9610 Federal Register / Vol. 77, No. 33 / Friday, February 17, 2012 / Proposed Rules 

neither an environmental assessment 

nor an environmental impact statement 

is required. 

III. Comments 

Interested persons may submit to the 

Division of Dockets Management (see 

ADDRESSES) either electronic or written 

comments regarding this document. It is 

only necessary to send one set of 

comments. Identify comments 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. 

Dated: February 13, 2012. 

Dennis M. Keefe, 

Director, Office of Food Additive Safety, 

Center for Food Safety and Applied Nutrition. 

[FR Doc. 2012–3744 Filed 2–16–12; 8:45 am] 

BILLING CODE 4160–01–P 

DEPARTMENT OF HEALTH AND 

HUMAN SERVICES 

Food and Drug Administration 

21 CFR Part 876 

[Docket No. FDA–2012–M–0076] 

Gastroenterology-Urology Devices; 

Reclassification of Sorbent 

Hemoperfusion Devices for the 

Treatment of Poisoning and Drug 

Overdose; Effective Date of 

Requirement for Premarket Approval 

for Sorbent Hemoperfusion Devices To 

Treat Hepatic Coma and Metabolic 

Disturbances 

AGENCY: Food and Drug Administration, 

HHS. 

ACTION: Proposed rule. 

SUMMARY: The Food and Drug 

Administration (FDA) is proposing to 

reclassify the sorbent hemoperfusion 

system, a preamendments class III 

device, into class II (special controls) for 

the treatment of poisoning and drug 

overdose, and to require the filing of a 

premarket approval application (PMA) 

or a notice of completion of a product 

development protocol (PDP) for the 

treatment of hepatic coma and 

metabolic disturbances. FDA is 

identifying the proposed special 

controls that the Agency believes will 

reasonably ensure the safety and 

effectiveness of the device for the 

treatment of poisoning and drug 

overdose. The Agency is also 

summarizing its proposed findings 

regarding the degree of risk of illness or 

injury designed to be eliminated or 

reduced by requiring the devices to 

meet the statute’s approval requirements 

and the benefits to the public from the 

use of the devices. In addition, FDA is 

announcing the opportunity for 

interested persons to request that the 

Agency change the classification of any 

of the devices mentioned in this 

document based on new information. 

This action implements certain statutory 

requirements. 

DATES: Submit either electronic or 

written comments by May 17, 2012. 

Submit requests for a change in 

classification by March 5, 2012. See 

section XVIII of this document for the 

proposed effective date of a final rule 

based on this proposed rule. 

ADDRESSES: You may submit comments, 

identified by Docket No. FDA–2012–M– 

0076, by any of the following methods: 

Electronic Submissions 

Submit electronic comments in the 

following way: 

• 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 or CD–ROM submissions): 

Division of Dockets Management (HFA– 

305), Food and Drug Administration, 

5630 Fishers Lane, rm. 1061, Rockville, 

MD 20852. 

Instructions: All submissions received 

must include the Agency name and 

Docket No. FDA–2012–M–0076 for this 

rulemaking. All comments received may 

be posted without change to http:// 

www.regulations.gov, including any 

personal information provided. For 

additional information on submitting 

comments, see the ‘‘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: 

Melissa Burns, Center for Devices and 

Radiological Health, Food and Drug 

Administration, 10903 New Hampshire 

Ave., Bldg. 66, rm. 1646, Silver Spring, 

MD 20993, 301–796–5616, 

melissa.burns@fda.hhs.gov. 

SUPPLEMENTARY INFORMATION: 

I. Background—Regulatory Authorities 

A. Requirement for Premarket Approval 

Application 

The Federal Food, Drug, and Cosmetic 

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

Medical Device Amendments (the 1976 

amendments) (Pub. L. 94–295), the Safe 

Medical Devices Act of 1990 (SMDA) 

(Pub. L. 101–629), Food and Drug 

Administration Modernization Act of 

1997 (FDAMA) (Pub. L. 105–115), the 

Medical Device User Fee and 

Modernization Act of 2002 (MDUFMA) 

(Pub. L. 107–250), the Medical Devices 

Technical Corrections Act (Pub. L. 108– 

214), and the Food and Drug 

Administration Amendments Act of 

2007 (Pub. L. 110–85) establish 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 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 21 CFR part 807. 

A preamendments device that has 

been classified into class III may be 

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marketed by means of premarket 

notification procedures (510(k) process) 

without submission of a PMA until FDA 

issues a final regulation under section 

515(b) of the FD&C Act (21 U.S.C. 

360e(b)) requiring premarket approval. 

Section 515(b)(1) of the FD&C Act 

establishes the requirement that a 

preamendments device that FDA has 

classified into class III is subject to 

premarket approval. A preamendments 

class III device may be commercially 

distributed without an approved PMA 

or a notice of completion of a PDP until 

90 days after FDA issues a final rule 

requiring premarket approval for the 

device, or 30 months after final 

classification of the device under 

section 513 of the FD&C Act, whichever 

is later. Also, a preamendments device 

subject to the rulemaking procedure 

under section 515(b) of the FD&C Act is 

not required to have an approved 

investigational device exemption (IDE) 

(see part 812 (21 CFR part 812)) 

contemporaneous with its interstate 

distribution until the date identified by 

FDA in the final rule requiring the 

submission of a PMA for the device. At 

that time, an IDE is required only if a 

PMA has not been submitted or a PDP 

completed. 

Section 515(b)(2)(A) of the FD&C Act 

provides that a proceeding to issue a 

final rule to require premarket approval 

shall be initiated by publication of a 

notice of proposed rulemaking 

containing: (1) The regulation; (2) 

proposed findings with respect to the 

degree of risk of illness or injury 

designed to be eliminated or reduced by 

requiring the device to have an 

approved PMA or a declared completed 

PDP and the benefit to the public from 

the use of the device; (3) an opportunity 

for the submission of comments on the 

proposed rule and the proposed 

findings; and (4) an opportunity to 

request a change in the classification of 

the device based on new information 

relevant to the classification of the 

device. 

