7446 Federal Register / Vol. 81, No. 29 / Friday, February 12, 2016 / Rules and Regulations 

regulations designed to help ensure the 

safety, purity, and potency of the 

licensed product, and that the product 

is not misbranded. 

In addition, FDA continues to help 

ensure the safety and effectiveness of 

licensed biological products through the 

development and application of 

additional standards and mechanisms. 

These mechanisms assist FDA in 

evaluating and monitoring the safety 

and effectiveness of biological products. 

C. Summary of Comments to the 

Proposed Rule 

FDA did not receive any comments on 

the proposed rule. 

D. General Overview of the Final Rule 

The final rule removes §§ 601.25 and 

601.26 of the regulations, which 

prescribe procedures for FDA’s review 

and classification of biological products 

licensed before July 1, 1972. FDA is 

taking this action because these 

regulations are obsolete and no longer 

necessary in light of other statutory and 

regulatory authorities established since 

1972, which allow FDA to evaluate and 

monitor the safety and effectiveness of 

all biological products. 

III. Legal Authority 

FDA is issuing this regulation under 

the biological products provisions of the 

PHS Act (42 U.S.C. 262 and 264) and 

the drugs and general administrative 

provisions of the FD&C Act (sections 

201, 301, 501, 502, 503, 505, 510, 701, 

and 704 (21 U.S.C. 321, 331, 351, 352, 

353, 355, 360, 371, and 374)). Under 

these provisions of the PHS Act and the 

FD&C Act, we have the authority to 

issue and enforce regulations designed 

to ensure that biological products are 

safe, pure, and potent; and to prevent 

the introduction, transmission, and 

spread of communicable disease. 

IV. Economic Analysis of Impacts 

We have examined the impacts of the 

final rule under Executive Order 12866, 

Executive Order 13563, the Regulatory 

Flexibility Act (5 U.S.C. 601–612), and 

the Unfunded Mandates Reform Act of 

1995 (Pub. L. 104–4). Executive Orders 

12866 and 13563 direct 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). We 

believe that this final rule is not a 

significant regulatory action as defined 

by Executive Order 12866. 

The Regulatory Flexibility Act 

requires Agencies to analyze regulatory 

options that would minimize any 

significant impact of a rule on small 

entities. Because this final rule removes 

regulations that are obsolete and no 

longer necessary in light of other current 

statutory and regulatory authorities, 

FDA certifies that the final rule will not 

have a significant economic impact on 

a substantial number of small entities. 

The Unfunded Mandates Reform Act 

of 1995 (section 202(a)) requires us to 

prepare a written statement, which 

includes an assessment of anticipated 

costs and benefits, before issuing ‘‘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 $144 million, using the 

most current (2014) Implicit Price 

Deflator for the Gross Domestic Product. 

This final rule would not result in any 

1-year expenditure that would meet or 

exceed this amount. 

V. Analysis of Environmental Impact 

We have determined under 21 CFR 

25.30(h) that this action is of a type that 

does not individually or cumulatively 

have a significant adverse effect on the 

human environment. Therefore, neither 

an environmental assessment nor an 

environmental impact statement is 

required. 

VI. Paperwork Reduction Act of 1995 

This final rule contains no collection 

of information. Therefore, clearance by 

OMB under the Paperwork Reduction 

Act of 1995 is not required. 

VII. Federalism 

We have analyzed this final rule in 

accordance with the principles set forth 

in Executive Order 13132. FDA has 

determined that the rule does not 

contain policies that would have 

substantial direct effects on the States, 

on the relationship between the 

National Government and the States, or 

on the distribution of power and 

responsibilities among the various 

levels of government. Accordingly, the 

Agency has concluded that the rule does 

not contain policies that have 

federalism implications as defined in 

the Executive order and, consequently, 

a federalism summary impact statement 

is not required. 

List of Subjects in 21 CFR Part 601 

Administrative practice and 

procedure, Biologics, Confidential 

business information. 

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, 21 CFR part 601 is amended 

as follows: 

PART 601—LICENSING 

■ 1. The authority citation for 21 CFR 

part 601 continues to read as follows: 

Authority: 15 U.S.C. 1451–1561; 21 U.S.C. 

321, 351, 352, 353, 355, 356b, 360, 360c– 

360f, 360h-360j, 371, 374, 379e, 381; 42 

U.S.C. 216, 241, 262, 263, 264; sec 122, 

Pub. L. 105–115, 111 Stat. 2322 (21 U.S.C. 

355 note). 

§ 601.25 [Removed] 

■ 2. Remove § 601.25. 

§ 601.26 [Removed] 

■ 3. Remove § 601.26. 

Dated: February 5, 2016. 

Leslie Kux, 

Associate Commissioner for Policy. 

[FR Doc. 2016–02884 Filed 2–11–16; 8:45 am] 

BILLING CODE 4164–01–P 

DEPARTMENT OF HEALTH AND 

HUMAN SERVICES 

Food and Drug Administration 

21 CFR Parts 868 and 870 

[Docket No. FDA–2012–N–1174] 

Anesthesiology Devices; 

Reclassification of Membrane Lung for 

Long-Term Pulmonary Support; 

Redesignation as Extracorporeal 

Circuit and Accessories for Long-Term 

Respiratory/Cardiopulmonary Failure 

AGENCY: Food and Drug Administration, 

HHS. 

ACTION: Final order. 

