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Jan B. Pietzsch Department of Management Scienceand Engineering, Stanford University, 380 PanamaWay, Stanford, CA94305-4026; Wing Tech Inc., 9916 Newhall Road, Potomac, MD20854 Lauren A. Shluzas Department of Management Scienceand Engineering, and Department of Mechanical Engineering, Stanford University, 380 PanamaWay, Stanford, CA94305-4026 M. Elisabeth Paté-Cornell Department of Management Scienceand Engineering, Stanford University, 380 PanamaWay, Stanford, CA94305-4026 Paul G. Yock Department of Bioengineering, Stanford University, James H. Clark Center, 318 Campus Drive, E-100, Stanford, CA94305-5428 John H. Linehan Department of Bioengineering, Stanford University, James H. Clark Center, 318 Campus Drive, E-100, Stanford, CA94305-5428; Clinical and Translational Sciences Institute, Northwestern University, 750 North LakeShoreDrive, Chicago, IL 60611 Stage-Gate Process for the Development of Medical Devices The medical device development process has become increasingly complex in recent years. The advent of new technology concepts, stricter regulatory requirements, and the ever increasing importance of reimbursement decisions for successful device commercial- ization require careful planning and strategy-setting, coordinated decisions, and consis- tent, rigorous business processes. The design and implementation of such processes, often captured in development models and accompanying standard operating procedures, have become a key determinant of the success of device commercialization. While various models may exist in the device industry, no comprehensive development model has been published. This paper reviews existing model representations and presents a new com- prehensive development model that captures all aspects of device development and com- mercialization from early-concept selection to postmarket surveillance. This model was constructed based on best-practice analysis and in-depth interviews with more than 80 seasoned experts actively involved in the development, commercialization, and regulation of medical devices. The stage-gate process includes the following five phases: (1) initia- tion - opportunity and risk analysis, (2) formulation - concept and feasibility, (3) design and development - verification and validation, (4) final validation - product launch prepa- ration, and (5) product launch and postlaunch assessment. The study results suggest that stage-gate processes are the predominant development model used in the medical device industry and that regulatory requirements such as the food and drug adminstration (FDA’s) Quality Systems Regulation play a substantive role in shaping activities and decisions in the process. The results also underline the significant differences between medical device innovation and drug discovery and development, and underscore current challenges associated with the successful development of the increasing number of com- bination products. !DOI: 10.1115/1.3148836" 1 Introduction Medical devices 1 contribute significantly to the continuous im- provement of healthcare. With product lifecycles that are some- times as short as 18 months, patients benefit from a continuous stream of innovation that hinges heavily on successful needs as- sessment and the experience and skills of engineers and other professionals involved in the innovation process. Yet, bringing a new product successfully from the bench to the bedside is highly complex and depends heavily on the implementation of rigorous processes. These processes need to allow developers to optimally phase development, testing, and other activities, and to success- fully execute on the manifold requirements of third parties, in- cluding regulators and payers. These additional requirements set medical device development apart from the development of other products. The objective of the empirical study presented here is to give a detailed overview and model representation of the medical device development process and its various activities and decisions. The motivation for this work is twofold. First, a thorough understand- ing of the multiple streams of activities and responsibilities in device development can help engineers and other professionals to execute the bench-to-bedside process of product development most effectively. By understanding the intricacies and challenges of development and commercialization, the development team can better anticipate external requirements and their implications for decision-making. This can contribute significantly to successful product innovation, especially in light of the many startup com- panies that provide innovation in the medical device industry. Sec- ond, the ongoing efforts by regulators and policymakers to design 1 In the context of this study, medical devices are defined as technologies used in the diagnosis, cure, mitigation, treatment, or prevention of diseases or conditions that do not achieve their primary treatment effect by pharmacological, immunological, or metabolic means. Manuscript received May 12, 2008; final manuscript received May 3, 2009; pub- lished online June 17, 2009. Review conducted by Paul A. Iaizzo. Journal of Medical Devices JUNE 2009, Vol. 3 / 021004-1 Copyright © 2009 by ASME Downloaded 17 Jun 2009 to 171.67.34.86. 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Jan B. PietzschDepartment of Management Scienceand

Engineering,StanfordUniversity,

380PanamaWay,Stanford, CA94305-4026;

WingTechInc.,9916Newhall Road,Potomac, MD20854

Lauren A. ShluzasDepartment of Management Scienceand

Engineering,andDepartment of Mechanical Engineering,

StanfordUniversity,380PanamaWay,

Stanford, CA94305-4026

M. Elisabeth Paté-CornellDepartment of Management Scienceand

Engineering,StanfordUniversity,

380PanamaWay,Stanford, CA94305-4026

Paul G. YockDepartment of Bioengineering,

StanfordUniversity,JamesH. ClarkCenter,

318CampusDrive,E-100,

Stanford, CA94305-5428

John H. LinehanDepartment of Bioengineering,

StanfordUniversity,JamesH. ClarkCenter,

318CampusDrive,E-100,

Stanford, CA94305-5428;Clinical andTranslational SciencesInstitute,

NorthwesternUniversity,750NorthLakeShoreDrive,

Chicago, IL60611

Stage-Gate Process for theDevelopment of Medical DevicesThe medical device development process has become increasingly complex in recentyears. The advent of new technology concepts, stricter regulatory requirements, and theever increasing importance of reimbursement decisions for successful device commercial-ization require careful planning and strategy-setting, coordinated decisions, and consis-tent, rigorous business processes. The design and implementation of such processes, oftencaptured in development models and accompanying standard operating procedures, havebecome a key determinant of the success of device commercialization. While variousmodels may exist in the device industry, no comprehensive development model has beenpublished. This paper reviews existing model representations and presents a new com-prehensive development model that captures all aspects of device development and com-mercialization from early-concept selection to postmarket surveillance. This model wasconstructed based on best-practice analysis and in-depth interviews with more than 80seasoned experts actively involved in the development, commercialization, and regulationof medical devices. The stage-gate process includes the following five phases: (1) initia-tion - opportunity and risk analysis, (2) formulation - concept and feasibility, (3) designand development - verification and validation, (4) final validation - product launch prepa-ration, and (5) product launch and postlaunch assessment. The study results suggest thatstage-gate processes are the predominant development model used in the medical deviceindustry and that regulatory requirements such as the food and drug adminstration(FDA’s) Quality Systems Regulation play a substantive role in shaping activities anddecisions in the process. The results also underline the significant differences betweenmedical device innovation and drug discovery and development, and underscore currentchallenges associated with the successful development of the increasing number of com-bination products.!DOI: 10.1115/1.3148836"

1 IntroductionMedical devices1 contribute significantly to the continuous im-

provement of healthcare. With product lifecycles that are some-times as short as 18 months, patients benefit from a continuousstream of innovation that hinges heavily on successful needs as-sessment and the experience and skills of engineers and otherprofessionals involved in the innovation process. Yet, bringing anew product successfully from the bench to the bedside is highlycomplex and depends heavily on the implementation of rigorousprocesses. These processes need to allow developers to optimally

phase development, testing, and other activities, and to success-fully execute on the manifold requirements of third parties, in-cluding regulators and payers. These additional requirements setmedical device development apart from the development of otherproducts.

