reflect the combination 

nature of the product or the fact that an 

adverse experience may be related to a 

particular constituent part of a 

combination product. This lack of 

regulatory clarity could also lead to 

incomplete or inconsistent reporting 

and to FDA not receiving important 

safety information. This could 

compromise the agency’s ability to make 

sound regulatory decisions about 

product safety and could jeopardize the 

public health. 

To address these concerns, to ensure 

appropriate ongoing postmarketing 

surveillance of risks, to ensure the 

consistency of the agency’s 

postmarketing regulation of 

combination products, to streamline 

requirements for reporters by avoiding 

duplicative reporting requirements, 

FDA proposes to create 21 CFR part 4, 

subpart B to clarify postmarketing safety 

reporting requirements for combination 

products.2


jlentini on DSKJ8SOYB1PROD with PROPOSALS
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3Section 227 of the Food and Drug 

Administration Amendments Act of 2007 (FDAAA) 

amended section 519(a)(1) of the FD&C Act (21 

U.S.C. 360i) to require 30-day malfunction reports 

under part 803 for only certain devices, such as 

class III devices and class II devices that are 

permanently implantable, life supporting, or life 

sustaining. Other devices, such as class I devices, 

are subject to summary reporting on a quarterly 

basis. See the proposed definition of malfunction 

report in proposed §§ 4.101 and 4.103(b)(2). 

II. Description of the Proposed Rule 

A. Background 

In the development of this proposed 

rule, FDA considered the fact that each 

constituent part of a combination 

product is governed by one of three 

differing sets of reporting provisions. 

The agency reviewed each set of 

regulations governing postmarketing 

safety reporting for drugs (parts 310 (21 

CFR part 310) and 314), biological 

products (parts 600 and 606 (21 CFR 

parts 600 and 606)), and devices (part 

803 (21 CFR part 803)). This review 

determined that each set of regulations 

contains many substantially similar 

requirements as well as certain 

important differences. 

In general, each set of regulations 

requires reports of death and serious 

adverse events; each provides for 

periodic and followup reports; and each 

provides a method to signal certain 

types of safety events that warrant 

expedited reporting. Because of these 

similarities, it is possible to consolidate 

the requirements so that the 

combination product is subject 

primarily to the reporting requirements 

associated with the type of marketing 

application under which the product is 

approved or cleared. However, there are 

certain significant differences in the 

three sets of regulations. These 

differences are designed to facilitate 

adverse experience reporting that 

adequately addresses the distinct 

characteristics and potential safety 

issues related to a particular type of 

product (i.e., drug, device, and 

biological product). The public health 

benefit of these unique provisions 

would be lost if the combination 

product were subject solely to the 

reporting requirements associated with 

the type of marketing application. FDA 

has identified five such provisions, 

unique to drugs, biologics, or devices, 

that need to be preserved to 

appropriately reflect the combination 

nature of the product and to ensure 

consistent and appropriate 

postmarketing safety reporting for 

combination products: 

1. 5-Day Report 

The Medical Device Reporting (MDR) 

regulation has a provision found in 

§ 803.53(a), which requires reporting no 

later than five work days after the day 

the reporter becomes aware that an MDR 

reportable event associated with the 

device necessitates remedial action to 

prevent an unreasonable risk of 

substantial harm to the public health. 

This section also allows FDA to make 

written requests for the submission of 

all subsequent events of the same nature 

that involve substantially similar 

devices for the time period specified in 

the written request. Reporters must also 

maintain a record of any report they 

submit under this provision. This 

provision is unique to devices; a similar 

provision is not found in the drug or 

biological product reporting regulations. 

2. 30-Day Device Malfunction Report 

The MDR regulation also includes 

§ 803.20(b)(3)(ii), which requires 

reporting no later than 30 calendar days 

after the day the reporter becomes aware 

of information that reasonably suggests 

the device has malfunctioned and that 

this device or a similar device that the 

reporter markets would be likely to 

cause or contribute to a death or serious 

injury if the malfunction were to recur.3

Reporters must also maintain a record of 

any report they submit under this 

provision. Like the 5-day MDR report, 

this situation is unique to devices, and 

the drug and biological product 

reporting regulations do not have 

comparable provisions. 

3. 15-Day ‘‘Alert Report’’ for Drugs and 

Biological Products 

A reporter must submit to FDA a 

report of an adverse experience 

associated with the use of a drug or 

biological product that is both serious 

and unexpected, whether foreign or 

domestic, as soon as possible but in no 

case later than 15 days of initial receipt 

of the information as set forth in 

§§ 314.80(c)(1) and (e), and 600.80(c)(1) 

and (e). Serious events are reportable 

within 30 days under § 803.20(b)(3)(i) 

for devices, regardless of whether or not 

they are expected. However, there is no 

requirement in the MDR regulation for 

expedited (15-day) reporting of an event 

that is both serious and unexpected. 

4. 3-Day Field Alert Report 

Another unique provision is 

§ 314.81(b)(1), which requires 

applicants to file ‘‘field alert reports’’ 

when there is information concerning 

certain types of problems with a drug in 

distribution, such as any bacteriological 

contamination, or any significant 

chemical, physical, or other change or 

deterioration in a distributed drug 

product, or any failure of one or more 

distributed batches of the drug to meet 

the specification established for it in its 

marketing application, or any incident 

that causes the drug product or its 

labeling to be mistaken for, or applied 

to, another article. Reporters must 

submit this information to the FDA 

district office that is responsible for the 

facility involved within 3 working days 

of its receipt. They must provide the 

information by telephone or other rapid 

communication means, with prompt 

written followup. Reporters must also 

maintain a record of any report they 

submit under this provision. These 

types of situations are specific to drug 

products, and neither set of regulations 

found in parts 600 (biological products) 

or 803 (devices) has a similar provision 

requiring expedited submission of these 

types of reports. 

5. Expedited Blood Fatality Report 

Section 606.170 requires expedited 

reporting of a complication of blood 

collection or transfusion confirmed to 

be fatal, by telephone, facsimile, express 

mail or electronically transmitted mail 

as soon as possible, and a written report 

within 7 days after the fatality. 

Reporters must also maintain a record of 

any report they submit under this 

provision. This situation is specific to 

blood products. Although parts 310, 

314, 600 and 803 require expedited 

reporting of deaths, they do not provide 

for the immediate notification of bloodrelated fatalities. 

B. General Principles 

Given the broad similarities in the 

regulations, the agency believes that the 

simplest and most straightforward way 

to ensure that combination products are 

regulated consistently is by continuing 

to require reporters to comply with the 

requirements for postmarketing safety 

reporting associated with the 

application used to approve or clear 

their combination product (proposed 

§ 4.103(a)), as long as the five unique 

specified provisions particular to each 

different set of regulations are, in fact, 

complied with by the reporter (proposed 

§ 4.103(b)). This supplementation 

reflects the combination nature of the 

product, and recognizes and preserves 

each constituent part’s unique 

characteristics. Specifically, these 

unique reporting requirements, along 

with any associated followup reports, 

are as follows: (1) submission of a ‘‘5- 

day report’’ related to the device 

constituent part of a combination 

product as described in § 803.53(a); (2) 

submission of a 30-day ‘‘malfunction 

report’’ related to the device constituent 

part of a combination product as 

described in section 227 of FDAAA and 

§ 803.20(b)(3)(ii); (3) submission of a 


jlentini on DSKJ8SOYB1PROD with PROPOSALS
Federal Register / Vol. 74, No. 189 / Thursday, October 1, 2009 / Proposed Rules 50747 

‘‘postmarketing 15-day ‘Alert report’’’ 

associated with the use of a drug or 

biological product constituent part of a 

combination product, as described in 

§§ 314.80(c)(1) and (e), and 600.80(c)(1) 

and (e); (4) submission of a 3-day ‘‘field 

alert report’’ as described in 

§ 314.81(b)(1); and (5) submission of an 

expedited ‘‘blood fatality report’’ as 

described in § 606.170. 

Given the unique nature of 

combination products, more than one 

applicant may be involved in the 

development of a combination product, 

or more than one marketing application 

may be submitted. For most 

combination products, however, a single 

marketing application is submitted for 

the combination product’s approval, 

clearance or licensure. In these cases, 

the marketing application covers all 

constituent parts of the combination 

product (e.g., both the drug and device 

constituent parts of a drug-device 

combination product). The applicable 

reporting requirements for this type of 

circumstance are described later in this 

section (section II.B of this document). 

In some cases, however, separate 

marketing applications are submitted for 

the various constituent parts of a 

combination product. This can occur 

when one applicant submits separate 

marketing applications for the various 

constituent parts of a combination 

product (e.g., an NDA for the drug 

constituent part and a premarket 

approval application (PMA) for the 

device constituent part), or when a 

combination product is developed by 

more than one applicant, each of which 

holds a marketing application for its 

respective constituent part of the 

combination product. For this type of 

circumstance, the applicable reporting 

requirements are described in section 

II.G of this document. 

Under the proposed rule, combination 

products marketed under a single 

application would be subject to the 

following reporting scheme: 

1. General Requirements (Proposed 

§ 4.103(a)) 

A reporter would use the 

requirements for postmarketing safety 

reporting associated with the approved 

or cleared application under which the 

combination product is marketed. In 

general, for combination products 

approved or cleared under the device 

provisions of the FD&C Act, a reporter 

would utilize medical device reporting 

under part 803; for combination 

products approved under the drug 

provisions of the FD&C Act, a reporter 

would use §§ 314.80 and 314.81; and for 

combination products licensed under 

the Public Health Service Act (PHS Act), 

a reporter would use §§ 600.80 and 

606.170. If you are the only reporter for 

a combination product (i.e., another 

reporter is not responsible for reporting 

for one of the constituent parts of the 

combination product), you would 

consider the combination product as a 

whole (i.e., all of its constituent parts) 

and the application under which it is 

approved or cleared when determining 

whether an event is required to be 

reported. 

2. Additional Requirements (Proposed 

§ 4.103(b)) 

When applicable, depending on the 

type of combination product and the 

nature of the reportable event, a reporter 

would submit additional types of 

reports and any associated followup 

reports, to appropriately reflect the 

combination nature of the product. 

These five types of reports, described 

above, would only be necessary if you 

would not otherwise (already) be 

required to provide them under the 

reporting framework associated with the 

application under which your product 

is approved, or if they would be 

required, but at a later timeframe. 

