Advanced Therapy Medicinal Product(ATMP) development processes are associated with ineficiencies due to lack of an eficient and efective management methods that can support scientists in working towards regulatory compliance. This research addresses this problem by proposing refined solutions based on knowledge-intensive Business Process Management(BPM). Here, methods will be developed to support scientists in planning a development process that is compliant with regulations. These methods will be based on the knowledge on process modelling, goal modelling and context-aware business processes. Thereby, this project will provide an exemplary approach for supporting compliance management in knowledge intensive processes. The methods will be implemented in a software and evaluated through a real-life ATMP development case.
Advanced Therapy Medicinal Products (ATMPs) are medicines for human use that ofer new
opportunities for treatment of many diseases, based on biomedical technology [
ATMPs are especially known for their complex regulatory framework. ATMP regulations do not induce strict rules on how things should be done throughout the development. Instead, they involve high-level goals that should be considered in order to demonstrate that the ATMP being developed is safe and efective. There are alternative ways of achieving these goals. Also, regulatory requirements vary depending on the development context. Here, context is defined by the properties of the ATMP. For instance, for diferent ATMP types (Tissue Engineered Product(TEP), Combined ATMP etc.) or diferent regulatory classifications of the components of an ATMP (e.g., biomaterial in an ATMP classified as starting material or excipient etc.), diferent regulatory requirements apply. Also, it is not possible to define the context fully before the development process starts. Instead, diferent options (e.g., classifying the ATMP as Combined ATMP or TEP) are investigated throughout the development. The flexibility in defining the context and variability of regulatory requirements based on context makes it challenging for scientists to manage the regulatory aspects of ATMP development.
Despite its complexity, management of regulatory aspects of ATMP development processes
is currently done by scientists in an ad-hoc fashion, which is not eficient. Research shows
that, ATMP development processes are associated with many hurdles such as reworks and even
withdrawal of the ATMP due to shortcomings in providing adequate evidence of regulatory
compliance [
Therefore, this project will focus on bridging the gap between scientific and regulatory aspects of the ATMP development to help scientists manage the process more eficiently and efectively.
In this project, I propose to support ATMP development processes with Business Process
Management (BPM). Traditional BPM focuses on managing predictable and routine work. However,
managing unpredictable, flexible KiPs, is an emerging topic within BPM [
Main Research Question: How to support preclinical ATMP development processes with BPM in order to help scientists manage regulatory aspects of development process more eficiently and efectively?
The focus of this project is to support scientists in working towards regulatory compliance.
For traditional business processes, business process compliance is a well-studied area of research
within BPM [
RQ-1: How to align scientific development processes with regulatory requirements to help scientists plan the development process?
RQ-1 aims to support scientists in creating a process plan that is in line with the regulatory compliance requirements. To formalize the ATMP regulatory requirements, I will use goal models and to represent development process plan, I will use flexible process models. Here, the challenge arises from the variability of ATMP regulations. ATMP regulatory requirements vary with respect to the context of development (See Section 1 for the definition of context) and this variability should be represented in the goal models. My intention is to introduce contextual goal models [9] for this purpose. I will also investigate context modelling approaches in BPM [10, 11]. Additionally, applicable regulatory requirements are determined as the context becomes certain throughout the process. So, the requirements are flexible. Therefore, I propose to develop a method that will check the alignment between the scientific development process plan and the goal model of the predefined context and provide recommendations (e.g., prioritization of activities that support multiple goals and/or that should be performed for a wide range of potential future contexts) to make sure the process plan addresses regulatory goals in an eficient and efective way.
In BPM, there exists previous studies to align goal models and process models [12, 13, 14, 15,
16]. Also, the concept of context is not new in BPM [
Building upon RQ-1, RQ-2 focuses on providing regulatory compliance support during execution of the scientific development process, formulated as below.
RQ-2: How to provide insights about the achievement of regulatory goals during the scientific development process to support scientists in making decisions about the adjustment of the planned development process?