SUMMARY: The Food and Drug 

Administration (FDA) is issuing a final 

order to redesignate membrane lung 

devices for long-term pulmonary 

support, a preamendments class III 

device, as extracorporeal circuit and 

accessories for long-term respiratory/

cardiopulmonary failure, and to 

reclassify the device to class II (special 

controls) in patients with acute 

respiratory failure or acute 

cardiopulmonary failure where other 

available treatment options have failed, 

and continued clinical deterioration is 

expected or the risk of death is 

imminent. A membrane lung device for 

long-term pulmonary support (>6 hours) 

refers to the oxygenator in an 

extracorporeal circuit used during longterm procedures, commonly referred to 


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Federal Register / Vol. 81, No. 29 / Friday, February 12, 2016 / Rules and Regulations 7447 

as extracorporeal membrane 

oxygenation (ECMO). Because a number 

of other devices and accessories are 

used with the oxygenator in the circuit, 

the title and identification of the 

regulation are revised to include 

extracorporeal circuit and accessories 

for long-term respiratory/

cardiopulmonary failure. Although an 

individual device or accessory used in 

an ECMO circuit may already have its 

own classification regulation when the 

device or accessory is intended for 

short-term use (≤6 hours), such device 

or accessory will be subject to the same 

regulatory controls applied to the 

oxygenator (i.e., class II, special 

controls) when evaluated as part of the 

ECMO circuit for long-term use (>6 

hours). On its own initiative, based on 

new information, FDA is revising the 

classification of the membrane lung 

device for long-term pulmonary 

support. 

DATES: This order is effective February 

12, 2016. 

FOR FURTHER INFORMATION CONTACT: 

Fernando Aguel, Center for Devices and 

Radiological Health, 10903 New 

Hampshire Ave., Bldg. 66, Rm. 1234, 

Silver Spring, MD 20993, 301–796– 

6326, fernando.aguel@fda.hhs.gov. 

SUPPLEMENTARY INFORMATION: 

I. Background—Regulatory Authorities 

The Federal Food, Drug, and Cosmetic 

Act (the FD&C Act), as amended by the 

Medical Device Amendments of 1976 

(the 1976 amendments) (Pub. L. 94– 

295), the Safe Medical Devices Act of 

1990 (Pub. L. 101–629), the Food and 

Drug Administration Modernization Act 

of 1997 (FDAMA) (Pub. L. 105–115), the 

Medical Device User Fee and 

Modernization Act of 2002 (Pub. L. 107– 

250), the Medical Devices Technical 

Corrections Act (Pub. L. 108–214), the 

Food and Drug Administration 

Amendments Act of 2007 (Pub. L. 110– 

85), and the Food and Drug 

Administration Safety and Innovation 

Act (FDASIA) (Pub. L. 112–144), among 

other amendments, established a 

comprehensive system for the regulation 

of medical devices intended for human 

use. Section 513 of the FD&C Act (21 

U.S.C. 360c) established three categories 

(classes) of devices, reflecting the 

regulatory controls needed to provide 

reasonable assurance of their safety and 

effectiveness. The three categories of 

devices are class I (general controls), 

class II (special controls), and class III 

(premarket approval). 

Under section 513(d) of the FD&C Act, 

devices that were in commercial 

distribution before the enactment of the 

1976 amendments, May 28, 1976 

(generally referred to as preamendments 

devices), are classified after FDA has: (1) 

Received a recommendation from a 

device classification panel (an FDA 

advisory committee); (2) published the 

panel’s recommendation for comment, 

along with a proposed regulation 

classifying the device; and (3) published 

a final regulation classifying the device. 

FDA has classified most 

preamendments devices under these 

procedures. 

Devices that were not in commercial 

distribution prior to May 28, 1976 

(generally referred to as 

postamendments devices) are 

automatically classified by section 

513(f) of the FD&C Act into class III 

without any FDA rulemaking process. 

Those devices remain in class III and 

require premarket approval unless, and 

until, the device is reclassified into class 

I or II or FDA issues an order finding the 

device to be substantially equivalent, in 

accordance with section 513(i) of the 

FD&C Act, to a predicate device that 

does not require premarket approval. 

The Agency determines whether new 

devices are substantially equivalent to 

predicate devices by means of 

premarket notification procedures in 

section 510(k) of the FD&C Act (21 

U.S.C. 360(k)) and part 807 (21 CFR part 

807). 

A preamendments device that has 

been classified into class III and devices 

found substantially equivalent by means 

of premarket notification procedures 

(510(k)) to such a preamendments 

device or to a device within that type 

(both the preamendments and 

substantially equivalent devices are 

referred to as preamendments class III 

devices) may be marketed without 

submission of a premarket approval 

application (PMA) until FDA issues a 

final order under section 515(b) of the 

FD&C Act (21 U.S.C. 360e(b)) requiring 

premarket approval or until the device 

is subsequently reclassified into class I 

or class II. 

On July 9, 2012, FDASIA was enacted. 

Section 608(a) of FDASIA (126 Stat. 

1056) amended section 513(e) of the 

FD&C Act, changing the mechanism for 

reclassifying a device from rulemaking 

to an administrative order. 

Section 513(e) of the FD&C Act 

provides that FDA may, by 

administrative order, reclassify a device 

based upon ‘‘new information.’’ FDA 

can initiate a reclassification under 

section 513(e) of the FD&C Act or an 

interested person may petition FDA to 

reclassify a preamendments device. The 

term ‘‘new information,’’ as used in 

section 513(e) of the FD&C Act, includes 

information developed as a result of a 

reevaluation of the data before the 

Agency when the device was originally 

classified, as well as information not 

presented, not available, or not 

developed at that time. (See, e.g., 

Holland-Rantos Co. v. United States 

Department of Health, Education, and 

Welfare, 587 F.2d 1173, 1174 n.1 (D.C. 

Cir. 1978); Upjohn v. Finch, 422 F.2d 

944 (6th Cir. 1970); Bell v. Goddard, 366 

F.2d 177 (7th Cir. 1966).) 

Reevaluation of the data previously 

before the Agency is an appropriate 

basis for subsequent action where the 

reevaluation is made in light of newly 

available authority (see Bell, 366 F.2d at 

181; Ethicon, Inc. v. FDA, 762 F.Supp. 