The objective of the empirical study presented here is to give adetailed overview and model representation of the medical devicedevelopment process and its various activities and decisions. Themotivation for this work is twofold. First, a thorough understand-ing of the multiple streams of activities and responsibilities indevice development can help engineers and other professionals toexecute the bench-to-bedside process of product developmentmost effectively. By understanding the intricacies and challengesof development and commercialization, the development team canbetter anticipate external requirements and their implications fordecision-making. This can contribute significantly to successfulproduct innovation, especially in light of the many startup com-panies that provide innovation in the medical device industry. Sec-ond, the ongoing efforts by regulators and policymakers to design

1In the context of this study, medical devices are defined as technologies used inthe diagnosis, cure, mitigation, treatment, or prevention of diseases or conditions thatdo not achieve their primary treatment effect by pharmacological, immunological, ormetabolic means.

Manuscript received May 12, 2008; final manuscript received May 3, 2009; pub-lished online June 17, 2009. Review conducted by Paul A. Iaizzo.

Journal of Medical Devices JUNE 2009, Vol. 3 / 021004-1Copyright © 2009 by ASME

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the least burdensome approaches to medical device regulation canbenefit from a thorough understanding of the invention and deci-sion processes in medical device development.

The article is structured as follows. Section 2 reviews existingdevelopment process representations. The methodology employedfor the interview and model building process is then introduced.Section 4 presents the development model and detailed informa-tion about the various activities and decisions involved in theprocess. Finally, the findings of the empirical study are discussedand put in perspective.

2 Background2.1 Product Innovation and Development Process Models.

Product innovation and the successful management of new prod-uct development has been the focus of both academic research andmanagerial concern for more than 2 decades !1,2". At the heart ofthese efforts is the development of an understanding of the factorsresponsible for new product success, and the desire to drive newproducts from idea to market faster and with fewer mistakes. Thisalso involves research on the optimal alignment of the New Prod-uct Development #NPD$ effort with the strategic objectives andcompetencies of the firm !3", and more recently, questions of op-timal product portfolios for innovating companies !4".

One of the most notable contributions of the last 2 decades hasbeen the development and implementation of stage-gate processesfor product development !5". These models are both conceptualand operational tools to move a new product from idea to launch,and recognize that product innovation is a process that can bemanaged !5". A stage-gate system divides the innovation processinto a predetermined set of stages, separated by gates character-ized by a set of criteria to be met before the product can advancein the process. Each stage, in turn, is composed of a number ofprescribed activities that are in many cases related and that canoccur in parallel. Typical stages in a new product developmentprocess involve preliminary assessment, detailed investigation,actual development, testing and validation, and full productionand market launch #compare Ref. !5"$. The rigor of a stage-gateprocess facilitates formal descriptions of various activities anddecisions. These descriptions are often summarized in standardoperating procedures and can be useful to define best-practiceapproaches to development.

While applications of formal development processes and simi-lar models have been described for a number of industries, includ-ing the automotive industry, no comprehensive process model fornew product development has been published for the medical de-vice industry. Rochford and Rudelius !6" outlined a number ofstages and successes for the development of medical products, butdo not provide a comprehensive process description or summaryof activities and decisions. Kaplan et al. !7" described several ofthe key activities of medical device development from prototypeto regulatory approval, but do not provide a model of the devicedevelopment process.

2.2 Existing Process Representations Associated WithMedical Device Development. A number of graphical represen-tations have been published that delineate various aspects of themedical device development process. They range from represen-

tations of the product definition and quality function deployment#QFD$processes to models of design control, and representationsof regulatory and reimbursement routes. Several of these modelsare briefly presented Secs. 2.2.1–2.2.5 as an overview of the avail-able literature and provide some perspective on the subsequentmodel presented here. Additional background on medical devicedevelopment can be found in pertinent textbooks, including Fries!8", King and Fries !9", Whitmore !10", and Kucklick !11".

2.2.1 Design Input and Product Definition Process Repre-sentation. Fries !12" graphically summarized what he calls theproduct definition process, including customer needs, companyneeds, company competency, and vendor/alliance competency.The process representation shows the progression from specifica-tions to available technologies and subsequent opportunities todefine applications, platforms, and enhancements based on thedeveloped technology concept #Fig. 1$.

2.2.2 QFD Matrices. In the context of design developmentand refinement, QFD gained attention in the 1990s in some seg-ments of the medical device industry. It is an overall methodologythat begins with the design process and attempts to map thecustomer-defined expectation and definition of quality into theprocesses and parameters that will fulfill them. QFD is closelyrelated to “house of quality” methods. A full understanding of thevarious customer needs, constraints, and technical possibilities,helps a manufacturer in planning processes and products that areefficient and have high customer appeal.

QFD often takes the form of a comprehensive matrix that in-cludes, among others, a customer information portion #“voice ofthe customer”$and a technical information portion. According toFries !12", a common result of QFD introduction is that buildingthe matrix becomes the main objective of the process, with posi-tive results such as a more comprehensive understanding of pa-tient needs. This, in turn, directly supports the developmentprocess.

The detailed construction of QFD matrices, including assess-ment of quantitative data and relationships, is not discussed here.Note, however, that QFD matrices and their representations can beunderstood as partial development models.

Fig. 2 Application of design controls to waterfall design pro-cess †13‡

Fig. 1 The product definition process „based on Ref. †12‡…

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2.2.3 Design Control Process Representations. The designprocess is often graphically depicted in terms of relatively simplewaterfall diagrams. These diagrams link user needs through de-sign input, design process, and design output to the completedmedical devices. Figure 2 shows a waterfall diagram that alsoincludes the iterative design control activities of Review, Verifica-tion, and Validation. While this model provides an understandingof the interaction among various development stages, it lackssome details, such as process requirements, health-economics, andreimbursement planning, which are critical to the successful com-mercialization of a new medical technology.

Figure 3, based on Ref. !14", is a linear representation of thedevice development phase, with focus on the design change life-cycle. It shows the four milestones “Start to Plan,” “Start to De-sign,” “End Design,” and “Commence Building,” with individualtasks and activities between these milestones, and a description ofvarious design control outputs throughout the phases.

Stark !15" presented a schematic overview of clinical researchactivities in the product development cycle #see Fig. 4$. The rep-resentation lists five product development phases #Concept—Prototype—Prepilot—Pilot—Production$, and for each phase,shows design control, product development, and clinical researchactivities next to each other, including some of the major relation-ships among them.

Risk management, i.e., the anticipation and reduction of thechances of failure and their consequences, is a critical element ofthe design control activities that has received significant attentionfrom regulators and manufacturers in recent years. Figure 5shows, in simplified form, the risk management process for medi-cal devices according to ANSI/AAMI/ISO 14971:2000.

The FDA !16" has published a more comprehensive schematicrepresentation of the integration of risk assessment into the formaldesign control activities #Fig. 6$. This description emphasizesvarious methods, including fault tree analysis #FTA$ and failuremode and effects analysis #FMEA$. It also puts verification andvalidation activities2 in perspective. A comprehensive overview ofthese methods can be found in Ref. !17".

2.2.4 Development Cycle Representations. Several develop-ment cycle models exist. One of the most prominent device-lifecycle representations has been created at the FDA by Feigal#Fig. 7$. The development aspect is covered in the first part of thecyclic model #design through clinical sciences$. The model em-phasizes the role of customer feedback and learning from onegeneration of a device to the next, and shows the intertwined flowof information. Comparable model representations can be foundin the literature, among them a representation by Califf et al. !19"that emphasizes the clinical and quality aspects in the therapeuticdevelopment cycle. The measures of quality and clinical outcomesare particularly relevant for all health-economic and outcomes-oriented considerations.

