[Federal Register Volume 64, Number 25 (Monday, February 8, 1999)]
[Proposed Rules]
[Pages 5987-5996]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 99-2689]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Part 876

[Docket No. 98N-1134]


Gastroenterology and Urology Devices; Reclassification of the 
Extracorporeal Shock Wave Lithotripter

AGENCY: Food and Drug Administration, HHS.

ACTION: Proposed rule.

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SUMMARY: The Food and Drug Administration (FDA) is issuing for public 
comment its proposal to reclassify from class III to class II the 
extracorporeal shock wave lithotripter, when intended for use to 
fragment kidney and ureteral calculi, and the recommendation of the 
Gastroenterology and Urology Devices Advisory Panel (the Panel) 
regarding this reclassification. The Panel made this recommendation 
after reviewing the relevant publicly available information and the 
proposed reclassification. FDA is also issuing for public comment its 
tentative findings on the Panel's recommendation. After considering any 
public comments on the Panel's recommendation and FDA's tentative 
findings, FDA will reclassify the device or retain it in class III. 
FDA's decision on the proposed reclassification will be announced in 
the Federal Register.

DATES: Written comments by May 10, 1999.
ADDRESSES: Submit written comments to the Dockets Management Branch 
(HFA-305), Food and Drug Administration, 5630 Fishers Lane, rm. 1061, 
Rockville, MD 20852.

FOR FURTHER INFORMATION CONTACT: John H. Baxley, Center for Devices and 
Radiological Health (HFZ-470), Food and Drug Administration, 9200 
Corporate Blvd., Rockville, MD 20850, 301-594-2194.

SUPPLEMENTARY INFORMATION:

I. Background

    The Federal Food, Drug, and Cosmetic Act (the act) (21 U.S.C. 301 
et. seq.), as amended by the Medical Device Amendments of 1976 (the 
1976 amendments) (Pub. L. 94-295), the Safe Medical Devices Act of 1990 
(the SMDA) (Pub. L. 101-629), and the Food and Drug Administration 
Modernization Act of 1997 (the FDAMA) (Pub. L. 105-115), established a 
comprehensive system for the regulation of medical devices intended for 
human use. Section 513 of the act (21 U.S.C. 360c) established three 
categories (classes) of devices, depending on 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 act, devices that were in commercial 
distribution before May 28, 1976 (the date of enactment of the 1976 
amendments), 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 classified 
automatically by statute (section 513(f) of the act (21 U.S.C. 
360c(f))) 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, under section 
513(i) of the act (21 U.S.C. 360c(i)), to a predicate device that does 
not require premarket approval. The agency determines whether new 
devices are substantially equivalent to previously offered devices by 
means of premarket notification procedures in section 510(k) of the act 
(21 U.S.C. 360(k)) and part 807 of the regulations (21 CFR part 807).
    A preamendments device that has been classified into class III may 
be marketed, by means of premarket notification procedures, without 
submission of a premarket approval application (PMA) until FDA issues a 
final regulation under section 515(b) of the act (21 U.S.C.360e(b)) 
requiring premarket approval.
    Reclassification of classified postamendments devices is governed 
by section 513(f)(2) of the act (21 U.S.C. 360c(f)(2)). This section 
provides that FDA may initiate the reclassification of a device 
classified into class III under section 513(f)(1) of the act, or the 
manufacturer or importer of a device may petition the Secretary of 
Health and Human Services (the Secretary) for the issuance of an order 
classifying the device in class I or class II. FDA's regulations in 21 
CFR 860.134 set forth the procedures for the filing and review of a 
petition for reclassification of such class III devices. In order to 
change the classification of the device, it is necessary that the 
proposed new class have sufficient regulatory controls to provide 
reasonable assurance of the safety and effectiveness of the device for 
its intended use.
    Section 216 of FDAMA replaced the ``four of a kind'' rule in the 
old section 520(h)(4) of the act (21 U.S.C. 360j(h)(4)) with a 
provision that frees agency use of data in PMA's approved 6 or more 
years before FDA undertakes certain regulatory actions, including 
device reclassifications. Under section 520(h)(4) of the act, as 
amended by FDAMA, the agency has supplemented other sources of 
information that support reclassification of the extracorporeal shock 
wave lithotripter with data contained in PMA's approved 6 or more years 
before the date of this proposal. In this instance, FDA has only used 
data that would have been available to the agency under the superseded 
four of a kind rule.
    Under section 513(f)(2)(B)(i) of the act (21 U.S.C. 
360c(f)(2)(B)(i)), the Secretary, for good cause shown, may refer a 
proposed reclassification to a

[[Page 5988]]

device classification panel. The Panel shall make a recommendation to 
the Secretary respecting approval or denial of the proposed 
reclassification. Any such recommendation shall contain: (1) A summary 
of the reasons for the recommendation, (2) a summary of the data upon 
which the recommendation is based, and (3) an identification of the 
risks to health (if any) presented by the device with respect to which 
the proposed reclassification was initiated.

II. Regulatory History of the Device

    The extracorporeal shock wave lithotripter intended for the 
fragmentation of kidney and ureteral calculi is a postamendments device 
classified into class III under section 513(f)(1) of the act. 
Therefore, this generic type of device cannot be placed in commercial 
distribution unless it is reclassified under section 513(f)(2), or is 
the subject of a PMA or notice of completion of a product development 
protocol (PDP) under section 515 of the act (21 U.S.C. 360e).
    In accordance with section 513(f)(2) of the act, FDA, on its own 
initiative, is proposing to reclassify this device from class III to 
class II when intended to fragment kidney and ureteral calculi. FDA 
referred the proposed reclassification to the Panel for its 
recommendation on the requested change in classification. This panel 
meeting was held on July 30, 1998, and is summarized further in Section 
VI.

III. Device Description

    An extracorporeal shock wave lithotripter is a device that focuses 
ultrasonic shock waves into the body to noninvasively fragment urinary 
calculi within the kidney and ureter. The primary components of the 
device are a shock wave generator, high voltage generator, control 
console, imaging/localization system, and patient table. Prior to 
treatment, the urinary stone is targeted using either an integral or 
stand-alone localization/imaging system. Shock waves are typically 
generated using electrostatic spark discharge (spark gap), 
electromagnetically repelled membranes, or piezoelectric crystal 
arrays, and focused onto the stone with either a specially designed 
reflector, dish, or acoustic lens. The shock waves are created under 
water within the shock wave generator, and are transferred to the 
patient's body through a water-filled rubber cushion or by direct 
contact of the patient's skin with the water. After the stone has been 
fragmented by the focused shock waves, the fragments pass out of the 
body with the patient's urine.

IV. Recommendations of the Panel

    At a public meeting on July 30, 1998, the Panel unanimously 
recommended that the extracorporeal shock wave lithotripter indicated 
for the fragmentation of kidney and ureteral calculi be reclassified 
from class III to class II. The Panel believed that the special 
controls of consensus standards, clinical performance testing, labeling 
restrictions, and physician training restrictions would provide 
reasonable assurance of the safety and effectiveness of the device.

V. Risks to Health

    After considering the information discussed by the Panel during the 
reclassification proceedings, the published literature, data in PMA 
applications available to FDA under section 520(h)(4) of the act, as 
amended by FDAMA, and the Medical Device Reports, FDA believes the 
following risks are associated with the use of the extracorporeal shock 
wave lithotripter in the fragmentation of kidney and ureteral calculi.

A. Bleeding

    Interaction between the shock waves and internal tissues can result 
in bleeding within the urinary tract. Lithotripsy-induced bleeding 
typically presents as either hematuria (blood in the urine) or renal 
hematoma. Hematuria occurs following most treatments (Refs. 4, 69, and 
85), is believed to be secondary to trauma to the renal parenchyma 
(Ref. 7), and usually resolves spontaneously within 24 to 48 hours of 
treatment (Refs. 8 and 69). Small, asymptomatic renal hematomas occur 
with 20 to 25 percent of treatments, which resolve without intervention 
(Ref. 52). In less than 1 percent of treatments, however, clinically 
significant intrarenal, subcapsular, or perirenal hematomas occur 
(Refs. 20 and 50). These patients typically present with severe, 
chronic flank pain (Refs. 4, 50, 52, and 84), and anuria secondary to 
renal compression has also been reported (Refs. 62 and 95). Although 
clinically significant hematomas often resolve with conservative 
management (Refs. 50, 52, and 84), severe hemorrhage (Refs. 4, 85, and 
92) or death (Refs. 66 and 92) has been reported. Management of severe 
renal hemorrhage includes the administration of blood transfusions 
(Refs. 50, 52, 81, 85, and 92), percutaneous drainage (Ref. 72), or 
surgical intervention, which may include nephrectomy (Refs. 4, 50, and 
62).
    Lithotripsy-induced bleeding is believed to be caused by vessel 
damage secondary to the collapse of cavitation bubbles at the shock 
wave focus (Refs. 17 and 65). The risk of serious bleeding is minimized 
by the use of conservative treatment parameters (Ref. 17) and careful 
evaluation of the patient post-treatment (Ref. 50).
    Patient characteristics associated with increased risk for the 
development of life threatening hemorrhage include the presence of 
coagulopathy or the use of anticoagulant therapy (including aspirin) 
(Refs. 45, 73, 85, and 91), presence of an arterial calcification or 
vascular aneurysm (Refs. 9, 19, and 91), and poorly-controlled 
hypertension (Refs. 49 and 50). For some of these high risk patients, 
however, lithotripsy can still be delivered safely as long as certain 
precautions are taken. Specifically, patients on anticoagulant therapy 
can undergo lithotripsy provided that their anticoagulation is 
temporarily reversed (Refs. 73 and 91). Furthermore, patients with an 
arterial calcification or vascular aneurysm have been treated without 
complication provided that the calcification or aneurysm is 
sufficiently outside of the shock wave path, treatment is limited to a 
minimum number of low-power shock waves, and the patient is carefully 
monitored (Refs. 9 and 19).

