This product is indicated for use with Saizen® [somatropin (rDNAorigin) for injection] for the long-term treatment of children with growth failure due to inadequate secretion of endogenous growth hormone.

Device Description

Clicker™ Needle-Free Self-Injection Device for Personal Use with Saizen® [somatropin (rDNA origin) for injection]. This submission changes the labeling of the Vitajet 3, (Innova) (K962625) to allow the device to be used for needle-free subcutaneous administration of Saizen® [somatropin (rDNAorigin) for injection]. There are no other significant changes to the Vitajet 3 (Innova) in device design or function.

AI/ML Overview

Here's a summary of the acceptance criteria and study details for the Bioject Clicker™ Needle-Free Self-Injection Device, based on the provided text:

1. Table of Acceptance Criteria and Reported Device Performance

Acceptance Criteria	Reported Device Performance
Pharmacokinetic Equivalence (Adults)
AUC (Area Under the Curve) 90% Confidence Interval (CI) for Test/Reference Ratio	(0.95, 1.12), falling within the (80%, 125%) required interval.
Cmax (Maximum Concentration) 90% Confidence Interval (CI) for Test/Reference Ratio	(0.81, 1.20), falling within the (80%, 125%) required interval.
tmax (Time to Maximum Concentration)	Not statistically different between needle and needle-free.
t1/2 (Half-life)	Assessed for assumptions, no significant difference.
Pharmacodynamic Equivalence (Adults)
Serum IGF-1 levels (24 hours)	Very similar to needle injection.
User Experience (Adults)
Pain	Trend toward less pain with jet-injector (p = 0.093).
Ease of Use	Highly significant preference for jet-injector (p = 0.017).
Convenience	Highly significant preference for jet-injector (p = 0.004).
Pleasantness	Highly significant preference for jet-injector (p = 0.011).
Less Apprehension	Highly significant preference for jet-injector (p = 0.0110).
Overall Preference	Highly significant preference for jet-injector (p = 0.053).
User Experience (Children)
Pain	Highly significant difference favoring needle-free (p < 0.01).
Unpleasantness	Highly significant difference favoring needle-free (p < 0.01).
Convenience	No significant difference.
Ease of Use	No significant difference.
Nervousness with first injection	Significantly more nervous than with familiar needle injection.
Drug Integrity (Shear Stress Testing)
Saizen® structure after injection	Results within assay variability for HPLC, physical tests, and pH, indicating no physical alteration.
Chemical Compatibility (Clear View Nozzle & Stem Tip)
Interaction with Saizen®	Results within assay variability for HPLC, physical tests, and pH, indicating suitability for use.
Chemical Compatibility (Vial Connector)
Particulates	No particulates observed at 7 and 14 days.
pH and Purity (SE-HPLC)	Results demonstrated within-assay variability for HPLC, physical tests, and pH, indicating suitability for use.
Microorganism Growth (Bioburden Study)
Microorganism growth in injected liquid	No microorganism growth in any sample.
Microorganism growth on nozzle surface	Growth in only one sample (non-pathogenic Staphylococcus species).
Microorganism growth on Stem Tip	Growth in two samples (mold (Aspergillus glaucus) and non-pathogenic bacteria (Bacillus lichenformis)). No growth on more concentrated filtration samples.
Microorganism growth in vial contents	Growth on only one sample (non-pathogenic mold (Aspergillus versicolor)).
Microorganism growth on vial adapter surface	Multiple occurrences of skin contaminants (non-pathogenic Staphylococcus species).
Absence of pathogenic microorganisms	All recovered isolates determined not to be Escherichia coli, Pseudomonas aeruginosa, Salmonella, or Staphylococcus aureus.
Clinically significant microorganisms	No clinically significant microorganisms found within the nozzle or vial over 14 days.