2.2.5 Regulatory and Reimbursement Representations. Sev-eral model representations of the device development and com-mercialization process exist to describe its regulatory and reim-bursement aspects. These aspects are highly relevant fordevelopment because they can have significant implications forthe design and testing of a new technology.

To represent the different regulatory pathways for medical de-vices, several flowcharts have been created. A comprehensive rep-resentation of the United States regulatory process presented byHelmus !20" is shown in edited form #Fig. 8$. The figure outlinesthe decision process that determines whether a device can bebrought to market via the 510#k$ premarket notification path, orthe alternative premarket approval #PMA$path. Note that exemptdevices #class I$are not shown in this representation, and neitherare the product development protocol #PDP$or humanitarian de-vice exemption #HDE$ paths. Additional background and a de-tailed review of United States medical device regulation can befound in Ref. !21". A detailed overview of the European deviceregulation is given in Ref. !22".

3 MethodologyThe purpose of the present study was to construct a comprehen-

sive representation of the medical device development process byconducting a field study #between October 2006 and September2007$ based on in-depth interviews of experts actively involvedwith the development, regulation, and use of medical devices.

2Verification: Establishing conformance of design outputs to design input. Valida-tion: Establishing conformance that final product meets user needs.

Fig. 3 Overview of a design change life cycle „based on Ref. †14‡…

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Among the interviewees were senior professional staff at theFDA, and executives and other experts in medical device compa-nies. Within the cohort of interviewees, all major groups involvedwith product development, starting with engineering and strategicplanning to marketing and sales, clinical, and manufacturing, wereincluded. The companies ranged in size from startups to early-stage to major medical manufacturers such as Medtronic Inc., Bi-omet, Boston Scientific, and Edwards Lifesciences. The casesstudied ranged from imaging and surgical devices, to implantableelectrophysiological and mechanical devices, to drug deliverytechnologies and in vitro diagnostic multivariate index assays#IVDMIA$.

For this empirical study, the data collected initially were used togenerate hypotheses about the device development process. Thehypotheses were presented to subsequent interviewees and itera-tively revised and improved. In addition to primary knowledgegeneration through interviews, information available from the lit-erature and other sources was used to build a body of knowledge.This research approach, known as grounded-theory building, orinductive theorizing, was chosen as a well established researchmethod to describe and understand complex phenomena #pro-cesses$from an empirical assessment of the diverse characteristicsof the investigated phenomenon !23".

The selected 86 interviewees comprised of individuals involvedat various stages of the development process, from research andinvention to early-concept definition, actual development, regula-tory approval, and postmarket feedback. In order to ensure thehighest possible validity and generalizability of the results, inter-viewees were chosen from various backgrounds, technology ar-eas, companies, and regions. In addition, we interviewed seniorFDA leaders, professional staff, and specialized consultants #regu-latory affairs, reimbursement, clinical trials planning$of the medi-cal device industry.

The protocol for the model construction process entailed sev-eral procedural steps as follows:

• Review of standard operating procedures (SOPs) of fourdevice companies #large, midsize, and startup companies in-cluded$

• Identification of different functional groups involved in de-vice development process. To ensure identification and inter-view inclusion of the right constituencies involved in medi-cal device development, a list outlining functional positionsand various job responsibilities was created.

• In the first round of interviews, a representative sample ofthe outlined functional groups was interviewed #ten inter-views total, with R&D receiving particular attention$. Allinterviewees were asked to share their perspective on thedevelopment process, and to outline their individual activi-ties and decisions in the development process #“bench-to-bedside”$.

• Based on the first interviews and reviewed SOPs, an initialdraft development model was constructed. This model out-lined the different phases in the development process, andthe activities performed in each function during thesephases, including the decisions taken at various projectstages.

• In a second round of interviews #50 interviews$, the initialprocess representation was presented to interviewees, andfeedback was obtained. Based on this feedback, some addi-tions and changes were made and continuously integrated.

Fig. 4 Schematic overview of clinical research in the product development cycle „based on Ref.†15‡…

Fig. 5 Schematic representation of the risk management pro-cess according to ANSI/AAMI/ISO 14971:2000

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In addition, the various activities and decisions identified inthe model were discussed in greater detail with each inter-viewee to ensure accurate and comprehensive description ofthese activities and decisions as part of the model presentedhere. A distinct decline of proposals for change in the modelover the course of the second round of interviews showedconvergence, and led us to conclude that the model pre-sented in this paper was accepted by interviewees as anaccurate representation of the development process.

• A third round of interviews involved the remaining 26 inter-viewees and focused on various specific aspects of the medi-cal commercialization process based on the constructedmodel. As part of the interview process, interviewees wereasked about the specific accuracy of our model. No addi-tional changes or adjustments were suggested by theinterviewees.

4 Results4.1 Constructed Development Model. As outlined in Sec. 3

of this paper, construction of the device development model reliedsignificantly on insights acquired during the sequence of in-depth

interviews. The model is presented in linear-form as a stage-gatedprocess, according to the feedback and information obtained in thefield study. In reality, many of the defined processes within themodel are likely to be iterative. The linearity of the model is thusa simplified representation of the actual process. To illustrate thispoint, a number of typical iterative loops are presented after in-troduction of the linear model.

4.1.1 Linear Model of Device Development. The linear modelis shown in Fig. 9. Throughout the five phases of development,activities are shown in conjunction with the various functionalgroups responsible for them.

The linear medical device development model identifies fivemajor phases, separated by four decision gates. Predevelopmentactivities occur prior to Gate I, development activities occur be-tween Gates I and III, and product launch and postmarket assess-ment occur after Gate IV. In the model, the major functionalgroups are identified in boxes on the left side of the chart. Majordecisions are shown #in parallelograms$ at the bottom of eachphase. Upper level activities for each functional area are high-lighted in boxes within each phase. The horizontal progressionrepresents a generalized timeline. The major milestones/gates can

Fig. 6 Integration of risk assessment with design control activities †16‡

Fig. 7 Total product life cycle †18‡

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occur at different times in the development process depending onthe type of device. The five major phases and decision gates in-clude the following:

• Phase 1/Gate 1:. initiation, opportunity, and risk analysis• Phase 2/Gate 2: formulation, concept, and feasibility• Phase 3/Gate 3: design and development, and verification

and validation• Phase 4/Gate 4: final validation, and product launch prepa-

ration• Phase 5: product launch and postlaunch assessment

It should be noted that although each development phase ispresented in a discrete manner, the iterative process of devicedevelopment does not always follow the linear idealized model,but rather involves fuzzy boundaries between decision gates. Be-cause of iterations in the process, some parts of a developmentproject may already be in a more advanced phase, while certainactivities of a previous phase need to be repeated at the same time.The model describes a process that is most applicable to PMA and510#k$ devices that require some form of clinical data, and todevices that are largely mechanical in nature. The model can besimplified for 510#k$devices that do not require any clinical dataregulatory clearance.

4.1.2 Description of Development Phases. In what follows,each of the five development phases captured in the diagram isdescribed in greater detail based on the comprehensive interviewresults. In addition, predevelopment activities that need to becompleted before the formal development process is initiated arepresented. For each phase, major responsibilities of selected func-tional groups are discussed. Deliverables for each phase and de-cisions faced at the four decision gates are collectively summa-rized in Table 1. The process can take anywhere from 15 monthsto several years, depending on the type and complexity of thetechnology, and the quality of process execution. Clinical testingof some heart valves, for example, can take several years. Simi-larly, technologies that are used in a small population only, can bedelayed because of insufficient enrollment in trials.