B. Renal Injury

    The focused shock waves delivered by all extracorporeal shock wave 
lithotripters cause some degree of acute trauma to the treated kidney 
with associated functional impairment (Refs. 1, 7, 41, and 101). As 
with bleeding, renal injury is probably secondary to the effects of 
cavitation at the shock wave focus (Refs. 16, 17, and 82).
    It is believed that renal trauma, with associated nephron loss and/
or tubule damage, occurs during nearly all lithotripsy treatments 
(Refs. 1 and 82), is dependent upon the applied shock wave dose (Refs. 
74, 82, and 86), and is typically limited to the size of the shock wave 
focal volume (Ref. 83). While a small region of renal scarring persists 
at the treated site (Refs. 74 and 86), any associated changes in renal 
function resolve within 30 days (Refs. 3, 6, 32, and 86). Although 
infrequently reported and of questionable clinical significance, 
permanent morphological changes to the kidney have been observed 
following lithotripsy (Refs. 6 and 74). The risk of renal injury is 
minimized by delivering fewer, less powerful shock waves (Refs. 70 and 
74), and using a lower shock wave repetition rate (Refs. 17 and 86).

[[Page 5989]]

    Patients with solitary kidneys or pre-existing impairment of renal 
function may be at increased risk for long-term changes (Refs. 74 and 
100). Additionally, although many short-term studies have been 
published regarding the safe use of extracorporeal shock wave 
lithotripsy in children (Refs. 53, 55, 69, and 70), questions still 
exist regarding the long-term effects of shock waves upon the function 
and growth of the immature kidney (Refs. 15, 27, 70, and 74).

C. Hypertension

    Early investigators reported new onset of hypertension in as many 
as 8 percent of patients between 1 and 2 years following extracorporeal 
shock wave lithotripsy to the kidney (Refs. 58 and 99). The 
physiological basis of this finding was theorized to be caused by the 
Page effect, secondary to the renal fibrosis that occurs following 
resolution of lithotripsy-induced intraparenchymal hemorrhage (Refs. 52 
and 99). Despite the hypertension incidence rates reported by these 
early studies, however, subsequent research indicates that hypertension 
is not a risk of lithotripsy. Lingeman et al. noted no difference at 2 
years in the rates of new onset of hypertension between patients who 
received lithotripsy and those who received alternative stone removal 
therapies, although a small but statistically significant increase in 
diastolic blood pressure was seen in the lithotripsy group (Ref. 61). 
In a subsequent report describing 3- and 4-year followup on the same 
patients, similar outcomes were observed (Ref. 60). In a similar 
investigation, Vaughan et al. observed no difference in either new 
onset of hypertension or blood pressure between lithotripsy and 
nonlithotripsy treated patients 2 years post-treatment (Ref. 98). The 
results of these controlled studies demonstrate that the development of 
hypertension is not an actual risk of lithotripsy among normal, healthy 
patients. However, due to the unknown effects of lithotripsy-induced 
damage to the growing kidney, concern has been raised that pediatric 
patients may be at increased risk of developing chronic hypertension 
(Ref. 74).

D. Cardiac Arrhythmia

    Cardiac arrhythmias, most commonly premature ventricular 
contractions, are generally reported during extracorporeal shock wave 
lithotripsy at fixed shock wave delivery in 2 to 20 percent of patients 
(Refs. 14 and 30). While the specific cause of lithotripsy-induced 
arrhythmias is not fully understood, researchers have postulated 
several causes, including irritation or mechanical stimulation of the 
myocardium by the shock wave, autonomic nerve stimulation, or the 
effects of the intravenous sedatives (Refs. 14 and 43). Arrhythmias 
resolve spontaneously upon synchronizing the shock waves with the 
refractory period of the ventricular cycle (i.e., electrocadiograph 
(ECG) gating) or terminating treatment (Refs. 14, 30, and 102). 
Although these cardiac disturbances rarely pose a serious risk to the 
healthy patient, there is the potential for life threatening events to 
occur in those with a pre-existing history of cardiac disease (Ref. 
43). Furthermore, patients with either cardiac pacemakers or 
implantable defibrillators may be at additional risk due to the 
possibility of the lithotripter interfering with the function of the 
pulse generator (Refs. 2, 91, and 97).
    The risk of serious cardiac events during lithotripsy can be 
minimized by monitoring the cardiac activity of all patients during 
treatment to detect any arrhythmias, and either terminating treatment 
or switching to an ECG-gated mode of shock wave delivery should an 
arrhythmia occur (Refs. 59 and 102). Additionally, the risks of 
lithotripter interference with cardiac pacemakers and implantable 
defibrillators can be minimized by temporarily reprogramming the pulse 
generator prior to treatment, verifying the correct function of the 
pulse generator during and after shock wave delivery, and maintaining 
sufficient distance between the shock wave path and the pulse generator 
(Refs. 2, 5, 91, and 97).

E. Urinary Obstruction

    Urinary obstruction occurs in up to 6 percent of patients following 
lithotripsy due to stone fragments becoming lodged in the ureter, and 
may be the result of either a single stone fragment or the accumulation 
of multiple small stone particles (i.e., Steinstrasse) (Refs. 24, 48, 
and 84). Patients with urinary obstruction typically present with 
persistent pain, and may be at risk of developing hydronephrosis with 
subsequent renal failure if the obstruction is not promptly treated 
(Ref. 29). Often, the obstructing fragments pass spontaneously and 
intervention is not necessary (Refs. 48 and 84). Intervention is 
indicated in the presence of severe pain, fever, sepsis, or failure of 
the obstruction to spontaneously resolve, and usually includes 
ureteroscopic manipulation or retrieval, electrohydraulic or laser 
lithotripsy, percutaneous nephrostomy drainage, open surgery, or repeat 
extracorporeal shock wave lithotripsy (Refs. 22, 48, 84, and 93).

F. Infection

    Urinary tract infection (UTI) occurs in 1 to 7 percent of patients 
following extracorporeal shock wave lithotripsy as a result of the 
release of bacteria from the fragmentation of infected calculi (Refs. 
18, 77, 80, and 84). Rarely, pyelonephritis secondary to lithotripsy 
has been reported (Refs. 77 and 84). Additionally, lithotripsy shock 
waves can cause local tissue trauma sufficient to permit bacteria to 
enter the bloodstream from the urinary tract, resulting in sepsis 
(Refs. 29 and 84). Although the incidence of sepsis following 
lithotripsy is not common, typically occurring in less than 1 percent 
of cases (Ref. 31), this complication has the potential for serious 
consequences (Ref. 84). Patients at greatest risk of developing severe 
infectious complications include those with pre-existing UTI and 
infected stones, as well as those who experience urinary obstruction 
due to the passage of stone fragments (Refs. 29, 38, and 84). 
Additionally, patients with cardiac disease, including valvular disease 
and implanted heart valves, and immunocompromised patients are at 
increased risk for developing bacterial endocarditis following 
lithotripsy (Ref. 68).
    The risk of infectious complications secondary to extracorporeal 
shock wave lithotripsy can be effectively minimized through the use of 
prophylactic antibiotics in patients with pre-existing UTI, infected 
stones, cardiac disease, and compromised immune systems (Refs. 18, 38, 
68, and 84).

G. Injury to Adjacent Organs

    Because multiple shock waves pass through the patient's body during 
treatment, extracorporeal shock wave lithotripsy has the potential to 
cause injury to nontarget organs. Examples of injury to adjacent organs 
include splenic rupture requiring splenectomy (Refs. 63 and 78), liver 
hematoma (Ref. 84), and pancreatitis (Ref. 84). In addition, the 
interaction of shock waves with air-filled organs, such as the lung or 
bowel, results in hemorrhage secondary to tissue damage (Refs. 36, 65, 
and 84). Serious injury to adjacent organs is rare, and is minimized 
through proper patient selection, careful targeting of the shock wave 
focus, and the use of conservative treatment parameters and retreatment 
intervals (Refs. 36, 76, and 84).
    In addition to the documented risks to adjacent organs described 
previously, extracorporeal shock wave lithotripsy

[[Page 5990]]

potentially represents significant hazards to other nontarget tissues. 
First, the administration of shock waves to pregnant animals at 
specific gestational stages has been shown to cause growth 
disturbances, serious injury, or death to the fetus (Refs. 33 and 71). 
As a result of these findings, pregnancy is regarded as an absolute 
contraindication of lithotripsy (Refs. 12, 74, 76, and 91). The medical 
community has raised the concern that lithotripsy for stones in the 
lower ureter in women of childbearing potential may cause irreversible 
damage to the ovary (Ref. 12). Although several investigators have 
failed to detect ovarian damage in women receiving extracorporeal shock 
wave lithotripsy to the lower ureter (Refs. 25 and 91), this potential 
risk has not been fully assessed (Ref. 12). Lastly, Yeaman et al. 
observed growth plate disturbances in the epiphyses of developing long 
bones in rats subjected to shock waves, indicating that extracorporeal 
shock wave lithotripsy may cause growth disturbances in children (Ref. 
103). Although these same growth disturbances were not duplicated in a 
subsequent animal study (Ref. 96), the long-term effects of lithotripsy 
shock waves upon nontarget pediatric tissues remain unknown.

