Medical Devices: legal, regulatory, and quality assurance considerations
by Pablo Gurman, MD
Quality Systems (QMS) for Medical Devices
Medical device advances have been possible because of modern technology, but modern medical devices are also only possible with the concomitant development of standards to ensure their safety and effectiveness. These standards are being developed by well recognized international organizations, such as the International Organization for Standardization (ISO), ASTM International (formerly known as the American Standard for Testing Materials), and the Institute of Electrical and Electronic Engineering (IEEE).
Standards derived by ISO, ASTM, IEEE, and many other recognized national or international organizations can also be adopted or modified by the FDA. The CDRH Standards Program/Standard Management Staff (SMS) at the FDA was established as a result of the Food and Drug Administration Modernization Act of 1997. It has developed a Recognized Consensus Standards database with national and international standards. One of these standards, ISO 13485:2003 "specifies requirements for a quality management system where an organization needs to demonstrate its ability to provide medical devices and related services that consistently meet customer requirements and regulatory requirements applicable to medical devices and related services." This standard establishes a number of interrelated processes related to manufacturing requirements for a specific medical device.
These requirements involve:
a) Quality Management Systems (QMS) in general (e.g., control of documents and records)
b) Management of QMS (quality planning).
c) Resource Management (e.g., quality policies, human resources).
d) Product realization - including those processes associated with determining product requirements, design and development of the product, materials and services need to supply finished product to the customer, actual manufacturing of the product with monitoring and measurement equipment used in the manufacturing process.
Based on the ISO 13485 standard, the FDA created the Quality System (QS) Regulation/Medical Device Good Manufacturing Practices system (QSReg) for medical devices, which is now a requirement for medical device manufacturers in order to obtain FDA approval for product commercialization. QSReg involves a number of requirements including:
- Design controls
- Document controls
- Purchasing controls
- Identification and traceability controls
- Production and processes controls
- Labeling and packaging controls
- Handling, storage, distribution, and installation controls
Design controls allow visibility during the device design process ensuring that translation into device production will ensure proper device performance. Design controls do not apply to feasibility studies and development of prototypes but to the final design ready for translation into production. This ensures that the FDA will not interfere with the creativity process while taking all the necessary precautions to avoid design errors which will be transferred into the production stage.
The procedures established by the manufacturer must ensure that current versions of the documents are used and obsolete documents are removed.
To ensure that purchasing of services or products follows the QSReg, the purchasing process by medical device manufacturers should be carried out with proper assessment and selection of contractors, consultants, and suppliers.
Identification and traceability controls:
Manufacturers must ensure that each medical device has a control number to identify each unit, lot or batch, and if necessary, its components.
Production and processes controls:
According to the QSR section 820.70, device manufacturers shall conduct the production process to ensure that a medical device meets its specifications.
Control of records
There are three types of records for medical devices each manufacturer must keep for quality assurance purposes:
1-Those pertaining to the design and development of the medical device
2-Those pertaining to a specific medical device or batch
3-Those related to the performance of the quality system
Records must be maintained for a period equivalent to the lifetime of the device but never less than 2 years.
Manufacturers should ensure that device packaging and shipping containers are protected from adulteration or damage during storage, handling, and distribution of the medical device (NATO; Amiram, 2008).
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Beyond Regulation: Off Label Use of Medical Devices
Medical devices intended to enter the market are evaluated by the FDA in order to ensure their safety and effectiveness. As described in the previous section, labeling represents an important issue for quality system regulation. The labeling of a medical product describes the scope of indications for which a product has received FDA approval in conjunction with its potential risks.
There are instances, however, in which a medical product is used for an indication for which it has not been FDA approved, i.e., off-label use. A medical device may have off-label use when it is used for treatment of a condition where no known treatment is available, or when a physician has decided to modify it to presumably make it more effective and safe.
Off-label use, like all medical practice, should involve best medical practices for patient care, and therefore the practice of off-label use and its legality are widely accepted, although many times performed without regulatory approval. From the FDA perspective, modification of an existing device is equivalent to initiating a new medical device investigation, thus requiring an Investigational Device Exemption (IDE) approval.