Section 515(b)(2)(B) of the FD&C Act 

provides that if FDA receives a request 

for a change in the classification of the 

device within 15 days of the publication 

of the notice, FDA shall, within 60 days 

of the publication of the notice, consult 

with the appropriate FDA advisory 

committee and publish a notice denying 

the request for change in reclassification 

or announcing its intent to initiate a 

proceeding to reclassify the device 

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

Section 515(b)(3) of the FD&C Act 

provides that FDA shall, after the close 

of the comment period on the proposed 

rule and consideration of any comments 

received, issue a final rule to require 

premarket approval or publish a 

document terminating the proceeding 

together with the reasons for such 

termination. If FDA terminates the 

proceeding, FDA is required to initiate 

reclassification of the device under 

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

the reason for termination is that the 

device is a banned device under section 

516 of the FD&C Act (21 U.S.C. 360f). 

If a proposed rule to require 

premarket approval for a 

preamendments device is finalized, 

section 501(f)(2)(B) of the FD&C Act (21 

U.S.C. 351(f)(2)(B)) requires that a PMA 

or notice of completion of a PDP for any 

such device be filed within 90 days of 

the date of issuance of the final rule or 

30 months after the final classification 

of the device under section 513 of the 

FD&C Act, whichever is later. If a PMA 

or notice of completion of a PDP is not 

filed by the later of the two dates, 

commercial distribution of the device is 

required to cease since the device would 

be deemed adulterated under section 

501(f) of the FD&C Act. 

The device may, however, be 

distributed for investigational use if the 

manufacturer, importer, or other 

sponsor of the device complies with the 

IDE regulations. If a PMA or notice of 

completion of a PDP is not filed by the 

later of the two dates, and the device 

does not comply with IDE regulations, 

the device is deemed to be adulterated 

within the meaning of section 

501(f)(1)(A) of the FD&C Act, and 

subject to seizure and condemnation 

under section 304 of the FD&C Act (21 

U.S.C. 334) if its distribution continues. 

Shipment of devices in interstate 

commerce will be subject to injunction 

under section 302 of the FD&C Act (21 

U.S.C. 332), and the individuals 

responsible for such shipment will be 

subject to prosecution under section 303 

of the FD&C Act (21 U.S.C. 333). In the 

past, FDA has requested that 

manufacturers take action to prevent the 

further use of devices for which no PMA 

or PDP has been filed and may 

determine that such a request is 

appropriate for the class III devices that 

are the subjects of this regulation. 

The FD&C Act does not permit an 

extension of the 90-day period after 

issuance of a final rule within which an 

application or a notice is required to be 

filed. The House Report on the 1976 

amendments states that ‘‘[t]he thirty 

month grace period afforded after 

classification of a device into class III 

* * * is sufficient time for 

manufacturers and importers to develop 

the data and conduct the investigations 

necessary to support an application for 

premarket approval (H. Rept. 94–853, 

94th Cong., 2d sess. 42 (1976)).’’ 

The SMDA added section 515(i) to the 

FD&C Act requiring FDA to review the 

classification of preamendments class III 

devices for which no final rule requiring 

the submission of PMAs has been issued 

and to determine whether or not each 

device should be reclassified into class 

I or class II or remain in class III. For 

devices remaining in class III, the 

SMDA directed FDA to develop a 

schedule for issuing regulations to 

require premarket approval. The SMDA 

does not, however, prevent FDA from 

proceeding immediately to rulemaking 

under section 515(b) of the FD&C Act on 

specific devices, in the interest of public 

health, independent of the procedures 

of section 515(i). Proceeding directly to 

rulemaking under section 515(b) of the 

FD&C Act is consistent with Congress’ 

objective in enacting section 515(i), i.e., 

that preamendments class III devices for 

which PMAs have not been previously 

required either be reclassified to class I 

or class II or be subject to the 

requirements of premarket approval. 

Moreover, in this proposed rule, 

interested persons are being offered the 

opportunity to request reclassification of 

any of the devices. 

B. Reclassification 

Section 513(e) of the FD&C Act 

governs reclassification of classified 

preamendments devices. This section 

provides that FDA may, by rulemaking, 

reclassify a device (in a proceeding that 

parallels the initial classification 

proceeding) based upon ‘‘new 

information.’’ FDA can initiate a 

reclassification under section 513(e) 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 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 regulatory action 

where the reevaluation is made in light 

of newly available regulatory authority 

(see Bell v. Goddard, supra, 366 F.2d at 

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

382, 388–389 (D.D.C. 1991)) or in light 

of changes in ‘‘medical science.’’ (See 

Upjohn v. Finch, supra, 422 F.2d at 

951.). Whether data before the Agency 

are past or new data, the ‘‘new 

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information’’ to support reclassification 

under section 513(e) must be ‘‘valid 

scientific evidence,’’ as defined in 

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

§ 860.7(c)(2) (21 CFR 860.7(c)(2)). (See, 

e.g., General Medical Co. v. FDA, 770 

F.2d 214 (D.C. Cir. 1985); Contact Lens 

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

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

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 secrets 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 520(h)(4) of the 

FD&C Act, added by FDAMA, provides 

that FDA may use, for reclassification of 

a device, certain information in a PMA 

6 years after the application has been 

approved. This includes information 

from clinical and preclinical tests or 

studies that demonstrate the safety or 

effectiveness of the device but does not 

include descriptions of methods of 

manufacture or product composition 

and other trade secrets. 

FDAMA added a new section 510(m) 

to the FD&C Act. New section 510(m) of 

the FD&C Act provides that a class II 

device may be exempted from the 

premarket notification requirements 

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

if the Agency determines that premarket 

notification is not necessary to assure 

the safety and effectiveness of the 

device. 