H. Other Complications

    Other reported complications of extracorporeal shock wave 
lithotripsy include pain/renal colic, skin irritation/bruising, nausea/
vomiting, fever, vasovagal syncope, autonomic dysreflexia, embedded 
stone fragments, and increased stone recurrence rate.
    Pain/renal colic and skin irritation/bruising commonly occur during 
and immediately after treatment (Refs. 22, 24, 47, and 84), are less 
severe with lithotripters that have less powerful shock waves and 
larger shock wave generator apertures (Refs. 22, 47, and 79), and 
typically resolve spontaneously (Ref. 22). Temporary pain/renal colic 
may also occur secondary to the passage of stone fragments, which is 
often managed with medication. Chronic pain may be indicative of 
ureteral obstruction or renal hematoma (Refs. 4, 84, and 92).
    Transient nausea and vomiting are occasionally reported immediately 
after lithotripsy (Refs. 22, 24, and 37), and may be associated with 
either pain or the administration of sedatives or analgesia.
    Fever has been reported after lithotripsy (Refs. 24, 31, 47, and 
77), and may be secondary to infection (Ref. 23).
    Vasovagal syncope (heart rate suppression concurrent with 
hypotension) has been reported during lithotripsy, although its 
incidence is rare (Ref. 44). Researchers attribute this serious 
condition to either patient anxiety or shock wave stimulation of renal 
peripheral autonomic nerve fibers, and conclude that the risks of this 
condition can be minimized by closely monitoring cardiac activity 
during treatment.
    Kabalin et al. demonstrated that while autonomic dysreflexia may 
occur in spinal cord injured patients during lithotripsy, this 
condition is effectively treated by terminating shock wave delivery and 
administering medical therapy (Ref. 42).
    Although infrequently noted, stone fragments have the potential to 
become embedded in the ureteral wall during lithotripsy (Ref. 28). 
Obstructing submucosal calculi may necessitate endoscopic removal.
    Some investigators have observed higher stone recurrence rates 
following extracorporeal shock wave lithotripsy as compared to 
alternative stone removal therapies, indicating that retained stone 
particles may act as a nidus for new stone formation (Ref. 10). 
However, the magnitude and significance of this finding are unclear and 
continue to undergo investigation.

VI. Summary of Reasons for Recommendation

    After reviewing the data provided by FDA, and after consideration 
of the open discussions during the Panel meeting and the Panel members' 
personal knowledge of and clinical experience with the device, the 
Panel gave the following reasons in support of its recommendation to 
reclassify the generic type extracorporeal shock wave lithotripter for 
use in fragmenting kidney and ureteral calculi from class III into 
class II: (1) The safety and effectiveness of the extracorporeal shock 
wave lithotripter in the fragmentation of kidney and ureteral calculi 
has become well-established since approval of the first device in 1984; 
(2) extracorporeal shock wave lithotripsy is effective in treating most 
kidney and ureteral calculi, with a typical stone-free rate of 75 
percent; and (3) the rates of serious complications from extracorporeal 
shock wave lithotripsy are low, and can be effectively minimized by: 
(a) Consensus standards regarding shock wave characterization 
measurements and general mechanical and electrical safety, (b) clinical 
performance testing, (c) labeling restrictions, and (d) physician 
training restrictions (Ref. 94). Based on information presented by FDA, 
along with the Panel members' personal knowledge and clinical 
experience, the Panel identified the following risks to health 
regarding the use of extracorporeal shock wave lithotripsy for the 
fragmentation of kidney and ureteral calculi: Bleeding and hematoma, 
renal injury and scarring, cardiac arrhythmia, urinary obstruction, 
urinary tract infection, and injury to adjacent organs. In addition, 
the Panel stated that the safety of lithotripsy among certain subgroups 
is unknown, such as pregnant women, children, and women of childbearing 
potential with lower ureteral stones. Although hypertension has 
historically been listed as a potential risk of extracorporeal shock 
wave lithotripsy, the Panel stated that sufficient evidence now exists 
to conclude that this condition should not be listed as an actual risk 
to health.
    The Panel believes that the extracorporeal shock wave lithotripter 
should be reclassified into class II because special controls, in 
addition to general controls, provide reasonable assurance of the 
safety and effectiveness of the device, and there is sufficient 
information to establish special controls to provide such assurance.

VII. Summary of Data Upon Which the Panel Recommendation Is Based

    Based on the information discussed by the Panel during the 
reclassification proceedings, the published literature, and data in 
premarket approval (PMA) applications available to FDA under section 
520(h)(4) of the act, as amended by FDAMA, FDA believes that there is 
reasonable knowledge of the benefits of the device when used for the 
fragmentation of kidney and ureteral calculi. Extracorporeal shock wave 
lithotripsy successfully fragments most urinary calculi. Effectiveness, 
expressed as the percentage of patients rendered stone-free within 3 
months, ranges between 55 to 98 percentage with a typical retreatment 
rate of 1 to 25 percentage (Refs. 11, 20, 22 to 24, 47, 51, 75, 84, 87, 
89, and 93). Successful treatment outcome has been achieved despite the 
use of different shock wave generator designs (i.e., electrostatic 
spark discharge, electromagnetically repelled membranes, piezoelectric 
crystal arrays) and wide range of shock wave characteristics. 
Similarly, extracorporeal shock wave lithotripter effectiveness is 
comparable among the different anatomical sites of the upper urinary 
tract. Specifically, similar stone-free rates are reported for stones 
in the kidney and the upper, middle, and lower ureter, making 
extracorporeal shock wave lithotripsy the first-line therapy for most 
upper urinary calculi (Refs. 11, 13, 21, 46, 66, and 90).
    Despite being capable of effectively fragmenting most urinary 
stones, there

[[Page 5991]]

are several limitations to the success of extracorporeal shock wave 
lithotripsy. Many studies have observed poor effectiveness with both 
staghorn and large (i.e., greater than 2 centimeters in largest 
dimension) stones, leading to the recommendation that alternative stone 
removal therapies should be considered for these cases (Refs. 57, 64, 
75, 84, and 88). Furthermore, some stone compositions, particularly 
cystine calculi, are more resistant to fragmentation than others, and, 
therefore, may require more shocks than other stone types (Refs. 34 and 
91). Because the effectiveness of lithotripsy is predicated on the 
resulting stone fragments passing from the urinary tract, patients with 
an obstruction distal to the stone cannot be successfully treated until 
resolution of the obstruction (Refs. 8, 29, and 57). Stones that are 
embedded or impacted within the tissue of the kidney or ureter are also 
not effectively treated with lithotripsy, due to the inability of the 
stone fragments to pass out of the body (Refs. 29 and 46). Lastly, 
lithotripsy is not effective in patients with anatomical conditions 
that prevent targeting of the shock wave focus at the stone, such as 
severe obesity (Refs. 29 and 91) or orthopedic deformity (Ref. 53).
    Although extracorporeal shock wave lithotripsy is effective for the 
treatment of most ureteral calculi, in some specific instances it is 
not effective as a first-line therapy. Many authors report poor 
localization of ureteral stones using ultrasound imaging, making 
lithotripsy difficult or impossible if the lithotripter does not 
incorporate or use an x-ray imaging system (Refs. 35, 47, and 90). 
Additionally, small stones in the middle or lower ureter (i.e., 4 to 6 
mm in largest dimension) have a high probability of passing 
spontaneously (Ref. 67), making the use of lithotripsy unnecessary 
unless immediate intervention is required.
    Since its introduction in the United States in 1984, extracorporeal 
shock wave lithotripsy has become the preferred treatment for kidney 
and ureteral calculi (Refs. 56 and 91). Not only is lithotripsy 
extremely effective, but the overall rate of serious risks from 
extracorporeal shock wave lithotripsy, primarily clinically significant 
renal hematoma, severe hemorrhage, chronic renal injury, and sepsis, is 
low and can be effectively minimized. Treatment is noninvasive, often 
delivered in an outpatient setting, and can be performed without 
general or regional anesthesia with many systems (Refs. 37, 56, and 
104). Compared to alternative therapies for the removal of urinary 
calculi, extracorporeal shock wave lithotripsy is either associated 
with less morbidity (e.g., open surgery, percutaneous nephrolithotomy, 
ureteroscopy) (Refs. 8, 54, 57, and 84) or increased success (e.g., 
watchful waiting) (Ref. 67).
    Based on the available information, FDA believes that the special 
controls discussed in section VIII of this document are capable of 
providing reasonable assurance of the safety and effectiveness of the 
extracorporeal shock wave lithotripter with regard to the identified 
risks to health of this device.