In order to comply with regulations, the physician who intends to perform a modification of an already approved medical device must submit an IDE. An IDE can be very expensive and time consuming. As a consequence, the medical practitioner who wishes to modify a medical device faces the decision as to whether to create the modification and use the device in a way that is not FDA approved with possible legal liability or try to pursue an IDE under the approval of the FDA, a cost and difficult undertaking. Furthermore, in addition to this tough choice, the physician who modifies a medical device and uses it off-label faces the fact that the Centers for Medicare & Medicaid Services (CMS) may decide not to reimburse for the medical device procedure considering the device as investigational (Starnes, 2013; Criado, 2006).
Off Label Use of Medical Devices: Case Studies
Case study#1: Off label Use of a Medical Device in Interventional Radiology (Smith, 1999; Smith, 2010)
A young woman presented to her obstetrician with worsening bilateral leg edema after recent uneventful vaginal delivery of her first child. The obstetrician ordered a sonogram of the patient's lower extremities which showed extensive bilateral deep vein thrombosis extending superiorly to the most proximally visualized portions of the common femoral veins. The patient was referred to a vascular surgeon who ordered an MR examination which showed extensive thrombi involving the external and common iliac veins bilaterally and in the distal portion of the inferior vena cava. The vascular surgeon felt there were no indications for surgery and referred the patient to an interventional radiologist.
The radiologist recommended catheterization and pharmacological intervention with thrombolytic drugs. In addition, the radiologist informed the patient that it might be necessary to place stents in the affected veins to avoid re-occlusion. Before proceeding, the radiologist advised the patient about the benefits and risk of the procedure and told the patient there were no guarantees that this procedure would cure her deep vein thrombosis. Re-thrombosis was a risk. The patient agreed to go ahead.
Two months after the procedure the patient noticed increasing lower extremity edema which had become intractable two months later. Imaging showed recurrent thromboses in the patient's lower extremity deep venous system with extension into the inferior vena cava. A second thrombolysis was unsuccessful, and systemic anticoagulation did not improve the patient's condition.
The patient filled a medical malpractice lawsuit against the radiologist claiming the radiologist negligently performed the thrombolysis and stenting. In addition, she also charged the radiologist was negligent in using stents in a manner not consistent with their approved FDA labeling. The stents were approved by the FDA only for use in arterial disease and not for venous use. The radiologist in response claimed he had used these stents previously to treat venous occlusion. He followed descriptions of the procedure that had appeared in peer-reviewed articles in respected medical journals. A defense expert for the radiologist in deposition stated off-label use is routine and legal under existing FDA regulations. The expert also stated the FDA regulates the marketing of medical products not the practice of medicine. The patient withdraw the lawsuit 1 week before trial.
This case shows off-label use of medical devices is well known in interventional radiology. It is permitted under FDA regulations, but malpractice liability remains a major consideration. Risk management regarding the off-label use of medical devices may lessen the likelihood of incurring a medical malpractice lawsuit and maximize the chance for a successful defense if a suit is filed (Smith, 1999).
Case study#2: Off Label Use of Radio-pharmaceuticals
The responsibility and the liability for off-label use rests with the prescribing physician. However, medical physicists and others responsible for safe and proper use of medical products may also have responsibility and liability for an off-label use of a medical product. In particular, off-label use of radio-pharmaceuticals constitute a challenge for the medical physicist (Thomadsen, 2010). Radio-pharmaceuticals, amongst other indications, are used in the treatment of metastatic cancer. An example of such use is the administration of Strontium Chloride Sr89 for the treatment of metastatic bone cancer.
Many radio-pharmaceuticals have a specified labeled dose that has been approved by the FDA based on clinical trials. None the less, a situation may occur in which a patient requires a different dosage which has not been specifically clinically tested and demonstrated to be safe and effective. In addition, there may be situations in which the physician decides to use a radioactive compound for a disease that is similar to but not the same as one for which the drug has been approved.