382, 388–391 (D.D.C. 1991)), or in light 

of changes in ‘‘medical science’’ 

(Upjohn, 422 F.2d at 951). Whether data 

before the Agency are old or new data, 

the ‘‘new information’’ to support 

reclassification under section 513(e) of 

the FD&C Act must be ‘‘valid scientific 

evidence,’’ as defined in section 

513(a)(3) of the FD&C Act and 21 CFR 

860.7(c)(2). (See, e.g., General Medical 

Co. v. FDA, 770 F.2d 214 (D.C. Cir. 

1985); Contact Lens Manufacturers 

Assoc. v. FDA, 766 F.2d 592 (D.C. Cir. 

1985), cert. denied, 474 U.S. 1062 

(1986).) 

FDA relies upon ‘‘valid scientific 

evidence’’ in the classification process 

to determine the level of regulation for 

devices. To be considered in the 

reclassification process, the ‘‘valid 

scientific evidence’’ upon which the 

Agency relies must be publicly 

available. Publicly available information 

excludes trade secret and/or 

confidential commercial information, 

e.g., the contents of a pending PMA (see 

section 520(c) of the FD&C Act (21 

U.S.C. 360j(c)).) 

Section 513(e)(1) of the FD&C Act sets 

forth the process for issuing a final 

reclassification order. Specifically, prior 

to the issuance of a final order 

reclassifying a device, the following 

must occur: (1) Publication of a 

proposed order in the Federal Register; 

(2) a meeting of a device classification 

panel described in section 513(b) of the 

FD&C Act; and (3) consideration of 

comments to a public docket. 

II. Regulatory History of the Device 

FDA published a proposed order to 

reclassify this device in the Federal 

Register of January 8, 2013 (78 FR 1158) 

(the ‘‘proposed order’’). As noted in the 

proposed order, on July 16, 1982, the 

Agency issued a final rule classifying all 

membrane lungs for long-term 

pulmonary support into class III (47 FR 

31130). On May 11, 1987, FDA 

published a final rule amending the 

codified language for this device to 

clarify that no effective date had been 


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7448 Federal Register / Vol. 81, No. 29 / Friday, February 12, 2016 / Rules and Regulations 

established for the requirement for 

premarket approval for membrane lungs 

for long-term pulmonary support 

devices (52 FR 17732 at 17735). This 

device is currently under product code 

BYS. 

As discussed in the proposed order, 

FDA considered the available 

information on these devices and 

concluded that these devices could be 

reclassified to class II, subject to the 

identified special controls. As required 

by section 513(e)(1) of the FD&C Act, 

FDA convened a meeting of a device 

classification panel described in section 

513(b) of the FD&C Act with respect to 

the membrane lung devices for longterm pulmonary support on September 

12, 2013, followed by a meeting on May 

7, 2014. The deliberations of the device 

classification panels are discussed in 

section IV of this order. FDA received 

and has considered two comments on 

the January 8, 2013, proposed order, as 

discussed in section III. Therefore, FDA 

has met the requirements for issuing a 

final order under section 513(e)(1) of the 

FD&C Act. 

III. Public Comments in Response to the 

Proposed Order 

FDA received two comments in 

response to the January 8, 2013, 

proposed order to reclassify membrane 

lung devices for long-term pulmonary 

support for conditions where imminent 

death is threatened by cardiopulmonary 

failure in neonates and infants or where 

cardiopulmonary failure results in the 

inability to separate from 

cardiopulmonary bypass following 

cardiac surgery. 

One comment supported FDA’s 

reclassification proposal but requested 

that the Agency clarify the population 

covered and the conditions included in 

the reclassification. According to the 

commenter, it seemed that the 

membrane lung device could be used for 

long-term support in neonates and 

infants only when imminent death is 

threatened by cardiopulmonary failure, 

but for the remaining population (e.g., 

pediatric and adult patients), the 

membrane lung could be used for longterm support only when 

cardiopulmonary failure results in the 

inability to separate from 

cardiopulmonary bypass following 

cardiac surgery. With respect to the 

conditions covered, the commenter 

sought clarification as to whether the 

reclassification was limited only to 

cardiopulmonary conditions or to 

cardiac failure as well. FDA is clarifying 

the intended uses covered by the 

reclassification in this final order. 

Specifically, after considering the input 

from the September 12, 2013, and May 

7, 2014, classification panel meetings, 

comments on the proposed order and all 

other available information, FDA has 

determined that the reclassification 

applies to ECMO as a system of devices 

and accessories that provide 

extracorporeal circulation and 

physiologic gas exchange of blood in 

patients with acute respiratory failure or 

acute cardiopulmonary failure where 

other available treatment options have 

failed, and continued clinical 

deterioration is expected or the risk of 

death is imminent. This revised scope 

better reflects use of ECMO as a tool that 

provides extracorporeal circulation and 

physiologic gas exchange of blood and 

more accurately reflects the function of 

the device. FDA has not cleared any 

ECMO devices that are indicated for 

specific patient populations or 

conditions. As such, FDA believes that 

the intended uses included in this final 

order should remain broad, rather than 

specify patient populations or 

conditions to be treated, to reflect use of 

ECMO as a tool. 

Another comment disagreed with 

FDA’s intent to reclassify membrane 

lung devices for long-term pulmonary 

support, stating that ‘‘ECMO devices 

must remain categorized as class III 

devices for all indications because they 

are life-sustaining devices for which 

clinical trials are necessary to provide 

reasonable assurance of safety and 

effectiveness.’’ FDA disagrees with this 

comment. According to section 

513(a)(1)(C) of the FD&C Act, a class III 

device is defined as a device which: (1) 

Cannot be classified as a class I device 

because insufficient information exists 

to determine that the application of 

general controls are sufficient to provide 

reasonable assurance of the safety and 

effectiveness of the device; and (2) 

cannot be classified as a class II device 

because insufficient information exists 

to determine that the special controls 

would provide reasonable assurance of 

its safety and effectiveness; and (3) is 

purported or represented to be for a use 

in supporting or sustaining human life 

or for a use which is of substantial 

importance in preventing impairment of 

human health; or (4) presents a potential 

unreasonable risk of illness or injury. 