2. Sample Size Used for the Test Set and Data Provenance

Clinical Efficacy (Adults) - Pharmacokinetic/Pharmacodynamic Study:
- Sample Size: 21 subjects (healthy adults aged 18-40 years).
- Data Provenance: Not explicitly stated, but clinical studies are generally prospective. Likely conducted in a single country, but not specified.
Clinical Efficacy (Children) - Acceptability Study:
- Sample Size: 29 children (adolescents aged 12-18 years) with Type I diabetes mellitus.
- Data Provenance: Not explicitly stated, but clinical studies are generally prospective. Likely conducted in a single country, but not specified.
Laboratory Studies (Shear Stress, Chemical Compatibility, Bioburden):
- Specific numbers of drug lots and jet-injectors are mentioned for some tests (e.g., 2 lots of 5.0mg Saizen, 1 lot of 8.8mg Saizen for shear stress; 12 jet-injectors for bioburden), but a single overall "test set" sample size isn't applicable in the same way as clinical studies. These are laboratory-based, prospective tests.

3. Number of Experts Used to Establish the Ground Truth for the Test Set and Their Qualifications

Not Applicable. For this device (a drug delivery system), the "ground truth" is established through quantifiable physiological responses (e.g., GH and IGF-1 levels, documented bioequivalence), objective measurements (e.g., HPLC, pH, physical tests for drug integrity), and patient-reported outcomes (e.g., pain, preference). There isn't a subjective "ground truth" established by experts in the typical sense of diagnostic imaging or clinical assessment. The "experts" involved would be the clinical researchers, statisticians, and laboratory technicians conducting the studies.

4. Adjudication Method for the Test Set

Not Applicable. As mentioned above, ground truth is based on quantitative data, not subjective expert consensus requiring adjudication. Statistical bioequivalence analysis (e.g., 90% confidence intervals) and p-values for statistical significance are the methods used for evaluating the results against the acceptance criteria.

5. If a Multi Reader Multi Case (MRMC) Comparative Effectiveness Study was done, If so, what was the effect size of how much human readers improve with AI vs without AI assistance

Not Applicable. This is a device for drug delivery, not a diagnostic imaging or AI-assisted interpretation tool. Therefore, MRMC studies are not relevant.

6. If a Standalone (i.e. algorithm only without human-in-the loop performance) was done

Not Applicable. This device does not involve an algorithm or AI. It is a mechanical medical device.

7. The Type of Ground Truth Used

Clinical Ground Truth:
- For pharmacokinetic/pharmacodynamic studies: Measured serum concentrations of Growth Hormone (GH) and Insulin-like Growth Factor 1 (IGF-1), analyzed statistically for bioequivalence.
- For patient experience: Patient-reported outcomes via questionnaires (e.g., pain, ease of use, preference).
Laboratory Ground Truth:
- For drug integrity: High-Pressure Liquid Chromatography (HPLC) analysis, physical tests, and pH measurements to assess the structural integrity and purity of Saizen®.
- For chemical compatibility: Same as drug integrity (HPLC, physical tests, pH), plus visual inspection for particulates.
- For microbiological safety: Culture-based methods to identify and quantify microorganisms, screened for specific pathogens.

8. The Sample Size for the Training Set

Not Applicable. This device does not use machine learning or AI, and therefore does not have a "training set" in that context. The studies described are validation studies for a physical medical device and drug delivery system.

9. How the Ground Truth for the Training Set Was Established

Not Applicable. See point 8.

Summary

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510(k) Summary (As required by 21 CFR 807.92(a))

ﻪ

A. Submitter Information

Bioject, Inc. 7620 SW Bridgeport Road Portland, Oregon 97224

Phone: 800-683-7221 ext. 424 Fax: 503-624-9002 Email: nancy@bioject.com Contact: Nancy J. Gertlar Manager, QA/RA December 17, 1999 Date:

B Device Information Trade/Proprietary Name:

Common Name:

Classification Name:

Predicate Device(s):

Device Description:

Intended Use:

C Comparison of Required Technological Characteristics:
Jet Injector, Non-Electrically Powered Fluid Injector

Needle Free Injector, Jet Injector

. Medi-Jector Needle-Free Bio-Tropin™ Drug Delivery System K960285
. Vitajet K962625

Clicker™

Clicker™ Needle-Free Self-Injection Device for Personal Use with Saizen® [somatropin (rDNA origin) for injection]. Needle Free Injector, Jet Injector

Clicker™ Needle-Free Self-Injection Device for Personal Use with Saizen® [somatropin (rDNA origin) for injection].