For example, a radio-pharmaceutical may be indicated for treatment of primary liver tumors but not metastases in the liver arising from tumors in other organs. Since the vasculature of primary liver tumors may differ from the vasculature of metastasis from distant organs, the prescribed radio-pharmaceutical dosage and indication can differ from the labeled dosage and indication for the radio-pharmaceutical. This in turn may lead to unwanted toxicity or lack of efficacy and produce a potentially liability not only for the treating physician but also for the radio-pharmacist or medical physicist (Thomadsen, 2010).
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Regulatory Barriers for Medical Device Innovation
Many issues influence the development and marketing of new medical products. Some of these tend to stifle medical innovation. Among the significant challenges for medical device innovation are the following:
- Time and cost limitations posed by the regulatory process
- Medical practice patterns and education being resistant to new innovations
- Small potential market size and difficult market penetration
- Greater than expected research and development (R&D) costs and unexpected device failures
- Novel technologies which confound established patterns for medical device research and development (e.g., nanotechnology)
- Intellectual property rights, patent limitations, and publication issues which slow development of new devices
- Poor reimbursements for new products
- Difficulty setting prices and receiving payments that reflect actual costs and provide for a profit
- Ethical considerations limiting testing of innovative products dissimilar to other marketed devices.
A brief description of regulatory barriers to medical device innovation is detailed below. More information on this subject can be found in Curfman, 2011.
Technology innovation in medical device development represents an important requirement for addressing unmet clinical needs. The role of the FDA to safeguard the public yet at the same time promote innovation is a daunting task. On the one hand, it is urged to speed up the process for approval for novel devices, but, on the other hand, it is urged to go slow to protect the public from unsafe or ineffective products.
Faster approval of medical devices can accelerate innovation, but the cost of having insufficient scientific data to support the safety of a new product could result in disastrous consequences if the device enters the market and is found to be ineffective or have serious side effects. A delay in the regulatory process allows more time to confirm a device is safe, but it can prevent timely public access to novel potentially life-saving products.
Therefore, some flexibility has emerged in the way the FDA performs the evaluation of medical devices. For example, products with incremental improvements, those that have features similar products on the market, go through the 510k pathway, which is a relatively short evaluation process with limited requirements in terms of scientific evidence for effectiveness and safety. Completely new devices, on the other hand, are required to have a premarket approval (PMA), which is a much more stringent pathway.
This bifurcated FDA strategy seems reasonable given the challenges the FDA faces. This strategy has been criticized for its potential to promote incremental improvements while discouraging the development and adoption of new, possibly disruptive technologies. As a result, the FDA has initiated a number of programs towards fostering innovation while keeping safety as a key priority for medical devices. Among these initiatives are the following - the Medical Device Innovation Consortium (MDIC), which is focused on creating a strategic partnership between the FDA, industry, and the public sector (nonprofit organizations); the Food and Drug Administration Safety and Innovation Act (FDASIA), signed in 2012, which is focused on accelerating the process of clinical investigations (IDE) for medical devices; the Critical Path Initiative (CPI), an FDA program dedicated to improving the scientific process through which medical products are developed. Finally, the FDA has created the Expedited Approval Pathway (EAP) for high risk devices by decreasing the amount of required premarket data to expedite the approval of medical devices designed to treat irreversible, debilitating, or life threatening diseases ensuring their timely access for patients.
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Summary Box 2: Nanotechnologies
The National Science Foundation (NSF) defines Nanotechnology as ”Research and technology development at the atomic, molecular or macromolecular levels, in the length scale of approximately 1 - 100 nanometer range, to provide a fundamental understanding of phenomena and materials at the nanoscale and to create and use structures, devices and systems that have novel properties and functions because of their small and/or intermediate size..." (NSF).
While micro-technologies like Micro-Electro-Mechanical-Systems (MEMS) have reached a state of maturity and are found in a number of FDA approved devices, nanodevices are still at an early stage of development. An important issue with nanotechnology is that due to the novel physical phenomena originating at the nanoscale, many properties of nanodevices are unknown which inherently increases the risk of using this technology. This raises increased concern about the safety and public health implications of nanotechnology based medical devices. Furthermore, due to their novelty nanoscale devices in general probably have to endure very stringent regulation, similar to that now occurring with more mainstream high risk medical devices that must undergo FDA PMA approval.