Although FDA considers membrane 

lung devices for long-term pulmonary 

support to be life-supporting, a 

viewpoint that was supported by the 

panel members at the September 12, 

2013 (2013 Panel), and May 7, 2014 

(2014 Panel), device classification panel 

meetings, FDA believes that the 

available information supports FDA’s 

determination that special controls, in 

addition to general controls, would be 

sufficient to provide a reasonable 

assurance of safety and effectiveness. 

Further, the 2013 and 2014 Panels 

largely supported reclassification of 

ECMO for use in patients with acute 

respiratory failure or acute 

cardiopulmonary failure as noted in 

section IV of this order. As mentioned 

previously and discussed further in 

section IV, ECMO is a tool which 

provides extracorporeal circulation and 

physiologic gas exchange of blood. The 

special controls identified in this final 

order, including clinical performance 

data, ensure that the device can function 

as intended to provide extracorporeal 

circulation and physiologic gas 

exchange of blood for the intended 

duration of device use. The Agency 

believes that the risks of ECMO devices 

are sufficiently understood based on 

valid scientific evidence and that the 

risks of ECMO devices can be mitigated 

with the special controls identified in 

this final order. The special controls 

mitigate the risks to health identified for 

the device as outlined in section IV, 

table 1. Therefore, FDA does not agree 

that membrane lung devices for longterm pulmonary support for use in 

patients with acute respiratory failure or 

acute cardiopulmonary failure should 

remain a class III device. 

The commenter also expressed 

concern that the reclassification of these 

devices would mean that companies 

manufacturing new versions of the 

device would not be required to show 

that their products are safe and 

effective. The commenter suggests that 

classification to class II (special 

controls) precludes FDA from 

requesting clinical data for these 

devices. FDA disagrees with this 

comment. FDA believes that the 

identified special controls provide a 

reasonable assurance of safety and 

effectiveness for membrane lung devices 

for long-term pulmonary support for use 

in patients with acute respiratory failure 

or acute cardiopulmonary failure, where 

other available treatment options have 

failed, and continued clinical 

deterioration is expected or the risk of 

death is imminent. FDA has determined 

that by complying with the identified 

special controls, the currently legally 

marketed devices within this 

classification regulation will be 

reasonably safe and effective when used 

for acute respiratory failure or acute 

cardiopulmonary failure. Future devices 

claiming substantial equivalence to an 

available predicate(s) must demonstrate 

that they are substantially equivalent, as 

defined under section 513(i) of the 

FD&C Act, to the predicate device and 

comply with all applicable FDA 

regulations and with the special 


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Federal Register / Vol. 81, No. 29 / Friday, February 12, 2016 / Rules and Regulations 7449 

controls in order to be classified into 

class II. Classification to class II (special 

controls) does not preclude FDA from 

requesting clinical data for these 

devices. In some cases, clinical data 

may be needed to comply with the 

special controls and demonstrate 

substantial equivalence to an available 

predicate. For example, special control 

§ 870.4100(b)(v) regarding in vivo 

evaluation of the device could include 

clinical trial data, clinical information 

from the literature, and/or animal study 

data. 

The commenter further expressed 

concern that reclassification for some 

indications will reduce the incentive to 

undertake future studies for untested 

indications due to the availability of the 

devices for ‘‘off-label’’ use. FDA notes in 

response to this comment that, 

generally, FDA regulates the use of a 

device as indicated by the party offering 

the device for interstate commerce. 

The commenter also sought assurance 

from FDA that membrane lung devices 

for long-term pulmonary support for 

indications not identified in the 

proposed order would remain in class 

III and therefore require the submission 

of a PMA. FDA notes that by identifying 

the intended uses covered by the 

revised classification regulation, uses 

that fall outside the definition would 

not be subject to the order but rather 

would be classified under section 513 of 

the FD&C Act. 

IV. Deliberations of the Panels and FDA 

Consideration of Panel Input 

As required by section 513(e)(1) of the 

FD&C Act, FDA convened a meeting of 

the Circulatory System Devices Panel to 

consider the existing valid scientific 

evidence to support reclassification to 

class II of membrane lung devices for 

long-term pulmonary support. One 

meeting was held on September 12, 

2013 (2013 Panel), regarding pediatric 

uses for ECMO and another meeting was 

held on May 7, 2014 (2014 Panel), 

regarding adult uses for ECMO (Refs. 1 

and 2). 

On September 12, 2013, FDA 

presented the risks associated with use 

of the membrane lung device for longterm pulmonary support. The 2013 

Panel mostly agreed that the risks to 

health were adequately captured as 

presented by FDA. Several 2013 Panel 

members discussed whether the list of 

risks to health should also include 

information on renal dysfunction, 

neurologic injury, disseminated 

intravascular coagulation, transfusion 

issues, and inflammatory responses. 

FDA explained that such effects are 

more appropriately characterized not as 

risks to health but rather as adverse 

events that may result from the risks to 

health. The 2013 Panel understood this 

distinction but requested that FDA 

consider expanding the definition of 

adverse tissue reaction to include 

inflammatory response. FDA considered 

the 2013 Panel’s input when updating 

the risks to health for the 2014 Panel 

and this final order. 

The 2013 Panel agreed that the 

available scientific evidence supported 

the safety and effectiveness for ECMO 

and its accessories for conditions where 

the subject is at threat of imminent 

death caused by acute reversible 

respiratory failure (e.g., meconium 

aspiration, congenital diaphragmatic 

hernia, pulmonary hypertension) in 

neonates and infants, or where acute 

cardiopulmonary failure results in the 

inability to separate from 

cardiopulmonary bypass following 

cardiac surgery in all pediatric patients. 