This submission changes the labeling of the Vitajet 3, (Innova) (K962625) to allow the device to be used for needle-free subcutaneous administration of Saizen® [somatropin (rDNAorigin) for injection].

There are no other significant changes to the Vitajet 3 (Innova) in device design or function.

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D Summary and Conclusion of Nonclinical and Clinical Tests:

GROWTH HORMONE DELIVERY USING A NEEDLE-FREE JET-INJECTOR

A number of clinical and laboratory studies were completed to prepare for an FDA submission for Saizen to be used with a needle-free device. These included laboratory studies designed to address the ability of Saizen to remain intact after administration through the jet-injector and measurement of any Saizen , which may adsorb to the plastic component parts. In addition, procedures were developed to measure and identify any microorganisms that may develop after seven daily injections with the same disposable plastic nozzle and vial connector.

LABORATORY STUDIES

The goals of the laboratory studies were to evaluate potential shearing and fragmentation of Saizen® and the interaction of growth hormone with the various plastic device components. In addition, a Bioburden study was performed to evaluate microorganism growth in and on the disposable clear nozzle as well as in the vial itself and on the vial connector. Four protocols were completed to reach the above goals.

SHEAR STRESS TESTING

Clicker" utilizes a spring to induce a high-pressure injection of growth hormone through the skin. Protocol P-00026-01 was conducted to determine the effect of shear stress on Saizen®. A total of two lots of the 5.0 mg vial Saizen® and one lot of 8.8 mg vial Saizen® were tested. Technical report R-00055-02 summarizes the results. Results were within assay variability for high-pressure liquid chromatography (HPLC) analysis, physical tests and pH. Therefore, shear stress caused by Clicker™ did not physically alter the structure of Saizen®.

CHEMICAL COMPATIBILITY TESTING

CLEAR VIEW NOZZLE STUDY

Clicker" utilizes a sterile plastic Stem Tip and Clear View Nozzle to perform a highpressure injection of growth hormone through the skin. Protocol P-00028-01 was performed to assess interaction of growth hormone with the plastic components of the needle-free jet-injector. Two lots of the 5.0 mg vial Saizen® and one lot of 8.8 mg vial Saison® were tested. Technical report R-00056-02 summarizes the results. Results were within assay variability for HPLC analysis, physical tests and pH. Therefore, the Clear View Nozzle and Stem Tip are suitable for use with Saizen®

VIAL CONNECTOR STUDY

Protocol P-00025-01 examined the Vial Connector needed on the vial of growth hormone to facilitate drawing up the material into the injector. The growth hormone

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samples were observed at seven and fourteen days for particulates by holding up to the light, checking against black paper and checking against white paper. The samples were also tested for pH and assessed for purity by SE-HPLC. Technical report R-00058-02 summarizes these results. Results demonstrated within- assay variability for HPLC analysis, physical tests and pH. Therefore, the Vial Connector is suitable for use with Saizen®.

BIOBURDEN STUDY

Protocol P-00027-02 investigates the effect of repeated use of Clicker" on the number and pathogenicity of microorganisms noted on the various component parts. The components (plastic Stem Tip and Clear View Nozzle) can be used for up to seven days, while the reconstituted vial of Saizen® can be used for up to 14 days. This study was conducted to determine the amount and type of microorganism growth on the injector components, in the vial and in the injected drug after 14 days of use.