4.1.2.1 Predevelopment activities (phase 0). In order to createa new medical device, inventors and device companies must focuson the right clinical need. To that effect, a wide range of clinicalneeds are first identified through direct observation, by speakingwith physicians, patients, and other health care providers, orthrough personal experiences, and by a review of the relevantclinical literature. Through a needs-finding funneling process #Fig.10$, inventors take a first pass at narrowing a large list of clinicalneeds based on the estimated market size and clinical impact as-sociated with each. To further narrow the list down, inventorsusually examine prior art related to each need to determine if thereare barriers to further development from an intellectual propertyperspective. This requires the very important step of defining pre-liminary product concepts. A preliminary market analysis is sub-sequently performed to ensure that there is a sufficient marketopportunity for each need. This analysis is expanded in Phase I.Inventors must also determine if they are in a position to effi-ciently follow up in order to seize an existing market opportunity.Once the list of clinical needs has been sufficiently narrowed,each remaining need tends to get further validated in terms ofregulatory considerations, reimbursement strategies, intellectualproperty, and business development objectives. In terms of com-pany development, the process is to further check that the productfits the company strategy and that the company has the capabilityof successfully commercializing the product.

4.1.2.2 Phase I: Initiation - opportunity, and risk analysis.The predevelopment activities within Phase I mark the beginningof the medical device development process, as defined here. Insome instances, this phase is also referred to as “ technologyphase.” It is characterized by the early evaluation of projectsaimed at addressing clinical needs as described in Phase 0. Veri-fication of the previously identified clinical need might involvetalking to physicians, patients, and hands-on technology users,such as nurses, operating room and lab technicians, and observingthem in the clinical setting. This phase also involves a review ofthe existing medical devices and procedures that are being used to

Fig. 8 Regulatory pathways for medical devices „representation based on Ref. †20‡…. Legend: QSRegulation: QSR; IDE: investigational device exemption; IRB: Institutional Review Board

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treat the condition. Next, a preliminary market analysis, financialreview, and competitive product assessment are often performed.A review of the existing IP landscape within a specific market orpathology area is also conducted, as well as an early-stage tech-

nology risk assessment. The IP review includes evaluation of thetechnology concepts that have been identified in Phase 0 and I.Potential regulatory paths and their associated risks are studiedand initial reimbursement strategies assessed.

Fig. 9 Linear medical device development model

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Understanding the market for a proposed medical device andthe likely financial return on the investment are critical compo-nents of the predevelopment phase. Note that each of the activitieslisted in the development model can include several subactivitiesthat are not explicitly shown on the diagram. Also, many depen-dencies can exist between the listed activities. “Financial Re-view,” for example, depends heavily on the results of other activi-ties such as market analysis, competitive assessment, technicalfeasibility, etc.

Market analysis/competitive assessmentMarket analysis involves needs assessment and validation, de-

mographics analysis, a SWOT #strengths, weaknesses, opportuni-ties, threats$ analysis to examine a product’s strengths, weak-nesses, opportunities, and threats; market research aimed atidentifying the market size and growth potential; and a competi-tive outlook analysis. Product positioning and launch strategy arealso key elements to medical device predevelopment activities.Analysts examine the current product mix and determine how the

Table 1 Deliverables and decisions at decision gates for Phases I–IV of development model

Fig. 10 Needs-finding funneling process and relationship to product development model

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new device should be ideally priced and positioned to make thegreatest market impact, without cannibalizing existing sales !12".Marketing and promotional launch activities are also examined atthat time.

Financial reviewOnce the market for a proposed medical device has been iden-

tified, it is necessary to perform a thorough financial review. Fi-nancial analysis entails calculating sales projections and projectedgross margins for a particular device or a proposed market !12". Inaddition, a financial analysis often includes a proposed royaltybreakout for physicians who contributed either to the primary de-vice concept or to intellectual property toward the development ofthe proposed device. A financial analysis may also include anassessment of what would happen if the device is not introducedto the market at the present time, or if it is introduced at a latertime #i.e., the pros and cons to having a first-mover advantage$.Projected inventory analyses are often performed in order to as-sess the number of units that would need to be built in order tosatisfy market demands.Legal/IP analysis

The initial review of the IP landscape during the predevelop-ment phase involves conducting a preliminary search of patentswithin and outside of the United States, including both applica-tions and issued patents. Depending on the existing IP landscape,a risk assessment is made to determine whether or not pursuingdevice development would be a viable investment !12". The pre-liminary IP review can also be used to establish design bound-aries. In order to avoid IPviolations, licensing agreements may beconsidered at this time if existing IP was generated from indepen-dent inventors #as opposed to major business competitors$.Regulatory and clinical path

The early-stage regulatory review involves identifying the pre-ferred domestic regulatory path, based on the type of proposeddevice and its market entry point #i.e., as a breakthrough product,line extension, addition to product family, etc.$. An internationalregulatory assessment could be performed to determine the infor-mation needed to obtain a conformitee europeenne #CE$mark #formarketing of a device in the European Union$ or other foreignregulatory approvals for the proposed product. A regulatory riskassessment and preliminary clinical plan assesses whether the ap-proval process will require clinical trials !12". The early regula-tory review is particularly important for a device manufacturer,because investment in a project with high regulatory risks couldresult in a net loss for the company if the device is not approvedfor use or if it requires unanticipated additional clinical studiesprior to launch.Reimbursement strategy

In order to commercialize a medical device, companies oftendevelop an early-stage reimbursement strategy. It is critical forcompanies to determine what will be required to secure a paymentstrategy, and how long it might take to implement such a strategy:“Understanding potential reimbursement rates is also imperativefor effectively pricing a new product. Particularly in medical de-vices, where the lifecycle from concept to launch is relativelyshort, entrepreneurs need to develop plans and processes to obtainreimbursement coverage prior to market entry. This is importantto facilitate market acceptance and help generate increased de-mand,” !24".Phase I: Deliverables and decision gate

The major deliverables of phase I and the key decisions to bemade at the decision gate are summarized in Table 1. A key de-liverable of Phase I is a business plan that is built on informationcollected during this phase. The elements of the business planinclude market assessment, unmet needs, product description, fi-nancial plan #P&L$, R&D plan including resource plans, regula-tory and clinical plan, marketing plan, manufacturing plan, distri-

bution plan, reimbursement plan, sales and distribution plan,supply chain strategy and plan, and a risk analysis for the variousfactors beyond pure design risk. The business plan is usually writ-ten beforemajor investments aremade. The information containedin the plan is critical to receiving project approval from manage-ment and resources for the project, or for a small company, capitalfrom investors.

4.1.2.3 Phase II: Formulation - concept and feasibility. If theproject is accepted by upper management, development proceedsto Phase II. Concept formulation and feasibility assessment occurduring this stage. A cross-functional project team is selected #oftenreferred to as “project core team”$, and a general project plan andtimeline is created !12". The team usually includes lead membersfrom R&D, quality assurance, manufacturing, marketing/sales,regulatory, clinical, and legal roles. Creation of a design plan is aformal requirement #per 21 CFR 820.30$ and signals the begin-ning of formal design controls. The R&D core team member oftenleads device development during Phase II and assumes the role ofproject manager. There are exceptions, in which case a separateproject manager will oversee timelines and general project plans.The team leader is responsible for initiating and managing thedesign history file #DHF$, or a record indicating that the devicewas developed in accordance with the approved design plan!25,26". The design plan is governed by FDA’s Quality SystemsRegulation and needs to be defined by senior management.