VIII. Special Controls

    In addition to general controls, FDA believes that the 
extracorporeal shock wave lithotripter should be subject to the special 
controls of labeling restrictions and a FDA guidance document to 
minimize the risks to health identified for this device.

A. Labeling Restrictions

    Labeling restrictions can control the risks of bleeding, renal 
injury, cardiac arrhythmia, urinary obstruction, infection, injury to 
adjacent organs, and other reported complications by providing 
information on patient selection, treatment practices, post-treatment 
followup, and potential adverse events. Specifically, FDA is proposing 
that extracorporeal shock wave lithotripters be subject to the labeling 
statements listed in the appendix as a special control, in addition to 
other required labeling information.
    Under 21 CFR 801.109(b)(ii) and section 520(e) of the act, FDA also 
proposes as described in the guidance document entitled ``Guidance for 
the Content of Premarket Notifications (510(k)s) for Extracorporeal 
Shock Wave Lithotripters Indicated for the Fragmentation of Kidney and 
Ureteral Calculi'' to require the following statement: ``CAUTION: 
Federal law restricts this device to sale by or on the order of a 
physician trained and/or experienced in the use of this device as 
outlined in an appropriate training program.''

B. FDA Guidance Document

    Adherence to the FDA guidance document entitled ``Guidance for the 
Content of Premarket Notifications (510(k)s) for Extracorporeal Shock 
Wave Lithotripters Indicated for the Fragmentation of Kidney and 
Ureteral Calculi'' (Ref. 26) can control the risks of bleeding, renal 
injury, cardiac arrhythmia, urinary obstruction, infection, injury to 
adjacent organs, and other reported complications by recommending: (1) 
Conformance to consensus standards, (2) shock wave characterization 
measurements, (3) assessment of localization accuracy, (4) clinical 
performance testing, and (5) physician training restrictions for 
premarket notifications for extracorporeal shock wave lithotripters. 
These sections of the guidance document correspond to the controls 
recommended by the Panel.
1. Conformance to consensus standards
    The FDA guidance document recommends conformance to the following 
consensus standards: (1) International Electrotechnical Commission 
(IEC) 60601-2-36 Medical electrical equipment--Part 2: Particular 
requirements for the safety of equipment for extracorporeally induced 
lithotripsy; (Ref. 39) and (2) IEC 61846 Ultrasonics--Pressure pulse 
lithotripters--Characteristics of fields (Ref. 40).
    Conformance with IEC 60601-2-36 can control the risks of bleeding, 
renal injury, and injury to adjacent organs by requiring that the 
device accurately localize stones at the shock wave focus and be 
designed to guard against unintentional shock wave delivery.
    Conformance with IEC 61846 can control the risks of bleeding, renal 
injury, and injury to adjacent organs by providing a standard method 
for characterizing the lithotripter's acoustic output for the purpose 
of determining whether its shock wave characteristics are within the 
range provided by existing systems.
2. Shock wave characterization measurements
    Shock wave characterization measurements can control the risks of 
bleeding, renal injury, and injury to adjacent organs by having each 
manufacturer assess whether the shock wave characteristics of its 
lithotripter are within the range provided by existing systems.
3. Assessment of localization accuracy
    Assessment of localization accuracy can control the risks of 
bleeding, renal injury, and injury to adjacent organs by having each 
manufacturer verify that its device accurately positions stones at the 
shock wave focus.
4. Clinical performance testing
    Clinical performance testing can control the risks of bleeding, 
renal injury, cardiac arrhythmia, and injury to adjacent organs by 
verifying that the device accurately locates the target stone, delivers 
shock waves in accordance with the parameters set by the operator, and 
does not present an unreasonable risk of injury to the patient. As 
recommended by the Panel, this testing can take the form of either a 
small, confirmatory clinical study or a larger clinical investigation 
of safety and

[[Page 5992]]

effectiveness, depending upon the technological characteristics of the 
particular device (Ref. 94). For extracorporeal shock wave 
lithotripters that generate shock waves using a similar method to that 
of legally marketed systems and have comparable shock wave 
characteristics, a small, confirmatory clinical study should be 
performed. However, for systems that use a novel method of shock wave 
generation or have shock wave characteristics that are outside of the 
range of current devices, a larger clinical investigation is necessary 
to assess safety and effectiveness.
5. Physician training restrictions
    Physician training restrictions can control the risks of bleeding, 
renal injury, cardiac arrhythmia, urinary obstruction, infection, 
injury to adjacent organs, and other reported complications by having 
each manufacturer develop a training program to instruct users of their 
device on both the operation of the particular lithotripsy system and 
the general practices for the safe and effective use of extracorporeal 
shock wave lithotripters (Ref. 76). Manufacturers should inform device 
users of this physician training restriction with the following 
labeling statement: ``CAUTION: Federal law restricts this device to 
sale by or on the order of a physician trained and/or experienced in 
the use of this device as outlined in a training program.''

IX. FDA's Tentative Findings

    The Panel and FDA believe that the extracorporeal shock wave 
lithotripter should be classified into class II because special 
controls, in addition to general controls, would provide reasonable 
assurance of the safety and effectiveness of the device, and there is 
sufficient information to establish special controls to provide such 
assurance.