II. Regulatory History of the Device 

In the preamble to the proposed rule 

(46 FR 7562, January 23, 1981, and 46 

FR 7630, January 23, 1981), the 

Gastroenterology-Urology Device 

Classification Panel (the Panel) 

recommended that sorbent 

hemoperfusion systems be classified 

into class III because the device is life 

sustaining and life supporting and 

because there was a lack of data on the 

absorption characteristics of this device 

regarding the possibility that it may, 

while removing toxic substances, also 

remove essential substances from the 

blood or cause loss or platelets and 

white cells. The Panel indicated that 

general controls alone would not be 

sufficient and that there was not enough 

information to establish a performance 

standard. Consequently, the Panel 

believed that premarket approval was 

necessary to assure the safety and 

effectiveness of the device. In 1983, 

FDA classified sorbent hemoperfusion 

systems into class III after receiving no 

comments on the proposed rule (48 FR 

53012, November 23, 1983). In 1987, 

FDA published a clarification by 

inserting language in the codified 

language stating that no effective date 

had been established for the 

requirement for premarket approval for 

sorbent hemoperfusion system devices 

(52 FR 17732 at 17738, May 11, 1987). 

In 2009, FDA published an order for 

the submission of information on 

sorbent hemoperfusion systems by 

August 7, 2009 (74 FR 16214, April 9, 

2009). In response to that order, FDA 

received one reclassification petition 

from a device manufacturer 

recommending that sorbent 

hemoperfusion systems be reclassified 

to class II. The manufacturers stated that 

safety and effectiveness of these devices 

may be assured by device design, 

performance testing, and labeling 

(special controls). 

III. Device Description 

A sorbent hemoperfusion system is a 

device that consists of an extracorporeal 

blood system and a container filled with 

adsorbent material that removes a wide 

range of substances, both toxic and 

normal, from blood flowing through it. 

The adsorbent materials are usually 

activated-carbon or resins, which may 

be coated or immobilized to prevent fine 

particles entering the patient’s blood. 

The generic type of device may include 

lines and filters specifically designed to 

connect the device to the extracorporeal 

blood system. Sorbent hemoperfusion 

systems may also include the machine 

or instrument used to drive and manage 

blood and fluid flow within the 

extracorporeal circuit, as well as any 

accompanying controllers, monitors, or 

sensors. 

IV. Proposed Reclassification 

FDA is proposing that sorbent 

hemoperfusion systems intended for the 

treatment of poisoning and drug 

overdose be reclassified from class III to 

class II. FDA believes that the identified 

special controls would provide 

reasonable assurance of safety and 

effectiveness. Therefore, in accordance 

with sections 513(e) and 515(i) of the 

FD&C Act and § 860.130 (21 CFR 

860.130), based on new information 

with respect to the devices, FDA, on its 

own initiative, is proposing to reclassify 

this preamendments class III device 

intended for the treatment of poisoning 

and drug overdose into class II. The 

Agency has identified special controls 

that would provide reasonable 

assurance of their safety and 

effectiveness. The Agency does not 

intend to exempt this proposed class II 

device from premarket notification 

(510(k)) submission as provided for 

under section 510(m) of the FD&C Act. 

V. Risks to Health 

After considering the information 

from the reports and recommendations 

of the advisory committees (panels) for 

the classification of these devices along 

with information submitted in response 

to the 515(i) order and any additional 

information that FDA has encountered, 

FDA has evaluated the risks to health 

associated with the use of sorbent 

hemoperfusion systems and determined 

that the following risks to health are 

associated with its use: 

• Extracorporeal leaks (blood loss)— 

Rupture of the extracorporeal circuit, 

cartridge, filters, and/or tubing, as well 

as disconnections, may lead to blood 

leaks and blood loss. 

• Platelet loss and 

thrombocytopenia—The adsorption 

characteristics of the device may cause 

large losses of platelets during 

hemoperfusion. 

• Leukopenia—The materials used, or 

the design of the device, may cause 

absorption of leukocytes, leading to the 

transient loss of leukocytes in a patient. 

• Hemolysis—The materials used, or 

the design of the blood pathways in the 

device, may cause the lysis of red blood 

cells. 

• Leak of adsorbent agent into fluid 

path (release of emboli)—Fine particles 

leached from the sorbent column of the 

device may be deposited in the 

arterioles of the lungs and other organ 

as particulate emboli. 

• Lack of sterility—Improper 

sterilization or compromise of the 

device packaging may lead to the 

introduction of microorganisms, which 

may be transmitted to a patient during 

use. 

• Toxic and/or pyrogenic reactions— 

Toxic substances may be leached from 

the device, causing a patient to have a 

pyrogenic reaction (sudden fever with 

collapse and chills). 

• Infection—Defects in the design or 

construction of the device preventing 

adequate cleaning and/or sterilization 

may allow pathogenic organisms to be 

introduced and may cause an infection 

in a patient. 

• Hypotension—Sudden fluid shifts 

within the patient, due to pressures 

exerted by the device, or to fluid being 

removed by the device, may cause 

sudden decreases in a patient’s blood 

pressure. 

• Lack of biocompatibility in 

materials or solutions contacting 

blood—The patient-contacting materials 

of the device may cause an adverse 

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immunological or allergic reaction in a 

patient. 

• Clotting (blood loss)—The materials 

used, or the design of the device, may 

cause a patient’s blood to form clots, 

which may obstruct the device’s 

extracorporeal circuit, interrupting or 

terminating treatments, and also leading 

to blood loss, because the blood 

entrapped in the clotted blood circuit 

often cannot be returned to the patient. 

• Removal or depletion of vital 

nutrients, hormones, vitamins, 

substances. and drugs (e.g., adsorption 

of glucose, unspecific removal 

characteristics, drop in patients’ 

hematocrit), due to device’s lack of 

specificity—The adsorption 

characteristics of the device may cause 

removal or depletions of nutrients, 

hormones, and other necessary 

substances. 

• Metabolic disturbances—The 

removal of normal metabolites along 

with undesirable substances may lead to 

metabolic disturbances. 

• Lack of effectiveness—The 

adsorption characteristics of the device 

may lead to the failure to remove drugs 

in the treatment of poisoning or drug 

overdose, or to bring on clinical 

improvement in hepatic coma and 

metabolic disturbances. 