3. Multiple Reporters (Proposed § 4.104) 

If you are not the only reporter for a 

combination product (e.g., you hold an 

application for one constituent part of 

the combination product, while another 

reporter holds an application for its 

other constituent part), you are subject 

to applicable requirements for 

postmarketing safety reporting for your 

constituent part of the combination 

product. In addition, to ensure the other 

reporter is aware of and can investigate 

and followup on events you may learn 

about, you must submit the information 

you receive about events to FDA or the 

other reporter within 5 calendar days of 

your receipt of the information. In turn, 

you must investigate and report 

information you receive about 

reportable events provided to you by 

FDA or another reporter for your 

combination product. 

4. Submission and FDA Review of 

Reports (Proposed § 4.105) 

With the exception of ‘‘field alert 

reports’’ that are submitted to the 

appropriate FDA district office, all 

reports, including the reports associated 

with the regulatory requirements 

applicable to your product or 

constituent part, and the additional 

types of reports (described previously) 

reflecting the combination nature of the 

product, would be submitted using the 

submission methods identified in the 

appropriate underlying regulations. The 

lead FDA center charged with review 

and regulation of the combination 

product will review the reports and may 

consult with other Centers as needed. 

5. Recordkeeping Requirements 

(Proposed § 4.106) 

Records would be kept in accordance 

with the existing underlying regulatory 

requirements applicable to each type of 

report. 

C. Specific Examples 

1. Drug/Device (Approved Under 

Section 505 of the FD&C Act) 

The proposed rule would preserve the 

unique postmarketing safety reporting 

requirements for drugs, devices, and 

biological products regardless of the 

type of marketing application for the 

combination product. For example, for a 

drug/device combination product 

regulated under the drug provisions of 

the FD&C Act and approved under an 

NDA, a reporter would follow the NDA 

reporting provisions set forth in 

§§ 314.80, 314.81, 314.98, or 314.540, as 

is the case for all products regulated 

under part 314. Although the language 

of part 314 refers specifically to the drug 

product, under the proposed rule, if you 

are the only reporter for the 

combination product, you would 

consider the combination product as a 

whole (i.e., all of its constituent parts 

including its device constituent parts) 

and the application under which it was 

approved or cleared when determining 

the reportability of an event under 

§ 314.80(c)(1) (15-day alerts report). For 

example, an event that is both serious 

and unexpected, whether associated 

with the drug or device constituent part 

of the combination product, would be 

reported within 15 calendar days of 

initial receipt of such information by the 

reporter. 

A reporter for a drug/device 

combination product, approved under 

an NDA, would also be required to 

submit a reportable device malfunction 

or a 5-day report when necessary for an 

event related to the device constituent 

part of their combination product, and 

to include such reports in the periodic 

reports submitted under § 314.80(c)(1). 

For example, a 30-day device 

malfunction report would be necessary 

when a reporter becomes aware of 

information that reasonably suggests 

that the device constituent part of the 

combination product malfunctioned and 

if the malfunction were to recur, it 

would be likely to cause or contribute 

to a death or serious injury. In that case, 

a reporter would submit, as appropriate, 

a malfunction report as described in 

section 227 of FDAAA, as well as any 

required followup reports. Similarly, a 


jlentini on DSKJ8SOYB1PROD with PROPOSALS
50748 Federal Register / Vol. 74, No. 189 / Thursday, October 1, 2009 / Proposed Rules 

4Even though, in this example, the combination 

product is approved under the device authorities, 

you would submit a 15-day alert report, if required, 

for the drug constituent part, regardless of whether 

the drug constituent part ‘‘caused or contributed to’’ 

a reportable event. 

reporter would submit a 5-day report, as 

defined in § 803.3 and described in 

§ 803.53(a), if there is a reportable event 

regarding a device constituent part of a 

combination product that necessitates 

remedial action to prevent an 

unreasonable risk of substantial harm to 

the public health. In either case, since 

the drug/device combination was 

approved under an NDA, the report 

would be submitted to the address 

specified in part 314. Any report 

submitted to FDA would also be 

described in the periodic reports 

required by § 314.80(c)(2). 

2. Biological Product/Device (Approved 

Under Section 351 of the PHS Act) 

The specified device reporting 

requirements would be similarly 

applied, as described in section II.C.1 of 

this document, if a biological product/ 

device combination product is approved 

under a biologics license application 

(BLA). A reporter would follow the 

biologics reporting provisions set forth 

in §§ 600.80 and 606.170 (for products 

with blood or blood component 

constituent parts) as would be the case 

for any product licensed under section 

351 of the PHS Act. In general, reporting 

under § 600.80 would also cover the 

device constituent part, not including 5- 

day MDR reports and 30-day MDR 

malfunction reports. As stated in the 

previous example, if you become aware 

of information that reasonably suggests 

that the device constituent part of the 

combination product malfunctioned and 

that if the malfunction were to recur it 

would be likely to cause or contribute 

to a death or serious injury, you would 

submit a 30-day malfunction report as 

described in section 227 of FDAAA, and 

any required followup reports. 

Likewise, you would submit a 5-day 

report for a reportable event regarding a 

device constituent part of a combination 

product that necessitates remedial 

action to prevent an unreasonable risk 

of substantial harm to the public health. 

Since the biological product/device 

combination was approved under a 

BLA, the reports would be submitted as 

described in § 600.80 and to the address 

specified in § 600.2. A reporter would 

also describe any 5-day and malfunction 

reports submitted to FDA in the 

periodic reports required by 

§ 600.80(c)(2). 

3. Drug or Biological Product/Device 

(Approved or Cleared Under the FD&C 

Act’s Device Authorities) 

The proposed rule would also 

preserve the unique reporting 

requirements relevant to drugs and 

biological products that may be 

constituent parts of a combination 

product, if the combination product is 

regulated under the device provisions of 

the FD&C Act. For example, if a drug/ 

device combination product is approved 

under a PMA or cleared under a 

premarket notification (510(k)), you 

would comply with the applicable 

postmarketing safety reporting 

requirements set forth in part 803, as 

you would for other products regulated 

under the device provisions of the FD&C 

Act. Although the language of part 803 

refers specifically to devices, under the 

proposed rule, if you are the only 

reporter for the combination product, 

you would, in general, submit 

postmarket safety reports for the 

combination product, including its drug 

or biological constituent parts, under 

part 803. You would also comply with 

the 15-day alert report requirements, 

under §§ 314.81(c)(1) or 600.80(c)(1), for 

the drug or biological product 

constituent parts, if such requirements 

applied. In addition, you would comply 

with a 3-day field alert report, for the 

drug constituent part, if § 314.81(b)(1) 

applied. For example, if a death or 

serious injury occurred, whether 

associated with the drug or device 

constituent part of the combination 

product, you would report it in 

accordance with part 803. However, if a 

serious, unexpected adverse experience 

occurred that is associated with the use 

of the drug constituent part of the 

combination product, you would 

investigate and submit a ‘‘postmarketing 

15-day ‘Alert’ report,’’ and any required 

followup reports, as described in 

§ 314.80(c)(1).4 A 30-day MDR report for 

this event would not be required. 

Likewise, if you receive a report that 

there is bacteriological contamination of 

the drug constituent part of your 

distributed combination product, or 

another type of event described in 

§ 314.81(b)(1) related to the drug 

constituent part of your distributed 

combination product, you would submit 

a field alert report to the appropriate 

FDA district office within 3 working 

days of your receipt of the information. 

Similarly, the proposed rule would 

also preserve the unique reporting 

requirements relevant to blood-related 

fatalities. If a device/biological product 

combination product containing blood 

or a blood component was approved 

under a PMA, a reporter would follow 

the reporting requirements described in 

part 803. However, a reporter would 

instead submit a ‘‘postmarketing 15-day 

‘Alert’ report’’ as described in 

§ 600.80(c)(1) for a serious, unexpected 

adverse experience associated with the 

use of the biological product constituent 

part of the combination product. A 30- 

day MDR report for this event would not 

be required. Similarly, a reporter would 

submit a report, as described in 

§ 606.170, for a blood-related fatality. 

Since the device/biological product 

combination was approved under a 

PMA, the reports would be submitted to 

the address specified in part 803. 

4. Drug/Biological Product (Approved 

Under Section 505 of the FD&C Act or 

Section 351 of the PHS Act) 

Drug and biological product reporting 

requirements are very similar, with two 

exceptions being § 606.170, the 

provision which concerns expedited 

reporting of blood-related fatalities and 

§ 314.81(b)(1) the provision which 

concerns reporting of certain types of 

problems with a drug in distribution, 

such as bacteriological contamination, a 

significant change in or deterioration of 

the drug, failure of the drug product to 

meet application specifications, or an 

incident that causes the drug product or 

its labeling to be mistaken for, or 

applied to, another article. A reporter 

with a drug/biological combination 

product approved under a BLA would 

be required to follow the postmarketing 

safety reporting procedures set forth in 

parts 600 and 606 (for a combination 

product with a blood or blood 

component constituent part). 

Compliance with these provisions 

would satisfy the reporting 

requirements for an adverse experience 

that is associated with the use of either 

the drug or biological product 

constituent parts of the combination 

product, unless you receive information 

of the type described in § 314.81(b)(1) 

concerning the drug constituent part of 

the product, in which case you would 

submit a ‘‘field alert report.’’ Similarly, 

a reporter with a drug/biological 

combination product approved under an 

NDA would follow the postmarketing 

safety reporting provisions described in 

part 314. Compliance with these 

provisions would satisfy the reporting 

requirements for an adverse experience 

associated with the use of either the 

drug or the biological product 

constituent part, unless the biological 

product constituent part contained 

blood or a blood component. In that 

case, if you have a drug/biological 

combination product that contained 

blood or a blood component approved 

under a NDA, you would comply with 

part 314, and, if applicable, submit an 

expedited blood fatality report as 

described in § 606.170. Reporting the 


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Federal Register / Vol. 74, No. 189 / Thursday, October 1, 2009 / Proposed Rules 50749 

event within the timeframe set forth in 

§ 606.170 would also fulfill your 

requirement to report a serious, 

unexpected event within 15 days under 

§ 314.80(c)(1). 

D. Additional Considerations 

FDA does not expect or desire that 

reporters submit duplicate reports, and 

this proposal is intended to ensure that 

duplicative reporting does not occur. 