X. References

    The following references have been placed on display in the Dockets 
Management Branch (address above) and may be seen by interested persons 
between 9 a.m. and 4 p.m., Monday through Friday:
    1. Akdas, A., L. N. Turkeri, Y. Ilker, F. Simsek, and K. Emerk, 
Short-Term Bioeffects of Extracorporeal Shockwave Lithotripsy, 
Journal of Endourology, 8(3):187-190, 1994.
    2. Albers, D. D., F. E. Lybrand, III, J. C. Axton, and J. R. 
Wendelken, ``Shockwave Lithotripsy and Pacemakers: Experience with 
20 Cases,'' Journal of Endourology, 9(4):301-303, 1995.
    3. Anderson, K. R., K. Kerbl, P. T. Fadden, M. R. Wick, E. M. 
McDougall, and R. V. Clayman, ``Effect of Piezoelectric Energy on 
Porcine Kidneys Using the EDAP LT.02,'' Journal of Urology, 
153:1295-1298, 1995.
    4. Antoniou, N. K., D. Karanastasis, and J. L. Stenos, ``Severe 
Perinephric Hemorrhage after Shock Wave Lithotripsy,'' Journal of 
Endourology, 9(3):239-241, 1995.
    5. Asroff, S. W., T. E. Kingston, and B. S. Stein, 
``Extracorporeal Shock Wave Lithotripsy in Patient with Cardiac 
Pacemaker in an Abdominal Location: Case Report and Review of the 
Literature,'' Journal of Endourology, 7(3):189-192, 1993.
    6. Atahan, O., T. Alkibay, U. Karaoglan, N. Deniz, and I. 
Bozkirli, ``Acute Bioeffects of Electromagnetic Lithotripsy,'' 
Scandinavian Journal of Urology and Nephrology, 30:269-272, 1996.
    7. Back, W., K. U. Kohrmann, J. Bensemann, J. Rassweiler, and P. 
Alken, ``Histomorphologic and Ultrastructural Findings of Shockwave-
Induced Lesions in the Isolated Perfused Kidney of the Pig,'' 
Journal of Endourology, 8(4):257-261, 1994.
    8. Bush, W. H. and G. E. Brannen, lithotripsy, Encyclopedia of 
Medical Devices and Instrumentation, J. G. Webster (ed.), John Wiley 
& Sons, New York, Vol. 3, pp. 1806-1820, 1988.
    9. Carey, S. W., and S. B. Streem, ``Extracorporeal Shock Wave 
Lithotripsy for Patients with Calcified Ipsilateral Renal Arterial 
or Abdominal Aortic Aneurysms,'' Journal of Urology, 148:18-20, 
1992.
    10. Carr, L. K., R. J. D. Honey, M. A. S. Jewett, D. Ibanez, M. 
Ryan, and C. Bombardier, ``New Stone Formation: A Comparison of 
Extracorporeal Shock Wave Lithotripsy and Percutaneous 
Nephrolithotomy,'' The Journal of Urology, 155:1565-1567, 1996.
    11. Cass, A. S., ``Comparison of First Generation (Dornier HM3) 
and Second Generation (Medstone STS) Lithotriptors: Treatment 
Results with 13,864 Renal and Ureteral Calculi,'' Journal of 
Urology, 153:588-592, 1995.
    12. Cass, A. S., ``Extracorporeal Shock Wave Lithotripsy for Mid 
and Lower Ureteral Stones,'' Journal of Endourology, 6(5):323-326, 
1992.
    13. Cass, A. S., ``Extracorporeal Shock Wave Lithotripsy for 
Ureteral Calculi,'' Journal of Urology, 147:1495-1498, 1992.
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Lithotripter,'' Journal of Urology, 156:896-898, 1996.
    15. Claro, J. D., F. Denardi, U. Ferreira, N. R. Netto, Jr., L. 
B. Saldanha, and J. F. Figueiredo, ``Effects of Extracorporeal 
Shockwave Lithotripsy on Renal Growth and Function: An Animal 
Model,'' Journal of Endourology, 8(3):191-194, 1994.
    16. Coleman, A. J. and J. E. Saunders, ``Review of the Physical 
Properties and Biological Effects of the High Amplitude Acoustic 
Fields Used in Extracorporeal Lithotripsy,'' Ultrasonics, 31(2):75-
89, 1993.
    17. Delius, M., W. Mueller, A. Goetz, H. Liebich, and W. 
Brendel, ``Biological Effects of Shock Waves: Kidney Hemorrhage in 
Dogs at a Fast Shock Wave Administration Rate of Fifteen Hertz,'' 
Journal of Lithotripsy and Stone Disease, 2(2):103-110, 1990.
    18. Deliveliotis, Ch., A. Giftopoulos, G. Koutsokalis, G. 
Raptidis, and A. Kostakopoulos, ``The Necessity of Prophylactic 
Antibiotics during Extracorporeal Shock Wave Lithotripsy,'' 
International Urology and Nephrology, 29(5):517-521, 1997.
    19. Deliveliotis, Ch., A. Kostakopoulos, N. Stavropoulos, E. 
Karagiotis, P. Kyriazis, and C. Dimopoulos, ``Extracorporeal Shock 
Wave Lithotripsy in 5 Patients with Aortic Aneurysm,'' Journal of 
Urology, 154:1671-1672, 1995.
    20. Drach, G. W., S. Dretler, W. Fair, B. Finlayson, J. 
Gillenwater, D. Griffith, J. Lingeman, and D. Newman, ``Report of 
the United States Cooperative Study of Extracorporeal Shock Wave 
Lithotripsy,'' Journal of Urology, 135:1127-1133, 1986.
    21. Ehreth, J. T., G. W. Drach, M. L. Arnett, R. B. Barnett, D. 
Govan, J. Lingeman, S. A. Loening, D. M. Newman, J. M. Tudor, and S. 
Saada, ``Extracorporeal Shock Wave Lithotripsy: Multicenter Study of 
Kidney and Upper Ureter Versus Middle and Lower Ureter Treatments,'' 
Journal of Urology, 152:1379-1385, 1994.
    22. Elabbady, A., G. Mathes, D. D. Morehouse, J. Honey, J. 
Pahira, R. Zeman, J. Paquin, R. Faucher, and M. M. Elhilali, 
``Safety and Effectiveness of Lithostar Shock Tube C in the 
Treatment of Urinary Calculi,'' Journal of Endourology, 9(3):225-
231, 1995.
    23. El-Damanhoury, H., T. Scharfe, J. Ruth, S. Roos, and R. 
Hohenfellner, ``Extracorporeal Shock Wave Lithotripsy of Urinary 
Calculi: Experience in Treatment of 3,278 Patients Using the Siemens 
Lithostar and Lithostar Plus,'' Journal of Urology, 145:484-488, 
1991.
    24. Elhilali, M. M., M. L. Stoller, T. C. McNamara, D. D. 
Morehouse, J. S. Wolf, Jr., and L. L. Keeler, Jr., ``Effectiveness 
and Safety of the Dornier Compact Lithotriptor: An Evaluative 
Multicenter Study,'' Journal of Urology, 155:834-838, 1996.
    25. Erturk, E., A. M. Ptak, and J. Monaghan, ``Fertility 
Measures in Women after Extracorporeal Shockwave Lithotripsy of 
Distal Ureteral Stones,'' Journal of Endourology, 11(5):315-317, 
1997.
    26. FDA Guidance Document (Draft),`` Guidance for the Content of 
Premarket Notifications (510(k)s) for Extracorporeal Shock Wave 
Lithotripters Indicated for the Fragmentation of Kidney and Ureteral 
Calculi'' (Currently available for comment.)
    27. Ferreira, U., J. D. Claro, N. R. Netto, Jr., F. Denardi, J. 
F. Figueiredo, and C. L. Z. Riccetto, ``Functional and Histologic 
Alterations in Growing Solitary Rat Kidney as a Result of 
Extracorporeal Shockwaves,'' Journal of Endourology, 9(1):45-49, 
1995.
    28. Grasso, M., J. Liu, B. Goldberg, and D. H. Bagley, 
``Submucosal Calculi: Endoscopic and Intraluminal Sonographic 
Diagnosis and Treatment Options,'' Journal of Urology, 153:1384-
1389, 1995.
    29. Grasso, M., P. Loisides, M. Beaghler, and D. Bagley, ``The 
Case for Primary Endoscopic Managment of Upper Urinary Tract 
Calculi: I. A Critical Review of 121 Extracorporeal Shock-Wave 
Lithotripsy Failures,'' Urology, 45(3):363-371, 1995.
    30. Greenstein, A., I. Kaver, V. Lechtman, and Z. Braf, 
``Cardiac Arrhythmias during Nonsynchronized Extracorporeal Shock 
Wave Lithotripsy,'' Journal of Urology, 154:1321-1322, 1995.

[[Page 5993]]

