Opinion ID: 223134
Heading Depth: 2
Heading Rank: 2

Heading: The Express2 System

Text: We begin with an overview of the Express2 system and BSC's gradual improvement of it, as this background is necessary to understand the nature and basis of the plaintiff's claims about Taxus. BSC's improvements to the Express2 system can be categorized into three phases on the undisputed evidence.
BSC began selling the Express2 system outside the United States in June 2001, and received FDA approval for U.S. sales in September 2002. The system was manufactured at company facilities in Maple Grove, Minnesota, and Galway, Ireland. In early 2003, BSC received 11 reports of complaints that the balloon on Express2 devices had not deflated, including 3 from the same manufacturing lot. While BSC had received occasional complaints of this problem since the product's launch, the increased rate and the existence of multiple no-deflates from the same batch caused BSC to conduct an inquiry. Multiple-complaint lots meant that the problem was not dispersed throughout all devices, and consequently that the normal method of calculating frequency did not apply. BSC initiated a Site Level Correction Action (SLCA) at Maple Grove led by Paul Weiss, and a corresponding Corrective and Preventative Action (CAPA) at Galway led by Niamh O'Byrne. SLCA and CAPA investigations are commenced to investigate issues that are systemic or could disrupt business operations. As part of their investigations, Paul Weiss and Niamh O'Byrne opened a Product Inquiry Report (PIR). A PIR is used to investigate and make recommendations for in-house actions or field actions to BSC's Field Action Committee (FAC), which has ultimate responsibility for instituting field actions such as recalls. Although the multiple-batch no-deflate complaints were about Express2, Taxus (which was only being sold outside the United States at the time) was included in the PIR because both systems were built using the same Express2 catheter. On May 15, 2003, the PIR team issued a report on the primary cause of the no-deflate problem. The team found that the problem was due to a condition known as focal necking or focal neckdown, where the distal outer (the portion of the catheter that is welded to the balloon) becomes elongated or stretched, preventing the withdrawal of the fluid used to inflate the balloon. The team further found that this focal necking had two primary causes: (1) excessive heat at the laser bond of the balloon and the distal outer, which could be caused by a laser that was too hot or misaligned, and (2) a subsequent excessive tensile force exerted in the area of the bond, which could occur either during or after manufacturing. While the team could not identify the specific cause of the tensile force, it was able to identify several in-house actions to prevent or lessen the incidence of focal necking. To address issues with the laser weld, it recommended reducing the laser energy settings, increasing the magnification of the alignment camera, and retraining operators. For the same reason, the team also recommended using only distal outers manufactured in Maple Grove, which were found to be more robust than those manufactured in Galway, and launching an investigation to understand why the Galway distal outers appeared more prone to focal necking. The PIR team also reported on the frequency of the no-deflate issue. For Express2 devices manufactured in Galway, it found twenty no-deflates out of over 260,000 revenue shipments, with two lots producing three complaints each; for those manufactured in Maple Grove, it found only one no-deflate. [2] For Taxus devices, which were only manufactured in Galway at the time, it found zero no-deflates out of over 31,000 revenue shipments. Given this low rate of occurrence combined with the limited severity in all but one case, the PIR team concluded that [n]o field action is recommended at this time. The team was asked at a May 22 meeting to determine the scope of the no-deflate issue in case a recall was needed, and it found no factors that could be used to identify some devices as being higher-risk. It considered data on numerous parameters of the focally necked devicesincluding laser weld, elongation, type of resin used, and extrusionsbut found no correlations from which to scope the problem. On May 23, the team issued a PIR with the same conclusions and recommendations that it had reached in the May 15 report. On May 27, the FAC accepted the PIR team's recommendations and conclusions. It agreed that a recall was not warranted at the time, finding that the product in the field was within all of its established specifications, the frequency of issues reported [from] the field were extremely low, and the consequences, while potentially severe in some cases are not outside those expected with this type of procedure. The Chairman of the FAC, Paul Sandman, later testified that the FAC did not institute a recall because there weren't any factors that indicated that these failures were caused by a manufacturing problem. The FAC also directed that the PIR be clarified to state that the issue involves units within specification, and indistinguishable from a visual standpoint, being subjected in the field to a level of tensile force exceeding that for which the product was designed. It is unclear whether this was meant to supplement, or replace, the PIR's statement that the tensile event may have also occurred during manufacturing. [3] In implementing the PIR team's suggestions, BSC sought to harmonize the robustness of the stent systems produced at Galway with those produced at Maple Grove. The changes focused on the properties of the distal outers and the proximal welding process. As to the proximal welding process, BSC increased the magnification used to line up the stent system components, making it identical with that in Maple Grove, and retrained the Galway operators on the proper alignment of the laser weld and the proper handling of the catheters to avoid tensile forces on the product. These changes were implemented in May. As to the quality of the distal outers, Galway immediately switched to using Maple Grove distal outers in its production, [4] and over the following three months, BSC implemented various changes to harmonize the manufacturing of distal outers at the facilities, including aligning their elongation testing equipment, extrusion parameters, and distal outer measurement methods. BSC also introduced changes to ensure that the area of the proximal weld was not exposed to excessive heat during laser welding, including implementing an in-process manufacturing acceptance criterion for the length of the weld (the Matte Finish Length). [5] Because none of these changes affected device design or performance specification, BSC determined that prior FDA approval was not required, and implemented them in accordance with its standard BSC Quality System procedures.