Lack of adequate records is a frequent cause of audit failure andcan jeopardize the project timeline and ability to support regula-tory filings. During the early development phase, the team’s mar-keting associate and R&D engineer often meet with potential us-ers #physicians, nurses, technicians, patients, among others$ toobtain customer input. Users state their needs, requirements, andearly design inputs #per 21 CFR Part 820.30$. User input, at thisstage, may range from a napkin sketch to a complete patent pro-posal that can be commercialized. It also is common for newdevice ideas to be generated from considering existing productcomplaints, which are either communicated directly from physi-cians or reviewed from the FDA’s MAUDE complaint database.User input enables device designers to gain a better understandingof the competitive landscape in a particular medical specialty area,and may motivate or dissuade a development team from pursuinga proposed device.Voice of customer/customer design input

Both during this early stage of development and throughout thedevelopment cycle, marketing is the functional area responsiblefor listening to the voice of the customer #VOC$and ensuring thatuser needs are met. Design inputs might include items such as theintended use of the device, testing requirements, biocompatibilityrequirements, functional requirements, and physical requirements#i.e., size, material, packaging, sterilization, environmental com-patibility, and appearance$ !26". Marketing also participates inearly-stage prototype evaluations by customer physicians, in con-junction with the R&D group.Concepts/prototype analysis

During Phase II, R&D is responsible for generating more elabo-rate concepts, based on the design inputs received from a team’smarketing associate and/or potential device users. Brainstormingsessions are often held during this stage of development withmembers of R&D, marketing, and physician consultants. Proto-type development and design analysis is often a highly iterativeprocess, whereby device designs are frequently changed and re-fined before the final design is established. A three-dimensionalsolid model of a proposed device is often developed in order toconduct computational analyses and construct physical proto-types. Computational analyses, such as finite element analysis#FEA$or computational fluid dynamics #CFD$, may be conductedto understand the theoretical behavior of a proposed device.Physical prototypes, such as mock-ups and stereolithography pro-totypes #SLAs$, are often evaluated in bench, cadaver, and early

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animal studies, to test the physical performance of a device. Con-tinuous interaction among engineers and future device users iscritical during prototype development, in order to ensure that thenew device will satisfy end-user requirements. Likewise, as a de-vice becomes more refined through multiple prototype iterationsand feasibility studies, the IP landscape is continually reviewed,and potential legal and liability risks are assessed. ThroughoutPhase II, R&D will often hold design reviews #per 21 CFR820.30$ with all cross-functional team members in order to sys-tematically assess a device’s design progress. It should be notedthat many companies begin prototyping efforts as early as Phase Ito inform their financial planning and support definition of theirproduct development strategy.Design risk analysis/risk management

Risk management is a critical component of the analysis, pro-totype, and design development phases. The FDA expects compa-nies to have a complete risk management plan and system inplace, which consists of the two aspects of risk analysis #identifi-cation and quantification of risks$ and risk management #mitiga-tion of the identified risks$. Several years ago, the industry sup-ported the creation of ISO 14971, which covers risk managementfor medical devices and outlines specific methods to identify andaddress risk. This standard is now cited in many other standardsand has been recognized and adopted in many countries.

A number of tools exist that are commonly employed to con-duct risk analysis and management during Phase II: Design Fail-ure Modes, Effects, and Criticality Analysis #dFMECA ordFMEA$is used to recognize and evaluate the potential failure ofa product or process and its effects !26". dFMEA is also used toidentify and prioritize actions that could mitigate the chance of afailure. FTA is another common risk assessment tool. FTA useslogic block diagrams that display the state of a system #top event$in terms of the states of its components #basic events$. It can beused to capture failures resulting from both human errors andhardware failures. Risks are mitigated to an acceptable level—generally as safe or safer than existing devices used for the samepurposes. Actual mitigation of risks needs to be verified as part ofthe design process. In the remainder of this paper, the term “riskanalysis” is in several instances used as a short form for riskanalysis and risk management. It explicitly includes risk mitiga-tion efforts.Design for manufacturing

Initial design for manufacturing #dFM$efforts begins in PhaseII, in parallel with device concept and prototype development!12". dFM involves developing an initial plan for how fixtures willbe made, how tooling will be developed, what machines should beused for the device’s manufacturing process, and whether or notmolds need to be created in order to build prototypes for verifica-tion and validation testing. For devices that build on existing de-vices on the market, a significant portion of manufacturing workcan be performed at this early development stage. However, forbreakthrough products, manufacturing largely supports R&D pro-totype efforts during Phase II, while contributing suggestions as tohow proposed devices can be manufactured for high-volume pro-duction.Regulatory and reimbursement strategies

The initial regulatory and reimbursement strategies that wereinitiated in Phase I are further developed during the concept andfeasibility stages of development. Different options are examinedregarding which regulatory path to pursue #for the United Statesmarket, for example, 510#k$ versus PMA; for Europe, differentroutes to CE marking; etc.$and whether or not clinical studies willbe required. The reimbursement team assesses whether or not ex-isting reimbursement codes #for the United States market, e.g.,CPT3 and DRG,4 for international markets, the codes used in the

respective countries$can be applied to a proposed device, and ifso, the amount that insurers and users might be willing to pay forthe proposed technology !27". Reimbursement information feedsdirectly into early-stage device development since it establishes aprice point that design and manufacturing efforts should target inorder to build devices capable of generating sufficient profit mar-gins.Phase II: Deliverables and decision gate

The major deliverables of Phase II and key decisions to bemade at the decision gate are summarized in Table 1.

4.1.2.4 Phase III: Design and Development - Verification &Validation. After a device concept has been formulated and sev-eral prototyping rounds have occurred to assess feasibility, thedevelopment proceeds into Phase III. During that phase, a verifi-cation and validation test matrix is created by cross-functionalteam members. The matrix is intended to outline the verificationand validation #V&V$tests that occur both before and after designfreeze #Phases III and IV$, as well as to provide a foundation forformal validation testing in Phase IV. V&V testing is conductedprimarily by research and development, test engineering, andquality engineering. Marketing often participates in validationtesting, such as physician prototype evaluations. Verification andvalidation studies including their methods of documentation aresubject to design controls. Without proper documentation, thestudies may not be usable from a regulatory standpoint since allV&V studies must be reproducible.Verification testing

Design verification characterizes a device through feasibilitystudies and verification testing, and ensures that device develop-ment complies with the quality system #QS$regulation, 21 Codeof Federal Regulation Part 820. Design verification also involvestesting and inspecting a device to ensure that design outputs sat-isfy design inputs. Testing examples include analytical, prelimi-nary performance, biocompatibility, and durability/longevity tests.An example of design inspection includes performing tolerancestack-ups on prints and drawings. Verification also involves awide range of feasibility studies, including bioburden, exposure/environmental, sterilization, cleaning, and packaging/ship testing!26".Validation testing

Customer prototype evaluations continue in Phase III to assessfinal prototypes, prior to design freeze. These types of validationactivities ensure that the new device successfully meets user needsand requirements !26". Design validation in Phase III involvessimulated use tests, which may require the use of anatomy modelsand/or cadavers. Design validation can also require studies to in-vestigate user interfaces and human factors. Validation could alsoinclude tests such as mechanical testing, clinical evaluations byphysician user groups, biocompatibility studies, mating part func-tional tests, exposure/environmental testing, or packaging/shipment testing and sterility. Human factors are an importantconsideration in validation testing, and have recently received in-creasing scrutiny by regulatory agencies.Risk management and process validation