The 2013 Panel also agreed that the 

probable benefits to health from use of 

the extracorporeal circuit and its 

accessories for long-term pulmonary 

and cardiopulmonary support for these 

uses outweigh the probable risks. As 

noted previously, FDA has further 

considered all available information and 

has determined that the risks to health 

identified for ECMO are the same across 

neonatal, infant, pediatric, and adult 

populations. This is consistent with 

input from the 2013 and 2014 Panels, 

which found that the risks to health for 

the pediatric and adult populations do 

not differ. Further, FDA believes that 

the available safety and effectiveness 

information supports use of ECMO as a 

tool to provide extracorporeal 

circulation and physiologic gas 

exchange of blood in patients with acute 

respiratory failure or acute 

cardiopulmonary failure, where other 

available treatment options have failed, 

and continued clinical deterioration is 

expected or the risk of death is 

imminent. FDA is providing greater 

clarity in this final order by simplifying 

the identification of ECMO devices in 

the classification regulation to better 

reflect what an ECMO circuit performs, 

not specify patient populations or 

conditions to be treated. Specific 

indications for use for ECMO, including 

specific patient populations and/or 

conditions, are further discussed in this 

document. 

In general, the 2013 Panel believed 

the special controls in the proposed 

order would mitigate the identified risks 

to health and provide reasonable 

assurance of safety and effectiveness of 

the extracorporeal circuit and its 

accessories. However, some 2013 Panel 

members recommended that 

compatibility of the various circuit 

accessories be evaluated to ensure that 

the circuit accessories can function 

together as intended. FDA believes that 

the special controls will be able to 

address the issue of circuit accessories’ 

compatibility. Specifically, the 

following special controls from the 

classification regulation address this 

concern: (1) The design characteristics 

of the device must ensure that the 

geometry and design parameters are 

consistent with the intended use; (2) 

non-clinical performance evaluation of 

the device must demonstrate substantial 

equivalence for performance 

characteristics on the bench, mechanical 

integrity, electromagnetic 

compatibility(where applicable), 

software, durability, and reliability; and 

(3) labeling must include a detailed 

summary of the non-clinical and 

clinical evaluations pertinent to use of 

the device and adequate instructions 

with respect to anticoagulation, circuit 

setup, performance characteristics with 

respect to compatibility with other 

circuit accessories, and maintenance 

during a procedure. 

The 2013 Panel unanimously agreed 

that the membrane lung device for longterm pulmonary support is lifesupporting. The 2013 Panel further 

stated that the available scientific 

evidence and the proposed special 

controls, in conjunction with general 

controls, supported the reclassification 

to class II of membrane lung devices for 

long-term pulmonary/cardiopulmonary 

support in pediatric patients. The 2013 

Panel expressed concern about not 

having had the opportunity to review 

data regarding use of the device in 

adults, given that use of ECMO in adults 

had increased significantly over the 

years. The 2013 Panel recommended 

that FDA convene another meeting to 

review the available literature regarding 

use of the membrane lung device for 

long-term pulmonary support in adults 

before finalizing the proposed 

reclassification. 

On May 7, 2014, FDA convened the 

2014 Panel to discuss the classification 

of the membrane lung for long-term 

support, specifically for adult 

pulmonary and cardiopulmonary 

indications. For both pulmonary and 

cardiopulmonary intended uses, the 

2014 Panel believed that the list of risks 

to health presented by FDA were 

comprehensive and adequately 

captured. Of note, in response to the 

2013 Panel’s recommendation regarding 

risks to health, FDA expanded the 

definition of adverse tissue reaction to 

include inflammatory response. 

The majority of the 2014 Panel 

believed that the available scientific 

evidence is adequate to support a 


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7450 Federal Register / Vol. 81, No. 29 / Friday, February 12, 2016 / Rules and Regulations 

reasonable assurance of safety and 

effectiveness of the extracorporeal 

circuit and its accessories for long-term 

pulmonary support in adults, but 

recommended that FDA modify the 

intended use from ‘‘pulmonary support’’ 

to ‘‘acute, hypoxic, reversible 

respiratory failure.’’ FDA agrees with 

the 2014 Panel that ‘‘respiratory failure’’ 

is a more accurate reflection of the use 

of ECMO as a tool to provide 

extracorporeal circulation and 

physiologic gas exchange of blood in 

patients rather than ‘‘pulmonary 

support.’’ FDA has considered this 

input from the panel and has 

determined that acute respiratory failure 

is the appropriate intended use from a 

clinical and regulatory perspective to 

reflect such use. This change is reflected 

in the classification regulation. The 

Panel also agreed that the available 

scientific evidence is adequate to 

support a reasonable assurance of safety 

and effectiveness of the device for longterm cardiopulmonary support in adults 

suffering from ‘‘cardiopulmonary failure 

due to acute catastrophic cardiogenic 

shock.’’ FDA agrees with the 2014 Panel 

that ‘‘acute cardiopulmonary failure’’ is 

a more accurate reflection of the use of 

ECMO as a tool to provide 

extracorporeal circulation and 

physiologic gas exchange of blood in 

patients rather than ‘‘cardiopulmonary 

support.’’ FDA has considered this 

input from the panel and has 

determined that acute cardiopulmonary 

failure is the appropriate intended use 

from a clinical and regulatory 

perspective to reflect such use. This 

change is reflected in the classification 

regulation. For both pulmonary and 

cardiopulmonary support in adults, the 

2014 Panel agreed that the probable 

benefits to health from use of the device 

outweigh the probable risks to health 

where other available treatment options 

have failed, and continued clinical 

deterioration is expected or the risk of 

death is imminent. 

The 2014 Panel agreed that FDA’s list 

of special controls were appropriate and 

comprehensive. The 2014 Panel further 

agreed that the special controls would 

mitigate the identified risks to health 

and provide reasonable assurance of 

safety and effectiveness for the device 

when used to provide long-term support 

in adults with acute respiratory failure 

or cardiopulmonary failure. 

