Advisors and FDA agree: Reclassify blood irradiators for malignancy prevention to high-risk
This week, a panel of the FDA’s Medical Devices Advisory Committee (MDAC) discussed the FDA proposal to reclassify blood irradiators, when used intraoperatively to prevent malignancy, into device Class III – high risk. Though the technology and application are decades old, the devices are understudied for this purpose, leading panel members to request a high bar for evidence to support safety and effectiveness.
Regulatory background: Medical device classification
- Medical device classifications are determined based on the relative risk of the product. Class I devices are the lowest-risk products, while Class II devices present a moderate risk and Class III devices are considered high-risk products (e.g., implanted, life-sustaining or life-supporting devices). Every category of medical device is classified by the FDA based on the agency’s understanding of – and experience with – the product, and the risk-based classification will determine the device’s pathway to market, as well as post-market activities.
- The classification of a device generally determines the way in which it will be marketed. While Class III (high risk) products typically need to submit a Pre Market Approval (PMA) application, Class II devices generally request market access under a 510(k) pre-market notification submission through which they demonstrate that their product is “substantially equivalent” to another device that is already legally marketed in the US, called the predicate device. In the circumstance in which a developer believes that their product is not high risk but there is no predicate on record (i.e., a novel, moderate-risk device), they may submit a De Novo request to have the FDA consider a new categorization.
- In general, the FDA considers a device’s classification based on the minimum level of oversight needed to ensure safety. While Class I devices are mostly exempt from the 510(k) process, manufacturers do need to comply with general controls (e.g., registration and listing, prohibitions against misbranding) established by the FDA. Class II devices are those for which general controls alone are not sufficient to ensure safety and efficacy and are therefore subject to both general and special controls (e.g., performance standards, post-market surveillance, patient registries). Special controls are typically device-specific and tailored to the specific safety concerns with the product’s use.
- There are also devices which for various reasons remain unclassified. The risk-based classification practice was formally introduced under the Medical Device Amendments of 1976 (MDA). When the MDA was implemented, all devices that were already on the market (“pre-amendment devices”) were considered grandfathered in. In effect, the owners of these devices did not need to re-apply for market access and can continue to market them without a 510(k) submission (although they must document that the product “has not been significantly changed or modified in design, components, method of manufacture, or intended use” compared to the pre-1976 version). However, new market entrants of unclassified device types typically need to submit a 510(k) notification, using the grandfathered unclassified device as a predicate.
- The reclassification processes. Since the implementation of the MDA, the FDA has been working to align the unclassified devices into the three risk-based categories to ensure appropriate oversight – with a particular focus on higher-risk products. The process by which the FDA can reclassify a medical device (including from unclassified to a risk-based category) includes several steps: the convening of a medical device advisory committee panel, a proposed order and a final order.
- Read more about the FDA’s device classification scheme in its explainer, here.
This week, the FDA convened an advisory committee to consider reclassification of blood irradiation devices to prevent malignancy
- The Radiological Devices Panel of the Medical Devices Advisory Committee (MDAC) assembled virtually on Tuesday, November 7 for a half-day review of considerations in the reclassification of blood irradiators to prevent malignancy. The meeting’s October 25 Federal Register announcement proposed moving these unclassified pre-amendments devices to Class III – general controls and premarket approval.
- At the start of the day, SCOTT MCFARLAND, regulatory counsel within the Center for Devices and Radiological Health (CDRH), walked attendees through the classification of medical devices and the reclassification process for pre-amendment devices. After reviewing the regulatory framework for the committee’s work for the day, McFarland set out “what we need from the panel.”
- “What we ask from the panel today is to provide input on the classification of blood irradiators for prevention of metastasis, and whether they should be classified into Class III, Class II, or Class I,” said McFarland. He added that “The input should include an identification of the risk to health presented by the device type,” along with a discussion of whether the device is “life supporting/life sustaining, of substantial importance in preventing impairment of human health, or if it presents a potential unreasonable risk of illness or injury,” according to statutory provisions. The panel was also tasked with discussing whether general controls alone are sufficient to provide reasonable assurance of safety and effectiveness for the device type, and if not, whether sufficient information exists to develop special controls.
