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U.S. Department of Health and Human Services

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OCD FY2005: Using Risk Information to Protect the Public

Protecting Human Research Subjects and Confronting Research Misconduct

The Bioresearch Monitoring (BIMO) program is entrusted with protecting the rights, safety, and welfare of human research subjects and insuring the quality and integrity of device research.

Application of Integrity Policy
Implementation of FDA's Application Integrity Policy involves investigations of sponsors that are suspected of submitting false or misleading data to the FDA. It also includes the review, evaluation, and monitoring of validity assessments required to be completed by sponsors found guilty of fraudulent activities. In FY 2005 CDRH invoked the Application Integrity Policy (AIP) against a manufacturer and a distributor of drugs of abuse test kits. This action effectively removed thousands of potentially inaccurate and ineffective diagnostic drugs of abuse test kits from the marketplace. Because of this action, CDRH suspended the substantive review of eight of the manufacturer’s pending 510(k) marketing submissions, and the manufacturer subsequently withdrew 18 additional cleared 510(k) marketing submissions due to widespread data inconsistencies and questionable design and research practices.

Removal From the Application Integrity Policy List and the Integrity Hold List
The Application Integrity Policy is invoked in cases where unreliable safety or effectiveness data is uncovered in numerous applications currently under FDA review and evaluation while the Integrity Hold is invoked when questionable data is uncovered in only one application under FDA review. In FY 2005, CDRH removed one sponsor from the AIP list and three sponsors from the integrity hold list. Removal from both lists are based upon the sponsor’s successful implementation of a corrective action plan that addresses shortcomings in the oversight of device research and assures higher quality marketing submissions.

Notice of Initiation of Disqualification Proceeding and Opportunity to Explain Letters (NIDPOE)
A NIDPOE letter informs the recipient clinical investigator that FDA is initiating an administrative proceeding to determine whether the clinical investigator should be disqualified from receiving investigational products pursuant to the Food and Drug Administration's regulations. Generally, FDA issues a NIDPOE letter when it believes it has evidence that the clinical investigator repeatedly or deliberately violated FDA's regulations governing the proper conduct of clinical studies involving investigational products or submitted false information to the sponsor. In FY 2005 CDRH issued two NIDPOE letters to clinical investigators, one of which resulted in a restricted agreement between the Agency and the clinical investigator.

Institutional Review Boards (IRBS) Failure To Implement Corrective Actions Resulted In FDA Withholding Approval of New Studies
In FY 2005 CDRH issued Warning Letters to two IRBs for continuing to fail to comply with FDA regulations applicable to IRBs. The Warning Letters were issued following inspections whose purpose was to determine if the IRBs had implemented corrective actions assured in their response to previous Warning Letters and to determine if the IRBs were presently functioning in compliance with applicable FDA regulations. The Warning Letters requested that the IRBs take immediate action to correct the violations. Furthermore, the Warning Letters notified the IRBs that as a continued result of their noncompliance, FDA would withhold approval of new studies reviewed by the IRBs, and that no new subjects could be admitted to ongoing studies that were currently under review by the IRBs. These restrictions would remain in effect until the FDA notified them in writing that their corrective actions were satisfactory.

CDRH BIMO INSPECTIONS
Fiscal Years 2001- 2005

Inspected Entity2001200220042005
Sponsor50727370
CI122151183183
IRB401287348
GLP261931

Figure 1. BIMO Warning Letters by Year Bar graph

Figure 2. BIMO Warning Letters by Year and Type

bar graph

Improving Product Quality And Safety Through Better Manufacturing Oversight

Developing a Compliance and Enforcement Tracking System
In FY 2005 CDRH’s Office of Compliance developed and received approval for the Vision Document, the initial phase in developing the compliance and enforcement component to the Center Tracking system (CTS), a work flow and work management system. The new CTS component will provide better tracking of regulatory actions and their outcomes. CDRH also participated in the requirements analysis for new and improved agency IT systems that will ensure that data collected will be meaningful and provide the data necessary for distributing resources and making risk-based prioritization schemes.

Protecting the Public
http://www.fda.gov/MedicalDevices/Safety/RecallsCorrectionsRemovals/ListofRecalls/default.htm
CDRH completed several administrative and judicial actions to protect the American public. In FY 05, CDRH processed:

  • 182 warning letters
  • 571 product recalls, including 25 highest-risk Class I, 423 Class II, and 123 Class III recalls

Prioritizing Compliance-Related Activities

CDRH continued to formulate a risk-based management program for inspection and enforcement actions. This process improves the decisions CDRH makes in regulating and monitoring the medical device industry. It not only impacts how inspections are prioritized, but will help to identify and prioritize other types of regulatory activities, such as device recalls, that present the greatest risk to public health.