Under this proposal, take, for example, 

a reporter who submits a 15-day alert 

report for a serious, unexpected adverse 

experience associated with the use of a 

drug constituent part of a drug/device 

combination product approved under a 

PMA and subject to part 803 as 

discussed previously (the reporter 

would follow the reporting 

requirements, standards and timeframes 

specified in part 803). In this case, 

submission of the 15-day alert report 

and any associated followup reports 

would fulfill the requirement for 

submission of a 30-day report under 

part 803 for a serious event, regardless 

of whether or not it was expected. In 

other words, reporting the serious, 

unexpected event that is associated with 

the drug constituent part of your 

combination product within 15 days 

would also fulfill your requirement to 

report a serious event, regardless of 

expectedness, within 30 days under the 

MDR regulation. Similarly, if the 

combination product is comprised of a 

biological product component 

containing blood and a drug component, 

submission of a ‘‘blood fatality report’’ 

and any associated followup reports, as 

soon as possible and with a written 

report within 7 days, would satisfy the 

requirement to report a death or serious 

injury within 15 days under part 314. 

We note that this proposed rule 

applies to mandatory safety reports 

submitted to the agency, i.e., those 

reports currently submitted on Form 

3500A or the CIOMS I or Vaccine 

Adverse Event Reporting System 

(VAERS) form, or their electronic 

equivalents, periodic safety reports, as 

well as ‘‘field alert reports’’ related to 

the drug constituent part of a 

combination product. This proposed 

rule does not change any annual or 

periodic reporting timeframes. 

Furthermore, the regulations proposed 

here do not supersede other reporting 

requirements found in 21 CFR parts 314, 

600, 606, 803, or 806. Finally, FDA’s 

authority to require additional 

postmarketing safety reporting for a 

particular product under other 

regulatory provisions, e.g., conditions of 

approval or postmarketing 

commitments, is unaffected by this rule. 

E. Role of Lead Center 

For a combination product approved 

or cleared under one marketing 

application, the ‘‘lead’’ Center, i.e., the 

Center with primary responsibility for 

the review and regulation of the 

combination product, will have lead 

responsibility for review of all 

postmarketing safety reports, regardless 

of whether a particular constituent part 

is associated with the event. After the 

lead Center receives the postmarketing 

safety report, it will consult as needed 

with the other Center(s). 

For example, for a drug/device 

combination product approved under an 

NDA by the Center for Drug Evaluation 

and Research (CDER), all reports 

required by part 314 under proposed 

§ 4.103(a), as well as under the two 

unique specified provisions for devices 

(5-day or 30-day device malfunction 

reports) under proposed § 4.103(b)(1) 

and (b)(2), would be submitted to the 

address required for all other 

postmarketing safety reports the reporter 

submits (in this case, those required by 

part 314). CDER would have the lead on 

their review, and CDER would consult 

the Center for Devices and Radiological 

Health (CDRH) as needed. 

F. Recordkeeping Requirements 

In considering the recordkeeping 

requirements that should apply for 

postmarketing safety reporting for 

combination products, the agency chose 

to use the time periods set forth in the 

regulations for drugs, devices, and 

biological products because both 

stakeholders and the agency are familiar 

with those requirements. As a result, 

under proposed § 4.106(a), records 

pertaining to reportable events under 

parts 310, 314 and 600 would be kept 

for 10 years, and records for reportable 

events under part 803 would be kept for 

2 years or the expected life of the 

combination product, whichever is 

longer. Under proposed § 4.106(b), the 

recordkeeping requirements for the five 

additional provisions specified in 

proposed § 4.103(b) would each be the 

same as those currently required by the 

underlying regulations from which 

these requirements were derived. 

G. Separate Applications and/or 

Reporters 

For some combination products, 

separate marketing applications are 

submitted for the individual constituent 

parts of a combination product. In some 

cases, one reporter holds all the 

applications used to approve or clear 

the combination product; in other cases, 

the reporter holds only one application 

that governs one constituent part of the 

combination product, while a different 

reporter holds the application for the 

other constituent part. 

Under proposed § 4.103(a), if you are 

the only reporter for a combination 

product, you would consider each of the 

reporting requirements specified in 

proposed § 4.103(a) and comply with 

each that is applicable to your 

combination product or constituent 

part. For example, if you hold a single 

marketing application covering the 

entire combination product, under 

proposed § 4.103(a), you would be 

subject primarily to the set of reporting 

requirements associated with that type 

of marketing application (e.g., part 803 

if your product is approved under a 

PMA). However, if you hold two 

marketing applications for your 

combination product (e.g., an NDA for 

the drug constituent part and a PMA for 

the device constituent part), under 

proposed § 4.103(a), you would be 

subject to the reporting requirements 

under part 803 for your device 

constituent part, and to the reporting 

requirements under part 314 for your 

drug constituent part. In the special 

circumstance of holding two marketing 

applications for your combination 

product, and you can reasonably 

determine the constituent part that 

caused the adverse event, you only 

consider that particular constituent part 

when determining your reporting 

requirements. For example, if you hold 

multiple marketing applications for a 

combination product and you 

reasonably conclude that the adverse 

event was related to the drug 

constituent part, you would only follow 

the reporting requirements under part 

314. Similarly, if the adverse event was 

related to the device constituent part, 

you would only follow the reporting 

requirements under part 803; if the 

adverse event was related to the 

biological product constituent part, you 

would only follow the reporting 

requirements under parts 600 and 606. 

If it is unclear which constituent part 

led to the adverse event, you would 

satisfy reporting requirements for each 

constituent part of the combination 

product. 

If you do not hold all of the 

applications used to approve or clear 

the constituent parts of your 

combination product, you would 

comply with the requirements for 

postmarketing safety reporting 

associated with the application used to 

approve or clear your constituent part of 

the combination product. Additionally, 

under proposed § 4.104(a), you would 

submit the information you receive 

about an adverse event to FDA or the 

reporter for the other constituent part of 


jlentini on DSKJ8SOYB1PROD with PROPOSALS
50750 Federal Register / Vol. 74, No. 189 / Thursday, October 1, 2009 / Proposed Rules 

5Under section 227 of FDAAA, if an importer is 

required, under part 803, to submit a report 

concerning a device malfunction to the 

manufacturer, the importer must submit the report 

to the manufacturer in accordance with part 803. 

the combination product within 5 

calendar days of your receipt of the 

information. Under proposed § 4.104(b), 

if the other reporter receives such 

information from you, that reporter 

would then investigate and report the 

event in accordance with the statutory 

provisions and regulatory requirements 

for postmarketing safety reporting for 

their constituent part of the combination 

product. For example, if you hold the 

application for a drug constituent part of 

a drug/device combination product 

approved under an NDA, and you 

receive information regarding an event, 

you would comply with part 314, i.e., 

the reporting provisions associated with 

your application, in determining 

reportability of the event. You would 

also send the information about the 

event to FDA or the reporter for the 

device constituent part of the 

combination product within 5 calendar 

days of receiving the information. If you 

choose to notify the device reporter 

within 5 calendar days, the device 

reporter would investigate and report 

the event in accordance with part 803, 

i.e., the reporting provisions associated 

with that reporter’s application. In some 

cases, the regulations will not require 

the other reporter to submit the report; 

in other circumstances, depending on 

the nature of the reportable event, the 

regulations will require the other 

reporter to submit a report. FDA 

recognizes that in these relatively rare 

circumstances, the agency may receive 

duplicate reports regarding one 

incident. However, FDA believes these 

requirements are necessary in order to 

promote and protect the public health 

by ensuring consistent and appropriate 

ongoing postmarketing surveillance of 

risks, and ensure both manufacturers are 

aware of and appropriately investigate 

and follow up on events involving their 

constituent part(s) of a combination 

product. 

H. Applicability of Proposed Rule to 

User Facilities and Importers and 

Distributors as Defined in Part 803 

The proposed rule does not apply to 

user facilities required to report to FDA 

under part 803. Section 803.30 requires 

user facilities to report deaths to FDA 

and serious injuries to the device 

manufacturer within 10 days. Since user 

facility reporting already includes early, 

expedited reporting of deaths and 

serious injuries, it encompasses the 

types of additional reports described in 

proposed § 4.103(b) related to drug and 

biological product constituent parts, i.e., 

serious and unexpected adverse 

experiences and blood-related fatalities. 

Therefore, no further supplementation 

is necessary in order for user facility 

reporting to reflect the combination 

nature of a product. 

The proposed rule also does not apply 

to distributors as defined in part 803, 

i.e., those who further the marketing but 

do not repackage or otherwise change 

the container, wrapper, or labeling. 

Under § 803.18(d), device distributors 

are required to maintain records of 

incidents but not to report to FDA. 

Importers of combination products 

subject to part 803 would be subject to 

the proposed rule. Under part 803, 

importers are required to report deaths 

and serious injuries to FDA, and device 

malfunctions to the manufacturer.5

Importers of combination products 

regulated under the device provisions of 

the FD&C Act would continue to be 

subject to part 803. Such importers 

would submit to FDA reports described 

in proposed § 4.103(b) to provide for 

earlier, expedited reporting of serious, 

unexpected adverse experiences 

associated with the drug or biological 

product constituent parts of a 

combination product they are 

importing. Importers would also submit 

expedited reporting of fatalities related 

to a blood constituent part of the 

imported combination product. 

I. Stakeholders’ Comments on 

Postmarketing Safety Reporting 

Applicable to Combination Products 

FDA held a public hearing on 

November 25, 2002, and a public 

workshop on July 8, 2003, to discuss 

various issues pertaining to combination 

products, including postmarketing 

safety reporting for combination 

products. Stakeholders provided a 

number of thoughtful written 

comments, regarding postmarketing 

safety reporting, to a docket, which FDA 

opened to further facilitate the 

discussion of combination product 

issues. The agency has carefully 

reviewed all the comments we received, 

and we have considered them in the 

development of this proposed rule. Two 

common themes that emerged from the 

comments were: (1) The need for 

consistency in reporting requirements 

and (2) avoidance of duplicative 

reporting. We believe that the 

provisions set forth in this proposal 

provide a framework that adequately 

addresses these concerns. 

Some stakeholders have suggested 

that FDA consider developing an 

entirely new postmarketing safety 

reporting scheme for combination 

products. Such a scheme might, for 

example, harmonize the varying 

definitions, reporting standards, 

timeframes, and other differences 

between the postmarketing safety 

reporting regulations for drugs, devices, 

and biological products. However, as 

described previously, given the broad 

similarities in the regulations, the 

agency determined that the simplest and 

most straightforward approach is to 

continue to require reporters to comply 

with the requirements for postmarketing 

safety reporting associated with the 

application used to approve or clear the 

combination product, as long as there is 

compliance, as appropriate, with the 

five unique provisions. This approach 

recognizes and preserves each 

constituent part’s unique characteristics, 

while allowing reporters and FDA to 

continue to use mechanisms for 

reporting that are currently in practice. 