Regulatory history and clinical uses of blood irradiators
- Next, JUSTINA TAM, FDA lead reviewer in CDRH’s Office of Radiological Health, reviewed what’s known about the devices themselves. Blood irradiators (FDA product code MOT) are used intra-operatively in conjunction with cell salvage during surgery, irradiating salvaged blood with the intended use of preventing metastatic proliferation by killing or disabling any malignant cells in the salvaged blood. This technique “does not appear to be widely used,” said Tam. The FDA’s exact indication for use is “in the irradiation of intra-operatively salvaged blood for cancer patients undergoing surgery to assist in the prevention of metastasis,” according to the FDA’s presentation.
- The devices had been in commercial use prior to 1976, in the pre-amendments era, said Tam. In 1993, the FDA’s Center for Biologics Evaluation and Research (CBER) released guidance on gamma irradiation of blood products. Later, in 2005, the FDA first cleared a blood irradiator for two indications: to reduce the risk of graft-versus-host disease (GVHD) in transfusion scenarios and for the prevention of metastasis.
- White blood cells and tumor cells are each more sensitive to radiation than other blood components such as red blood cells, Tam explained. This can be exploited both to remove activated T-cells to prevent transfusion-associated GVHD, and to kill tumor cells. Blood irradiators could thus be used in oncology surgeries with significant blood loss where intra-operative blood salvage occurs because of patient preference or other reasons. Irradiation can be done with x-rays or certain radioisotopes, but radioisotope blood irradiators were excluded from the scope of this MDAC meeting.
- The GVHD indication for use was the subject of a 2012 MDAC panel, which recommended classifying blood irradiators for this use as Class II, with special controls, and therefore eligible for the 510k pathway. The 2012 panel did not discuss use for metastasis prevention, an indication for use for just one of the 12 blood irradiator devices cleared at the time. In 2016, a second blood irradiator device was cleared for GVHD and prevention of metastasis.
- Tam asked the panel broadly to fill the gap from the 2012 panel’s assessment of blood irradiators by discussing “the current landscape of product technology, indications for use, safety and effectiveness, and risks to health, on which to base the classification of blood irradiators for the prevention of metastasis,” according to her presentation.
- A literature review conducted by the FDA to look at evidence for safety and effectiveness of blood irradiators to prevent metastasis found that, between 2002 and April 2023, there were no reports that evaluated risks or performance issues, though two studies reported that irradiation added some time (less than 20 minutes) to surgical procedures. A single study found no difference in tumor recurrence with irradiation, and another two studies found in vitro evidence of damage to tumor cells that kept them from proliferating, though no in vivo studies were found. As the FDA’s executive summary on its review of the devices noted, “No definitive conclusion can be drawn on whether irradiation of intraoperatively salvaged blood prevents metastasis.”
- A review of Medical Device Report data showed seven reports in total, five of which were related to the irradiators themselves. In two cases, there was low x-ray output; one case involved a user suggestion to upgrade a failure alarm; and two cases couldn’t be analyzed because they didn’t have narratives. No accidental radiation occurrences were reported. Just one recall was recorded, a Class II recall for a problem with a door interlock. The FDA concluded that there’s “no evidence that blood irradiators as medical devices pose a serious health hazard.”
- Given the dearth of solid data regarding the safety history for these products, the FDA proposed to the committee that they be classified as Class III devices. In support, the agency cited uncertainty about any long-term safety risks, such as those related to cancer outcome (with the potential for secondary malignancy for irradiation) and patient recovery time and survival. Specific additional risks could include unintended damage to off-target blood products, unintended radiation exposure to the operator or others, electrical injury, and added delay or interruption of re-transfusion, among others. These potential risks, said Tam, might not be mitigated by special controls, so the FDA is seeking more stringent oversight.
- In sum, “FDA proposes that blood irradiators intended to irradiate intra-operatively salvaged blood from cancer patients to prevent metastasis meet the statutory definition of a Class III device because insufficient information exists to determine that general and special controls are sufficient to provide reasonable assurance of their safety and effectiveness,” according to FDA’s executive summary of its review of the devices. “Additionally,” wrote the agency, “blood irradiators for this indication present a potential unreasonable risk of illness or injury based on the limited clinical information that has been obtained.”
CDRH posed a hefty set of questions to the MDAC panel
- The FDA’s questions for the committee were provided in a document that ran to nearly six pages. These questions were discussed, but not voted upon. In summary, the FDA solicited comments from the panel on the specific set of risks it discussed during Tam’s presentation, asking whether all should be included, and whether additional risks should be added. Additionally, the FDA asked whether the panel felt there was a “reasonable assurance of safety” for the devices and the proposed indication for use.