Risk-Based Inspection Work-Plan and Regulatory Actions
In FY 2005 CDRH continued using the inclusive risk-based inspection work plan process. This process ensures that all Center program offices have an opportunity to provide input into the prioritization of special emphasis inspections.

In addition, CDRH analyzed 132 Warning Letters previously issued to medical device manufacturers. In the analysis, CDRH found that 75 percent of the citations related to GMP violations and 24 percent related to MDR violations. This information also helped making decisions on inspection priorities and regulatory actions.

Exceeding Yearly Inspection Goals
CDRH coordinated with the Office of Regulatory Affairs (ORA) and provided technical support, as necessary, for inspections. In FY 2005 FDA surpassed all CDRH fiscal year inspection goals. FDA conducted:

  • 1,265 inspections of registered domestic Class II and Class III medical device manufacturers, exceeding the goal of the goal of 20 percent of the 5,520 registered manufactures
  • 230 foreign inspections, exceeding the goal of 7 percent of 2,500 registered foreign Class II and Class III medical device manufacturers
  • 335 BIMO inspections with an emphasis on scientific misconduct, data integrity, innovative products, and vulnerable populations, again exceeding its goal of 295 domestic and foreign BIMO inspections.

Clinical Laboratories Improvements Act (CLIA)

CLIA established quality standards for all laboratory testing to ensure accurate, reliable and timely patient test results regardless of where a test was performed.  Of central importance to the CLIA program is the assignment of a complexity category to commercially marketed diagnostic tests. The tests are categorized into one of three CLIA regulatory categories based on their complexity (i.e., potential risk to public health) and laboratories may only purchase and use a particular test based on the laboratory’s level of CLIA certification.

Streamlining the CLIA Application Processs
Since CDRH reviews the premarket applications for these tests, streamlining the CLIA application process necessitates a transfer of responsibility for complexity determinations from the Center for Disease Control and Prevention (CDC) to FDA. During 2004 FDA completed the delegation of authority to FDA (CDRH) for CLIA complexity determinations and finalized a 5-year Interagency Agreement with the Centers for Medicare and Medicaid Services (CMS) for CLIA waiver authority. In 2005 FDA published draft guidance for the waiver process. The agency is reviewing the comments received in response to the guidance.

Mammography Quality Standards Act (MQSA)

MQSA Facility Inspections
CDRH conducted annual inspections of over 9,000 mammography facilities nationwide. The Center ensured that 98 percent of mammography facilities met inspection standards. Less than 2 percent of the facilities inspected had level 1 problems. CDRH worked with each of those facilities to assure adequate corrective action is taken.

10 Years of MQSA Inspections
In FY 2005 CDRH commemorated 10 years of MQSA inspections. So far, MQSA inspectors have completed 93,000 facility inspections nationwide. The percent of inspections without adverse observations has more than doubled in that time, and the trend continues to rise.

Radiation Safety

Radiological Health Implementation Program
The CDRH Radiological Health Implementation Program Core Group was commissioned in Spring 2005 to consider all previous radiation health program studies and make recommendations for the program's future. Radiological Health activities are critical to providing expertise for the review and approval of treatment and therapy systems, for the prevention of excessive radiation exposures from diagnostics examinations such as fluoroscopy, and for monitoring and evaluation of radiation emitting products such as security screening devices. The recommendations are included in a report titled, “The CDRH Radiological Health Program - Adapting to Current Public Health Needs - 2005–2010”. The new direction of the radiological health program will increase its relevance to, and impact on, the most pressing current public health problems in the radiological health arena and anticipate the evolution of medical radiation systems. FY 2006 efforts will shift to implementing the recommendations.

Reducing Unnecessary Exposure From Sources Regulated By FDA
In the Fall of 2005 CDRH held a meeting to provide a wide range of organizations involved in radiological health an opportunity for dialogue about collective efforts to reduce unnecessary exposure from sources regulated by FDA.

Amending Global Laser Regulation
CDRH proposed amendments to the Federal Laser Performance Standards, 21 CFR 1040.10 and 1040.100, which adopt by reference and with national exceptions the International Electrotechnical Commission (IEC) laser standards as the new Federal standard. The amendments move to create a single global regulatory environment for laser product manufacturers, reducing the regulatory burden on industry and updating the Federal standard to reflect current laser technology and bioeffects research.