Risk management in Phase III involves collaboration among allmembers of the cross-functional team, with particular emphasison the quality, manufacturing, and R&D functional areas. Designcontrol deliverables, such as the dFMECA are updated during thisphase. The development team initiates the process FMECA#pFMEA or pFMECA$to ensure the success of the manufacturingprocess and the production of safe and effective medical devices!26". A process validation plan is also created in Phase III toensure that a manufacturing facility is in compliance with GMPs#Good Manufacturing Practices; part of the FDA’s Quality Sys-

3CPT®: Current Procedural Terminology 4DRG: Diagnosis Related Groups

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tems Regulation$. A process plan involves a protocol for an instal-lation qualification #IQ$, operational qualification #OQ$, perfor-mance qualification #PQ$, and product performance qualification#PPQ$ !28". After a design is frozen at the end of Phase III, aprocess validation plan is often executed by the team’s manufac-turing engineer and quality engineer in Phase IV. Process excel-lence tools such as Lean Six Sigma are commonly employed inthis phase and the subsequent phase of the development process.Regulatory and clinical

During Phase III, several additional activities are conducted bymembers of the regulatory and clinical departments. Regulatoryactivities include submitting design and test data to the FDA forreview and regulatory approval. FDA submission is a major mile-stone in the device development process. Preparing for a submis-sion requires a strong collaboration among several cross-functional areas, such as clinical, R&D, quality, and regulatory.The regulatory group of a product development team generallyincludes a Regulatory Affairs associate who handles submissionsand market clearance, and a Regulatory Compliance associatewho administers the quality system. A team’s regulatory groupoversees the completion of requirements needed for internationalproduct use, such as the European CE mark mentioned earlier. If adevice requires clinical trials for regulatory submission, the team’sregulatory group submits an investigational device exemption#IDE$ to allow the device to be used in a clinical study !25".Regulatory associates will also oversee the clinical trials, analyzeresults, and submit data required for regulatory submission. Clini-cal trials are of substantial importance for the successful commer-cialization of medical devices, and thus need to be carefullyplanned and conducted. A detailed discussion of the various con-siderations for clinical trial planning is beyond the scope of thispaper. Additional background and information on this topic can befound in pertinent textbooks !29–31".Patent review and reimbursement update

The patent review process is continued in Phase III #sometimesalso earlier, in Phase II$to ensure that initially filed IP is sufficientto protect the developed technology, and to perform a secondcheck on possible conflicts that could limit the company’s free-dom to operate !32".

The device’s reimbursement strategy is further established inPhase III, as reimbursement codes and part numbers are assignedto the new device.Phase III: Deliverables and decision gate

The major deliverables of phase III and key decisions to bemade at the decision gate are summarized in Table 1.

4.1.2.5 Phase IV: Final validation - product launchpreparation. Phase IV of the medical device development is char-acterized by the creation of formal design prints, final productverification and validation, sales launch preparation, and regula-tory approval.Final design drawings and specifications

Once a design is frozen, formal manufacturing prints are gen-erated for the new device, consisting of both component andassembly-level drawings. Final prints must conform to geometricdimensioning and tolerancing #GD&T$ standards to ensure thatdesign requirements are effectively communicated to suppliersand manufacturers. The same holds for final specifications of elec-tronic components. Tolerance stack-ups are also conducted on thefinal design to ensure that there are no mating part interferenceswithin a device, or between a device and another instrument withwhich the device interacts !12". Material specifications, packagingdrawings, and marking and labeling specifications are also final-ized during Phase IV.Design and process validation

Closure of recommended risk mitigating action items per thecompany’s risk management system #compare earlier comment

about ISO 14971$occurs during the final verification and valida-tion phase of device development. These accompanying designcontrol deliverables are “ living” documents, which remain activethroughout the life of the device. A process validation/qualification plan, which includes an IQ, OQ, PQ, and PPQ, isexecuted by a quality engineer and a manufacturing engineer inPhase IV. The IQ documents that a correct manufacturing instru-ment was received and installed properly, an OQ tests that aninstrument meets specifications in the user environment, and a PQtests that the system performs the selected application correctly. APPQ demonstrates that the “process has not adversely affected thefinished product and that the product meets its predeterminedspecifications and quality attributes” !33". In Phase IV, manufac-turing efforts are often scaled-up in preparation for high-volumedevelopment, although not all production efforts require high-volume scale-up. Statistical process control #SPC$ standards areestablished !26" during this phase of development, and a numberof specific indices are commonly used in this context. The so-called “Cp” is an indicator of process capability !12". “Cpk,” theprocess capability index, involves the adjustment of Cp for theeffect of noncentered distributions. That is, Cpk measures “howclose a process is running to its specification limits, relative to thenatural variability of the process” !34".

Sales launch preparationSeveral sales and marketing activities must take place prior to

the launch of a new medical device. A critical decision that mustbe made at the outset of this process is the choice of the appro-priate distribution channels, and whether internal or external salesrepresentatives will be used. A team’s marketing associate mustprepare and equip sales representatives with items such as a sur-gical technique guide that defines how the device is used, videosillustrating product use, and sample product kits for physicians.The device is often advertised in medical journals and then show-cased at a large meeting or medical conference for physician cus-tomers. Sales rep training sites are established, and a training pro-tocol is created for both sales reps and physicians. Specifichospitals, often referred to as limited market release #LMR$sites,are identified for initial product release. Product branding occursin Phase IV, as marketing works with the legal department toconduct trademark searches in an effort to determine an appropri-ate product name. Also, an artist or marketing communicationsfirm is often hired to create a new logo for the device. Finally,marketing must communicate with manufacturing and operationsto ensure that product inventory/launch quantities will be avail-able to fulfill projected sales forecasts.

FDA approval, quality systems, and reimbursementA key requirement that must be fulfilled before a medical de-

vice can be launched in the United States market is regulatoryapproval/clearance by the FDA. This requirement includes the de-velopment and implementation of a working quality system. Also,a company’s reimbursement strategy for the new device must befinalized in Phase IV. Clinical validation continues before andafter FDA approval has been granted in order to continue moni-toring device performance and possibly expand a device’s indica-tions for use.

For new medical devices, establishing a quality system is alarge critical task. If the product is a line extension to an existingdevice or product family, then a quality system may already be inplace and working well. The quality system starts with defining,documenting and formally approving and releasing %90% of thebusiness document/systems, both product specific #product spec$and administrative #purchasing controls$. This is a resource inten-sive, time consuming task on a scale similar to the developmentprocess. It is normally done in parallel with the product develop-ment, and cannot be done retrospectively.

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Phase IV: Deliverables and decision gateThe major deliverables of Phase IV and key decisions to be

made at the decision gate are summarized in Table 1.4.1.2.6 Phase V: Product launch and post-launch assessment.