Finally, some stakeholders have 

recommended that the agency develop a 

comprehensive information technology 

(IT) system for postmarketing safety 

reporting of combination products. The 

agency acknowledges the need to make 

IT accommodations to have its 

postmarketing safety reporting 

procedures work efficiently. The agency 

is developing an internal electronic 

infrastructure for combination product 

safety reports. We anticipate that we 

will be able to implement this 

infrastructure prior to the effective date 

of any final rule based on this proposed 

rule. In parallel with that project, we are 

currently enhancing mechanisms for 

FDA to receive combination product 

postmarketing safety reports 

electronically and for intercenter 

consultation of these reports upon their 

receipt. Additionally, we recognize that 

it may be necessary to make minor 

changes to the Form FDA 3500A, the 

VAERS form, the periodic safety report, 

the Form FDA 3331, and Form FDA 

3486, or their electronic equivalents 

and/or instructions to accommodate the 

postmarketing safety information 

required by this rule. We invite 

comment on what changes might be 

necessary and will provide further 

instructions for practical 

implementation in conjunction with any 

final rule that may issue after this 

proposed rule. 

FDA believes these proposed 

postmarketing safety reporting 

requirements will ensure the 

consistency and appropriateness of 

postmarketing safety reporting for 

combination products. The rule 

provides that, regardless of the type of 

marketing application used to approve 

or clear the product or the Center with 

primary responsibility for its review, 

each combination product will be 


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Federal Register / Vol. 74, No. 189 / Thursday, October 1, 2009 / Proposed Rules 50751 

subject to similar postmarketing safety 

reporting requirements. The rule 

recognizes and incorporates the 

similarities of the reporting 

requirements in the different sets of 

regulations, while also ensuring 

appropriate reporting by recognizing 

and preserving the unique provisions 

which embody necessary safety signals, 

given the combination nature of the 

product. These safety reporting 

requirements will help ensure the 

submission of necessary and 

appropriate information to expedite 

FDA’s safety review and evaluation, and 

thereby will enhance the agency’s 

ability to promote and protect the public 

health. The proposed rule when 

finalized will affect postmarketing 

safety reports submitted on or after the 

effective date of any final rule issued as 

a result of this proposed rule. 

III. Legal Authority 

The agency derives its authority to 

issue the regulations in proposed 21 

CFR part 4 from 21 U.S.C. 321, 331, 351, 

352, 353, 355, 360, 360b–360f, 360h– 

360j, 360l, 360hh–360ss, 360aaa– 

360bbb, 371(a), 372–374, 379e, 381, 383, 

and 394, Federal Food, Drug, and 

Cosmetic Act, and 42 U.S.C. 216, 262, 

263a, 264, and 271, Public Health 

Service Act. Of these, certain authorities 

are particularly significant. For a drug 

approved under an NDA or an 

abbreviated new drug application, 

section 505(k) requires the applicant to 

submit reports, concerning clinical 

experience, to FDA and to establish and 

maintain related records. Section 505(k) 

provides the agency with authority to 

specify, by regulation, which data or 

information must be submitted in such 

reports. FDA used this statutory 

authority, among others, in issuing the 

agency’s regulation concerning 

postmarketing reporting of adverse drug 

experiences. This regulation is set forth 

in § 314.80. 

For a device, section 519 of the FD&C 

Act (21 U.S.C. 360i) requires 

manufacturers and importers to 

establish and maintain records, make 

reports, and provide information, as 

FDA may reasonably require to assure 

that such device is not adulterated or 

misbranded and to otherwise assure its 

safety and effectiveness. FDA utilized 

this statutory authority, in addition to 

other authorities, in issuing the MDR 

regulation, found in part 803. 

For a biological product, section 351 

of the PHS Act (42 U.S.C. 262) requires 

FDA to approve a BLA on the basis of 

a demonstration that the product is safe, 

pure, and potent (section 351(a)(2)(C) of 

the PHS Act). Section 351(a)(2)(A) of the 

PHS Act requires FDA to establish, by 

regulation, requirements for the 

approval, suspension, and revocation of 

BLAs. Section 351(b) also prohibits 

falsely labeling a biological product. 

FDA used section 351 as statutory 

authority, along with other sources of 

statutory authority, in issuing the 

postmarketing reporting of adverse 

experiences regulation for biological 

products. This regulation is found in 

§ 600.80. In proposing § 600.80, FDA 

indicated that information made 

available to the agency through the 

adverse experience reports 

contemplated under § 600.80 could 

establish that a biological product is not 

safe or properly labeled and that the 

license should be revoked (55 FR 11611 

at 11613, March 29, 1990). 

There is considerable overlap in the 

postmarket safety reporting 

requirements for drug, devices, and 

biological products. The regulatory 

schemes for adverse event reporting for 

drugs and biological products are 

identical in most respects. The MDR 

regulation has many similarities to the 

drug and biological product postmarket 

safety reporting regulations. Overall, the 

regulatory framework governing 

postmarket safety reporting for each 

type of product is intended to achieve 

the same general goals. 

Nevertheless, these three sets of 

regulations differ somewhat because 

each is tailored to the characteristics of 

the types of products for which it was 

designed. For instance, each set of 

regulations contains certain specific 

requirements, pertaining to particular 

products or types of adverse events, 

which are not found in the other sets of 

regulations. These are as follows: MDR 

5-day Reports, MDR 30-day malfunction 

reports, Drugs/Biologics 15-day alert 

reports, Drugs 3-day field alert reports, 

and Expedited Blood Fatality Reports. 

As set forth in this proposal, it is crucial 

that these requirements be met if they 

apply. 

The legal framework underlying this 

proposed rule is twofold. The first is 

that drugs, devices, and biological 

products do not lose their discreet 

regulatory identities when they become 

constituent parts of a combination 

product. In general, the postmarket 

safety reporting requirements specific to 

each constituent part of a combination 

product also apply to the combination 

product itself. Therefore, all 

combination products are subject to at 

least two sets of postmarketing safety 

reporting requirements. For example, in 

the case of a device and biological 

product combination product, the MDR 

regulation in part 803 and the biological 

product postmarket reporting of adverse 

experiences regulation in § 600.80 

would apply to the combination 

product. However, this proposed rule is 

intended to clarify that a reporter must 

only comply with the postmarketing 

safety requirements associated with the 

application used to approve or clear the 

combination product. In the example 

above of a device-biologic combination 

product, if the combination product has 

an approved BLA, the reporter would 

use § 600.80 to report postmarketing 

adverse experiences for the combination 

product. In addition, as explained in 

this proposal, the reporter must comply 

with whichever of five specific 

requirements apply. In the case of a 

device-biologic combination product 

with an approved BLA, the reporter 

would also have to file MDR 5-day 

Reports and MDR 30-day malfunction 

reports if the criteria for such reports 

were met. Under this legal framework, 

if you demonstrate compliance with the 

applicable requirements of the set of 

regulations (e.g., biological product 

postmarket safety reporting) associated 

with the approved application (e.g., 

BLA), and comply with any applicable 

specified unique provisions (e.g., MDR 

30-day malfunction reporting), you will 

be considered to have satisfied all 

applicable requirements from the other 

set of reporting regulations (e.g., MDR 

regulation). 

The legal authority for this approach 

is based on the following. Although 

combination products retain the 

regulatory identities of their constituent 

parts, the FD&C Act also recognizes 

combination products as a category of 

products that are distinct from products 

that are solely drugs, devices, or 

biological products. For example, 

section 503(g)(4)(A) of the FD&C Act, 

requires the Office of Combination 

Products (OCP) to ‘‘designate’’ a product 

as a combination product as well as to 

ensure ‘‘consistent and appropriate 

postmarket regulation of like products 

subject to the same statutory 

requirements.’’ Further, section 563 of 

the FD&C Act, governs the 

‘‘classification’’ of products as ‘‘drug, 

biological product, device, or a 

combination product subject to section 

503(g)’’ (emphasis added). In this 

respect, the FD&C Act identifies a 

combination product as a distinct type 

of product that could be subject to 

specialized regulatory controls. In 

addition, for the efficient enforcement of 

the FD&C Act under section 701, FDA 

has the authority to develop regulations 

to ensure sufficient and appropriate 

ongoing assessment of the risks 

associated with combination products. 

The second legal framework for the 

proposed rule is founded on the 

postmarket safety reporting regulatory 


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50752 Federal Register / Vol. 74, No. 189 / Thursday, October 1, 2009 / Proposed Rules 

scheme associated with the application, 

under which the product is approved, 

plus any applicable requirements of the 

five unique reporting provisions listed 

in this proposal. Although similar in 

effect to the first framework described 

previously, this approach is based on 

the legal authority FDA used to issue 

each of its three existing regulations for 

postmarket safety reporting for drugs, 

devices, and biological products. In the 

context of this proposal, such authority 

would include, but not be limited to, 

sections 505(k) and 519 of the FD&C 

Act, and section 351 of the PHS Act. 

Under this authority FDA is now issuing 

additional requirements based on the 

five unique reporting provisions. This 

means that in the case, for example, of 

a device-biologic combination product, 

approved under a BLA, section 351 of 

the PHS Act (in addition to other 

applicable authorities), would provide 

the authority for FDA to require 

postmarket safety reporting under 

§ 600.80. Furthermore, section 351 

would provide the authority for the 

agency to require additional reporting 

for devices (MDR 5-Day Reports and 

MDR 30-Day Malfunction Reports if the 

criteria for such reports are met). 

This legal theory applies to all 

combination products subject to this 

proposal. It is particularly relevant, 

however, for those combination 

products involving a drug constituent 

part and approved under a BLA or 

approved or cleared under the device 

authorities. This is because section 

505(k) of the FD&C Act requires the 

submission of reports ‘‘in the case of 

any drug for which an approval of an 

application filed under subsection (b) or 

(j) [of section 505] is in effect * * *’’. 

IV. Environmental Impact 

FDA has determined under 21 CFR 

25.30(a), 25.30(h), 25.30(j), and 25.31(a) 

through (c) that this action is of a type 

that does not individually or 

cumulatively have a significant effect on 

the human environment. Therefore, 

neither an environmental assessment 

nor an environmental impact statement 

is required. 