New Technical Standards for Fluoroscopy Equipment
CDRH promulgated amendments to the Federal radiation-safety standard improving the performance of diagnostic x-ray systems and their major components. The amended technical standards, published as a final rule in the Federal Register on June 10, 2005, will require a number of new equipment features that will significantly reduce unnecessary exposure to x-rays, especially in fluoroscopy, while maintaining the level of image quality requisite for diagnostic efficacy. All fluoroscopic equipment manufactured on or after June 10, 2006, will be required to display values of the rate, duration, and cumulative amount of radiation emissions, thereby enabling a fluoroscopist to adjust techniques in real time to reduce patient exposure. Over the decade following implementation of this final rule, the expected improvement in the quality of health care is projected to reduce the annual U.S. population dose by more than 7,000 person-sievert.2 The dose reduction could decrease annual cancer deaths by over 200 and create annual savings of over $300 million.

Promoting Development of Consistent Policies on Reducing Exposure to the General Public
CDRH served on the Interagency Steering Committee on Radiation Standards (ISCOR), and in this capacity, promoted development of consistent policies on reducing exposure to the general public. Efforts included recommendations for appropriate use of security products and medical imaging equipment that exposes the public to ionizing radiation.

Assessing the Impact of Legal and Illegal Use of Radiation-Emitting Products
CDRH performed an assessment of the impact of legal and illegal use of radiation-emitting products in response to reports of green lasers directed at aircraft with the intent of distracting or temporarily flash-blinding the crew. FDA briefed House Science Committee staff in January 2005 on its authorities regarding the manufacture and use of laser products. FDA worked with the Federal Aviation Administration (FAA), Department of Homeland Security (DHS) and Department of Defense (DoD) to address this problem by providing technical consults in developing aircraft and pilot protective measures. FDA published and contributed to public information regarding safe use of laser pointers and cautioned against internet sales of laser products through various print media outlets and on the Internet. FDA took action against firms that sell modified green lasers that emit radiation in excess of the limit for general public use.

Radiological Health Civil Money Penalty Assessed Against a Manufacturer of Television Products
In FY 2005 ADI Corporation agreed to pay the second installment of the Radiological Health Civil Money Penalty consent decree for $200,000 by August 2005. The total fine of $475,000 was filed against ADI in May 2003 for unlawful importation of certified television products when the ADI quality control testing program was disapproved. This was the first Radiological Health Civil Money Penalty assessed against a manufacturer of television products.

Expanding Patient Protection Through Applied Research

CDRH research contributes to the internal review process as well as to the development of guidance for industry in the development of innovative technologies. FY 2005 areas of activity included:

  • Device safety in Magnetic Resonance Imaging (MRI) environments
  • Expiration date for medical gloves
  • Mechanical strength of vertebrae following injections with bone glue
  • Exposure to electromagnetic fields and its effects on implanted devices
  • Effectiveness and safety of Intraocular lenses (IOLs)
  • Combined approach to evaluate circulatory assist devices
  • Effects of optical energy
  • Device-tissue interfaces
  • Better animal models and improved biomarkers
  • Reuse of single use devices
  • Drug eluting stents
  • Modeling to propose design changes to left ventricular assist device
  • Computer assisted diagnostic systems
  • Performance testing of pulse oximeters
  • Test methods for high intensity focused ultrasound
  • CDRH standards program

Device Safety in Magnetic Resonance Imaging (MRI) Environments
CDRH developed a new standard practice for marking medical devices and other items safe in the Magnetic Resonance environment. The revised system replaced the old system whose confusing MRI compatible terminology may have resulted in patient injuries.

Expiration Date for Medical Gloves
CDRH developed and validated a method for assigning an accurate expiration date for medical gloves. This work is critical to protect patients as well as health care workers from the transmission of infectious diseases or agents used in terrorist activities.

Mechanical Strength of Vertebrae Following Injections With Bone Glue
CDRH conducted research on the improvement in mechanical strength of vertebrae following injections with bone glue. This has become the most common treatment for compression fractures, a condition estimated to eventually affect a quarter of all women over the age of 50. The findings showed that the procedure can be effective if the bone density has not dropped too low.