Final product launch and postmarket surveillance occur in PhaseV of the medical device development cycle. “Centers of excel-lence” are hospitals, labs, or physician’s office used for initialproduct release. These include hospitals and medical centersstaffed with physicians who have received prelaunch training inthe use of the new device. These sites can be identical with thepreviously mentioned LMR sites, but do not have to be. Once adevice has proven successful in a limited number of medical fa-cilities, it will be marketed and distributed for widespread clinicaluse. A peer-to-peer physician education model is often used toseed marketing and promote rapid product adoption. That is, phy-sicians who helped to develop a product and who participated invalidation testing are often involved with regional and local train-ing sessions #i.e., cadaver, bioskills, or didactic$. Clinical trials arefrequently performed by select physicians following productlaunch. These trials aid in gaining reimbursement support andadditional marketing literature, as well as expanding further indi-cations for use, which requires FDA approval.Post-launch R&D

Following product launch, R&D efforts are transferred to engi-neers responsible for managing design changes, often referred toas process engineering groups. This functional area is responsiblefor the continual improvements and changes made to either theproduct itself or the processes used to create the product through-out the life of the device. When a product complaint is receivedfrom the field, one of several courses of action may be taken: forinstance, a label change !35" occurs when an aspect of the devicehas failed that was not properly indicated on the instructions foruse #IFU$; a customer/feasibility change is made to satisfy therequests of a specific physician customer; and a total product re-design may occur when there is a major flaw in the design and/orwhen the product has been recalled !36" from the market by theFDA.5 Design control deliverables are required throughout the lifeof a medical device. The Device master record is released as partof the design transfer process, and in it, further design changes aremanaged. In addition, companies need to implement a postmarketsurveillance system that is compliant with the Quality SystemsRegulation. Surveillance and reporting of product performance inthe field has recently received increasing attention by the FDA,partly as a result of highly publicized product recalls.

4.1.2.7 Iterations in the development process. A typical pat-tern of medical device innovation is its iterative nature. In manycases, technologies are developed in several generations, with thenext generation of a device incorporating new technological in-sights and experiences gained during field use of the previousgeneration of a device. In many technologies, lifecycles are thusvery short. Similarly, the development process of a specific gen-eration of a technology can be highly iterative, with various ac-tivities and decisions in the linear model revisited. Such iterativeloops include design improvements based on clinician feedback,redesigns after failed verification or validation testing, or designimprovements based on unexpected results of bench and animaltesting #so-called preclinical testing loops$. Therefore, as pointedout earlier, the linear stage-gate model should not be misunder-stood as accurately describing what in reality can be a highlyiterative process.

Figure 11 shows a typical example of such iteration, in whichunsuccessful verification and validation testing leads to redesignand retesting of the product. Note that a critical decision in the

design process is “design freeze,” after which no element of theproduct’s design is allowed to be changed anymore. A late designfreeze may reduce the likelihood of a subsequent iteration, butalso can lead to a substantial delay in bringing the product to themarket. Finding the right balance between the two alternatives canbe a major challenge for the development team. A similar chal-lenge is the appropriate determination of the value and benefit ofiterations. It is obvious that iterations of high-cost activities, suchas clinical trials, should be avoided whenever possible.

5 DiscussionSeveral activities within the device development process have

been represented as schematic models in the past, among them thequality function deployment, risk management, and regulatory ap-proval processes. Similarly, a number of overarching models ofthe development and commercialization process have been pub-lished in the past, for example, the FDA’s waterfall model or therepresentation of the commercialization process of PMA devices.None of these representations, however, document comprehen-sively the medical device development process.

The feedback and responses obtained from interviewees duringthe model building process led to a relatively rapid convergencetoward the final linear stage-gate structure presented here. In con-junction with the diverse empirical sample, this suggests that theconstructed model applies to a broad range of medical technolo-gies and innovation settings.

The stage-gate process is comprised of five phases frominitiation/opportunity and risk analysis to postlaunch and post-launch surveillance. Some minor process differences exist for de-vices requiring clinical studies #the so-called IDE process forPMA devices and 510#k$ devices that require clinical data$, andfor non-IDE devices #the technologies not subject to clinicalevaluations during development$. The model presented in this pa-per embodies the more complete process by including clinicalstudies.

The apparent uniformity of the development process across de-vices and types of companies can be explained by the promulga-tion of the very detailed and comprehensive Quality SystemsRegulation #QSR-21 CFR 820$by the FDA. The QSR prescribesthe elements of the design process, including definition of designinput, design output, specification development, testing, riskanalysis, process qualification, etc. A review of the documentshows that significant aspects of the development process are gov-erned by, or at least subject to, regulatory requirements. Regula-tory requirements substantively impact the manner in which medi-cal devices are developed and brought to market and, byimpacting the time to FDA approval, largely determine when thedevice can brought to the clinic. By standardizing the develop-ment process, the public is assured that critical elements of gooddesign practices are not omitted. But standardization does not al-ways permit streamlining developmental processes where it wouldmake sense.

5Note that recalls do not necessarily need to result in a withdrawal and redesign ofa product. In many cases, recalls are handled with field corrections or notices tousers.

Fig. 11 Design iteration based on failed verification andvalidation

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It should be appreciated that nonadherence to regulatory re-quirements #and thus, nonadherence to a systematic developmentprocess as the one outlined in this study$ can lead to significantdelays or even the discontinuation of device development. Assuch, knowledge about the regulatory requirements and a rigorousquality system and documentation process are essential successfactors of any device company. In the public discussion, theirimpact might sometimes be underestimated, as the focus of dis-cussion is often limited to the regulatory pathways to approval andthe associated data requirements. Early, innovation-oriented tech-nology assessment during development #see, for example, Ref.!37"$that takes these requirements and the expected performanceof the technology into account, may present an opportunity forboth industry and regulators in further streamlining the innovationprocess.

Despite the benefits associated with a rigorous process andclearly defined procedures, innovation often occurs in a nonlinear,less structured way, sometimes under unexpected circumstances.In implementing development processes in organizations, it istherefore necessary to strike a balance between sufficient processrigor and enough room for flexibility and creativity. It can beargued that evolutionary product development benefits from struc-ture, while revolutionary product development is catalyzed by aless rigorous process environment. Striking the appropriate bal-ance presents a continued challenge for any organization invent-ing and developing technologies, and will often require adjust-ment of general process structures to the individual requirementsof an organization. Complexity in process management is addedwhen innovation is not a purely internal process within an orga-nization, but requires outside collaborations, in-licensing and in-tegration of new technologies, processes, or competences. This isoften the case in medical device development.Drug-device differences and their implications

Several important differences exist between medical devicesand pharmaceuticals in general, and their development processes,in particular, #compare, for example, Refs. !38,39"$. These differ-ences need to be understood to appreciate the inherently differentdevelopment processes and regulatory requirements between de-vices and drugs. Drug-device differences are also important tounderstand since they help elucidate the challenges associatedwith the development of combination products, which increas-ingly blur the distinctions between medical devices and pharma-ceuticals.

Discernable differences between “classic” devices and drugs#not considering cells and biomaterials$ include the following:

• Devices tend to be more heterogeneous #see below$ as agroup than drugs.

• Devices usually have a localized treatment effect, as op-posed to the often systemic application found in drugs.

• Devices are engineering-based physical objects, while drugsare chemistry-based compounds.

• Devices tend to require significant user interaction, whilepharmaceuticals do not.

• Devices are invented, often with the involvement of physi-cian users; pharmaceuticals are discovered in laboratory-based research processes

The phrase “device heterogeneity” refers to the wide differ-ences in mode of operation, and the wide variety of technologieswith attendant indication-specific design features #ranging fromtongue depressors and implantable joints to implantable defibril-lators and artificial corneas$. Among other factors, heterogeneityleads to a much wider variety in the way devices are tested #e.g.,wide differences in the types of bench studies performed$ andregulated. While all new drugs are subject to a single approvalprocess, medical devices can be approved through various regula-tory pathways with differing requirements that influence the dura-tion and complexity of the development process. A major reason

for the different risk-based regulatory pathways for devices is theengineering-based nature of devices, which makes the risk profilemore easily understood and quantifiable. This is a substantive dif-ference to drugs, which require comprehensive toxicology, phar-macokinetic and pharmacodynamic tests for their approval.