    31. Grenabo, L., K. Lindqvist, H. Adami, R. Bergstrom, and S. 
Pettersson, ``Extracorporeal Shock Wave Lithotripsy for the 
Treatment of Renal Stones,'' Archives of Surgery, 132:20-26 1997.
    32. Groshar, D., O. Israel, J. Ginessin, D. R. Levin, B. 
Moskovitz, D. Front, and A. Frenkel, ``Effect of Extracorporeal 
Piezoelectric Lithotripsy Shock Waves on Renal Function Measured by 
Tc-99m-DMSA Using Spect,'' Urology, 38(6):537-539, 1991.
    33. Gumus, B., M. Lekili, A. R. Kandiloglu, A. Isisag, G. 
Temeltas, O. Nazli, and C. Buyuksu, ``Effects of Extracorporeal 
Shockwave Lithotripsy at Different Stages of Pregnancy in the 
Rabbit,'' Journal of Endourology, 11(5):323-326, 1997.
    34. Gupta, M., D. M. Bolton, and M. L. Stoller, ``Etiology and 
Management of Cystine Lithiasis,'' Urology, 45(2):344-355, 1995.
    35. Hamdy, S., D. D. Morehouse, H. Laporte, and M. M. Elhilali, 
Early Experience with ``Extracorporeal Shockwave Dornier 
Lithotriptor,'' Journal of Endourology, 9(3):219-223, 1995.
    36. Holmberg, G., S. Spinnell, and J. Sjodin, ``Perforation of 
the Bowel during SWL in Prone Position,'' Journal of Endourology, 
11(5):313-314, 1997.
    37. Hosking, M. P., S. A. Morris, F. A. Klein, and C. Dobmeyer-
Dittrich,`` Anesthetic Management of Patients Receiving Calculus 
Therapy with a Third-Generation Extracorporeal Lithotripsy 
Machine,'' Journal of Endourology, 11(5):309-311, 1997.
    38. Ilker, Y., L. N. Turkeri, V. Korten, T. Tarcan, and A. 
Akdas, ``Antimicrobial Prophylaxis in Management of Urinary Tract 
Stones by Extracorporeal Shock-Wave Lithotripsy: Is It Necessary?,'' 
Urology, 46(2):165-167, 1995.
    39. International Electrotechnical Commission, International 
Standard IEC 60601-2-36 Medical electrical equipment--Part 2: 
Particular requirements for the safety of equipment for 
extracorporeally induced lithotripsy, 1997 (IEC address: 3, rue de 
Varembe Geneva, Switzerland; IEC web site: ``http://www.iec.ch'').
    40. International Electrotechnical Commission, International 
Standard IEC 61846 Ultrasonics--Pressure pulse lithotripters--
Characteristics of fields, 1998 (IEC address: 3, rue de Varembe 
Geneva, Switzerland; IEC web site: ``http://www.iec.ch'').
    41. Janetschek, G., F. Frauscher, R. Knapp, G. Hofle, R. 
Peschel, and G. Bartsch, ``New Onset of Hypertension after 
Extracorporeal Shock Wave Lithotripsy: Age Related Incidence and 
Prediction by Intrarenal Resistive Index,'' Journal of Urology, 
158:346-351, 1997.
    42. Kabalin, J. N., S. Lennon, H. S. Gill, V. Wolfe, and I. 
Perkash, ``Incidence and Management of Autonomic Dysreflexia and 
Other Intraoperative Problems Encountered in Spinal Cord Injury 
Patients Undergoing Extracorporeal Shock Wave Lithotripsy without 
Anesthesia on a Second Generation Lithotriptor,'' Journal of 
Urology, 149:1064-1067, 1993.
    43. Kataoka, H., ``Cardiac Dysrhythmias Related to 
Extracorporeal Shock Wave Lithotripsy Using a Piezoelectric 
Lithotripter in Patients with Kidney Stones,'' Journal of Urology, 
153:1390-1394, 1995.
    44. Kataoka, H. and T. Tanigawa, ``Vasovagal Syncope Elicited by 
Extracorporeal Shock Wave Lithotripsy,'' American Heart Journal, 
126:258-259, 1993.
    45. Katz, R., D. Admon, and D. Pode, ``Life-Threatening 
Retroperitoneal Hematoma Caused by Anticoagulant Therapy for 
Myocardial Infarction after SWL,'' Journal of Endourology, 11(1):23-
25, 1997.
    46. Kim, H. H., J. H. Lee, M. S. Park, S. E. Lee, and S. W. Kim, 
``In Situ Extracorporeal Shockwave Lithotripsy for Ureteral Calculi: 
Investigation of Factors Influencing Stone Fragmentation and 
Appropriate Number of Sessions for Changing Treatment Modality,'' 
Journal of Endourology, 10(6):501-505, 1996.
    47. Kim, S. C. and Y. T. Moon, ``Experience with EDAP LT02 
Extracorporeal Shockwave Lithotripsy in 1363 Patients: Comparison 
with Results of LT01 SWL in 1586 Patients,'' Journal of Endourology, 
11(2):103-111, 1997.
    48. Kim, S. C., C. H. Oh, Y. T. Moon, and K. D. Kim, ``Treatment 
of Steinstrasse with Repeat Extracorporeal Shock Wave Lithotripsy: 
Experience with Piezoelectric Lithotriptor,'' Journal of Urology, 
145:489-491, 1991.
    49. Knapp, P. M., and T. B. Kulb, ``Extracorporeal Shock Wave 
Lithotripsy Induced Perirenal Hematomas,'' Journal of Urology, 
137:142A, abstract 155, 1987.
    50. Knapp, P. M., T. B. Kulb, J. E. Lingeman, D. M. Newman, J. 
H. O. Mertz, P. G. Mosbaugh, and R. E. Steele, ``Extracorporeal 
Shock Wave Lithotripsy-Induced Perirenal Hematomas,'' Journal of 
Urology, 139:700-703, 1988.
    51. Kohrmann, K. U., J. J. Rassweiler, M. Manning, G. Mohr, T. 
O. Henkel, K. P. Junemann, and P. Alken, ``The Clinical Introduction 
of a Third Generation Lithotripter: Modulith SL 20,'' Journal of 
Urology, 153:1379-1383, 1995.
    52. Krishnamurthi, V. and S. B. Streem, ``Long-Term Radiographic 
and Functional Outcome of Extracorporeal Shock Wave Lithotripsy 
Induced Perirenal Hematomas,'' Journal of Urology, 154:1673-1675, 
1995.
    53. Kroovand, R. L., ``Pediatric Urolithiasis,'' Urologic 
Clinics of North America, 24(1):173-184, 1997.
    54. Lehtoranta, K., ``Cost Effectiveness of Different Treatment 
Alternatives in Urinary Stone Practice,'' Scandinavian Journal of 
Urology and Nephrology, 29:437-447, 1995.
    55. Lim, D. J., R. D. Walker, III, P. I. Ellsworth, R. C. 
Newman, M. S. Cohen, M. A. Barraza, and P. S. Stevens, ``Treatment 
of Pediatric Urolithiasis between 1984 and 1994,'' Journal of 
Urology, 156:702-705, 1996.
    56. Lingeman, J. E., ``Extracorporeal Shock Wave Lithotripsy: 
Development, Instrumentation, and Current Status,'' Urologic Clinics 
of North America, 24(1):185-211, 1997.
    57. Lingeman, J. E., ``Lithotripsy and Surgery,'' Seminars in 
Nephrology, 16(5):487-498, 1996.
    58. Lingeman, J. E. and T. B. Kulb, ``Hypertension following 
Extracorporeal Shock Wave Lithotripsy,'' Journal of Urology, 
137:142A, abstract 154, 1987.
    59. Lingeman, J. E., D. M. Newman, Y. I, Siegel, T. Eichhorn, 
and K. Parr, ``Shock Wave Lithotripsy with the Dornier MFL 5000 
Lithotripter Using an External Fixed Rate Signal,'' Journal of 
Urology, 154:951-954, 1995.
    60. Lingeman, J. E., J. R. Woods, and D. R. Nelson, ``Commentary 
on ESWL and Blood Pressure,'' Journal of Urology, 154:2-4, 1995.
    61. Lingeman, J. E., J. R. Woods, and P. D. Toth, ``Blood 
Pressure Changes Following Extracorporeal Shock Wave Lithotripsy and 
Other Forms of Treatment for Nephrolithiasis,'' The Journal of the 
American Medical Association, 263(13):1789-1794, 1990.
    62. Lipski, B., J. Miller, G. Rigaud, G. Stack, and C. Marsh, 
``Acute Renal Failure from a Subcapsular Hematoma in a Solitary 
Kidney: An Unusual Complication of Extracorporal Shock Wave 
Lithotripsy,'' Journal of Urology, 157:2245, 1997.
    63. Marcuzzi, D., R. Gray, and T. Wesley-James, ``Symptomatic 
Splenic Rupture following Extracorporeal Shock Wave Lithotripsy,'' 
Journal of Urology, 145:547-548, 1991.
    64. Meretyk, S., O. N. Gofrit, O. Gafni, D. Pode, A. Shapiro, A. 
Verstandig, T. Sasson, G. Katz, and E. H. Landau, ``Complete 
Staghorn Calculi: Random Prospective Comparison Between 
Extracorporeal Shock Wave Lithotripsy Monotherapy and Combined with 
Percutaneous Nephrostolithotomy,'' Journal of Urology, 157:780-786, 
1997.
    65. Miller, D. L. and R. M. Thomas, ``Thresholds for Hemorrhages 
in Mouse Skin and Intestine Induced by Lithotripter Shock Waves,'' 
Ultrasound in Medicine and Biology, 21(2):249-257, 1995.
    66. Mobley, T. B., D. A. Myers, J. McK. Jenkins, W. B. Grine, 
and W. R. Jordan, ``Effects of Stents on Lithotripsy of Ureteral 
Calculi: Treatment Results with 18,825 Calculi Using the Lithostar 
Lithotripter,'' Journal of Urology, 152:53-56, 1994.
    67. Morse, R. M. and M. I. Resnick, ``Ureteral Calculi: Natural 
History and Treatment in an Era of Advanced Technology,'' Journal of 
Urology, 145:263-265, 1991.
    68. Muller-Mattheis, V. G. O., D. Schmale, M. Seewald, H. Rosin, 
and R. Ackermann, ``Bacteremia During Extracorporeal Shock Wave 
Lithotripsy of Renal Calculi,'' Journal of Urology, 146:733-736, 
1991.
    69. Myers, D. A., T. B. Mobley, J. McK. Jenkins, W. B. Grine, 
and W. R. Jordan, ``Pediatric Low Energy Lithotripsy with the 
Lithostar,'' Journal of Urology, 153:453-457, 1995.
    70. Newman, D. M., and M. Kaefer, ``Pediatric ESWL: Suitability 
Hinges on Long-Term Renal Effects,'' Contemporary Urology, pp. 71-
76, September, 1992.
    71. Ohmori, K., T. Matsuda, Y. Horii, and O. Yoshida, ``Effects 
of Shock Waves on the Mouse Fetus,'' Journal of Urology, 151:255-
258, 1994.
    72. Pacik, D., T. Hanak, P. Kumstat, M. Turjanica, P. Jelinek, 
and J. Kladensk , ``Effectiveness of SWL for Lower-Pole Caliceal 
Nephrolithiasis: Evaluation of 452 Cases,'' Journal of Endourology, 
11(5):305-307, 1997.
    73. Phillips, M. T., W. H. Merrell, and R. P. Knobloch, 
``Extracorporeal Shock Wave Lithotripsy in a Patient on Chronic

[[Page 5994]]