• Treatment interruptions or 

discontinuations—Inadequate 

safeguards in the device may lead to 

treatment interruptions or 

discontinuations in the case of power 

failures. 

• Electrical shock due to lack of 

electrical safety—Inadequate safeguards 

in the device may lead to electrical 

shocks in patients using them. 

• Electromagnetic interference, which 

may lead to adverse interactions with 

other patient systems—Inadequate 

safeguards in the device may lead to its 

interference with other patient systems, 

causing adverse events in the patient, as 

well as adversely affecting the 

performance of the other patient 

systems. 

VI. Summary of Reasons for 

Reclassification 

FDA believes that sorbent 

hemoperfusion systems intended for the 

treatment of poisoning and drug 

overdose should be reclassified into 

class II because special controls, in 

addition to general controls, can be 

established to provide reasonable 

assurance of the safety and effectiveness 

of the device. In addition, there is now 

adequate effectiveness information 

sufficient to establish special controls to 

provide such assurance. 

VII. Summary of Data Upon Which the 

Reclassification Is Based 

Since the time of the original Panel 

recommendation, sufficient evidence 

has been developed to support a 

reclassification of sorbent 

hemoperfusion system to class II with 

special controls for the treatment of 

poisoning and hepatic coma. Evidence 

including reports of clinical evaluations 

and case studies of the use of these 

devices in the treatment of poisoning 

and drug overdose, and bench studies in 

which the devices’ abilities to remove 

certain drugs have been well 

characterized. 

VIII. Proposed Special Controls 

FDA believes that the following 

special controls are sufficient to mitigate 

the risks to health described in section 

IV in this document for the treatment of 

poisoning and drug overdose: 

• The device should be demonstrated 

to be biocompatible; 

• Performance data to demonstrate 

the mechanical integrity of the device 

(e.g., tensile, flexural, and structural 

strength), including testing for the 

possibility of leaks, ruptures, release of 

particles and/or disconnections; 

• Performance data to demonstrate 

device sterility and shelf life; 

• Bench performance data to 

demonstrate device functionality in 

terms of substances, toxins, and drugs 

removed by the device, and the extent 

that these are removed when the device 

is used according to its labeling; 

• Summary of clinical experience 

with the device that discusses and 

analyzes device safety and performance, 

including a list of adverse events 

observed during the testing; 

• Labeling controls, including 

appropriate warnings, precautions, 

cautions, and contraindications 

statements to alert and inform users of 

proper device use and potential clinical 

adverse effects, including blood loss, 

platelet loss, leukopenia, hemolysis, 

hypotension, clotting, metabolic 

disturbances, and loss of vital nutrients 

and substances. Labeling 

recommendations must be consistent 

with the performance data obtained for 

the device, and must include a list of 

the drugs the device has been 

demonstrated to remove, and the extent 

of removal/depletion; and 

• For those devices that incorporate 

electrical components, appropriate 

analysis and testing to validate electrical 

safety and electromagnetic 

compatibility. 

IX. Dates New Requirements Apply 

In accordance with section 515(b) of 

the FD&C Act, FDA is proposing to 

require that a PMA or a notice of 

completion of a PDP be filed with the 

Agency for class III devices within 90 

days after issuance of any final rule 

based on this proposal. An applicant 

whose device was legally in commercial 

distribution before May 28, 1976, or 

whose device has been found to be 

substantially equivalent to such a 

device, will be permitted to continue 

marketing such class III devices during 

FDA’s review of the PMA or notice of 

completion of the PDP. FDA intends to 

review any PMA for the device within 

180 days and any notice of completion 

of a PDP for the device within 90 days 

of the date of filing. FDA cautions that 

under section 515(d)(1)(B)(i) of the 

FD&C Act, the Agency may not enter 

into an agreement to extend the review 

period for a PMA beyond 180 days 

unless the Agency finds that ‘‘the 

continued availability of the device is 

necessary for the public health.’’ 

FDA intends that under § 812.2(d), the 

preamble to any final rule based on this 

proposal will state that, as of the date on 

which the filing of a PMA or a notice 

of completion of a PDP is required to be 

filed, the exemptions from the 

requirements of the IDE regulations for 

preamendments class III devices in 

§ 812.2(c)(1) and (c)(2) will cease to 

apply to any device that is: (1) Not 

legally on the market on or before that 

date or (2) legally on the market on or 

before that date but for which a PMA or 

notice of completion of a PDP is not 

filed by that date, or for which PMA 

approval has been denied or withdrawn. 

If a PMA or notice of completion of 

a PDP for a class III device is not filed 

with FDA within 90 days after the date 

of issuance of any final rule requiring 

premarket approval for the device, 

commercial distribution of the device 

must cease. The device may be 

distributed for investigational use only 

if the requirements of the IDE 

regulations are met. The requirements 

for significant risk devices include 

submitting an IDE application to FDA 

for its review and approval. An 

approved IDE is required to be in effect 

before an investigation of the device 

may be initiated or continued under 

§ 812.30. FDA, therefore, cautions that 

IDE applications should be submitted to 

FDA at least 30 days before the end of 

the 90-day period after the issuance of 

the final rule to avoid interrupting 

investigations. 

X. Proposed Findings With Respect to 

Risks and Benefits 

As required by section 515(b) of the 

FD&C Act, FDA is publishing its 

proposed findings regarding: (1) The 

degree of risk of illness or injury 

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9614 Federal Register / Vol. 77, No. 33 / Friday, February 17, 2012 / Proposed Rules 

designed to be eliminated or reduced by 

requiring that this device have an 

approved PMA or a declared completed 

PDP when indicated for the treatment of 

hepatic coma and metabolic 

disturbances and (2) the benefits to the 

public from the use of the sorbent 

hemoperfusion system for treatment of 

hepatic coma and metabolic 

disturbances. 

