Inspections, Compliance, Enforcement, and Criminal Investigations
Ansar Group, Inc. d/b/a Ansar Medical Technologies, Inc 11/2/12
Department of Health and Human Services
|Public Health Service|
Food and Drug Administration
900 U.S. Customhouse
2nd and Chestnut Streets
Philadelphia, PA 19106
VIA UNITED PARCEL SERVICE
November 2, 2012
Mr. Robert G. Welch
President and CEO
Ansar Group, Inc.
240 South 8th Street
Philadelphia, Pennsylvania, 19107-5728
Dear Mr. Welch:
During an inspection of your firm located in Philadelphia, Pennsylvania, on May 30, through June 13, 2012, an investigator from the United States Food and Drug Administration (FDA) determined that your firm manufactures the ANX Version 3.0 Autonomic Nervous System Monitor. Under section 201(h) of the Federal Food, Drug, and Cosmetic Act (the Act), 21 U.S.C. § 321(h), this product is a device because it is intended for use in the diagnosis of disease or other conditions or in the cure, mitigation, treatment, or prevention of disease, or to affect the structure or any function of the body.
This inspection revealed that ANX Version 3.0 Autonomic Nervous System Monitor is adulterated under section 501(h) of the Act, 21 U.S.C. § 351(h); misbranded under section 502(t) of the Act, 21 U.S.C. § 352(t)(2); adulterated under section 501(f)(1)(B) of the Act, 21 U.S.C. § 352(f)(1)(B); and misbranded under section 502(o) of the Act, 21 U.S.C. § 352(o). Your firm’s response dated July 13, 2012, to the Form FDA 483 (FDA 483) was not reviewed because it was not received within fifteen business days of issuance of the FDA 483. The response may be evaluated along with any other written material provided in response to the violations cited in this Warning Letter.
This inspection revealed that this device is adulterated within the meaning of section 501(h) of the Act, 21 U.S.C. § 351(h), in that the methods used in, or the facilities or controls used for, its manufacture, packing, storage, or installation are not in conformity with the current good manufacturing practice requirements of the Quality System regulation found at Title 21, Code of Federal Regulations (CFR), Part 820.
These violations include, but are not limited to, the following:
1. Failure to establish and maintain adequate plans that describe or reference the design and development activities and define responsibility for implementation; identify and describe the interfaces with different groups or activities that provide, or result in, input to the design and development process; and review, update, and approve the plans as design and development evolves, as required by 21 CFR 820.30(b).
For example: In your firm’s (b)(4), section (b)(4) states, “(b)(4).” Our review of the Design History File (DHF) for the ANX 3.0 Autonomic Nervous System Monitor revealed that there was no design and development plan.
2. Failure to establish and maintain adequate procedures to ensure that the design requirements relating to a device are appropriate and address the intended use of the device, including the needs of the user and patient. The procedures shall include a mechanism for addressing incomplete, ambiguous, or conflicting requirements. The design input requirements shall be documented and shall be reviewed and approved by designated individuals. The approval, including the date and signature of the individuals approving the requirements, shall be documented, as required by 21 CFR 820.30(c).
For example: In your firm’s (b)(4), section (b)(4) states, “(b)(4).” During review of the DHF for the ANX 3.0 Autonomic Nervous System Monitor, there were no design input requirements identified or documented.
3. Failure to establish and maintain adequate procedures for defining and documenting design output in terms that allow an adequate evaluation of conformance to design input requirements, as required by 21 CFR 820.30(d).
For example: In your firm’s (b)(4),section (b)(4) states, “(b)(4).” During review of the DHF for the ANX 3.0 Autonomic Nervous System Monitor, there were no design outputs defined or documented.
4. Failure to establish and maintain adequate procedures for verifying the device design to confirm that the design output meets the design input requirements. The results of the design verification, including identification of the design, methods, the date, and the individuals performing the verification, shall be documented in the DHF, as required by 21 CFR 820.30(f).
For example: In your firm’s (b)(4), section (b)(4) states, “(b)(4).” Section (b)(4) states, “(b)(4).” Furthermore, section (b)(4) of the same procedure states, “(b)(4).” During review of the DHF for the ANX 3.0 Autonomic Nervous System Monitor, there were no Verification & Validation Plans or evidence of any design verification activities.