For both acute respiratory and acute 

cardiopulmonary indications in adults, 

the 2014 Panel unanimously agreed that 

the membrane lung device for long-term 

support is life-supporting. The 2014 

Panel further believes that the available 

scientific evidence and the proposed 

special controls support the 

reclassification to class II of membrane 

lung devices for long-term support in 

adults with acute respiratory failure or 

acute cardiopulmonary failure. 

After considering input from both the 

2013 and 2014 Panels, FDA believes 

that the risks to health identified can be 

mitigated by the special controls as 

outlined in Table 1. 

TABLE 1—HEALTH RISKS AND MITIGATION MEASURES FOR ECMO DEVICES

Identified risk Mitigation measures 

Thrombocytopenia .................................................................................... Technological characteristics; Non-clinical performance evaluation; In 

vivo evaluation; Labeling. 

Hemolysis ................................................................................................. Technological characteristics; Biocompatibility testing; Non-clinical performance evaluation; Labeling. 

Adverse tissue reaction (including inflammatory response) .................... Biocompatibility testing; Labeling. 

Inadequate gas exchange ........................................................................ Non-clinical performance evaluation; In vivo evaluation; Labeling. 

Gas embolism ........................................................................................... Non-clinical performance evaluation; In vivo evaluation; Labeling. 

Mechanical failure ..................................................................................... Technological characteristics; Non-clinical performance evaluation; Labeling. 

Hemorrhage .............................................................................................. In vivo evaluation; Labeling. 

Hemodilution ............................................................................................. Non-clinical performance evaluation; In vivo evaluation; Labeling. 

Thrombosis/thromboembolism ................................................................. Non-clinical performance evaluation; In vivo evaluation; Labeling. 

Infection .................................................................................................... Sterility; Shelf life testing. 

Mechanical injury to access vessels ........................................................ Non-clinical performance evaluation; In vivo evaluation; Labeling. 

At both the 2013 Panel and 2014 

Panel meetings, FDA provided a 

summary of information from the 

clinical literature regarding specific 

patient populations and conditions to be 

treated using ECMO (Refs.1 and 2). Of 

note, FDA has not cleared any ECMO 

devices that are indicated for specific 

patient populations or conditions. As 

such, FDA believes that the intended 

uses included in this final order should 

remain broad to reflect use of ECMO as 

a tool to provide extracorporeal 

circulation and physiologic gas 

exchange of blood in patients with acute 

respiratory failure or acute 

cardiopulmonary failure, where other 

available treatment options have failed, 

and continued clinical deterioration is 

expected or the risk of death is 

imminent. However, FDA believes that 

there are specific indications (patient 

populations and/or conditions) that 

would fall within this broader intended 

use and therefore be within the scope of 

this regulation as outlined in this 

document. 

Specifically, FDA has reviewed the 

clinical literature and has determined 

that there are sufficient data available to 

support labeling ECMO devices for the 

following specific indications (patient 

populations and/or conditions) at this 

time: Meconium aspiration in neonates 

and infants; congenital diaphragmatic 

hernia in neonates and infants; 

pulmonary hypertension in neonates 

and infants; failure to wean from 

cardiopulmonary bypass following 

cardiac surgery in pediatric and adult 

patients; and ECMO-assisted 

cardiopulmonary resuscitation in 

adults. 

FDA has further evaluated data from 

the clinical literature and determined 

that the data available do not support 

labeling ECMO devices for certain 

specific indications (patient populations 

and/or conditions) at this time without 

additional clinical data from sponsors to 

support such uses, consistent with the 

identified special controls, including 

but not limited to: High risk 

percutaneous coronary intervention; 

trauma resuscitation; failed heart or 

lung transplant; acute respiratory 

distress syndrome; and/or acute 

decompensation of chronic obstructive 

pulmonary disease. 

For ECMO devices that have not been 

legally marketed prior to the effective 

date of the final order, or models (if any) 

that have been legally marketed but are 

required to submit a new 510(k) under 

§ 807.81(a)(3) because the device is 


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Federal Register / Vol. 81, No. 29 / Friday, February 12, 2016 / Rules and Regulations 7451 

about to be significantly changed or 

modified, manufacturers must obtain 

510(k) clearance, among other relevant 

requirements, and demonstrate 

compliance with the special controls 

included in the final order, before 

marketing the new or changed device. 

V. The Final Order 

Under section 513(e) of the FD&C Act, 

FDA is adopting its findings as 

published in the preamble to the 

proposed order (78 FR 1158) with 

modifications as discussed in section IV 

of this final order. FDA is issuing this 

final order to reclassify the membrane 

lung devices for long-term pulmonary 

support from class III to class II for use 

in patients with acute respiratory failure 

or acute cardiopulmonary failure, where 

other available treatment options have 

failed and continued clinical 

deterioration is expected or the risk of 

death is imminent, and to establish 

special controls. FDA is removing the 

regulation from 21 CFR part 868 

(Anesthesiology Devices) and adding it 

to 21 CFR part 870 (Cardiovascular 

Devices) to better align this device type 

(and the review thereof) with other 

similar types of cardiovascular devices. 

The title and identification of 

§ 870.4100 (21 CFR 870.4100) reflects 

the Agency’s intent to regulate ECMO 

and the accessories used in ECMO 

under the same set of regulatory 

controls. However, an individual device 

or accessory in an ECMO circuit may 

already have its own classification 

regulation when intended for short-term 

use (≤6 hours) and, in those instances, 

such device or accessory is subject to 

the preexisting regulation(s). 

Following the effective date of this 

final order, firms marketing membrane 

lung devices for long-term pulmonary 

support for use in patients with acute 

respiratory failure or acute 

cardiopulmonary failure, where other 

available treatment options have failed 

and continued clinical deterioration is 

expected or the risk of death is 

imminent, must comply with the 

particular mitigation measures set forth 

in the special controls. 