- Some clinicians on the committee pointed to specific known risks and sounded a note of caution for potential unknowns. For example, the University of Pittsburgh’s JONATHAN WATERS explained that when blood irradiators are used, they’re usually situated in a blood blank for irradiating units of blood to prevent transfusion-associated GVHD. Intraoperatively salvaged blood must thus be taken from the operating room to the irradiator, creating the potential for mixups. “I have seen mismatching where the unit went to the wrong place and was transfused after processing,” said Waters, citing “significant risk” in this transfer.
- ANDY CHEN, of Oregon Health & Science University, emphasized his concern that irradiation could itself be the cause of new malignancy; other panelists wondered about added operative time and the potential to damage immune-fighting white blood cells – desirable in fighting GVHD, but highly undesirable for cancer patients. All agreed these questions were either understudied or completely unexamined.
- The FDA also posed the question of whether there was a reasonable assurance of effectiveness for irradiators, and whether the panel agreed with the Class III proposed reclassification, asking for justification with agreement or disagreement. The FDA also requested committee members to specify what kind of clinical information “would be necessary to provide reasonable assurance of safety and effectiveness.”
- DANIEL BOURLAND, a radiation oncologist at Wake Forest School of Medicine, zeroed in on the “lack of probable benefit,” where “I would say the great unknown exists.” Though the radiation risks themselves might not be large, the sum of logistical and other risks is unknown but potentially significant, he said, summing up the committee’s discussion.
- As to the kinds of clinical information required, private practice psychologist NATALIE COMPAGNI-PORTIS proposed that overall survival endpoints would be needed – a time-consuming and expensive clinical study to undertake. Others called for randomized controlled trials of various tumor types, of sufficient size and representativeness to yield the “reasonable assurance” the FDA would require.
- VICTOR VAN BERKEL of the University of Louisville called for a “clearly delineated clinical profile” of patients who could benefit from the device, with evidence of “short-term and long-term oncologic benefit.” But he also gave a realistic appraisal of the commercial context: “I feel that we may be getting a little bit into the weeds on something that’s perhaps not necessarily relevant to what we’re talking about here today,” he said. “I don’t think, practically speaking, that there is going to be a premarket application for any of these devices. I can’t imagine that someone is going to design a trial that is going to look at these things in such a small-use patient population.”
- JULIE SULLIVAN, who directs CDRH’s Division of Radiological Imaging and Radiation Therapy Services, summarized the discussion and consensus of the committee – which was almost completely in line with the FDA’s. The committee acknowledged that her characterizations were accurate.
- The FDA provided a summary of likely next steps for committee members in a fact sheet. Should the FDA issue a final rule classifying these devices into Class III – a likely scenario based on the day’s events – then “companies wishing to continue to market existing devices of this type must file a premarket approval (PMA) application within the specified timeframe that is designated in the final classification rule,” according to the fact sheet. “To support approval, the information in the PMA (including clinical data) would have to demonstrate a reasonable assurance of safety and effectiveness. New devices or changes to existing devices would require approval of a PMA or PMA supplement. If a company does not file a PMA within the specified timeframe or otherwise does not receive an approval order for their product, the products are considered to be misbranded and should be removed from the market.”
- Reclassification into Class II seems less likely. In this case, devices would continue to be subject to 510(k) premarket notification requirements, along with any special controls that might be included in the final rule.
- As a practical matter, not only are PMA applications more onerous than those made through the 510(k) pathway, but so are postmarket requirements. “Once a PMA is approved, the PMA holder must report all design, manufacturing, and labeling changes made to the approved device to FDA via PMA supplements and PMA annual reports. PMA holders are also typically subject to ongoing postmarket requirements,” wrote the FDA in its executive summary for the panel. Minor device or labeling changes to 510(k) devices do not need to be submitted, and annual reports aren’t required.
- “Regardless of the classification of this device type, FDA does not regulate the practice of medicine, specifically, which devices clinicians can use and how they use them,” the FDA observed in the summary. This point was also raised and clarified at the meeting – if irradiators for GVHD remain on the market, it’s up to clinician discretion whether they would continue to be used for malignancy prevention.
Featuring previous research by Laura DiAngelo.
Key Documents and Dates
- November 7, 2023: Radiological Devices Panel of the Medical Devices Advisory Committee (all documents and video link are here)