5. Failure to establish and maintain adequate design validation procedures to ensure that devices conform to defined user needs and intended uses; to ensure software validation and risk analysis is completed where appropriate; and to ensure the results of the design validation, including identification of the design, methods, the date, and the individuals performing the validation are documented in the DHF, as required by 21 CFR 820.30(g).
a. In your firm’s (b)(4), section (b)(4) states, “(b)(4).” Section (b)(4) states, “(b)(4).” Section (b)(4) goes on to list the following examples of design validation activities: clinical studies, consumer preference testing, bench testing using simulation, review of labeling, and review of scientific literature. Furthermore, section (b)(4) of the same procedure states, “(b)(4).” During review of the DHF for the ANX 3.0 Autonomic Nervous System Monitor, the file did not contain or reference any pre-approved Verification & Validation Plans or evidence of completed design validation activities.
b. Your firm’s software version history for the ANX 3.0 was requested and reviewed, however it only contained version history from (b)(4) until present, even though the ANX 3.0 device has been commercially marketed since 2001. During the inspection, your firm provided the investigator with two documents describing design changes made in versions (b)(4) of the device software, as a correction to this observation. However, these documents did not include results of software validation activities for these changes, to include the methods, the date, and the individuals performing the design validation activities.
c. Alpha and beta testing documentation for a (b)(4) software upgrade for version (b)(4) of the ANX 3.0 device software, was present in the DHF. The release notes for the ANX 3.0 Version (b)(4) documented it was a major release that improved earlier software versions, to include an improved (b)(4) that was substantially redesigned to reflect current scientific knowledge. It could not be determined, from the validation activities (alpha and beta testing) for the new software functionality, if the software performed as intended and met pre-determined user needs.
6. Failure to establish and maintain adequate procedures for the identification, documentation, validation, or where appropriate verification, review, and approval of design changes before their implementation, as required by 21 CFR 820.30(i).
a. In your firm’s (b)(4), section (b)(4) requires documentation of design changes in a Change Control Board Record, including: a description of the change, reason for the change, impact assessment (determinations for validation, regulatory filings, risk management activities), and final approval of the change. Instead, your firm documented software revisions identified as (b)(4) on Design Review Report forms and failed to document a description of the change, a reason for the change, impact assessments, and final approval.
b. There was no design change documentation for a device software change from a (b)(4) based spectral analyzer in the first generation device (ANS-C3000) to a (b)(4) based spectral analyzer for the second generation device (ANX 3.0), to ensure that the ANX 3.0 device performed as intended and met user needs.
7. Failure to establish and maintain an adequate DHF for each type of device to demonstrate that the design was developed in accordance with the approved design plan and design control requirements, as required by 21 CFR 820.30(j).
For example: Your firm failed to maintain a DHF for the first generation device (ANS-C3000), which was commercially released in 1999 and has completed a partial DHF for the second generation device (ANX 3.0), which was commercially released in 2001.
8. Failure to establish and maintain adequate procedures to ensure that all purchased or otherwise received product and services conform to specified requirements, as required by 21 CFR 820.50.
For example: Section (b)(4) of your firm’s (b)(4), requires a Supply Agreement as part of a Supplier Quality Plan, to ensure purchased components meet pre-determined specifications and quality requirements. However, your firm did not provide any supplier agreements it has with its vendors. When asked to explain this further, your firm stated that it only used a purchase order for specifying the accessories and/or components that are used with the ANX 3.0.
9. Failure to establish and maintain adequate procedures for finished device acceptance to ensure that each production run, lot, or batch of finished devices meets acceptance criteria and finished devices shall not be released for distribution until: (1) the activities required in the device master record (DMR) are completed; (2) the associated data and documentation is reviewed; (3) the release is authorized by the signature of a designated individual(s); and (4) the authorization is dated, as required by 21 CFR 820.80(d).
For example: The current physiological monitor manufactured by (b)(4) and used as a component of the ANX Version 3.0 Autonomic Nervous System Monitor, has not been qualified following a pre-approved test protocol to assure that all final specifications for release of the finished device system are met.
10. Failure to establish and maintain adequate procedures to ensure that equipment is routinely calibrated, inspected, checked, and maintained, as required by 21 CFR 820.72(a).