Multiple drug lots were tested with 12 jet-injectors. Technical report R-00057-01 summarizes the results. The liquid contents injected from the nozzle showed no microorganism growth in any sample, while the nozzle surface itself showed growth in only one sample. The Stem Tip exhibited growth in two samples, but did not show growth on the same, more concentrated filtration samples. One culture grew a nonpathogenic Staphylococcus species and another grew a mold (Aspergillus glaucus) and non-pathogenic bacteria (Bacillus lichenformis). The vial contents exhibited growth on only one sample. This single isolate was a non-pathogenic mold (Aspergillus versicolor). The vial adapter surface showed multiple occurrences of skin contaminants (non- pathogenic Staphylococcus species) only. All recovered isolates were determined not to be Escherichia coli, Pseudomonas aeauginosa, Salmonella or Staphylococcus aureus by screening on selective agar.

In summary, there are no clinically significant microorganisms found within the nozzle or within the Saizen® vial over a period of 14 days. Only minor expected surface contaminants were seen on the outer surface of the Vial Connector, Stem Tip and Clear View nozzle.

CLINICAL STUDIES

Clinical studies included a randomized crossover pharmacokinetic, pharmacodynamic study comparing a conventional needle injection to Clicker™. A second study evaluated the acceptability of the needle-free device following a single jet-injection compared to needle injection in 29 children (ages 12-18), with Type I diabetes mellitus. The children with diabetes mellitus were taking daily or more frequent insulin needle injections for a period of one to five years. Two separate clinical studies were completed on 21 adults and 29 children.

PHARMACOKINETIC AND PHARNACODYNAMIC CYNAMIC STUDIES IN ADULTS

A randomized, single-dose, two-way crossover relative bioavailability study of Saizen® administered subcutaneously by needle or needle-free device in normal

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healthy adult subjects (ages 18- 40 years) was completed to determine bioequivalence between the conventional subcutaneous needle injection of GH and GH administered using a needle-free device. Statistical bioequivalence analyses were based on 21 subjects. In the clinical pharmacokinetic study, the measured GH levels from subjects using the needle injection and the needle-free device were similar during the entire 24 hours of blood monitoring. (Figure 1)

Image /page/3/Figure/2 description: The image is a graph titled "Figure 1" that shows the serum concentration of growth hormone over a 24-hour period. The x-axis represents the sampling time in hours, ranging from 0 to 24. The y-axis represents the serum concentration (geometric mean) of growth hormone. Two lines are plotted on the graph, representing two different treatments: a jet injector and a syringe.

The maximum concentration of GH and the peak time for the maximum GH concentration were also not statistically different. The data for AUC, AUCtiast) and Cmax were log transformed prior to analysis. The data for tmax and t1/2 were assessed for adherence to assumptions. For AUC 138, the 90 % confidence interval for the ratio of test to reference expressed, as a percentage was (0.95, 1.12) falling within the (80%, 125%) interval required for bioequivalence as specified in the protocol. For Cmax the 90 % confidence interval for the ratio of test to reference expressed as a percentage was (0.81, 1.20), falling within the (80%, 125%) interval required for bioequivalence as specified in the protocol.

For untransformed tmax the p-values associated with the Shapiro-Wilks tests of normality were not statistically significant for intrasubject error (p = 0.428) and

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intersubject error (p = 0.857). The test for formulation differences between the reference formulation and the test formulation twas not statistically significant (p = 0.523). Period effects were also not statistically significant (p = 0.472).

The serum IGF1 values measured every six hours for 24 hours after injection were very similar when comparing both the needle and needle-free device. (Figure 2) After log transforming the data, the p-values for the Shapiro-Wilks test of normality for both the intrasubject and intersubject error were not significant (p = 0.840 for intrasubject error, p = . 0599 for intersubject error).