V. Paperwork Reduction Act Analysis 

This proposed rule contains 

information collections that are subject 

to review by OMB under the Paperwork 

Reduction Act of 1995 (44 U.S.C. 3501– 

3520). A description of these provisions 

is given below with an estimate of the 

annual reporting and recordkeeping 

burden. Included in the estimate is the 

time for reviewing instructions, 

searching existing data sources, 

gathering and maintaining the data 

needed, and completing and reviewing 

each collection of information. 

FDA invites comments on the 

following topics: (1) Whether the 

proposed collection of information is 

necessary for the proper performance of 

FDA’s functions, including whether the 

information will have practical utility; 

(2) the accuracy of FDA’s estimate of the 

burden of the proposed collection of 

information, including the validity of 

the methodology and assumptions used; 

(3) ways to enhance the quality, utility, 

and clarity of the information to be 

collected; and (4) ways to minimize the 

burden of the collection of information 

on respondents, including through the 

use of automated collection techniques, 

when appropriate, and other forms of 

information technology. 

Title: Postmarketing Safety Reporting 

for Combination Products 

Description: This proposed rule 

clarifies postmarketing safety reporting 

requirements for combination products. 

In the development of this proposed 

rule, the agency considered the fact that 

each constituent part of a combination 

product is governed by one of three 

differing sets of reporting provisions for 

drugs, devices, and biological products. 

The agency reviewed each set of 

regulations governing postmarketing 

safety reporting for drugs (parts 310 and 

314), biological products (parts 600 and 

606), and devices (part 803). The review 

determined that each set of regulations 

contains many substantially similar 

requirements. Given the broad 

similarities in the regulations, the 

agency determined that the simplest and 

most straightforward way to ensure that 

combination products are regulated 

consistently is by continuing to require 

reporters to comply with the regulatory 

requirements for postmarketing safety 

reporting associated with the 

application used to approve or clear the 

combination product, as long as the five 

unique provisions particular to each 

different set are also applied. This 

supplementation reflects the 

combination nature of the product, and 

recognizes, preserves, and distinguishes 

each constituent part’s unique 

characteristics. Specifically, these 

unique reporting requirements, along 

with any associated followup reports, 

are: (1) submission of a ‘‘5-day report’’ 

related to the device constituent part of 

a combination product as described in 

§ 803.53(a); (2) submission of a 30-day 

‘‘malfunction report’’ related to the 

device constituent part of a combination 

product as described in section 27 of 

FDAAA and § 803.20(b)(3)(ii); (3) 

submission of a ‘‘postmarketing 15-day 

‘Alert report’’’ for a serious, unexpected 

adverse experience associated with the 

use of a drug or biological product 

constituent part of a combination 

product, as described in §§ 310.305(c), 

314.80(c)(1) and (e), and 600.80(c)(1) 

and (e); (4) submission of a 3-day ‘‘field 

alert report’’ related to the drug 

constituent part of a combination 

product as described in § 314.81(b)(1); 

and (5) submission of an expedited 

‘‘blood fatality report’’ concerning a 

fatality related to the blood or blood 

component constituent part of a 

combination product as described in 

§ 606.170. 

We note that the postmarketing safety 

reporting information collections for 

drugs, biological products, and devices 

found in §§ 314.80, 314.81, and 600.80, 

600.81, 606.170, 803.20, and 803.53 

have already been approved and are in 

effect. The pertinent postmarketing 

safety reporting information collection 

provisions for § 314.80(c) and (e), as 

well as for § 314.81(b) are approved 

under OMB Control No. 0910–0001, 

which expires May 31, 2011, OMB 

Control No. 0910–0230, which expires 

July 31, 2012, and OMB Control No. 

0910–0291, which expires December 31, 

2011. The information collection 

provisions for §§ 600.80 and 600.81 are 

approved under OMB Control No. 0910– 

0308, which expires on September 30, 

2011. Those for § 606.170 are approved 

under OMB Control No. 0910–0116, 

which expires February 29, 2012. 

Finally, the information collection 

provisions for §§ 803.20 and 803.53 are 

approved under OMB Control No. 0910– 

0437, which expires on July 31, 2012. 

As a result, the information collection 

described here refers only to the 

reporting and recordkeeping 

requirements for the five unique 

reporting requirements that are being 

applied because the product is a 

combination product. FDA does not 

expect or desire that reporters submit 

duplicate reports, and this proposal is 

intended to ensure that duplicative 

reporting does not occur. 

These proposed requirements are 

necessary to: (1) Ensure consistent 

postmarketing safety reporting, (2) 

ensure that the agency receives 

necessary information to promote and 

protect the public health, (3) avoid 

duplicative reporting, (4) ensure 

appropriate ongoing assessment of risks, 

and (5) ensure consistent and 

appropriate postmarketing regulation of 

combination products. 

Description of Respondents: Any 

person required to submit or record a 

reportable event under §§ 310.305, 314, 

600, 606, or 803, except for user 

facilities and device distributors as 

defined in part 803. 


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Proposed § 4.103(b)(1) requires 

reporters for combination products 

comprised of a device constituent part 

to report no later than 5 work days after 

the day the reporter becomes aware that 

an MDR reportable event associated 

with the device constituent part of the 

combination product necessitates 

remedial action to prevent an 

unreasonable risk of substantial harm to 

the public health. This section also 

allows FDA to make written requests for 

the submission of all subsequent events 

of the same nature that involve 

substantially similar devices or device 

constituent parts of a combination 

product for the time period specified in 

the written request. This section only 

applies to reporters who would not 

otherwise submit a ‘‘5-day report’’ 

under the requirements associated with 

the application used to approve/clear 

the combination product with the 

device constituent part. Reporters must 

also maintain a record of any report they 

submit under this provision. 

Proposed § 4.103(b)(2) requires 

reporters for combination products 

comprised of a device constituent part 

to report no later than 30 calendar days 

after the day the reporter becomes aware 

of information that reasonably suggests 

the device constituent part of the 

combination product has malfunctioned 

and that this device constituent part or 

a similar device constituent part that the 

reporter markets would be likely to 

cause or contribute to a death or serious 

injury if the malfunction were to recur. 

This section only applies to reporters 

who would not otherwise submit a 30- 

day ‘‘malfunction report’’ under the 

requirements associated with the 

application used to approve/clear the 

combination product with the device 

constituent part. Reporters must also 

maintain a record of any report they 

submit under this provision. 

Proposed § 4.103(b)(3) requires 

reporters for combination products 

comprised of a drug or a biological 

product constituent part to report each 

adverse experience associated with the 

use of the drug or biological product 

constituent part of the combination 

product that is both serious and 

unexpected, whether foreign and 

domestic, as soon as possible but in no 

case later than 15 calendar days of 

initial receipt of the information by the 

sponsor. This section only applies to 

reporters who would not otherwise 

submit a ‘‘postmarketing 15-day ‘Alert 

report’’’ under the requirements 

associated with the application used to 

approve/clear the combination product 

with the drug or biological product 

constituent part(s). Reporters must also 

maintain a record of any report they 

submit under this provision. 

Proposed § 4.103(b)(4) requires 

reporters for combination products 

comprised of a drug constituent part to 

report information concerning any 

bacteriological contamination, or any 

significant chemical, physical, or other 

change or deterioration in the drug 

constituent part of a distributed 

contribution product, or any failure of 

one or more distributed batches of the 

drug constituent part of a combination 

product to meet the specification 

established for it in its marketing 

application. Reporters must submit this 

information to the FDA district office 

that is responsible for the facility 

involved within 3 working days of its 

receipt. They must provide the 

information by telephone or other rapid 

communication means, with prompt 

written followup. This section only 

applies to reporters who would not 

otherwise submit a 3-day ‘‘field alert 

report’’ under the requirements 

associated with the application used to 

approve/clear the combination product 

with the drug product constituent part. 

Reporters must also maintain a record of 

any report they submit under this 

provision. 

Proposed § 4.103(b)(5) requires 

reporters for combination products 

comprised of a biological product 

constituent part containing blood or a 

blood component, if a complication of 

blood collection or transfusion is 

confirmed to be fatal as described in 

§ 606.170(b), to report by telephone, 

facsimile, express mail or electronically 

transmitted mail as soon as possible, 

and a written report within 7 days after 

the fatality. This section only applies to 

reporters who would not otherwise 

report such an event within this 

timeframe under the statutory 

provisions and regulatory requirements 

associated with the application used to 

approve/clear the combination product 

with the biological product constituent 

part containing blood or a blood 

component. Reporters must also 

maintain a record of any report they 

submit under this provision. 

Information Collection Burden Estimate 

FDA estimates the burden for this 

information collection as follows: 

TABLE 1.—ESTIMATED ANNUAL REPORTING BURDEN FOR HUMAN DRUGS1

21 CFR Section No. of 

Respondents 

Annual Frequency 

per Response 

Total Annual 

Responses 

Hours per 

Response Total Hours 

4.103(b)(1) 5 1 5 1 5 

4.103(b)(2) 20 15 300 1 300 

4.103(b)(3) 20 15 300 1 300 

4.103(b)(4) 5 1 5 1 5 

4.103(b)(5) 5 1 5 1 5 

Totals 55 615 615 

TABLE 2.—ESTIMATED ANNUAL POSTMARKETING SAFETY RECORDKEEPING BURDEN FOR COMBINATION PRODUCTS1

21 CFR Section No. of 

Recordkeepers 

Annual Frequency 

of Recordkeeping 

Total Annual 

Records 

Hours per 

Record Total Hours 

4.103(b)(1) 5 1 5 .5 2.5 

4.103(b)(2) 20 15 300 .5 150 


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6The proposed rule seeks to clarify which 

adverse event reporting requirements apply when 

drugs, devices, and biological products are used to 

create combination products. The agency notes that 

there are no express preemption provisions of the 

act applicable to prescription drugs or biological 

products. Section 521 of the act (51 U.S.C. 360k) 

contains an express preemption provision that 

applies to devices; nonetheless, the Supreme Court 

concluded in Medtronic, Inc. v. Lohr, 581 U.S. 470, 

500–01 (1996), that requirements not applicable to 

a particular device do not preempt State law under 

section 521. Device adverse event reporting 

requirements, like the good manufacturing practice 

requirements at issue in the Medtronic case, are 

general requirements that do not preempt under 

section 521. 