For example: Your firm continues to use the (b)(4) patient simulator, S/N (b)(4), as part of final acceptance testing activities for the ANX 3.0 Autonomic Nervous System Monitor, when the testing equipment manufacturer disclaims in their operating and service manual the use of this product as a certification test instrument for medical devices. Also, a review of the Ansar Master Equipment List revealed that the (b)(4) patient simulator required an annual calibration that had not been done.
11. Failure to establish and maintain adequate procedures for receiving, reviewing, and evaluating complaints by a formally designated unit, as required by 21 CFR 820.198(a).
For example: Your firm’s (b)(4), requires the use of (b)(4) to receive, review, and evaluate complaints. However, a copy of (b)(4) had not been prepared for this product. Instead, your firm was recording events that meet your written procedure’s definition of a complaint on service report forms. Your firm does not perform servicing for this device.
12. Failure of management with executive responsibility to review the suitability of the quality system at defined intervals and with sufficient frequency according to established procedures to ensure that the quality system satisfies the requirements of this part, as required by 21 CFR 820.20(c).
For example: Your firm’s (b)(4), requires in section (b)(4) that “(b)(4).” Section (b)(4) requires that the management representative prepare an agenda for the Management Review using (b)(4), to include at a minimum, a list of specified inputs. The only (b)(4) provided by your firm were for 2010 and 2011, which documented a yearly review of the “Quality Manual and SOP.” There is no evidence that Management Reviews were performed twice a year.
13. Failure to establish and maintain adequate procedures for quality audits and conduct such audits to assure that the quality system is in compliance with the established quality system requirements and to determine the effectiveness of the quality system. These quality audits shall be conducted by individuals who do not have direct responsibility for the matters being audited, as required by 21 CFR 820.22.
For example: your firm’s (b)(4), defines the process and instructions for performing Quality Audits within the establishment to assure compliance with established requirements. Section (b)(4) states, “(b)(4).” However, when your firm’s President was asked if it has conducted quality audits, he stated that he conducts quality assessments. Your firm’s President did not provide documentation of completed quality assessments to confirm that they had taken place and he said that there was no documentation of these assessments.
14. Failure to have sufficient personnel with the necessary education, background, training, and experience to assure that all activities are correctly performed, as required by 21 CFR 820.25(a).
For example: Your firm’s (b)(4), documents in section (b)(4), that executive management will identify a management representative who has the background and qualifications including training and background in regulatory requirements and standards and quality management systems knowledge. During the inspection, training records were reviewed and it was found that the appointed management representative did not have any training documentation on file.
Our inspection also revealed that your ANX Version 3.0 Autonomic Nervous System Monitor is misbranded under section 502(t)(2) of the Act, 21 U.S.C. § 352(t)(2), in that your firm failed or refused to furnish material or information respecting the device that is required by or under section 519 of the Act, 21 U.S.C. § 360i, and 21 CFR Part 803 - Medical Device Reporting (MDR). Significant violations include, but are not limited to, the following:
Failure to implement written MDR procedures, as required by 21 CFR 803.17.
For example: Your firm’s (b)(4), states that your firm must document the process used to determine the cause of the event and the results of an investigation as part of documenting a reportability decision. However, the information included in the (b)(4) for complaints received by your firm does not include documentation of your firm’s reportability decisions.
Please note that your firm’s (b)(4), includes references to baseline reporting, which is no longer required. See 73 FR 53686 (September 17, 2008). You should consider removing all references to Baseline Reports from your firm’s MDR procedure.
If your firm wishes to submit MDR reports via electronic submission it can follow the directions stated at the following URL:
If your firm wishes to discuss MDR reportability criteria or to schedule further communications, it may contact the MDR Policy Branch at 301-796-6670 or by email at MDRPolicy@fda.hhs.gov.
Our inspection also revealed that your firm’s ANX Version 3.0 Autonomic Nervous System Monitor device is misbranded under section 502(t)(2) of the Act, 21 U.S.C. § 352(t)(2), in that your firm failed or refused to furnish material or information respecting the device that is required by or under section 519 of the Act, 21 U.S.C. § 360i, and 21 CFR Part 806 – Medical Devices; Reports of Corrections and Removals. Significant violations include, but are not limited to, the following:
Failure to submit a written report to FDA of a correction or removal of a device that was initiated to remedy a violation of the Act caused by the device that may present a risk to health, unless the information has already been provided as set forth in 21 CFR 806.10(f) or the correction or removal action is exempt from the reporting requirements under 806.1(b), as required by 21 CFR 806.10(a)(2).