Image /page/4/Figure/2 description: The image is a line graph titled "Figure 2" that shows the mean serum concentration of IGF-1 over a 26-hour period. The x-axis represents the sampling time in hours, ranging from 0 to 26. The y-axis represents the mean serum concentration of IGF-1, ranging from 100 to 400. Two lines are plotted on the graph, representing two different treatments: Jet Injector and Syringe.

Analog scales were developed to evaluate drug penetration of the skin, bleeding and bruising immediately after injection, thirty minutes after injection and twenty-four hours after injection. Inspections of these count data suggested that there was no statistically significant difference between both treatments (needle vs. needle- free) with respect to the number of subjects injected and events at various time points (0, 30 minutes and 24 hours after injection).

There were no serious adverse events or deaths in this study and no subjects withdrew prematurely from the study. The mild adverse reactions that were reported did not appear to be device related.

The adult questionnaire (ages 18-40 years) indicated a trend toward less pain with the jet-injector (p = 0.093). However, the response to specific questions relating to "ease of use" (p = 0.017), " convenience" (p = 0.004), "pleasantness" (p = 0.011), " less

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apprehension" (p = 0.0110 and "overall preference" (p = 0.053) showed a highly significant preference for the needle-free jet-injector over the conventional needle injection.

QUESTIONNAIRES IN CHILDREN WITH TYPE I DIABETES MELLITUS

Twenty-nine adolescents with one to five years of insulin dependent diabetes mellitus were asked to compare a single, self-administered needle-free dose of saline with the previous six months of needle injections of insulin. Questionnaires were administered shortly after their needle-free injection. The questionnaires in the group of 29 adolescents with Type I diabetes mellitus (ages 12-18 years) demonstrated highly significant differences relating to both "pain" and "unpleasantness" favoring the needle-free jet-injector over needle injections. The subjects chose the needle as the method that would hurt more by a count of 22 to 7. This confirmed the level of pain data and was again highly significant, p < 0.01. The needle-free device was chosen as more pleasant to use by a 22 to 7 ratio (p < 0.01). However, in this population, there was no significant difference between the needle-free device and the needle injections in regard to "convenience" or "ease of use". The adolescent group also found that the first needle-free jet-injection made them significantly more nervous than their familiar needle injection.

SUMMARY

In summary, both clinical studies suggest that the needle-free device is easier to use, convenient, more pleasant and generally less painful than conventional needle injection. The adult study demonstrated a clear preference for the needle-free device over needle injection. Measurements of GH and IGF-1 hormone levels demonstrated bioequivalence between needle and needle-free delivery of growth hormone.

The Center for Disease Control in the United States clearly favors the use of needlefree injections to reduce the incidence of Hepatitis B, C, and HIV infection as well as to diminish the pain from needle injection. This new technology is rapidly replacing conventional needle therapy. In recent years, a number of safety features have been devised for the needle and syringe to reduce occupational hazards and associated costs. Needle-free injection is an alternative method that does not require a needle and its wide spread use should reduce the incidence of contagious infections related to needles and at the same time reduce the environmental burden that needle disposal poses on a nation.

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Image /page/6/Picture/1 description: The image shows the logo for the U.S. Department of Health and Human Services. The logo is a circular seal with the words "DEPARTMENT OF HEALTH & HUMAN SERVICES - USA" around the perimeter. Inside the circle is an abstract image of an eagle or bird-like figure, represented by three curved lines that suggest wings and a head.

Public Health Service

JUN 2 2 2000

Food and Drug Administration 9200 Corporate Boulevard Rockville MD 20850

Ms. Nancy J. Gertlar Manager, QA/RA Bioject, Incorporated 7620 SW Bridgeport Road Portland, Oregon 97224

Re: K994384 Clicker Trade Name: Regulatory Class: II Product Code: KZE Dated: April 11, 2000 Received: April 12, 2000

Dear Ms. Gertlar:

We have reviewed your Section 510(k) notification of intent to we have reviewed referenced above and we have determined the market the device fally equivalent (for the indications for use stated in the enclosure) to devices marketed in interstate use stated in the encrobate, co as researchmont date of the Medical Device Amendments, or to devices that have been reclassified in accordance with the provisions of the Federal Food, Drug, and Cosmetic Act (Act). You may, therefore, rood, brug, and occmeblect to the general controls provisions The general controls provisions of the Act of the Act. of the nee? Incents for annual registration, listing of devices, good manufacturing practice, labeling, and prohibitions against misbranding and adulteration.