Although BSC determined that a recall was not necessary, it nevertheless decided to further investigate the no-deflate issue. Internal correspondence from this period shows that the no-deflate issue was seen by some in the company as urgent and a severe compliance risk. So in Galway, a six sigma team was initiated on May 28, 2003 to investigate the cause of focal necking. [6] In addition, following up on the CAPA investigation's finding that the material properties of the distal outer shaft could contribute to the robustness of the proximal balloon weld, BSC created a team in Maple Grovewhere the distal outer shafts had been found to be more robust to develop a new design specification for the distal outer. Over the next four months, the Maple Grove team developed a proposal that focused on the elongation properties of the distal outer. Elongation served as an indirect measure of the molecular orientation and crystallinity of the polymer material used in the distal outer. By setting a length that the distal outer could be stretched before breaking, BSC aimed to ensure that each of its distal outers had material properties that would increase its robustness to subsequent thermal processing that occurs when the outer is laser welded to the balloon component of the delivery system. On October 3, 2003, BSC filed a supplement to its Express2 Premarket Approval (PMA) with the FDA, seeking permission to implement a test method to evaluate the elongation property of the extruded distal outer shaft component for the Express2. In this document, BSC stated that the change was meant to address no-deflate complaints. BSC disclosed that it had received a small number of field complaints (approximately 0.0148% complaint rate) regarding the delivery system balloon's failure to deflate and provided a table listing the no-deflates by month and manufacturing site for January through August 2003. It explained that although it had been unable to definitively confirm the root cause of the failure, its investigation had determined that at least part of the root cause is due to inconsistent material properties of the distal outer shaft component, and that the new design specification was intended (1) to improve the robustness of the distal outer shaft, and (2) to improve the consistency between distal outer shafts manufactured at BSC's [Maple Grove and Galway] facilities. Finally, BSC notified the FDA in this supplement of all of the May 2003 corrective actions that it had taken, explaining its determination that these changes did not require FDA approval. It also reported on the success of these measures, noting that the fifteen no-deflate complaints for Express2 devices that it had received between May and August 2003 were for devices built prior to the implementation of the changes. The FDA approved BSC's request on October 24, 2003.
At the same time that BSC was implementing the elongation specification, the six sigma team was completing its report on the laser shift. It found that by shifting the location of the laser used to bond the balloon to the distal outer, from .4 mm to .8 mm, focal necking would be prevented, regardless of the settings of the other factors. [7] However, as Peter Delmer, who headed the effort in Galway, stated, an awful lot more work would have to be done in order to implement that solution. The company needed to verify that the change would not introduce new problems and also confirm whether .8 mm was the ideal position, or whether .7 mm would be better. This validation work was assigned to Kevin Griffin, a Process Development Engineer at Maple Grove. On September 2, Griffin created a plan estimating that a proposal could be submitted to the FDA in November. However, he stated even at this time that the plan was a bit optimistic. [8] His team was advised to keep those working on Taxus, a different group, informed because any manufacturing change submitted to the FDA would need to be assessed for its impact to the Taxus PMA. In the following months, the team worked to develop a validation protocol, which involved discussions with various branches of the company, including manufacturing and regulatory. At this point, as of the beginning of the Class Period in November, there had been only two no-deflate complaints for the tens of thousands of Express2 and Taxus devices manufactured at Galway after the introduction of the May 2003 changes, and there had been only three no-deflates ever on Express2 devices manufactured at Maple Grove. Consequently, Paul Weiss, the leader of the no-deflate PIR, concluded on November 26, 2003 that the interim actions have been very effective.