For example: Your firm failed to report a correction or removal of the patient monitor component of the ANX Version 3.0 Autonomic Nervous System Monitor in order to reduce known incidents of (b)(4) failures. This failure mode may present a risk to health and must be reported as a correction or removal.
Our inspection also revealed that your firm is promoting and marketing the ANX Version 3.0 Autonomic Nervous System Monitor in the United States without the required marketing clearance or approval, in violation of the Act. When there are significant changes or modifications in the design, components, method of manufacture, or intended use of a cleared device, a new application must be submitted under section 510(k) of the Act, 21 U.S.C. § 360(k), and cleared prior to marketing. See 21 CFR 807.81(a)(3).
Your firm obtained clearance of the “Respiratory and Cardiac Spectral Frequency Signal Processor” or ANS C3000 (K941252) under section 510(k) with the following intended use:
“The ANS-C3000 is intended to be used as an accessory to a patient monitor to provide heart rate and respiratory spectral frequency data for the purpose of perioperative patient monitoring. Further, the device is intended for use by medical doctors or other healthcare professionals to monitor patient ECG and respiratory data in hospitals or other patient care facilities. The devices perform the primary basic functions of receiving, storing, arithmetically analyzing and displaying ECG and respiratory data.”
During the inspection, FDA collected labeling and promotional materials for the ANX 3.0 and has determined that your firm is promoting and marketing the ANX 3.0 in the United States for uses for which your firm has not received required premarket clearance or approval, in violation of the Act. Specifically, version 3.0 of the User’s Operations Manual contains the following claims:
“How does ANX technology revolutionize medicine? Chronic sympathovagal imbalance in the ANS can be the result of autonomic nerve damage along vital neural control paths. Identifying this imbalance early enables physicians to adjust patient treatment to slow or stop nerve damage and before end organ damage occurs, including cardiovascular and non-cardiovascular systems damage. This means sympathovagal assessment can be strategically applied to a broad practice of medicine, including the following applications:
- Diagnosis of disease on an individual patient basis,
- Evaluation and tracking of the severity of disease based on a patient’s own physiologic baseline,
- Determination of risk factors and prognosis, and
- Monitoring of the effects and titration of medication and other treatment interventions specifically for the individual.”
In addition, we note that in both the User’s Operations Manual and the Technician’s Training Manual, your firm has included information on how to interpret Ansar ANX 3.0 test data that includes specific drug treatment recommendations for both initiating and changing existing regimens based on the results of the tests performed by the device. These represent major changes in the intended use of the device. For example:
“Is the patient in balance, i.e., is SB between 0.4 and 3.0? (This affects mortality and longevity)
o Yes, continue to read the report.
- If SB too low (resting PE*), recommend raising SB by increasing anti-cholinergics or reducing sympathetic blockade, history dependent;
- If SB too high (resting SE*), recommend lowering SB by decreasing anti-cholinergics or increasing sympathetic blockade, history dependent.”
“Is there Valsalva or standing PE (This affects morbidity and quality of life)
o Yes, if cardiovascular disease (including high BP) recommend switching beta blocker to Carvedilol if symptoms (e.g., reports of fatigue or low energy, frequent headache or migraine, depression-like symptoms, or dizziness upon standing), history dependent, if not recommend low-dose anti-cholinergic therapy.
o No, continue to read the report.”
During the review of K941252, your firm was advised that there were not data adequate to correlate the device frequency bands with the parasympathetic and sympathetic nervous system. Your firm was explicitly asked to remove all claims related to being able to measure simultaneously and independently both the sympathetic and parasympathetic autonomous nervous system. Your firm was also advised to remove all claims related to clinical interpretation of the data. We are not aware of data to substantiate these claims. Please provide data to substantiate these claims to the address below. If your firm cannot substantiate these claims, the ANX Version 3.0 Autonomic Nervous System Monitor’s labeling may be false or misleading, causing the device to be misbranded under section 502(a) of the Act, 21 U.S.C. 21 U.S.C. § 352(a).