Exposure to Electromagnetic Fields and Its Effects On Implanted Devices
CDRH measured and modeled exposure to electromagnetic fields and the effects on implanted devices from hand held and walk through security systems, cellular telephones, hand-held computers, and MRI systems. This research included models of the head for evaluation of cell phone exposure and of pregnant woman models for 9 gestational ages of the fetus for heating during MRI. This effort resulted in the standardization of specific absorption rate (SAR) across multiple systems. Results of this work include:

  • Five journal articles and 14 proceedings and other presentations during the past year
  • support from the FAA/TSA (for the security system studies)
  • establishment of a CRADA to further the virtual family modeling
  • participation in CDRH’s Epidemiology Grand Rounds on wireless medical devices

Modeling of the heating effects of MRI upon implanted pacemakers, ICDs, neural stimulators, and cardiac stents helped define the parameters for acceptable application of MRI for individuals with these implanted medical devices and has a potentially large impact on public health.

Effectiveness and Safety of Intraocular Lenses (IOLs)
CDRH developed a significantly more accurate and applicable confocal laser method for testing (IOL) diopter power. Precise measurement is critical for evaluating the effectiveness and safety of IOLs, which are implanted during cataract surgery. The test method has been used to evaluate samples of new IOL designs and on IOLs on regulatory hold because of questions about the labeled power. This work resulted in a pending patent, more than 10 proceedings publications and presentations during the past year, and has been submitted to Nature Methods.

Combined Approach to Evaluate Circulatory Assist Devices
CDRH developed a combined approach of review and laboratory expertise to evaluate proposed ‘subtle’ design changes to critical components of life-sustaining mechanical circulatory assist devices. Design of the blood path in these devices is critical for avoiding damage to blood components, stroke, and embolism. CDRH’s new combined approach for review significantly reduces the review burden while reducing the uncertainty of the evaluations.

Effects of Optical Energy
CDRH evaluated the effects of optical energy on cellular and intracellular structures and components. This resulted in improved understanding of the effects of light on energy production in cells. CDRH developed a new confocal fiber-optic nanobiosensing system that enables measurements at resolutions better than the theoretical half wavelength limit, resulting in work below the 200 nanometer range. This work, supported in part by an interagency agreement with the Air Force Office of Scientific Research, resulted in four journal articles, numerous proceedings and presentations during the past year, and a proposal to the Army’s Telemedicine and Advanced Technologies Research Center to evaluate optical methods of stimulation that may enhance the field of neuro-prostheses.

Device-Tissue Interfaces
CDRH also worked towards developing a better understanding of the   device-tissue interface for optical spectroscopy leading to improvements in the efficiency of spectroscopic methods for minimally invasive disease detection. This area has the potential to improve the detection of mucosal cancers and the monitoring of changes following therapeutic applications. This work resulted in two journal articles and five proceedings published during the past year.

Better Animal Models and Biomarkers to Improve Public Health 
CDRH conducted research to stimulate the development of new evaluation tools - biomarkers and clinically-relevant preclinical models - for assessing the safety and efficacy of new medical products. An animal model of subclinical renal insufficiency that was able to detect known nephrotoxicants at doses that were non-toxic in “healthy” control animals was developed and partially validated. The regulatory impact is significant in that adverse effects detected using the disease model would have been missed using healthy animal models typically used to test medical devices. CDRH also evaluated a new kidney toxicity biomarker, kidney injury molecule that can be measured in kidney tissue and urine, and appears to be more sensitive for renal injury detection than traditional clinical markers. The public health impact is significant in that the new biomarker may be useful to identify patients with subtle renal disease at an earlier stage and prevent pathogenesis of renal failure as well as reduce uncertainties in the preclinical assessment of FDA-regulated products.

Infection Control: Reuse of Single Use Devices and Cleaning Validation
CDRH conducted research to develop and validate cleaning and disinfection/sterilization methods to insure no microbial contamination, misdiagnosis due to tissue contamination, and toxicity resulting from residual detergents and disinfection/sterilization agents remaining on the device. CDRH has determined that total organic carbon is an effective marker of residual soil from patients exposed to the devices and residual chemicals used in reprocessing on cleaned devices versus measuring total protein only as an endpoint of cleaning. The research will improve safety of patients exposed to single-use and reuseable medical devices. Protein residual data from CDRH research have provided an endpoint for device reprocessors to meet requirements of supplemental validation submissions for single-use devices, and aided CDRH reviews and inspection functions.

Drug Coated Stents: Drug Eluting Stents Associated Thrombosis
The drug eluting stents have been shown to exhibit late-stent thrombosis which may be mediated by an increased expression of tissue factor (TF) and decreased levels of thrombomodulin in endothelial cells that line the arteries. CDRH research on the treatment of endothelial cells with either rapamycin or paclitaxel resulted in a slight increase in coagulation activity. However, addition of VEGF significantly augmented the coagulation cascade. Coagulation correlated with increased expression of TF in endothelial cells. Thrombomodulin expression was unaffected by either rapamycin or paclitaxel in the presence of VEGF. Data suggest that platelets and rapamycin/taxol may elevate TF expression. However, platelets themselves are not affected by either drug. These results suggest that anti-proliferative drugs exhibit prothrombotic effects which could be potentiated by VEGF. These findings imply that high levels of VEGF in atherosclerotic plaques could potentially contribute to thrombotic effects observed following drug eluting stent implants.