These findings are based on the 

reports and recommendations of the 

advisory committees (panels) for the 

classification of these devices along 

with information submitted in response 

to the 515(i) Order, (74 FR 16214) and 

any additional information that FDA has 

encountered. Additional information 

regarding the risks as well as 

classification associated with this 

device type can be found in 46 FR 7630, 

46 FR 7562, and 48 FR 53023. 

For the treatment of hepatic coma and 

metabolic disturbances, FDA concludes 

that the safety and effectiveness of these 

devices have not been established by 

adequate scientific evidence, and the 

Agency continues to agree with the 

Panel’s recommendation. The review of 

the published scientific literature 

revealed mostly observational studies 

performed with sorbent hemoperfusion 

devices. Only a few randomized, 

controlled trials were found, but sample 

sizes were small and not adequately 

powered, and etiologies and control 

group criteria were varied. Furthermore, 

based on FDA’s experience reviewing 

these devices for use in the treatment of 

hepatic coma and metabolic 

disturbances, bench testing is not 

adequate in establishing the devices’ 

safety and effectiveness, particularly 

since characterizing a sorbent 

hemoperfusion system’s performance 

and adsorption capabilities has not 

correlated to patient outcomes, such as 

resolution of the patients’ hepatic coma, 

or improvements in mortality. The 

scientific literature also revealed that 

there is no consensus on the clinical 

endpoints necessary to adequately 

evaluate sorbent hemoperfusion devices 

for the treatment of hepatic coma and 

metabolic disturbances or on the patient 

populations who will benefit the most 

from the use of these devices. 

XI. PMA Requirements 

A PMA for sorbent hemoperfusion 

system indicated for the treatment of 

hepatic coma and metabolic 

disturbances must include the 

information required by section 

515(c)(1) of the FD&C Act. Such a PMA 

should also include a detailed 

discussion of the risks identified 

previously, as well as a discussion of 

the effectiveness of the device for which 

premarket approval is sought. In 

addition, a PMA must include all data 

and information on: (1) Any risks 

known, or that should be reasonably 

known, to the applicant that have not 

been identified in this document; (2) the 

effectiveness of the device that is the 

subject of the application; and (3) full 

reports of all preclinical and clinical 

information from investigations on the 

safety and effectiveness of the device for 

which premarket approval is sought. 

A PMA must include valid scientific 

evidence to demonstrate reasonable 

assurance of the safety and effectiveness 

of the device for its intended use (see 

§ 860.7(c)(2)). Valid scientific evidence 

is ‘‘evidence from well-controlled 

investigations, partially controlled 

studies, studies and objective trials 

without matched controls, welldocumented case histories conducted by 

qualified experts, and reports of 

significant human experience with a 

marketed device, from which it can 

fairly and responsibly be concluded by 

qualified experts that there is reasonable 

assurance of the safety and effectiveness 

of a device under its conditions of use. 

* * * Isolated case reports, random 

experience, reports lacking sufficient 

details to permit scientific evaluation, 

and unsubstantiated opinions are not 

regarded as valid scientific evidence to 

show safety or effectiveness. * * *’’ 

(§ 860.7(c)(2)). 

XII. PDP Requirements 

A PDP for sorbent hemoperfusion 

system indicated for the treatment of 

hepatic coma and metabolic 

disturbances may be submitted in lieu 

of a PMA and must follow the 

procedures outlined in section 515(f) of 

the FD&C Act. A PDP must provide: (1) 

A description of the device, (2) 

preclinical trial information (if any), (3) 

clinical trial information (if any), (4) a 

description of the manufacturing and 

processing of the devices, (5) the 

labeling of the device, and (6) all other 

relevant information about the device. 

In addition, the PDP must include 

progress reports and records of the trials 

conducted under the protocol on the 

safety and effectiveness of the device for 

which the completed PDP is sought. 

XIII. Opportunity To Request a Change 

in Classification 

Before requiring the filing of a PMA 

or notice of completion of a PDP for a 

device, FDA is required by section 

515(b)(2)(A)(i) through (b)(2)(A)(iv) of 

the FD&C Act and § 860.132 to provide 

an opportunity for interested persons to 

request a change in the classification of 

the device based on new information 

relevant to the classification. Any 

proceeding to reclassify the device will 

be under the authority of section 513(e) 

of the FD&C Act. 

A request for a change in the 

classification of these devices is to be in 

the form of a reclassification petition 

containing the information required by 

§ 860.123 (21 CFR 860.123), including 

new information relevant to the 

classification of the device. 

The Agency advises that to ensure 

timely filing of any such petition, any 

request should be submitted to the 

Division of Dockets Management (see 

ADDRESSES) and not to the address 

provided in § 860.123(b)(1). If a timely 

request for a change in the classification 

of these devices is submitted, the 

Agency will, within 180 days after 

receipt of the petition, and after 

consultation with the appropriate FDA 

resources, publish an order in the 

Federal Register that either denies the 

request or gives notice of its intent to 

initiate a change in the classification of 

the device in accordance with section 

513(e) of the FD&C Act and § 860.130 of 

the regulations. 

XIV. Environmental Impact 

The Agency has determined under 21 

CFR 25.30(h) 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. 

XV. Analysis of Impacts 

FDA has examined the impacts of the 

proposed 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). The Agency 

believes that this proposed rule is not a 

significant regulatory action 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. 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 

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Federal Register / Vol. 77, No. 33 / Friday, February 17, 2012 / Proposed Rules 9615 

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 $136 

million, using the most current (2010) 

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. 

A. Objective of the Proposed Rule 

The objective of this proposed rule is 

to classify sorbent hemoperfusion 

devices, which are preamendments 

class III devices. These devices are used 

in the treatment of drug overdose, 

poisoning, hepatic coma, and metabolic 

disturbances. The classification of these 

devices will be split into two parts 

based on the indication of use. Devices 

indicated for treatment of poisoning and 

drug overdose will be reclassified into 

class II with special controls. Devices 

indicated for treatment in hepatic coma 

and metabolic disturbances will be 

maintained in class III with PMA or PDP 

requirements. Sorbent hemoperfusion 

systems were originally classified as 

class III because they are life sustaining 

and life supporting, and there was lack 

of data to establish an adequate 

performance standard for these devices. 