TABLE 2.—ESTIMATED ANNUAL POSTMARKETING SAFETY RECORDKEEPING BURDEN FOR COMBINATION PRODUCTS1— 

Continued 

21 CFR Section No. of 

Recordkeepers 

Annual Frequency 

of Recordkeeping 

Total Annual 

Records 

Hours per 

Record Total Hours 

4.103(b)(3) 20 15 300 .5 150 

4.103(b)(4) 5 1 5 .5 2.5 

4.103(b)(5) 5 1 5 .5 2.5 

Totals 55 615 307.5 

Burden 

Based on FDA’s experience regarding 

receipt of postmarketing safety reports 

for combination products, the agency 

estimates that there will be 55 reporters 

(who will keep corresponding records) 

submitting a total of 615 reports under 

proposed 4.103(b) annually (and 

maintaining the records of those 

reports). In other words, the agency 

estimates that there will be 55 reporters 

who will avail themselves of these new 

streamlined reporting requirements and 

benefit from the associated burden 

reductions. For example, manufacturers 

of drug-device combination products 

marketed under an NDA will now be 

able to submit postmarket safety reports 

following the requirements for drug 

products and no longer have to submit 

additional postmarket safety reports 

following the requirements for devices 

so long as they comply with the 

reporting and recordkeeping 

requirements of sections 4.103(b)(1) and 

4.103(b)(2). 

Further, FDA estimates, based on its 

experience with information collection 

regarding postmarketing safety reporting 

provisions for drugs, biological 

products, and devices, that each report 

will take approximately 1 hour to 

prepare and submit, and half an hour to 

fulfill the corresponding recordkeeping 

requirements. 

FDA believes that there are no 

significant operating and maintenance 

costs associated with this collection of 

information because, in order to legally 

market their products, reporters are 

required to develop and maintain 

systems for reporting and maintaining 

records of postmarketing safety events. 

Therefore, appropriate mechanisms for 

postmarketing safety reporting should 

already be in place, and reporters will 

accrue no significant additional costs to 

fulfill the requirements set forth here. 

We welcome comments on our 

estimates of the number of respondents 

who will avail themselves of the new 

streamlined reporting requirements and 

our burden estimates. Based on these 

comments, we will revise our estimates 

accordingly of the burden reductions 

associated with the reporting and 

recordkeeping requirements of 

§§ 314.80, 314.81, and 600.80, 600.81, 

606.170, 803.20, and 803.53. 

In compliance with the Paperwork 

Reduction Act of 1995 (44 U.S.C. 

3507(d)), the agency has submitted the 

information collection provisions of this 

proposed rule to OMB for review. 

The information collection provisions 

of the proposed rule have been 

submitted to OMB for review. Interested 

persons are requested to fax comments 

regarding information collection by 

November 2, 2009, to the Office of 

Information and Regulatory Affairs, 

OMB. To ensure that comments on 

information collection are received, 

OMB recommends that written 

comments be faxed to the Office of 

Information and Regulatory Affairs, 

OMB, Attn: Desk Officer, FAX: 202– 

395–6974. 

VI. Federalism 

FDA has analyzed this proposed rule 

in accordance with the principles set 

forth in Executive Order 13132. Section 

4(a) of the Executive Order requires 

agencies to ‘‘construe * * * a Federal 

statute to preempt State law only where 

the statute contains an express 

preemption provision or there is some 

other clear evidence that the Congress 

intended preemption of State law, or 

where the exercise of State authority 

conflicts with the exercise of Federal 

authority under Federal statutes.’’ The 

sole statutory provision giving 

preemptive effect to the proposed rule is 

section 751 of the act (21 U.S.C. 379r), 

which would apply only with respect to 

OTC drug components of 

combinations.6

VII. Analysis of Impacts 

A. Introduction 

FDA has examined the impacts of the 

proposed rule under Executive Order 

12866 and the Regulatory Flexibility Act 

(5 U.S.C. 601–612), and the Unfunded 

Mandates Reform Act of 1995 (Public 

Law 104–4). Executive Order 12866 

directs agencies to assess all costs and 

benefits of available regulatory 

alternatives and, when regulation is 

necessary, to select regulatory 

approaches that maximize net benefits 

(including potential economic, 

environmental, public health and safety, 

and other advantages; distributive 

impacts; and equity). In accordance 

with Executive Order 12866, FDA has 

carefully analyzed the economic effects 

of this proposal and has determined that 

the final rule, if issued, will not be a 

significant regulatory action as defined 

by the Executive order. 

The Regulatory Flexibility Act 

requires agencies to analyze regulatory 

options that would minimize any 

significant impact of a rule on small 

entities. Because this rule clarifies 

existing requirements and will have no 

recurring impact on the majority of 

small firms, the agency proposes to 

certify that the final rule will not have 

a significant economic impact on a 

substantial number of small entities. 

Section 202(a) of the Unfunded 

Mandates Reform Act of 1995 requires 

that agencies prepare a written 

statement, which includes an 

assessment of anticipated costs and 

benefits, before proposing ‘‘any rule that 

includes any Federal mandate that may 

result in the expenditure by State, local, 

and tribal governments, in the aggregate, 

or by the private sector, of $100,000,000 

or more (adjusted annually for inflation) 

in any one year.’’ The current threshold 

after adjustment for inflation is $133 

million, using the most current (2008) 


jlentini on DSKJ8SOYB1PROD with PROPOSALS
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7Wage is based on the 2007 Bureau of Labor 

Statistic’s survey, National Industry Specific 

Occupational Employment and Wage Estimate, for 

standard occupational code 13–1041, compliance 

officer in pharmaceutical and medicine 

manufacturing (NAICS 325400). The mean wage of 

$30.08 was increased by 40 percent to account for 

fringe benefits for a loaded wage of $42 per hour. 

http://www.bls.gov/oes/current/naics4_325400.htm

#b23-0000. 

Implicit Price Deflator for the Gross 

Domestic Product. FDA does not expect 

this proposed rule to result in any 1- 

year expenditure that would meet or 

exceed this amount. 

B. The Rationale Behind This Proposed 

Rule 

The purpose of the proposed rule is 

to codify the postmarketing safety 

reporting requirements for combination 

products to ensure their consistent and 

appropriate regulation. The current 

regulations and reporting standards for 

drugs, devices, and biological products 

are similar but each has certain unique 

requirements. A separate rule specific to 

combination products will clarify how 

to apply these provisions to 

combination products and avoid 

applying duplicative or unnecessary 

requirements. The proposed rule will 

benefit public health by helping to 

ensure that the necessary reports are 

submitted and directed to the 

appropriate center and that records are 

maintained for the appropriate length of 

time. 

C. Impact of Proposed Rule 

The proposed rule will affect all of the 

approximately 300 manufacturers of 

combination products. Industry should 

benefit from reduced uncertainty 

regarding how to apply the separate 

regulations to combination products and 

from more consistent enforcement 

across the agency. This is especially true 

for developing standard operating 

procedures (SOPs) for new combination 

products. All firms would incur onetime costs to assess their current 

compliance level to the proposed 

requirements. In addition, some firms 

may need to alter or add SOPs and 

recordkeeping practices. Estimating the 

one-time costs is problematic because 

the costs would vary depending on the 

size of the firm, their current business 

practice, and the number and nature of 

their products. Currently we cannot 

identify how many combination 

products there are or the extent of the 

changes that would be needed. Some 

firms could spend as little as 30 minutes 

while other firms with a variety of 

combination product types, may have to 

alter or add a number of SOPs. This 

could take 10 to 20 hours per SOP. 

The reporting requirements under 

proposed § 4.103(b) will also generate 

some annually recurring costs. Because 

all of the firms have reporting systems 

in place and the reports are submitted 

on the same form as the other types of 

postmarket safety reports (with the 

exception of field alert reports 

(proposed § 4.103(b)(4)), we estimate 

that the incremental time to comply 

with this requirement is about 1.5 hours 

and that we would receive about 615 

reports from 55 firms annually. 

Assuming an hourly wage plus benefit 

rate of $42,7 the annually recurring cost 

for these requirements would be 

$38,745 (1.5 hours x $42/hr x 615 

reports). These costs could be at least 

partly offset because some of the 

proposed reports would be submitted in 

lieu of an existing reporting 

requirement. 

About 80 to 85 percent of the firms 

affected by this proposed rule are 

considered small, based on the Small 

Business Administration’s definition of 

a small entity (500 employees for 

medical device and biological product 

firms and 750 employees for drug 

firms). Most of these small entities are 

medical device firms and produce 

combination products where the 

primary modes of action are attributable 

to medical devices. The impact on 

individual firms will depend on the 

nature of the changes to SOPs needed, 

the number and type of combination 

products produced, and the number of 

reports filed annually. Most products 

will not have any postmarket safety 

reports in a given year and thus there 

would be no annually recurring costs for 

them. The largest potential cost would 

be a one-time cost to modify existing 

SOPs. The cost to make such 

modifications is generally lower for 

small firms than for large firms. 

VIII. Request for Comments 

Interested persons may submit to the 

Division of Dockets Management (see 

ADDRESSES) written or electronic 

comments regarding this document. 

Submit a single copy of electronic 

comments or two paper copies of any 

mailed comments, except that 

individuals may submit one paper copy. 

Comments are to be identified with the 

docket number found in brackets in the 

heading of this document. Received 

comments may be seen in the Division 

of Dockets Management between 9 a.m. 

and 4 p.m., Monday through Friday. 

IX. Proposed Effective Date 

The agency is proposing that any final 

rule that may issue based upon this 

proposed rule become effective 180 days 

after its date of publication in the 

Federal Register. 

List of Subjects in 21 CFR Part 4 

Combination products, Biological 

products, Devices, Drugs, and Human 

cell, tissue, and cellular and tissuebased products, Regulation of 

combination products. 

Therefore, under the Federal Food, 

Drug, and Cosmetic Act, the Public 

Health Service Act, and under authority 

delegated to the Commissioner of Food 

and Drugs, it is proposed that 21 CFR 

part 4 be further amended as proposed 

to be added at 73 FR 48430, September 

23, 2009 as follows: 

PART 4—REGULATION OF 

COMBINATION PRODUCTS 

1. Add subpart B to part 4 to read as 

follows: 

Subpart B—Postmarketing Safety 

Reporting for Combination Products 

General Provisions 

Sec. 