Additionally, your firm is marketing the ANX Version 3.0 Autonomic Nervous System Monitor with the following claims:
“Improved Test Interpretation Algorithm” that “has been substantially redesigned to reflect current scientific knowledge,” according to its ANX 3.0 Version L Software Release Notes. Specific modifications include:
- “Paradoxic Parasympathetic Syndrome (PPS) is replaced by a functional description of the condition: excess parasympathetic activity
- Excess parasympathetic activity may also be observed during Valsalva phase when the change is greater than six times compared to that during the Baseline phase. This is reflected in the new ANS Test Results and Multi-Parameter Graphical Report pages.
- Indications for the possibility or risk of syncope have been improved to reflect functional descriptions of the autonomic imbalances
- Ranges for other parameters have been adjusted to better account for borderline conditions.”
The modifications to the device software and addition of the blood pressure monitor significantly change the technology in ways that significantly affect safety or effectiveness and constitute major changes in the intended use of ANX Version 3.0 Autonomic Nervous System.
As a result of these significant changes to both intended use and technology, the device is adulterated under section 501(f)(1)(B) of the Act, 21 U.S.C. § 351(f)(1)(B), because your firm does not have an approved application for premarket approval (PMA) in effect pursuant to section 515(a) of the Act, 21 U.S.C. § 360e(a), or an approved application for an investigational device exemption under section 520(g) of the Act, 21 U.S.C. § 360j(g). The device is also misbranded under section 502(o) the Act, 21 U.S.C. § 352(o), because your firm did not notify the agency of its intent to introduce the changed device into commercial distribution, as required by section 510(k) of the Act, 21 U.S.C. § 360(k). For a device requiring premarket approval, the notification required by section 510(k) is deemed satisfied when a PMA is pending before the agency. [21 CFR 807.81(b)] The kind of information that your firm needs to submit in order to obtain approval or clearance for the device is described on the Internet at
http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/HowtoMarketYourDevice/default.htm. The FDA will evaluate the information that your firm submits and decide whether the product may be legally marketed.
Your firm should immediately cease marketing the ANX Version 3.0 Autonomic Nervous System Monitor for unapproved uses such as those described above and take prompt action to correct the violations addressed in this letter. Failure to promptly correct these violations may result in regulatory action being initiated by the FDA without further notice. These actions include, but are not limited to, seizure, injunction, and civil money penalties. Also, federal agencies may be advised of the issuance of Warning Letters about devices so that they may take this information into account when considering the award of contracts. Additionally, premarket approval applications for Class III devices to which the Quality System regulation violations are reasonably related will not be approved until the violations have been corrected. Requests for Certificates to Foreign Governments will not be granted until the violations related to the subject device have been corrected.
Please notify this office in writing within fifteen business days from the date you receive this letter of the specific steps your firm has taken to correct the noted violations, as well as an explanation of how your firm plans to prevent these violations, or similar violations, from occurring again. Include documentation of the corrections and/or corrective actions (including any systemic corrective actions) that your firm has taken. If your firm’s planned corrections and/or corrective actions will occur over time, please include a timetable for implementation of those activities. If corrections and/or corrective actions cannot be completed within fifteen business days, state the reason for the delay and the time within which these activities will be completed. Your firm’s response should be comprehensive and address all violations included in this Warning Letter.
Your firm’s written response should be sent to: U.S Food and Drug Administration, U.S. Customhouse Room 900, 2nd and Chestnut Streets, Philadelphia, PA 19106, Attn: Kristina Donohue, Compliance Officer. If you have any questions about the contents of this letter, Kristina Donohue can be reached at (215) 717-3078.
Finally, you should know that this letter is not intended to be an all-inclusive list of the violations at your firm’s facility. It is your firm’s responsibility to ensure compliance with applicable laws and regulations administered by FDA. The specific violations noted in this letter and in the Inspectional Observations, Form FDA 483 (FDA 483), issued at the close of the inspection may be symptomatic of serious problems in your firm’s manufacturing and quality management systems. Your firm should investigate and determine the causes of the violations, and take prompt actions to correct the violations and bring the products into compliance.
Kirk D. Sooter
Philadelphia District Office