Anticoagulant Therapy,'' Journal of Lithotripsy and Stone Disease, 
3(4):353-356, 1991.
    74. Preminger, G. M., ``Review: In Vivo Effects of 
Extracorporeal Shock Wave Lithotripsy: Animal Studies,'' Journal of 
Endourology, 7(5):375-378, 1993.
    75. Psihramis, K. E., M. A. S. Jewett, C. Bombardier, D. Caron, 
M. Ryan, and the Toronto Lithotripsy Associates, ``Lithostar 
Extracorporeal Shock Wave Lithotripsy: The First 1,000 Patients,'' 
Journal of Urology, 147:1006-1009, 1992.
    76. Radiation Safety Committee of the European Federation of 
Societies for Ultrasound in Medicine and Biology, ``Guidelines for 
the Safe Use of Extracorporeal Shock-Wave Lithotripsy (ESWL) 
Devices,'' Ultrasound in Medicine and Biology, 20(3):315-316, 1994.
    77. Rahav, G., H. Strul, D. Pode, and M. Shapiro, ``Bacteriuria 
following Extracorporeal Shock-Wave Lithotripsy in Patients Whose 
Urine Was Sterile before the Procedure,'' Clinical Infectious 
Diseases, 20:1317-1320, 1995.
    78. Rashid, P., D. Steele, and J. Hunt, ``Splenic Rupture after 
Extracorporeal Shock Wave Lithotripsy,'' Journal of Urology, 
156:1756-1757, 1996.
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``Second-Generation Lithotripters: A Comparative Study,'' Journal of 
Endourology, 2(2):193-204, 1988.
    80. Raz, R., A. Zoabi, M. Sudarsky, and J. Shental, ``The 
Incidence of Urinary Tract Infection in Patients without Bacteriuria 
Who Underwent Extracorporeal Shock Wave Lithotripsy,'' Journal of 
Urology, 151:329-330, 1994.
    81. Robertson, J. B., M. O. Koch, F. K. Kirchner, Jr., and J. A. 
Smith, Jr., ``Suboptimal Treatment Results with the Therasonics 
Lithotripter,'' Journal of Urology, 152:317-319, 1994.
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W. F. Wieland, ``Mechanisms of Shockwave Action in the Human 
Kidney,'' Journal of Endourology, 9(6):443-448, 1995.
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S. Thuroff, and C. Chaussy, ``Side Effects of High-Energy Shockwaves 
in the Human Kidney: First Experience with Model Comparing Two 
Shockwave Sources,'' Journal of Endourology, 10(6):507-511, 1996.
    84. Roth, R. A. and C. F. Beckmann, ``Complications of 
Extracorporeal Shock-Wave Lithotripsy and Percutaneous 
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1988.
    85. Ruiz, H. and B. Saltzman, ``Aspirin-Induced Bilateral Renal 
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1990.
    86. Ryan, P. C., B. J. Jones, E. W. Kay, P. Nowlan, E. A. Kiely, 
E. F. Gaffney, and M. R. Butler, ``Acute and Chronic Bioeffects of 
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LT.01),'' Journal of Urology, 145:399-404, 1991.
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``Urologic Experience with the Dornier Multipurpose Lithotripter MPL 
9000,'' Journal of Lithotripsy and Stone Disease, 3(3):241-248, 
1991.
    88. Segura, J. W., G. M. Preminger, D. G. Assimos, S. P. 
Dretler, R. I. Kahn, J. E. Lingeman, J. N. Macaluso, Jr., and D. L. 
McCullough, ``Nephrolithiasis Clinical Guidelines Panel Summary 
Report on the Management of Staghorn Calculi,'' Journal of Urology, 
151:1648-1651, 1994.
    89. Simon, D., ``Experience with 500 Extracorporeal Shockwave 
Lithotripsy Patients Using a Low-Cost Unit,'' Journal of 
Endourology, 9(3):215-218, 1995.
    90. Singal, R. K. and J. D. Denstedt, ``Contemporary Management 
of Ureteral Stones,'' Urologic Clinics of North America, 24(1):59-
70, 1997.
    91. Streem, S. B., ``Contemporary Clinical Practice of Shock 
Wave Lithotripsy: A Reevaluation of Contraindications,'' Journal of 
Urology, 157:1197-1203, 1997.
    92. Stoller, M. L., L. Litt, and R. G. Salazar, ``Severe 
Hemorrhage after Extracorporeal Shock-Wave Lithotripsy,'' Annals of 
Internal Medicine, 111(7):612-613, 1989.
    93. Tolon, M., C. Miroglu, H. Erol, J. Tolon, D. Acar, E. 
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Shock Wave Lithotripsy Results on 1,569 Renal Units in an Outpatient 
Clinic,'' Journal of Urology, 145:695-698, 1991.
    94. Transcripts of the Gastroenterology and Urology Devices 
Advisory Panel meeting, July 30, 1998.
    95. Tuteja, A. K., J. P. Pulliam, T. H. Lehman, and L. W. 
Elzinga, ``Anuric Renal Failure from Massive Bilateral Renal 
Hematoma following Extracorporeal Shock Wave Lithotripsy,'' Urology, 
50(4):606-608, 1997.
    96. Van Arsdalen, K. N., S. Kurzweil, J. Smith, and R. M. Levin, 
``Effects of Lithotripsy on Immature Rabbit Bone and Kidney 
Develoment,'' Journal of Urology, 146:213-216, 1991.
    97. Vassolas, G., R. A. Roth, and F. J. Venditti, Jr., ``Effect 
of Extracorporeal Shock Wave Lithotripsy on Implantable Cardioverter 
Defibrillator,'' PACE, 16:1245-1248, 1993.
    98. Vaughan E. D., Jr., J. N. Tobin, M. H. Alderman, R. E. Sosa, 
G. W. Drach, and the NEMA Kidney Stone Blood Pressure Study Group 
(KSBPS), ``Extracorporeal Shock Wave Monotherapy Does Not Cause 
Renal Dysfunction or Elevated Blood Pressure,'' Journal of Urology, 
155:539A, abstract 915, 1996.
    99. Williams, C. M., J. V. Kaude, R. C. Newman, J. C. Peterson, 
and W. C. Thomas, ``Extracorporeal Shock Wave Lithotripsy: Long-Term 
Complications,'' American Journal of Roentgenology, 150:311-315, 
1988.
    100. Willis, L. R., A. P. Evan, B. A. Connors, N. S. Fineberg, 
and J. E. Lingeman, ``Effects of SWL on Glomerular Filtration Rate 
and Renal Plasma Flow in Uninephrectomized Minipigs,'' Journal of 
Endourology, 11(1):27-32, 1997.
    101. Willis, L. R., A. P. Evan, B. A. Connors, G. Reed, N. S. 
Fineberg, and J. A. Lingeman, ``Effects of Extracorporeal Shock Wave 
Lithotripsy to One Kidney on Bilateral Glomerular Filtration Rate 
and PAH Clearance in Minipigs,'' Journal of Urology, 156:1502-1506, 
1996.
    102. Winters, J. C. and J. N. Macaluso, Jr., ``Ungated Medstone 
Outpatient Lithotripsy,'' Journal of Urology, 153:593-595, 1995.
    103. Yeaman, L. D., C. P. Jerome, and D. L. McCullough, 
``Effects of Shock Waves on the Structure and Growth of the Immature 
Rat Epiphysis,'' Journal of Urology, 141:670-674, 1989.
    104. Zommick, J., R. Leveillee, A. Zabbo, L. Colasanto, and D. 
Barrette, ``Comparison of General Anesthesia and Intravenous 
Sedation-Analgesia for SWL,'' Journal of Endourology, 10(6):489-491, 
1996.

XI. Environmental Impact

    The agency has determined under 21 CFR 25.34(b) that this 
reclassification 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.

XII. Analysis of Impacts

    FDA has examined the impacts of the proposed rule under Executive 
Order 12866 and the Regulatory Flexibility Act (5 U.S.C. 601-612) (as 
amended by subtitle D of the Small Business Regulatory Fairness Act of 
1996 (Pub. L. 104-121), and the Unfunded Mandates Reform Act of 1995 
(Pub. L. 104-4)). Executive Order 12866 directs agencies to assess all 
costs and benefits of available regulatory alternatives and, when 
regulation is necessary, to select regulatory approaches that maximize 
net benefits (including potential economic, environmental, public 
health and safety, and other advantages, distributive impacts and 
equity). The agency believes that this reclassification action is 
consistent with the regulatory philosophy and principles identified in 
the Executive Order. In addition, the reclassification action is not a 
significant regulatory action as defined by the Executive Order and so 
is not subject to review under the Executive Order.
    The Regulatory Flexibility Act requires agencies to analyze 
regulatory options that would minimize any significant impact of a rule 
on small entities. Reclassification of the device from class III to 
class II will relieve manufacturers of the cost of complying with the 
premarket approval requirements in section 515 of the act. Because 
reclassification will reduce regulatory costs with respect to this 
device, it will impose no significant economic impact on any small 
entities, and it may permit small potential competitors to enter the 
marketplace by lowering their costs. The agency therefore certifies 
that this reclassification action, if finalized, will

[[Page 5995]]

not have a significant economic impact on a substantial number of small 
entities. In addition, this reclassification action will not impose 
costs of $100 million or more on either the private sector or state, 
local, and tribal governments in the aggregate, and therefore a summary 
statement of analysis under section 202(a) of the Unfunded Mandates 
Reform Act of 1995 is not required.

XIII. Request for Comments

    Interested persons may, on or before May 10, 1999 submit to the 
Dockets Management Branch (address above) written comments regarding 
this document. Two copies of any comments are to be submitted, except 
that individuals may submit one copy. Comments are to be identified 
with the docket number found in brackets in the heading of this 
document. Received comments may be seen in the office above between 9 
a.m. and 4 p.m., Monday through Friday.

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--GASTROENTEROLOGY-UROLOGY 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. Sec. 876.5990 is added to subpart F to read as follows:

Sec. 876.5990  Extracorporeal shock wave lithotripter.

    (a) Identification. An extracorporeal shock wave lithotripter is a 
device that focuses ultrasonic shock waves into the body to 
noninvasively fragment urinary calculi within the kidney and ureter. 
The primary components of the device are a shock wave generator, high 
voltage generator, control console, imaging/localization system, and 
patient table. Prior to treatment, the urinary stone is targeted using 
either an integral or stand-alone localization/imaging system. Shock 
waves are typically generated using electrostatic spark discharge 
(spark gap), electromagnetically repelled membranes, or piezoelectric 
crystal arrays, and focused onto the stone with either a specially 
designed reflector, dish, or acoustic lens. The shock waves are created 
under water within the shock wave generator, and are transferred to the 
patient's body through a water-filled rubber cushion or by direct 
contact of the patient's skin with the water. After the stone has been 
fragmented by the focused shock waves, the fragments pass out of the 
body with the patient's urine.
    (b) Classification. Class II (special controls).
    (1) Labeling that contains the statements listed in the appendix in 
addition to other required labeling information.
    (2) FDA guidance document entitled ``Guidance for the Content of 
Premarket Notifications (510(k)'s) for Extracorporeal Shock Wave 
Lithotripters Indicated for the Fragmentation of Kidney and Ureteral 
Calculi.''