4.100 What is the scope of this subpart? 

4.101 What are the definitions applicable to 

this subpart? 

4.102 Who reports to FDA? 

4.103 What are the reporting requirements? 

4.104 How do I report if another reporter is 

responsible for a constituent part of my 

combination product? 

4.105 How, where, and when do I submit 

postmarketing safety reports for 

combination products? 

4.106 What are the postmarketing safety 

reporting recordkeeping requirements? 

Authority: 21 U.S.C. 321, 331, 351, 352, 

353, 355, 360, 360b–360f, 360h–360j, 360l, 

360hh–360ss, 360aaa–360bbb, 371(a), 372– 

374, 379e, 381, 383, 394; 42 U.S.C. 216, 262, 

263a, 264, 271. 

§ 4.100 What is the scope of this subpart? 

(a) This subpart establishes 

requirements for postmarketing safety 

reporting for combination products. 

(b) This subpart applies to the 

configurations of combination products 

described in § 3.2(e)(1), (e)(2), and (e)(3) 

of this chapter. This subpart does not 

apply to investigational combination 

products as defined in § 3.2(e)(4) of this 

chapter. 

(c) This subpart applies to all 

reporters required to report under parts 

314, 600, 606, and 803 of this chapter, 

except for user facilities and device 

distributors as defined in part 803 of 

this chapter. 

(d) This subpart supplements and 

does not supersede other provisions of 

this chapter, including the provisions in 

parts 314, 600, 606, 803, and 806 of this 

chapter. 

§ 4.101 What are the definitions applicable 

to this subpart? 

Act means the Federal Food, Drug, 

and Cosmetic Act. 


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Adverse experience, as described in 

§§ 310.305(b), 314.80(a), and 600.80(a) 

of this chapter and as modified for 

purposes of this subpart, means any 

adverse event associated with the use of 

a drug or biological product constituent 

part of a combination product in 

humans, whether or not considered 

drug or biological product related, 

including the following: An adverse 

event occurring in the course of the use 

of a drug or biological product in 

professional practice, an adverse event 

occurring from drug or biological 

product overdose whether accidental or 

intentional, an adverse event occurring 

from drug or biological product abuse, 

an adverse event occurring from drug or 

biological product withdrawal, and any 

failure of expected pharmacological 

action. 

ANDA means abbreviated new drug 

application as defined at § 314.3(b) of 

this chapter. 

Application, for purposes of this 

subpart, means a new drug application, 

an abbreviated new drug application, a 

device premarket approval application, 

a device premarket notification 

submission, a humanitarian device 

exemption application, and/or a 

biologics license application, including 

all amendments and supplements to 

them. 

Biological product has the meaning 

set forth in § 3.2(d) of this chapter. 

BLA means biologics license 

application as described in section 351 

of the Public Health Service Act (42 

U.S.C. 262) and § 601.2 of this chapter. 

Blood as defined in § 606.3(a) of this 

chapter means whole blood collected 

from a single donor and processed 

either for transfusion or further 

manufacturing. 

Blood component as defined in 

§ 606.3(c) of this chapter means a blood 

component or part of a single-donor’s 

blood separated by physical or 

mechanical means. 

Blood fatality report means the report 

described in § 606.170 of this chapter of 

a complication of blood collection or 

transfusion confirmed to be fatal, by 

telephone, facsimile, express mail, or 

electronically transmitted mail as soon 

as possible, and a written report within 

7 days after the fatality. 

Combination product has the meaning 

set forth in § 3.2(e) of this chapter. 

Constituent part is a drug, device, or 

biological product that is part of a 

combination product as defined in 

§ 3.1(e) of this chapter. 

Device has the meaning set forth in 

section 201(h) of the act (21 U.S.C. 

321(h)). 

Drug has the meaning set forth in 

§ 3.2(g) of this chapter. 

FDA means the Food and Drug 

Administration. 

Field alert report, as described in 

§ 314.81(b)(1) of this chapter and as 

modified for purposes of this subpart, 

means a report submitted on Form FDA 

3331 within 3 working days to the 

appropriate FDA district office when 

there is information concerning any 

incident that causes the drug 

constituent part of a distributed 

combination product or its labeling to 

be mistaken for, or applied to, another 

article; or that contains information 

concerning any bacteriological 

contamination, or any significant 

chemical, physical, or other change or 

deterioration in the drug constituent 

part of a distributed combination 

product, or any failure of one or more 

distributed batches of a drug constituent 

part of a combination product to meet 

the specification established for it in the 

application. 

5-day report, as described in §§ 803.3 

and 803.53 of this chapter and as 

modified for purposes of this subpart, 

means a medical device report (MDR) 

that must be submitted by a reporter to 

FDA under § 803.53(a) of this chapter no 

later than 5 work days after the day the 

reporter becomes aware that a MDR 

reportable event necessitates remedial 

action to prevent an unreasonable risk 

of substantial harm to the public health. 

FDA can also make a written request for 

a 5-day report for all subsequent events 

of the same nature that involve 

substantially similar devices or device 

constituent parts of a combination 

product for the time period specified in 

the written request. 

Followup report as described in 

§§ 314.80(c)(1)(ii), 600.80(c)(1)(ii), and 

803.56 of this chapter and as modified 

for purposes of this subpart, is a report 

of supplemental, additional or followup 

information related to a reportable 

event. 

HDE means humanitarian device 

exemption as discussed in § 814.100 of 

this chapter. 

Malfunction, as described in § 803.3 

of this chapter and as modified for 

purposes of this subpart, means the 

failure of a device constituent part of a 

combination product to meet its 

performance specifications or otherwise 

perform as intended. Performance 

specifications include all claims made 

in the labeling for the combination 

product. The intended performance of a 

device constituent part refers to the 

intended use or indication for which the 

combination product is labeled or 

marketed. 

Malfunction report, as required under 

section 227 of FDAAA, as described in 

§ 803.20(b)(3)(ii) of this chapter, and as 

modified for purposes of this subpart, is 

a report submitted no later than 30 

calendar days after the day that the 

reporter becomes aware of information 

that reasonably suggests that one of the 

marketed device constituent parts of a 

combination product has malfunctioned 

and that the device constituent part or 

a similar device or device constituent 

part of a combination product marketed 

by the reporter would be likely to cause 

or contribute to a death or serious injury 

if the malfunction were to recur. A 

reporter must submit a 30-day 

malfunction report for malfunctions of 

the following devices: A Class III device; 

a Class II device that is permanently 

implantable, life supporting, or life 

sustaining; or a type of device that FDA, 

by notice in the Federal Register or 

letter, indicates should be subject to part 

803 of this chapter to protect the public 

health. For Class I and certain Class II 

devices a reporter must submit 

reportable malfunctions on a quarterly 

basis using a summary format. 

MDR means a medical device report 

as defined in § 803.3 of this chapter. 

MDR reportable event, as described in 

§ 803.3 of this chapter and as modified 

for purposes of this subpart, means an 

event about which the reporter has 

received or become aware of 

information that reasonably suggests 

that one of their marketed combination 

products: 

(1) May have caused or contributed to 

a death or serious injury; or 

(2) Has malfunctioned and that the 

device constituent part or a similar 

device or device constituent part of a 

combination product marketed by the 

reporter would be likely to cause or 

contribute to a death or serious injury if 

the malfunction were to recur. 

NDA means new drug application as 

defined in § 314.3(b) of this chapter. 

PMA means a device premarket 

approval application as defined in 

§ 814.3 of this chapter. 

Postmarketing 15-day ‘‘alert report,’’ 

as described in §§ 314.80(c)(1) and 

600.80(c)(1) of this chapter and as 

modified for the purposes of this 

subpart, is a report the reporter must 

make to FDA for each adverse 

experience as defined in this subpart 

that is both serious and unexpected, 

whether foreign or domestic, as soon as 

possible but in no case later than 15 

calendar days of initial receipt of the 

information by the reporter. 

Premarket notification submission 

means a submission as described in 

§ 807.87 of this chapter. 

Reportable event, for purposes of this 

subpart, is an event that is reportable 

under this subpart or parts 314, 600, 

606, or 803 of this chapter. 


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Reporter, for purposes of this subpart, 

is any person or entity responsible for 

evaluating and determining whether an 

event meets the criteria for 

postmarketing safety reporting or who is 

required to submit or record a reportable 

event under this subpart or parts 314, 

600, 606, or 803 of this chapter. This 

term is used interchangeably with the 

term ‘‘you.’’ This term does not include 

user facilities or device distributors as 

defined in part 803 of this chapter. 

Serious adverse experience, as 

described in §§ 314.80(a) and 600.80(a) 

of this chapter and as modified for 

purposes of this subpart, is any adverse 

experience occurring at any dose 

associated with the use of a drug or 

biological product constituent part of a 

combination product that results in any 

of the following outcomes: Death, a lifethreatening adverse experience, 

inpatient hospitalization or 

prolongation of existing hospitalization, 

a persistent or significant disability/ 

incapacity, or a congenital anomaly/ 

birth defect. Important medical events 

that may not result in death, be lifethreatening, or require hospitalization 

may be considered a serious adverse 

experience when, based upon 

appropriate medical judgment, they may 

jeopardize the patient or subject and 

may require medical or surgical 

intervention to prevent one of the 

outcomes listed in this definition. 

Examples of such medical events 

include allergic bronchospasm requiring 

intensive treatment in an emergency 

room or at home, blood dyscrasias or 

convulsions that do not result in 

inpatient hospitalization, or the 

development of drug dependency or 

drug abuse. 

Serious injury means the injuries that 

are defined in § 803.3 of this chapter. 

This means an injury or illness that: 

(1) Is life-threatening, 

(2) Results in permanent impairment 

of a body function or permanent damage 

to a body structure, or 

(3) Necessitates medical or surgical 

intervention to preclude permanent 

impairment of a body function or 

permanent damage to a body structure. 

Unexpected adverse experience, as 

described in §§ 314.80(a) and 600.80(a) 

of this chapter and as modified for the 

purposes of this subpart, means any 

adverse experience as defined in this 

subpart that is not listed in the current 

labeling for the combination product. 

This includes events that may be 

symptomatically and 

pathophysiologically related to an event 

listed in the labeling, but differ from the 

event because of greater severity or 

specificity. 

We means FDA. 

§ 4.102 Who reports to FDA? 

Any person or entity required to 

submit to FDA postmarketing safety 

reports for a combination product under 

parts 314, 600, 606, or 803 of this 

chapter must report under this subpart. 