Since that time, sufficient evidence has 

been accumulated to develop special 

controls for the treatment of poisoning 

and drug overdose, and the risks to 

health are now well characterized and 

understood. However, there is 

insufficient scientific evidence to 

develop special controls for these 

devices when used for the treatment of 

hepatic coma and metabolic 

disturbances. The call for PMAs or PDPs 

will allow for adequate evaluation of the 

device, particularly with respect to the 

clinical data necessary to support the 

safety and effectiveness of these devices 

when used in the treatment of these 

conditions. 

B. Sorbent Hemoperfusion Systems for 

the Treatment of Poisoning and Drug 

Overdose 

This rule proposes to reclassify 

sorbent hemoperfusion devices for the 

treatment of drug overdose and 

poisoning into class II devices with 

special controls. Currently, 

manufacturers of sorbent hemoperfusion 

devices are subject to premarket 

notification requirements similar to 

most class II devices, with 

manufacturers receiving clearance to 

market via a 510(k) premarket 

notification submission with no 

premarket approval (PMA) requirement. 

FDA has concluded that special controls 

are sufficient for ensuring the safety and 

effectiveness of these devices and that 

these devices may be reclassified to 

class II (special controls). 

FDA’s Premarket Notification 510(k) 

database identifies five manufacturers of 

six sorbent hemoperfusion devices. All 

six of these devices have been cleared 

for use in the treatment of drug overdose 

and poisoning. According to the 2005– 

2009 annual reports of the American 

Association of Poison Control Centers’ 

National Poison Data Systems, 

hemoperfusion was used in an average 

of 27 cases per year, which suggests 

limited use of this device for these 

indications. 

The proposed rule would require that 

manufacturers who wish to market new 

sorbent hemoperfusion devices or 

implement changes to existing marketed 

devices indicated for the treatment of 

poisoning and drug overdose submit 

510(k)s that comply with the proposed 

special controls. As current practice, the 

Agency already recommends that 

manufacturers adopt the risk mitigations 

that are being proposed as special 

controls, so this rule would essentially 

formalize current practice as a 

regulation for these devices. Hence, this 

reclassification will not result in any 

significant changes in how 510(k)s for 

the affected devices are prepared or in 

how they are reviewed, and compliance 

with the special controls proposed for 

this device will not yield significant 

new costs for affected manufacturers. 

Because the formal reclassification of 

the affected devices from class III to 

class II with special controls is 

consistent with current FDA and 

industry practice, the Agency concludes 

that the proposed rule would impose no 

additional regulatory burdens on the 

manufacturing and marketing of sorbent 

hemoperfusion devices for the treatment 

of drug overdose and poisoning. 

C. Sorbent Hemoperfusion Systems for 

the Indications of Hepatic Coma and 

Metabolic Disturbances 

1. Benefits 

The proposed requirement for PMAs 

or PDPs for sorbent hemoperfusion 

systems for treatment of hepatic coma 

and metabolic disturbances would 

generate social benefits equal to the 

value of information generated by the 

safety and effectiveness tests that 

producers of the device would be 

required to conduct under the proposed 

call for PMAs or PDPs. Provided first to 

FDA, this information would assist 

physicians, patients, and insurance 

providers to make more informed 

decisions regarding the safe and proper 

use of these devices, which would also 

be expected to improve some patient 

outcomes. There are currently no 

actively marketed products that are 

cleared for the indication of hepatic 

coma and metabolic disturbances. 

However, FDA projects that two firms 

are likely to enter the market in the near 

future. 

Hepatic coma is characterized as the 

final state of hepatic encephalopathy, a 

complication of liver failure in which 

the brain function progressively 

deteriorates. Hepatic encephalopathy is 

a condition in which toxic substances 

that are normally cleared from the body 

by the liver accumulate in the blood, 

eventually traveling to the brain. 

Hepatic coma marks the final stage of 

encephalopathy, at which the 

disturbance of the brain function leads 

to loss of consciousness. Sorbent 

hemoperfusion systems can be used as 

a treatment device to compensate for 

liver failure by removing toxins from the 

blood. 

Data from the Healthcare Cost and 

Utilization Project, a nationally 

representative sample of hospital 

discharges, suggest that hepatic coma 

related hospitalizations are associated 

with prolonged and costly hospital 

stays. In 2009, there were approximately 

43,500 patients hospitalized in the 

United States for a primary diagnosis of 

hepatic coma. The number of discharges 

rises to over 115,000 when accounting 

for all-listed diagnoses, which include 

all diagnoses that coexist at the time of 

admission or that develop during 

hospitalization. For patients admitted 

with a primary diagnosis of hepatic 

coma, the mean length of stay was 5.8 

days, with a mean cost of $10,000 per 

stay. In-hospital mortality was nearly 8 

percent in 2009, while the survival rate 

after 3 years among patients with 

hepatic encephalopathy is estimated to 

be 25 percent (Ref. 1). 

There is limited scientific evidence 

regarding the effectiveness of sorbent 

hemoperfusion systems for the 

indication of hepatic coma, which could 

partially be due to the fragile nature of 

the patient population (i.e., individuals 

who are acutely ill due to liver disease, 

and thus face poor clinical prognosis 

and high mortality). Because the risks 

and benefits of these devices for this 

indication are unknown and therefore 

cannot be adequately characterized, it is 

impossible to estimate the direct effect 

of the devices on patient outcomes. 

However, if they are approved, the 

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9616 Federal Register / Vol. 77, No. 33 / Friday, February 17, 2012 / Proposed Rules 

devices have the potential to greatly 

improve patient outcomes relative to the 

current baseline, since there are no 

alternative devices currently on the 

market. The PMA requirement will 

provide clinical testing to establish the 

safety and efficacy of the devices, to 

characterize their performance, and to 

determine the patient populations who 

will benefit most from the use of these 

devices. Clinical trials may also identify 

design issues that would have gone 

unnoticed in a premarket notification 

process, thereby reducing the potential 

of device failures. Furthermore, PMA 

requirements allow for continuing 

postmarketing evaluation and periodic 

reporting to FDA on the safety, 

effectiveness, and reliability of the 

device for its intended use. 