APPENDIX TO Sec. 876.5990: Labeling Restrictions

a. Contraindications:
Do not use the device in patients with:
    Anatomy which precludes focusing the device at the target stone, 
such as severe obesity or excessive spinal curvature.
    Arterial calcification or vascular aneurysm in the lithotripter's 
shock wave path.
    Coagulation abnormalities (as indicated by abnormal prothrombin 
time, partial thromboplastin time, or bleeding time) or those currently 
receiving anticoagulants (including aspirin).
    Confirmed or suspected pregnancy.
    Urinary tract obstruction distal to the stone.
b. Warnings:
    Air-filled interfaces in shock wave path: Do not apply shock waves 
to air-filled areas of the body, i.e., intestines or lungs. Shock waves 
are rapidly dispersed by passage through an air-filled interface, which 
can cause bleeding and other harmful side effects.
    Anticoagulants: Patients receiving anticoagulants (including 
aspirin) should temporarily discontinue such medication prior to 
extracorporeal shock wave lithotripsy to prevent severe hemorrhage.
    Bilateral stones: Do not perform bilateral treatment of kidney 
stones in a single treatment session, because either bilateral renal 
injury or total urinary tract obstruction by stone fragments may 
result. Patients with bilateral kidney stones should be treated using a 
separate treatment session for each side. In the event of total urinary 
obstruction, corrective procedures may be needed to ensure drainage of 
urine.
    Cardiac arrhythmia during treatment: If a patient experiences 
cardiac arrhythmia during treatment at a fixed shock wave repetition 
rate, shock wave delivery should either be terminated or switched to an 
ECG-gated mode (i.e., delivery of the shock wave during the refractory 
period of the patient's cardiac cycle). As a general practice, patients 
with a history of cardiac arrhythmia should be treated in the ECG-gated 
mode. (If the system is capable of delivering shock waves at a fixed 
frequency.)
    Cardiac disease, immunosuppression, and diabetes mellitus: 
Prophylactic antibiotics should be administered prior to extracorporeal 
shock wave lithotripsy treatment to patients with cardiac disease 
(including valvular disease), immunosuppression, and diabetes mellitus, 
to prevent bacterial and/or subacute endocarditis.
    Cardiac monitoring: Always perform cardiac monitoring during 
lithotripsy treatment, because the use of extracorporeal shock wave 
lithotripsy has been reported to cause ventricular cardiac arrhythmias 
in some individuals. This warning is especially important for patients 
who may be at risk of cardiac arrhythmia due to a history of cardiac 
irregularities or heart failure.
    Infected stones: Prophylactic antibiotics should be administered 
prior to treatment whenever the possibility of stone infection exists. 
Extracorporeal shock wave lithotripsy treatment of pathogen-harboring 
calculi could result in systemic infection.
    Pacemaker or implantable defibrillator: To reduce the incidence of 
malfunction to a pacemaker or implantable defibrillator, the pulse 
generator should be programmed to a single chamber, non-rate responsive 
mode (pacemakers) or an inactive mode (implantable defibrillators) 
prior to lithotripsy, and evaluated for proper function post-treatment. 
Do not focus the lithotripter's shock wave through or near the pulse 
generator.
c. Precautions:
    Impacted or embedded stones: The effectiveness of extracorporeal 
shock wave lithotripsy may be limited in patients with impacted or 
embedded stones. Alternative procedures are recommended for these 
patients.
    Radiographic followup: All patients should be followed 
radiographically after treatment until stone-free or there are no 
remaining stone fragments which are likely to cause silent obstruction 
and loss of renal function.
    Renal injury: To reduce the risk of injury to the kidney and 
surrounding tissues, it is recommended that: (1) The number of shock 
waves administered during each treatment session be minimized; (2) 
retreatment to the same

[[Page 5996]]

kidney/anatomical site occur no sooner than 1 month after the initial 
treatment; and (3) each kidney/anatomical site be limited to a total of 
three treatment sessions.
    Small ureteral stones: Small middle and lower ureteral stones, 4 to 
6 mm in largest dimension, are likely to pass spontaneously. Therefore, 
the risks and benefits of extracorporeal shock wave lithotripsy should 
be carefully assessed in this patient population.
    Staghorn stones: The effectiveness of extracorporeal shock wave 
lithotripsy may be limited in patients with either staghorn or large 
( 20 mm in largest dimension) stones. Alternative procedures 
are recommended for these patients.
d. Patient Selection and Treatment:
    Children: The safety and effectiveness of this device in the 
treatment of urolithiasis in children have not been demonstrated. 
Although children have been treated with shock wave therapy for upper 
urinary tract stones, experience with lithotripsy in such cases is 
limited. Studies indicate that there are growth plate disturbances in 
the epiphyses of developing long bones in rats subjected to shock 
waves. The significance of this finding to human experience is unknown.
    Women of childbearing potential: The treatment of lower ureteral 
stones should be avoided in women of childbearing potential. The 
application of shock wave lithotripsy to this patient population could 
possibly result in irreversible damage to the female reproductive 
system and to the unborn fetus in the undiagnosed pregnancy.
e. Adverse Events:
Potential adverse events associated with the use of extracorporeal 
shock wave lithotripsy include those listed below, categorized by 
frequency and individually described:
1. Potential Adverse Events of Extracorporeal Shock Wave Lithotripsy 
Categorized by Frequency:
    a. Commonly reported (> 20 percentage of patients): Hematuria, 
pain/renal colic, skin redness at shock wave entry site.
    b. Occasionally reported (1 to 20 percentage of patients): Cardiac 
arrhythmia, urinary tract infection, urinary obstruction/steinstrasse, 
skin bruising at shock wave entry site, fever (> 38EC), nausea/
vomiting.
    c. Infrequently reported (< 1 percentage of patients): Hematoma 
(perirenal/intrarenal), renal injury.
2. Description of Adverse Events of Extracorporeal Shock Wave 
Lithotripsy:
    Cardiac arrhythmia: Cardiac arrhythmias, most commonly premature 
ventricular contractions, are generally reported during extracorporeal 
shock wave lithotripsy at fixed shock wave delivery in 2 to 20 
percentage of patients. These cardiac disturbances rarely pose a 
serious risk to the healthy patient, and typically resolve 
spontaneously upon synchronizing the shock waves with the refractory 
period of the ventricular cycle (i.e., ECG gating) or terminating 
treatment.
    Fever (> 38 C): Fever is occasionally reported after lithotripsy, 
and may be secondary to infection.
    Hematoma (perirenal/intrarenal): Clinically significant intrarenal 
or perirenal hematomas occur in < 1 percentage of lithotripsy 
treatments. Typically patients who experience this complication present 
with severe flank pain. Although clinically significant hematomas often 
resolve with conservative management, severe hemorrhage and death have 
been reported. Management of severe renal hemorrhage includes the 
administration of blood transfusions, percutaneous drainage, or 
surgical intervention.
    Hematuria: Hematuria occurs following most treatments, is believed 
to be secondary to trauma to the renal parenchyma, and usually resolves 
spontaneously within 24 to 48 hours of treatment.
    Nausea/vomiting: Transient nausea and vomiting are occasionally 
reported immediately after lithotripsy, and may be associated with 
either pain or the administration of sedatives or analgesia.
    Pain/renal colic: Pain/renal colic commonly occurs during and 
immediately after treatment, and typically resolves spontaneously. 
Temporary pain/renal colic may also occur secondary to the passage of 
stone fragments, and can be managed with medication.
    Renal injury: Extracorporeal shock wave lithotripsy procedures have 
been known to cause damage to the treated kidney. The potential for 
injury, its long-term significance, and its duration are unknown.
    Skin bruising at shock wave entry site: Skin bruising at the shock 
wave entry site occasionally occurs after treatment, and it typically 
resolves spontaneously.
    Skin redness at shock wave entry site: Skin redness at the shock 
wave entry site commonly occurs during and immediately after treatment, 
and typically resolves spontaneously.
    Urinary obstruction/steinstrasse: Urinary obstruction occurs in up 
to 6 percent of patients following lithotripsy due to stone fragments 
becoming lodged in the ureter, and may be the result of either a single 
stone fragment or the accumulation of multiple small stone particles 
(i.e., steinstrasse). Patients with urinary obstruction typically 
present with persistent pain, and may be at risk of developing 
hydronephrosis with subsequent renal failure if the obstruction is not 
promptly treated. Intervention is necessary if the obstructing 
fragments do not pass spontaneously.
    Urinary tract infection: Urinary tract infection (UTI) occurs in 1 
to 7 percent of patients following extracorporeal shock wave 
lithotripsy as a result of the release of bacteria from the 
fragmentation of infected calculi, and infrequently results in 
pyelonephritis or sepsis. The risk of infectious complications 
secondary to extracorporeal shock wave lithotripsy can be minimized 
through the use of prophylactic antibiotics in patients with UTI and 
infection stones.

    Dated: January 21, 1999.
 Linda S. Kahn,
 Deputy Director for Regulations Policy, Center for Devices and 
Radiological Health.
[FR Doc. 99-2689 Filed 2-5-99; 8:45 am]
BILLING CODE 4160-01-F