This subpart uses the term ‘‘reporters’’ 

to refer to persons or entities 

responsible for evaluating and 

determining whether an event meets the 

criteria for postmarketing safety 

reporting or who are required to submit 

or record a reportable event. 

Additionally, the term ‘‘you’’ as used in 

this subpart refers to reporters. This 

subpart does not apply to user facilities 

or device distributors subject to medical 

device reporting as defined in part 803 

of this chapter. 

§ 4.103 What are the reporting 

requirements? 

(a) General requirements. You must 

consider each of the following reporting 

requirements and comply with each that 

is applicable to your combination 

product or your constituent part(s), if 

another reporter is responsible for the 

other constituent part(s) of the 

combination product. If you are the only 

reporter for the combination product, 

you must consider the combination 

product as a whole (i.e., all of its 

constituent parts), when determining 

whether an event is required to be 

reported. 

(1) If your combination product or 

your device constituent part is approved 

under a PMA or HDE, or is cleared 

under a premarket notification, you 

must comply with the requirements for 

postmarketing safety reporting 

described in part 803 of this chapter 

with respect to that combination 

product or device constituent part. 

(2) If your combination product or 

your drug constituent part is approved 

under an NDA or an ANDA, you must 

comply with the requirements for 

postmarketing safety reporting 

described in part 314 of this chapter 

with respect to that combination 

product or drug constituent part. 

(3) If your combination product or 

your biological product constituent part 

is approved under a BLA, you must 

comply with the requirements for 

postmarketing safety reporting 

described in parts 600 and 606 of this 

chapter with respect to that combination 

product or biological product 

constituent part. 

(4) If your combination product or 

your device constituent part is not 

subject to a marketing application under 

the device provisions of the act because 

it was legally marketed prior to May 28, 

1976, or is exempt from premarket 

notification, you must comply with the 

requirements for postmarketing safety 

reporting described in part 803 of this 

chapter with respect to that combination 

product or device constituent part. 

(b) Additional requirements. If you are 

the only reporter for the combination 

product, depending on the type of 

combination product and the nature of 

the reportable event, you must submit, 

as applicable, the following additional 

reports and any associated followup 

reports. You must submit these 

additional reports only if the reports are 

not otherwise required to be reported by 

you under paragraph (a) of this section, 

or would be required, but at a later 

timeframe than specified as follows: 

(1)(i) If your combination product 

contains a device constituent part, you 

must submit a ‘‘5-day report’’ no later 

than 5 work days after the day that you 

become aware that: 

(A) An MDR reportable event 

associated with the use of the device 

constituent part of your combination 

product necessitates remedial action to 

prevent an unreasonable risk of 

substantial harm to the public health. 

You may become aware of the need for 

remedial action from any information, 

including any trend analysis; or 

(B) We have made a written request 

for the submission of a 5-day report. If 

you receive such a written request from 

us, you must submit, without further 

requests, a 5-day report for all 

subsequent events of the same nature 

that involve substantially similar 

devices or device constituent parts of a 

combination product for the time period 

specified in the written request. We may 

extend the time period stated in the 

original written request if we determine 

it is in the interest of the public health. 

(ii) You must also submit any 

required followup reports to a ‘‘5-day 

report’’ required by § 803.56 of this 

chapter. 

(2) If your combination product 

contains a device constituent part, you 

must submit a ‘‘malfunction report’’ no 

later than 30 calendar days after the day 

that you become aware of information 

that reasonably suggests the device 

constituent part, described in this 

paragraph, of your combination product 

has malfunctioned and that this device 

constituent part or a similar device or 

device constituent part that you market 

would be likely to cause or contribute 

to a death or serious injury if the 

malfunction were to recur. You must 

submit a 30-day malfunction report for 

reportable malfunctions of the following 

devices: A Class III device; a Class II 

device that is permanently implantable, 

life supporting, or life sustaining; or a 

type of device that FDA, by notice in the 

Federal Register or letter, indicates 


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50758 Federal Register / Vol. 74, No. 189 / Thursday, October 1, 2009 / Proposed Rules 

should be subject to part 803 of this 

chapter to protect the public health. For 

Class I and certain Class II devices you 

must submit reportable malfunctions on 

a quarterly basis using a summary 

format. You must also submit any 

required followup reports to a 

‘‘malfunction report’’ required by 

§ 803.56 of this chapter. 

(3) If your combination product 

contains a drug or a biological product 

constituent part, you must submit a 

postmarketing 15-day ‘‘alert report’’, for 

each adverse experience associated with 

the use of a drug or biological product 

constituent part of the combination 

product, whether or not considered drug 

or biological product related, that is 

both serious and unexpected, whether 

foreign or domestic, as soon as possible 

but in no case later than 15 calendar 

days of initial receipt of the information 

by the reporter, as required by 

§ 314.80(c)(1)(i) or § 600(c)(1)(i) of this 

chapter. You must also promptly 

investigate and submit any required 

followup reports to a postmarketing 15- 

day ‘‘alert report’’ as required by 

§ 314.80(c)(1)(ii) or § 600(c)(1)(ii) of this 

chapter. 

(4) If your combination product 

contains a drug constituent part, you 

must submit a field alert report within 

3 working days of your receipt to the 

FDA district office that is responsible 

for the facility involved, by telephone or 

other rapid communication means and 

prompt written followup, information 

concerning: 

(i) Any incident that causes the drug 

constituent part of a distributed 

combination product or its labeling to 

be mistaken for, or applied to, another 

article; or 

(ii) Any bacteriological contamination 

or any significant chemical, physical, or 

other change or deterioration in the drug 

constituent part of a distributed 

combination product, or any failure of 

one or more distributed batches of a 

drug constituent part of a combination 

product to meet the specification 

established for it in the application. 

(5) If your combination product 

contains a biological product 

constituent part containing blood or a 

blood component, and a complication of 

blood collection or transfusion is 

confirmed to be fatal as described in 

§ 606.170(b) of this chapter, you must 

submit a blood fatality report by 

telephone, facsimile, express mail, or email as soon as possible, and a written 

report within 7 days after the fatality. 

(c) Periodic reports. (1) If your 

combination product is approved under 

an NDA, ANDA, or BLA, you must also 

include information in reports 

submitted in accordance with 

paragraphs (b)(1), (b)(2), and (b)(5) of 

this section in the periodic reports you 

submit under §§ 314.80(c)(2)(ii)(a) and 

600.80(c)(2)(ii)(a) of this chapter. 

Information on these additional reports 

should be treated as 15-day alert reports, 

i.e., included in narrative summary and 

analysis of the information in the report 

and an analysis of the 15-day alert 

reports submitted during the reporting 

interval (all 15-day alert reports being 

appropriately referenced by the 

applicant’s patient identification 

number, adverse reaction term(s), and 

date of submission to FDA). The history 

of actions taken since the last report 

because of adverse drug experiences (for 

example, labeling changes or studies 

initiated) should include information on 

the combination products as a whole 

(i.e., all of its constituent parts). 

(2) If your combination product is 

approved under a PMA, you must also 

include information in reports 

submitted in accordance with 

paragraphs (b)(3), (b)(4), and (b)(5) of 

this section in the periodic reports you 

submit under §814.82(a)(7) of this 

chapter. 

§ 4.104 How do I report if another reporter 

is responsible for a constituent part of my 

combination product? 

(a) If another person holds an 

application used to approve or clear a 

constituent part of your combination 

product, or legally markets a constituent 

part of your combination product 

without an approved or cleared 

marketing application, in addition to the 

requirements of § 4.103(a), you must 

submit the information you received 

about the event to FDA or the other 

person within 5 calendar days of your 

receipt of the information. 

(b) If you receive information from the 

other person that holds an application 

used to approve or clear a constituent 

part of your combination product, or 

legally markets a constituent part of 

your combination product without an 

approved or cleared marketing 

application, you must investigate and, if 

required, report the event in accordance 

with § 4.103(a) and (b). 

§ 4.105 How, where, and when do I submit 

postmarketing safety reports for 

combination products? 

(a) You must submit the field alert 

reports described in § 4.103(b)(4) to the 

FDA district office that is responsible 

for the facility involved within 3 

working days of receipt of the 

information. 

(b) You must submit all other 

postmarketing safety reports required 

under this subpart (i.e., required under 

§ 4.103(a), (b)(1), (b)(2), (b)(3), (b)(5), and 

(c)) using the submission methods and 

timeframes identified in the regulations 

applicable under § 4.103(a), (b), and (c) 

for your combination product or your 

constituent part. 

§ 4.106 What are the postmarketing safety 

reporting recordkeeping requirements? 

(a) You must maintain records of 

postmarketing safety reports required by 

§ 4.103(a) in accordance with the 

recordkeeping requirements of the 

underlying regulation(s) identified in 

§ 4.103(a) that are applicable to your 

combination product or your 

constituent part. 

(b) You must maintain records of 

reportable events required by § 4.103(b) 

and (c) for the time period specified as 

follows: 

(1) 5-day and malfunction reports 

described in § 4.103(b)(1) and (b)(2): for 

2 years or the expected life of the 

combination product, whichever is 

longer; 

(2) Postmarketing 15-day ‘alert 

reports’ field alert reports, and blood 

fatality reports described in 

§ 4.103(b)(3), (b)(4), and (b)(5), and 

periodic reports as described in 

§ 4.103(c): for 10 years. 

Dated: September 24, 2009. 

David Horowitz, 

Assistant Commissioner for Policy. 

[FR Doc. E9–23519 Filed 9–30–09; 8:45 am] 

BILLING CODE 4160–01–S 

DEPARTMENT OF THE TREASURY 

Internal Revenue Service 

26 CFR Part 1 

[REG–139068–08] 

RIN 1545–BI31 

Modification to Consolidated Return 

Regulation Permitting an Election To 

Treat a Liquidation of a Target, 

Followed by a Recontribution to a New 

Target, as a Cross-Chain 

Reorganization; Correction 

AGENCY: Internal Revenue Service (IRS), 

Treasury. 

ACTION: Correction to a notice of 

proposed rulemaking by cross-reference 

to temporary regulations. 

SUMMARY: This document contains 

corrections to a notice of proposed 

rulemaking by cross-reference to 

temporary regulations (REG–139068–08) 

that were published in the Federal 

Register on Friday, September 4, 2009 

(74 FR 45789) modifying the election 

under which a consolidated group can 

avoid immediately taking into account 


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