Section 510(m) of the FD&C Act 

provides that FDA may exempt a class 

II device from the premarket notification 

requirements under section 510(k) of the 

FD&C Act if FDA determines that 

premarket notification is not necessary 

to provide reasonable assurance of the 

safety and effectiveness of the devices. 

FDA has determined that premarket 

notification is necessary to provide 

reasonable assurance of safety and 

effectiveness of membrane lung devices 

for long-term pulmonary support for use 

in patients with acute respiratory failure 

or acute cardiopulmonary failure, where 

other available treatment options have 

failed, and continued clinical 

deterioration is expected or the risk of 

death is imminent, and, therefore, this 

device type is not exempt from 

premarket notification requirements. 

VI. Analysis of Environmental Impact 

The Agency has determined under 21 

CFR 25.34(b) 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. 

VII. Paperwork Reduction Act of 1995 

This final order refers to previously 

approved collections of information 

found in FDA regulations. These 

collections of information are subject to 

review by the Office of Management and 

Budget (OMB) under the Paperwork 

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

3520). The collections of information in 

21 CFR part 812 have been approved 

under OMB control number 0910–0078; 

the collections of information in 21 CFR 

part 807, subpart E, have been approved 

under OMB control number 0910–0120; 

the collections of information in 21 CFR 

part 814, subpart B, have been approved 

under OMB control number 0910–0231; 

and the collections of information under 

21 CFR part 801 have been approved 

under OMB control number 0910–0485. 

VIII. Codification of Orders 

Prior to the amendments by FDASIA, 

section 513(e) of the FD&C Act provided 

for FDA to issue regulations to reclassify 

devices. Although section 513(e) of the 

FD&C Act as amended requires FDA to 

issue final orders rather than 

regulations, FDASIA also provides for 

FDA to revoke previously issued 

regulations by order. FDA will continue 

to codify classifications and 

reclassifications in the Code of Federal 

Regulations (CFR). Changes resulting 

from final orders will appear in the CFR 

as changes to codified classification 

determinations or as newly codified 

orders. Therefore, under section 

513(e)(1)(A)(i) of the FD&C Act, as 

amended by FDASIA, in this final order, 

we are revoking the requirements in 21 

CFR 868.5610 related to the 

classification of membrane lung for 

long-term pulmonary support as class III 

devices and codifying under § 870.4100 

the reclassification of membrane lung 

for long-term pulmonary support for use 

in patients with acute respiratory failure 

or acute cardiopulmonary failure, where 

other available treatment options have 

failed, and continued clinical 

deterioration is expected or the risk of 

death is imminent into class II (special 

controls). 

IX. References 

The following references are on 

display in the Division of Dockets 

Management (HFA–305), Food and Drug 

Administration, 5630 Fishers Lane, Rm. 

1061, Rockville, MD 20852, and are 

available for viewing by interested 

persons between 9 a.m. and 4 p.m., 

Monday through Friday; they are also 

available electronically at http://

www.regulations.gov. FDA has verified 

the Web site addresses, as of the date 

this document publishes in the Federal 

Register, but Web sites are subject to 

change over time. 

1. The panel transcript and other meeting 

materials for the September 12, 2013, 

Circulatory System Devices Panel are 

available on FDA’s Web site at http://

www.fda.gov/AdvisoryCommittees/

CommitteesMeetingMaterials/Medical

Devices/MedicalDevicesAdvisory

Committee/CirculatorySystemDevices

Panel/ucm342357.htm. 

2. The panel transcript and other meeting 

materials for the May 7, 2014, 

Circulatory System Devices Panel are 

available on FDA’s Web site at. http://

www.fda.gov/AdvisoryCommittees/

CommitteesMeetingMaterials/Medical

Devices/MedicalDevicesAdvisory

Committee/CirculatorySystemDevices

Panel/ucm395638.htm 

List of Subjects in 21 CFR Parts 868 and 

870 

Medical devices. 

Therefore, under the Federal Food, 

Drug, and Cosmetic Act and under 

authority delegated to the Commissioner 

of Food and Drugs, 21 CFR parts 868 

and 870 are amended as follows: 

PART 868—ANESTHESIOLOGY 

DEVICES 

■ 1. The authority citation for 21 CFR 

part 868 continues to read as follows: 

Authority: 21 U.S.C. 351, 360, 360c, 360e, 

360j, 371. 

§ 868.5610 [Removed] 

■ 2. Remove § 868.5610. 

PART 870—CARDIOVASCULAR 

DEVICES 

■ 1. The authority citation for 21 CFR 

part 870 continues to read as follows: 

Authority: 21 U.S.C. 351, 360, 360c, 360e, 

360j, 371. 

■ 2. Add § 870.4100 to subpart E to read 

as follows: 


srobinson on DSK5SPTVN1PROD with RULES
7452 Federal Register / Vol. 81, No. 29 / Friday, February 12, 2016 / Rules and Regulations 

§ 870.4100 Extracorporeal circuit and 

accessories for long-term respiratory/

cardiopulmonary failure. 

(a) Identification. An extracorporeal 

circuit and accessories for long-term 

respiratory/cardiopulmonary support 

(>6 hours) is a system of devices and 

accessories that provides assisted 

extracorporeal circulation and 

physiologic gas exchange of the 

patient’s blood in patients with acute 

respiratory failure or acute 

cardiopulmonary failure, where other 

available treatment options have failed, 

and continued clinical deterioration is 

expected or the risk of death is 

imminent. The main devices and 

accessories of the system include, but 

are not limited to, the console 

(hardware), software, and disposables, 

including, but not limited to, an 

oxygenator, blood pump, heat 

exchanger, cannulae, tubing, filters, and 

other accessories (e.g., monitors, 

detectors, sensors, connectors). 