2. Costs 

The proposed rule would require 

producers of sorbent hemoperfusion for 

treatment of hepatic coma and 

metabolic disturbances to obtain a PMA 

or PDP prior to marketing new products. 

Currently, producers of sorbent 

hemoperfusion systems receive 

clearance to market these devices 

through the less costly 510(k) premarket 

notification process. The incremental 

cost of this rule for those who are 

developing devices to treat hepatic 

coma and metabolic disturbance would 

be the difference between the cost of 

preparing and submitting a premarket 

approval application and the cost of 

preparing and submitting a 510(k) 

application. The cost of preparing an 

average 510(k) application has been 

estimated to be $21 per page, or $37 

after adjusting for inflation (Ref. 2). 

According to FDA industry experts, the 

number of pages in 510(k) submissions 

can range from an average of 400 for 

simple devices to 4,000 pages for more 

complicated systems. Assuming that the 

devices for this indication of treatment 

are complex in nature due to the 

intricate health conditions of the 

intended patient population, we use 

4,000 pages as our primary estimate. At 

a cost per page of $37, this yields an 

average cost of preparing and submitting 

a 510(k) of $148,000. FDA has estimated 

an upper bound on the cost of preparing 

and submitting a PMA at approximately 

$1,000,000 (see, for example, 73 FR 

7498 at 7502, February 8, 2008), which 

rises to $1,019,000 after inflation. This 

yields a difference of $871,000 between 

the costs of PMA and 510(k) 

preparation. Manufacturers must also 

pay FDA user fees. For fiscal year 2012, 

the user fee for a 510(k) submission is 

$4,049 for large firms and $2,024 for 

small firms (76 FR 45826 at 45828, 

August 1, 2011). The user fee for a 

premarket application (PMA or PDP) is 

currently set at $220,050 for large firms 

and $55,013 for small firms (76 FR 

45828). This yields a cost difference of 

PMA and 510(k) submission costs of 

$216,001 for large companies and 

$52,989 for small businesses. The total 

incremental upfront rule-induced cost 

to industry of preparing and submitting 

a PMA or PDP is $1,083,950 for large 

firms and $908,901 for small firms. 

Manufacturers also incur postmarketing 

annual fees for periodic reporting to 

FDA, with the standard fee for annual 

reports currently set at $7,702 for large 

firms and $1,925 for small firms. 

In addition to the cost to industry of 

preparing and submitting PMAs or 

PDPs, the proposed rule would impose 

review costs on FDA. It has been 

estimated that, for devices reviewed by 

FDA’s Center for Devices and 

Radiological Health in 2003 and 2004, 

review costs were $563,000 per PMA 

and $13,400 per 510(k) (Ref. 3). Updated 

for inflation to 2010 dollars, these 

review costs become $653,000 per PMA 

and $15,500 per 510(k). This yields an 

incremental cost to FDA of $637,500. A 

portion of this total will be paid by 

industry in the form of user fees, with 

the remainder borne by general 

revenues. 

The social costs per PMA would be 

the sum of the difference between a 

PMA and a 510(k) and the additional 

FDA costs of reviewing the PMA, or 

$1,508,500 (= $871,000 + $637,500). The 

annual cost of the proposed rule would 

be the number of submissions 

multiplied by the cost per submission. 

Because we project that few entities will 

introduce this device, the number of 

submissions in most years will be zero. 

FDA requests comments on the methods 

and results of our estimation. 

D. Impact on Small Entities 

The Regulatory Flexibility Act 

requires Agencies to prepare an initial 

regulatory analysis if a proposed rule 

would have a significant effect on a 

substantial number of small businesses, 

nonprofit organizations, local 

jurisdictions, or other entities. The 

proposed rule will yield no new costs 

for the five producers of sorbent 

hemoperfusion devices for the treatment 

of drug overdose and poisoning, as the 

rule is essentially a formalization of 

current industry practice. There are 

currently no companies actively 

participating in the market for the 

indications of hepatic coma and 

metabolic disturbance, which will 

require PMAs or PDPs as a result of the 

proposed rule. FDA projects that very 

few entities will enter this market in the 

near future. If a small entity were to 

enter the market, the reduced user fees 

would provide some relief. FDA 

requests comments on the overall effect 

of the proposed classification on the 

potential entry of small entities. 

Because this proposed rule would 

impose no additional regulatory 

burdens for manufacturers of sorbent 

hemoperfusion devices currently in the 

market and there is limited participation 

in the market for devices that will 

require PMAs or PDPs, FDA concludes 

that this proposed rule would not have 

a significant economic impact on a 

substantial number of small entities. 

XVI. Federalism 

FDA has analyzed this proposed rule 

in accordance with the principles set 

forth in Executive Order 13132. FDA 

has determined that the proposed rule, 

if finalized, would 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 tentatively 

concludes that the proposed 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. 

XVII. Paperwork Reduction Act of 1995 

This proposed rule 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. 

XVIII. Proposed Effective Date 

FDA is proposing that any final rule 

based on this proposal become effective 

on the date of its publication in the 

Federal Register or at a later date if 

stated in the final rule. 

XIX. Comments 

Interested persons may submit to the 

Division of Dockets Management (see 

ADDRESSES) either electronic or written 

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Federal Register / Vol. 77, No. 33 / Friday, February 17, 2012 / Proposed Rules 9617 

comments regarding this document. It is 

only necessary to submit one set of 

comments. Identify comments with the 

docket number found in the 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. 

XX. References 

The following references have been 

placed on display in the Division of 

Dockets Management (see ADDRESSES) 

and may be seen by interested persons 

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

through Friday. (FDA has verified the 

Web site address, but FDA is not 

responsible for any subsequent changes 

to the Web site after this document 

publishes in the Federal Register.) 

1. Schiano, T.D., ‘‘Clinical Management of 

Hepatic Encephalopathy,’’ vol. 30, pp. 

