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

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

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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).

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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

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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.

14. Cass, A. S., ``The Use of Ungating with the Medstone

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.

79. Rassweiler, J., A. Westhauser, P. Bub, and F. Eisenberger,

``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.

82. Roessler, W., P. Steinbach, R. Seitz, F., Hofstaedter, and

W. F. Wieland, ``Mechanisms of Shockwave Action in the Human

Kidney,'' Journal of Endourology, 9(6):443-448, 1995.

83. Roessler, W., W. F. Wieland, P. Steinbach, F. Hofstaedter,

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

Nephrolithotomy,'' Urologic Clinics of North America, 15(2):155-166,

1988.

85. Ruiz, H. and B. Saltzman, ``Aspirin-Induced Bilateral Renal

Hemorrhage after Extracorporeal Shock Wave Lithotripsy Therapy:

Implications and Conclusions,'' Journal of Urology, 143:791-792,

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

Single and Multiple Doses of Piezoelectric Shockwaves (EDAP

LT.01),'' Journal of Urology, 145:399-404, 1991.

87. Schmidt, A., J. Seibold, P. Bub, and F. Eisenberger,

``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.

Bazmanoglu, A. Erkan, and S. Amato, ``A Report on Extracorporeal

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 ( 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