(b) Classification—Class II (special 

controls). The special controls for this 

device are: 

(1) The technological characteristics 

of the device must ensure that the 

geometry and design parameters are 

consistent with the intended use, and 

that the devices and accessories in the 

circuit are compatible; 

(2) The devices and accessories in the 

circuit must be demonstrated to be 

biocompatible; 

(3) Sterility and shelf-life testing must 

demonstrate the sterility of any patientcontacting devices and accessories in 

the circuit and the shelf life of these 

devices and accessories; 

(4) Non-clinical performance 

evaluation of the devices and 

accessories in the circuit must 

demonstrate substantial equivalence of 

the performance characteristics on the 

bench, mechanical integrity, 

electromagnetic compatibility (where 

applicable), software, durability, and 

reliability; 

(5) In vivo evaluation of the devices 

and accessories in the circuit must 

demonstrate their performance over the 

intended duration of use, including a 

detailed summary of the clinical 

evaluation pertinent to the use of the 

devices and accessories to demonstrate 

their effectiveness if a specific 

indication (patient population and/or 

condition) is identified; and 

(6) Labeling must include a detailed 

summary of the non-clinical and in vivo 

evaluations pertinent to use of the 

devices and accessories in the circuit 

and adequate instructions with respect 

to anticoagulation, circuit setup, 

performance characteristics with respect 

to compatibility among different devices 

and accessories in the circuit, and 

maintenance during a procedure. 

Dated: February 8, 2016. 

Leslie Kux, 

Associate Commissioner for Policy. 

[FR Doc. 2016–02876 Filed 2–11–16; 8:45 am] 

BILLING CODE 4164–01–P 

DEPARTMENT OF HEALTH AND 

HUMAN SERVICES 

Food and Drug Administration 

21 CFR Part 878 

[Docket No. FDA–2016–N–0237] 

Medical Devices; General and Plastic 

Surgery Devices; Classification of the 

Scalp Cooling System To Reduce the 

Likelihood of Chemotherapy-Induced 

Alopecia 

AGENCY: Food and Drug Administration, 

HHS. 

ACTION: Final order. 

SUMMARY: The Food and Drug 

Administration (FDA) is classifying the 

scalp cooling system to reduce the 

likelihood of chemotherapy-induced 

alopecia into class II (special controls). 

The special controls that will apply to 

the device are identified in this order 

and will be part of the codified language 

for the scalp cooling system to reduce 

the likelihood of chemotherapy-induced 

alopecia’s classification. The Agency is 

classifying the device into class II 

(special controls) in order to provide a 

reasonable assurance of safety and 

effectiveness of the device. 

DATES: This order is effective February 

12, 2016. The classification was 

applicable on December 8, 2015. 

FOR FURTHER INFORMATION CONTACT: Neil 

Ogden, Center for Devices and 

Radiological Health, Food and Drug 

Administration, 10903 New Hampshire 

Ave., Bldg. 66, Rm. G414, Silver Spring, 

MD 20993–0002, 301–796–6397. 

SUPPLEMENTARY INFORMATION: 

I. Background 

In accordance with section 513(f)(1) of 

the Federal Food, Drug, and Cosmetic 

Act (the FD&C Act) (21 U.S.C. 

360c(f)(1)), devices that were not in 

commercial distribution before May 28, 

1976 (the date of enactment of the 

Medical Device Amendments of 1976), 

generally referred to as postamendments 

devices, are classified automatically by 

statute into class III without any FDA 

rulemaking process. These devices 

remain in class III and require 

premarket approval, unless and until 

the device is classified or reclassified 

into class I or II, or FDA issues an order 

finding the device to be substantially 

equivalent, in accordance with section 

513(i) of the FD&C Act, to a predicate 

device that does not require premarket 

approval. The Agency determines 

whether new devices are substantially 

equivalent to predicate devices by 

means of premarket notification 

procedures in section 510(k) of the 

FD&C Act (21 U.S.C. 360(k)) and part 

807 (21 CFR part 807) of the regulations. 

Section 513(f)(2) of the FD&C Act, as 

amended by section 607 of the Food and 

Drug Administration Safety and 

Innovation Act (Pub. L. 112–144), 

provides two procedures by which a 

person may request FDA to classify a 

device under the criteria set forth in 

section 513(a)(1) of the FD&C Act. 

Under the first procedure, the person 

submits a premarket notification under 

section 510(k) of the FD&C Act for a 

device that has not previously been 

classified and, within 30 days of 

receiving an order classifying the device 

into class III under section 513(f)(1) of 

the FD&C Act, the person requests a 

classification under section 513(f)(2). 

Under the second procedure, rather than 

first submitting a premarket notification 

under section 510(k) of the FD&C Act 

and then a request for classification 

under the first procedure, the person 

determines that there is no legally 

marketed device upon which to base a 

determination of substantial 

equivalence and requests a classification 

under section 513(f)(2) of the FD&C Act. 

If the person submits a request to 

classify the device under this second 

procedure, FDA may decline to 

undertake the classification request if 

FDA identifies a legally marketed device 

that could provide a reasonable basis for 

review of substantial equivalence with 

the device or if FDA determines that the 

device submitted is not of ‘‘lowmoderate risk’’ or that general controls 

would be inadequate to control the risks 

and special controls to mitigate the risks 

cannot be developed. 

In response to a request to classify a 

device under either procedure provided 

by section 513(f)(2) of the FD&C Act, 

FDA will classify the device by written 

order within 120 days. This 

classification will be the initial 

classification of the device. 

On March 6, 2015, Target Health, Inc. 

(on behalf of Dignitana AB) submitted a 

request for classification of the 

DigniCapTM Scalp Cooling System 

under section 513(f)(2) of the FD&C Act. 

The manufacturer recommended that 

the device be classified into class II (Ref. 

1). 

In accordance with section 513(f)(2) of 

the FD&C Act, FDA reviewed the 


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