If your device is classified (see above) into either class II (Special Controls) or class III (Premarket Approval), it may be subject to such additional controls. Existing major regulations affecting your device can be found in the Code of Federal Regulations, Title 21, Parts 800 to 895. A substantially equivalent determination assumes compliance with the Good Manufacturing Practice for Medical Devices: General (GMP) regulation (21 CFR Part 820) and that, through periodic GMP inspections, the Food and Drug Administration (FDA) will verify such assumptions. Failure to comply with the GMP regulation may result in regulatory action. In addition, FDA may publish further announcements concerning your device in the Federal Register. Please note: this response to your premarket notification submission does not affect any obligation you might have under sections 531 through 542 of the Act for devices under the Electronic Product Radiation Control provisions, or other Federal laws or regulations.

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Page 2 - Ms. Gertlar

This letter will allow you to begin marketing your device as described in your 510(k) premarket notification. The FDA finding of substantial equivalence of your device to a legally marketed predicate device results in a classification for your device and thus, permits your device to proceed to the market.

If you desire specific advice for your device on our labeling requlation (21 CFR Part 801 and additionally 809.10 for in vitro diagnostic devices), please contact the Office of Compliance at (301) 594-4692. Additionally, for questions on the promotion and advertising of your device, please contact the Office of Compliance at (301) 594-4639. Also, please note the regulation entitled, "Misbranding by reference to Other general information on your responsibilities under the Act may be obtained from the Division of Small Manufacturers Assistance at its toll-free number (800) 638-2041 or (301) 443-6597 or at its internet address "http://www.fdag.gov/cdrh/dsmamain.html".

Sincerely yours,

Timothy A. Ulatowski

Director Division of Dental, Infection Control, and General Hospital Devices Office of Device Evaluation Center for Devices and Radiological Health

Enclosure

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Page 1 of 1

510(k) Number (if known): new submission

Device Name: Clicker™

Indications for Use:

This product is indicated for use with Saizen® [somatropin (rDNAorigin) for . injection] for the long-term treatment of children with growth failure due to inadequate secretion of endogenous growth hormone.
Contraindications:

This product is not recommended for patients:

Who are visually impaired, .
Who have neuromuscular or arthritic conditions which would make winding the . Clicker™ difficult,
Who are not able to understand and follow the procedure for safe use of the . device,
Who bruise or bleed easily, or are taking anti-coagulant medication (blood . thinners), or any other medication or therapy which may contribute to excess bleeding or bruising after injections,
Who are not willing to fully comply with the procedures of use of the device and . with the recommended frequency for replacement of the disposable accessories,
Where Saizen® [somatropin (rDNAorigin) for injection] is contraindicated for . treatment of that patient.

(PLEASE DO NOT WRITE BELOW THIS LINE – CONTINUE ON ANOTHER PAGE IF NEEDED)

Concurrence of CDRH, Office of Device Evaluation (ODE)

Patricia Cucenito

Division Sign-Off) Division of Dental, Infection Control, and General Hospital Devices 510(k) Number

Prescription Use
(Per 21 CFR 801.109)

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Over-The-Counter Use

Regulation Number and Section

§ 880.5430 Nonelectrically powered fluid injector.

(a)
Identification. A nonelectrically powered fluid injector is a nonelectrically powered device used by a health care provider to give a hypodermic injection by means of a narrow, high velocity jet of fluid which can penetrate the surface of the skin and deliver the fluid to the body. It may be used for mass inoculations.(b)
Classification. Class II (performance standards).