With the explosion in nanotechnology research the FDA has been actively involved in creating nanotechnology programs. As a result, in 2006 the Nanotechnology Task Force was created. It provides oversight for the regulatory and scientific challenges that nanotechnology represents. Many FDA regulated products are expected to incorporate nanotechnology in the future. The CDRH (nanotechnology) also has nanotechnology regulatory science research projects which are primarily addressing the following:
- "Understanding the mechanistic behavior of nanomaterials from physical, chemical and biological aspects including:
Physico-chemical stability/interaction of nanomaterials and their interaction with nanoscale surfaces; Toxicity and behavior of nanomaterials in in-vitro and in-vivo environments; Biocompatibility of nanomaterials exposed to blood elements; and Gene expression models for evaluating adverse reactions to nanomaterials. A number of these studies are being conducted using silver nanomaterials as silver is used in many devices for its antimicrobial properties.
- Advancing knowledge regarding the characterization of nanomaterials including:
Existing methods/technologies for characterization of nanomaterials and their limitations; Characterization of optical coherence tomography-based imaging approaches; and Optical nanobiosensors for minimally invasive intracellular monitoring."
An important step towards nanotechnology regulation was the development of the Nanotechnology Characterization Laboratory (NCL), a joint effort carried out by the FDA and the National Cancer Institute (NCI). This laboratory provides comprehensive characterization of nanomaterials. Since nanomaterials constitute the cornerstone for future nanomedical devices, their study will promote the safe and responsible introduction of nanoscale based devices in the market (Huff, 2012).
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Regulation of medical devices is performed in the United States by the Food and Drug Administration (FDA). The FDA has developed a classification of medical devices according to the risk they present to the patient (e.g. device failure). Based on this classification, medical devices follow different regulatory pathways for ensuring their safety and effectiveness. These regulation pathways vary in complexity according to the device risk.
Medical devices have to comply with quality standards developed by international organizations, such as the International Organization for Standardization (ISO). Some of these standards have been adopted by the FDA. These standards apply to the entire device development process from design to fabrication and testing. Failure to comply with these standards can result in device approval rejection and economical and legal consequences for medical device manufacturers.
Medical device manufacturing is tightly controlled and devices that enter the market have been tested following FDA guidelines. Medical practice, however, is not subject to FDA regulation. This has important implications, since the medical practitioner can design new procedures for or modify an existing device based on what the practitioner considers best medical practice. This is termed off-label use of a device.
Off-label use of medical devices constitutes a practice that is widely used and legally approved, although it is not regulated. As a consequence, the use of off-label medical devices could entail legal consequences not foreseen by the medical practitioner.
Overcoming regulatory barriers to medical device innovation constitutes a challenging endeavor. The FDA has initiated a number of programs in order to address this challenge. Ultimately, it will be the continued joint collaboration between manufacturers, regulators, and health care professionals that will bring new medical devices to the patient in a timely manner.
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Amiram D, Kimmelman, editors. The FDA and worldwide quality system requirements guidebook for medical devices. 2nd ed. Milwaukee, Wisconsin: ASQ Quality Press; 2008.
Criado FJ. Off-label use of devices: friend or foe? J Endovasc Ther 2006; 13 (4): 505-506.
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Huff MA. Medical applications of micro-electro-mechanical-systems. In: Rosen Y, Elman N, editors. Biomaterials Science: an integrated clinical and engineering approach: Boca Raton, FL: CRC Press; 2012. p. 30-84.
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Smith JJ. Off-label use of medical devices in radiology: regulatory standards and recent developments. J Am Coll Radiol 2010; 7 (2): 115-119.
Starnes BW. A surgeon’s perspective regarding the regulatory, compliance, and legal issues involved with physician-modified devices. J Vasc Surg 2013; 57: 829-831.
Thomadsen BR, Heaton HT II, Jani SK, Masten JP, Napolitano ME, Ouhib Z, Reft CS, Rivard MJ, Robin TT, Subramanian M, Suleiman OH. Off-label use of medical products in radiation therapy: summary of the report of AAPM Task Group No. 121. Med Phys 2010; 37 (5): 2301-2309.
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