Computational Fluid Dynamics of Left Ventricular Assist Device
CDRH laboratory conducted a study to aid in the evaluation of a post-approval study change for a pediatric left ventricular assist device (LVAD). The sponsor proposed to make a change to the blood flow path within the pump that could have adversely affected hemolysis and thrombogenesis in the pump such that patient safety and/or device efficacy could have been compromised. It would have been extremely difficult, if not impossible, to validate the design changes using animal or human data. After discussions and a meeting with FDA staff, the sponsor agreed to provide experimental (flow visualization, hemolysis) and analytical (computational fluid dynamics [CFD]) testing to support the design changes. CDRH experts recommended appropriate CFD models to the sponsors and analyzed the results.

Computer-Assisted Diagnostic Systems
CDRH scientists have also played a leading role in the development of new models and methods for the assessment of computer-assisted diagnostic systems. The techniques were first developed during our review of digital mammography systems, and have since been extended to the development of systems for breast cancer screening, lung cancer screening, and CT colonoscopy. Having these tools and methods available has greatly assisted developers of these innovative imaging and CAD-assist devices.

Performance Testing of Pulse Oximeters
CDRH scientists and engineers have developed test methods for a range of non-invasive monitoring devices. CDRH laboratory studies on pulse oximeter performance, for example, enabled substantial improvements in the ISO/IEC standard and the CDRH Guidance Document. This testing facilitated the development of a single test protocol for SpO2 accuracy studies, which simplified the pre-market evaluation process by unifying the basis for establishing substantial equivalence. The work has established the groundwork to enable the extensions of claims being made for perfusion measurements and established acceptable performance criteria. 

Test Methods for High Intensity Focused Ultrasound
The lack of standardized methods to assess the acoustic and thermal characteristics of the focused beams has challenged the regulatory review of these devices, especially in the pre-clinical phase, and has been burdensome to the industry. In the past CDRH scientists and engineers have developed measurement instrumentation and computational modeling techniques for characterizing other types of medical ultrasound devices such as diagnostic imaging and therapeutic ultrasound, and this work has resulted in the creation of numerous regulatory guidance and standards documents. This expertise is being used to accelerate the review of submissions for HIFU devices. For example, in a device for the ablation of uterine fibroids, CDRH-developed computational modeling was used to predict the performance of the device under conditions that would have been difficult to investigate experimentally, thus shortening the review time.

CDRH Standards Program
The Standards Management Staff develops and manages the standards used for regulatory assessments. The standards staff facilitates the participation of CDRH and other FDA staff in developing standards. In addition, SMS increases the recognition of voluntary consensus standards for medical devices and radiation-emitting electronic products. As part of this responsibility, the staff publishes lists of recognized standards annually and consistently increases the list of available standards. In 2005, CDRH recognized 48 new standards; and in addition, 110 standards were withdrawn and replaced by new versions, incorporated 98 changes to the existing recognized standards, and 14 standards were withdrawn.

Regulations and Guidance Development

CDRH’s guidance information is available at http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/default.htm.

In 2005 CDRH worked to streamline guidance development. Center efforts included:

  • prioritizing its guidance workload
  • establishing performance goals
  • developing and implementing tracking mechanisms
  • engaging industry stakeholders in the early stages of guidance development
  • increasing the use of contract experts.

CDRH issued 28 guidance documents and accomplished its performance goals. Among these documents were four draft guidance documents; several device-specific and special control guidance documents, including a guidance for intravascular stents and a guidance providing clarity on indications for implanted cardioverter defibrillators; and two key cross-cutting guidance documents - Software used in Medical Devices and Format and Content of 510(k) submissions. The latter document will assist manufacturers in the preparation of 510(k) submissions and should lead to more efficient and timely reviews.

CDRH also worked with the Office of General Counsel and the Office of Policy Regulation editorial staff to review and revise the boilerplate Guidance Development Templates for all guidance documents. These templates are available to Center staff on the Center’s intranet web site.

In FY 05, CDRH’s guidance and regulation staff responded to nine citizen petitions and published sixteen final rules and forty-seven notices.