10S–15S, Pharmacotherapy, 2010. 

2. Blozan, C.F. and S.A. Tucker, ‘‘Premarket 

Notifications: The First 24,000,’’ pp. 59– 

69, Medical Device & Diagnostic 

Industry, 1986. 

3. Geiger, D.R., ‘‘FY 2003 and FY 2004 Unit 

Costs for the Process of Medical Device 

Review,’’ (http://www.fda.gov/ 

downloads/MedicalDevices/

DeviceRegulationandGuidance/ 

Overview/MedicalDeviceUserFeeand

ModernizationActMDUFMA/ucm

109216.pdf), September 2005. 

List of Subjects in 21 CFR Part 876 

Medical devices. 

Therefore, under the Federal Food, 

Drug, and Cosmetic Act and under 

authority delegated to the Commissioner 

of Food and Drugs, it is proposed that 

21 CFR part 876 be amended as follows: 

PART 876—GASTROENTEROLOGYUROLOGY DEVICES 

1. The authority citation for 21 CFR 

part 876 continues to read as follows: 

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

360j, 360l, 371. 

2. Section 876.5870 is amended by 

revising paragraphs (b) and (c) to read 

as follows: 

§ 876.5870 Sorbent hemoperfusion 

system. 

* * * * * 

(b) Classification. (1) Class II (special 

controls) when the device is intended 

for the treatment of poisoning and drug 

overdose. The special controls for this 

device are: 

(i) The device should be demonstrated 

to be biocompatible; 

(ii) Performance data to demonstrate 

the mechanical integrity of the device 

(e.g., tensile, flexural, and structural 

strength), including testing for the 

possibility of leaks, ruptures, release of 

particles, and/or disconnections; 

(iii) Performance data to demonstrate 

device sterility and shelf life; 

(iv) Bench performance data to 

demonstrate device functionality in 

terms of substances, toxins, and drugs 

removed by the device, and the extent 

that these are removed when the device 

is used according to its labeling; 

(v) Summary of clinical experience 

with the device that discusses and 

analyzes device safety and performance, 

including a list of adverse events 

observed during the testing; 

(vi) Labeling controls, including 

appropriate warnings, precautions, 

cautions, and contraindications 

statements to alert and inform users of 

proper device use and potential clinical 

adverse effects, including blood loss, 

platelet loss, leukopenia, hemolysis, 

hypotension, clotting, metabolic 

disturbances, and loss of vital nutrients 

and substances; Labeling 

recommendations must be consistent 

with the performance data obtained for 

the device, and must include a list of 

the drugs the device has been 

demonstrated to remove, and the extent 

for removal/depletion; and 

(vii) For those devices that 

incorporate electrical components, 

appropriate analysis and testing to 

validate electrical safety and 

electromagnetic compatibility. 

(2) Class III (premarket approval) 

when the device is intended for the 

treatment of hepatic coma and 

metabolic disturbances. 

(c) Date premarket approval 

application (PMA) or notice of 

completion of product development 

protocol (PDP) is required. A PMA or 

notice of completion of a PDP is 

required to be filed with FDA on or 

before [date 90 days after date of 

publication of the final rule in the 

Federal Register], for any sorbent 

hemoperfusion system indicated for 

treatment of hepatic coma or metabolic 

disturbances that was in commercial 

distribution before May 28, 1976, or that 

has, on or before [date 90 days after date 

of publication of the final rule in the 

Federal Register], been found to be 

substantially equivalent to any sorbent 

hemoperfusion device indicated for 

treatment of hepatic coma or metabolic 

disturbances that was in commercial 

distribution before May 28, 1976. Any 

other sorbent hemoperfusion system 

device indicated for treatment of hepatic 

coma or metabolic disturbances shall 

have an approved PMA or declared 

completed PDP in effect before being 

placed in commercial distribution. 

Dated: February 14, 2012. 

Nancy K. Stade, 

Deputy Director for Policy, Center for Devices 

and Radiological Health. 

[FR Doc. 2012–3810 Filed 2–16–12; 8:45 am] 

BILLING CODE 4160–01–P 

DEPARTMENT OF DEFENSE 

Defense Acquisition Regulations 

System 

48 CFR Part 242 

RIN 0750–AH52 

Defense Federal Acquisition 

Regulation Supplement; DoD Voucher 

Processing (DFARS Case 2011–D054) 

AGENCY: Defense Acquisition 

Regulations System, Department of 

Defense (DoD). 

ACTION: Proposed rule; clarification. 

SUMMARY: DoD is clarifying the rule 

published on January 19, 2012, 

proposing to amend the Defense Federal 

Acquisition Regulation Supplement 

(DFARS) to update DoD’s voucher 

processing procedures and better 

accommodate the use of Wide Area 

WorkFlow to process vouchers. 

DATES: Comments on the proposed rule 

published January 19, 2012, at 77 FR 

2682, continue to be accepted until 

March 19, 2012. 

FOR FURTHER INFORMATION CONTACT: Mr. 

Mark Gomersall, Defense Acquisition 

Regulations System, OUSD (AT&L) 

DPAP (DARS), Room 3B855, 3060 

Defense Pentagon, Washington, DC 

20301–3060. Telephone 703–602–0302; 

facsimile 703–602–0350. 

SUPPLEMENTARY INFORMATION: DoD is 

clarifying the proposed rule published 

on January 19, 2012 (77 FR 2682), which 

proposes to revise requirements for 

approving interim vouchers. Interim 

vouchers that are selected using riskbased sampling methodologies will be 

reviewed and approved by the contract 

auditors for provisional payment and 

sent to the disbursing office after the 

pre-payment review. Interim vouchers 

not selected for a pre-payment review 

will be considered acceptable for 

payment and will be sent directly to the 

disbursing office. All interim vouchers 

are subject to an audit of actual costs 

incurred after payment. The sampling 

process will be accomplished largely 

within the Wide Area WorkFlow 

system. 

The rule proposes to revise the 

requirements for approving interim 

vouchers by replacing the direct 

submission process currently referenced 

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