One of the results of the differences in the regulatory approvalprocesses for devices and drugs are the usually shorter lifecyclesfor medical devices. Once the basic safety and effectiveness pro-file of a device has been evaluated, testing and approval of newgenerations of the device can leverage already existing informa-tion about the device. Shorter lifecycles in devices are also evi-dence of the important role of user feedback in device innovation.Integration of user feedback can significantly increase the usabil-ity and effectiveness of a device, and is a major impetus drivingproduct innovation for the benefit of patients.

The fundamental differences between the science-based drugdiscovery process and the engineering-based, hands-on device in-vention and development process also lead to vastly differentcapital requirements. These differences are evident in the struc-tural differences between the medical device and pharmaceuticalindustry. While the medical device industry is much more frag-mented, with many small to midsize companies contributing toinnovation, the pharmaceutical industry is dominated by a smallnumber of large companies that have the financial resources tosupport the much more costly pharmaceutical development pro-cess.

The differences between drugs and devices also result in differ-ent quality system requirements, which lead to substantial differ-ences in the way testing and manufacturing processes are de-signed and managed. For example, shelf-life requirements as partof the validation process play a much more significant role inpharmaceuticals. Similarly, batch testing is a standard requirementin drug manufacturing and is not required in medical devices.Combination product development

Drug-device combinations such as the drug-eluting stents aswell as other combination products that involve combinations ofdevices with biomaterials or cells begin to play an increasinglyimportant role in health care innovation. In light of the devicedevelopment model presented here and the discussed differencesbetween device and pharmaceuticals, some of the challenges andopportunities of combination product development and their re-sulting implications are briefly discussed here.

On the regulatory side, FDA has responded to the increasingnumber of combination products with the creation of its Office ofCombination Products #OCP$ in 2002. OCP has the coordinatingresponsibility of assessing combination products throughout theirproduct lifecycles !40". The primary regulatory responsibilities,however, remain with one of the product centers #Center for DrugEvaluation and Research #CDER$, the Center for Biologics Evalu-ation and Research #CBER$, or the Center for Devices and Radio-logical Health #CDRH$$, based on the product’s primary mode ofaction. This means that the principal regulatory pathways of therespective centers are—until now—still guiding the review andapproval process !41". A combination product assigned to the Of-fice of Device Evaluation #ODE$, for example, is subject to theregulatory requirements outlined earlier.

The nature of certain activities outlined in the stage-gate devel-opment model are influenced by differences in preclinical #benchand animal$ testing !42". For drug-coated devices, for example,fatigue and corrosion testing of drug coatings requires new bench-top test methods employed to ensure that drug coatings do notcrack or “flake-off” during extended product use !43". Also, interms of testing for shelf-life and stability, combination productspresent new challenges for preclinical testing. The testing of tra-ditional “bare” medical devices often uses the effects of acceler-ated aging to simulate the effects of real-time aging. Yet, whendrug compounds become part of a product, the effects of drugcompound stability must be carefully examined, in terms of drugelution, impurities and particulates !43,44".

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Verification and validation activities, outlined in Phases III andIV of the linear stage-gate model, also have to be adapted incertain types of combination products. As mentioned earlier, thecurrent good manufacturing practices #cGMPs$for drugs and de-vices are different, hence following different regulations and ap-plicable standards. The cGMPs for finished pharmaceuticals ordrug products are codified in 21 CFR Parts 210 and 211. Devicesmust be manufactured in accordance with the QS regulation, per21 CFR Part 820. When marketed separately or when manufac-tured separately as constituent parts of a combination that willlater be combined, each part of a combination product remainssubject only to its governing cGMP regulations #21 CFR 3.2$.However, if combination products are produced as a single entityor are copackaged, both sets of cGMPs are applicable during andafter joining the constituent parts together. Therefore, companiesare challenged to ensure that combination products comply withone or both manufacturing standards, as needed !45".

Unlike noncombination medical devices, which can undergoprocess changes rather quickly, combination products requiremanufacturers to carefully study a drug’s output and stabilitywhenever a product’s manufacturing process is modified. In addi-tion, manufacturers of combination products “must perform moreproduct and process characterization earlier in the developmentcycle than they would with traditional devices,” !46". In terms ofproduct characterization, traditional medical devices are oftenmanufactured from well characterized raw materials; but combi-nation products involve the use of novel drug excipients, whichmust be fully characterized early in the development process.

Combination product development is largely influenced andchallenged by the differences in innovation cycles between phar-maceuticals and medical devices. Pharmaceutical innovationcycles tend to occur every 10–20 years !47", whereas devices canbecome obsolete within a period of months. Therefore, in order toproduce new products on a more frequent basis, combinationproduct manufacturers may choose to innovate through develop-ing new device delivery systems that are compatible with existingdrug therapies #e.g., new generations of a drug-eluting stent$.However, robust material testing and a complete evaluation ofdevice/pharmaceutical interactions must occur for every deviceiteration !46", again requiring adjustments in the linear stage-gatedevelopment model.

The development of combination products is distinctive in thatit requires integrating the knowledge base of several disciplines#i.e., biology, chemistry, and engineering$, each of which rely onspecific terminology and design methodologies. Consequently,companies developing combination products must establish ateam structure that is different from that of either traditional phar-maceutical or medical device development !45". For example, inaddition to the functional areas presented in the linear stage-gatemodel of device development, combination product developmentrequires an additional R&D analytical testing group. Mergingteams of individuals from pharmaceutical and device develop-ment, in general, will require increased cross-functional coordina-tion !46".

Based on these differences and additional challenges, it shouldbe evident that the development process of combination productsis more complex than the classic medical device developmentprocess. Some of the most notable adjustments that need to bemade if the linear stage-gate process model is used in combinationproduct development include the following: #1$Drug-dosing andcoatings need to be established prior or during Phase I of thedevelopment model; #2$ an additional R&D analytical testinggroup needs to be added; #3$ new preclinical testing modalitiesneed to be considered for Phase II; #4$for specific products, boththe device and pharmaceutical quality systems need to governactivities in Phases III and IV of the process; and #5$ supplierquality is required as a separate group in combination productdevelopment, distinct from the manufacturing and operationsgroups in the traditional device development process.

6 ConclusionsThe linear stage-gate model gives a comprehensive description

of the various activities and decisions associated with the devel-opment of medical devices. A good understanding of this processcan benefit all stakeholders in the bench-to-bedside process ofdevice commercialization: investors, who need to allocate theirresources in the most efficient way, and who need to understandthe funding requirements of different types of developmentprojects; engineers and researchers who aim at improving the de-sign and benefit of a technology; and regulators who need to en-sure the safety and effectiveness of new products in the mostefficient way.

The process mapping presents several opportunities for the de-velopment of quantitative models to support decision-making atvarious levels. First, information can be used to create early-stagetechnology assessment and risk management models to informengineering and funding decisions. These models can subse-quently be integrated into more comprehensive lifecycle risk man-agement models that allow for continuous updating of failure riskand the expected performance of new technologies, informationthat can be very useful to both industry and regulators.

As discussed in this paper, the medical device developmentprocess differs substantially from the development process forpharmaceutical products. An appreciation of these differences isessential to the appropriate design of future development modelsand regulatory requirements for various types of combinationproducts that cross the line between devices, pharmaceuticals, andbiomaterials.

AcknowledgmentThis paper was written based on the research performed by the

authors as part of a study “Medical Device Development Models,”funded by the Institute of Health Technology Studies #InHealth$.The authors gratefully acknowledge the financial support by In-Health.

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