The method will provide insights about how the results obtained throughout development process contribute to the achievement of regulatory goals. Based on this insight, the expert will be able to make informed decisions about the adjustment of the development plan, e.g. changing the context or redoing process steps. This insight will be provided by reasoning with goal models[17]. Since regulatory goals in ATMP development do not indicate crisp boundaries and values for assessment, the reasoning approach will be enhanced by fuzzy decision making approaches.
In BPM, there are some approaches developed for guiding KiPs in adjustment decisions, that are relevant for RQ-2 [18, 19, 20, 21]. However, these approaches support decisions based on historical knowledge about previous cases. ATMP development is a new field with also a huge variability between diferent projects. Also, no historical data from previous projects is available for use. Therefore, existing approaches are not suitable for our project. Consequently, input from experts will be used to make the adjustment decisions.
Lastly, RQ-3 will be answered to evaluate the methods developed.
RQ-3: How can the proposed methods be evaluated?
This PhD project is a part of Horizon2020 iPSpine project1, in which an ATMP for lower back pain is being developed. The methods will be demonstrated on the iPSpine process management platform, to be developed for iPSpine project, and evaluated by questionnaires with scientists using the platform. Please see Figure 3 in the Appendix for the positioning of research questions.
The proposed research methodology, explained on Figure 1, is based on the design science research framework created by Hevner et al.[22].
The PhD project helps to improve the eficiency and efectiveness of ATMP development processes, by developing a BPM-based approach that supports scientists in managing regulatory aspects of ATMP development processes in a structured way. Thereby, from the BPM point of view,this PhD project provide an exemplary approach for supporting compliance management in flexible KiPs with vague and flexible regulatory requirements. service management case, Lecture Notes in Business Information Processing 256 (2016) 43–54. [7] A. Zasada, A Box of Bricks for Modelling Domain-Specific Compliance Pattern, Proceedings - IEEE International Enterprise Distributed Object Computing Workshop, EDOCW 2018October (2018) 37–42. [8] A. Holfter, S. Haarmann, L. Pufahl, M. Weske, Checking Compliance in Data-Driven Case
Management, volume 362 LNBIP, Springer International Publishing, 2019. [9] A goal-based framework for contextual requirements modeling and analysis, Requirements
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Journal of Business Process Integration and Management 3 (2008) 47–60. [12] A. Van Lamsweerde, Goal-oriented requirements engineering: A guided tour, Proceedings of the IEEE International Conference on Requirements Engineering (2001) 249–261. [13] A. R. Silva, V. García-Díaz, Integrating activity- and goal-based workflows: A data model based design method, Lecture Notes in Business Information Processing 256 (2016) 352–363. [14] G. Poels, K. Decreus, B. Roelens, M. Snoeck, Research review: Investigating goal-oriented requirements engineering for business processes, Journal of Database Management 24 (2013) 35–71. [15] P. Kueng, Goal-based business process models: Creation and evaluation, Business Process
Management Journal 3 (1997) 17–38. [16] R. Guizzardi, A. N. Reis, A method to align goals and business processes, Lecture Notes in Computer Science (including subseries Lecture Notes in Artificial Intelligence and Lecture Notes in Bioinformatics) 9381 (2015) 79. [17] P. Giorgini, J. Mylopoulos, E. Nicchiarelli, R. Sebastiani, Reasoning with goal models, Lecture Notes in Computer Science (including subseries Lecture Notes in Artificial Intelligence and Lecture Notes in Bioinformatics) 2503 (2002) 167–181. [18] B. Weber, W. Wild, R. Breu, CBRFlow: Enabling adaptive workflow management through conversational case-based reasoning, Lecture Notes in Computer Science (including subseries Lecture Notes in Artificial Intelligence and Lecture Notes in Bioinformatics) 3155 (2004) 434–448. [19] I. Barba, B. Weber, C. Del Valle, A. Jiménez-Ramírez, User recommendations for the optimized execution of business processes, Data & Knowledge Engineering 86 (2013) 61–84. [20] S. Voorberg, R. Eshuis, W. van Jaarsveld, G. J. van Houtum, Decision support for declarative artifact-centric process models, volume 360, Springer International Publishing, 2019. [21] S. Huber, M. Fietta, S. Hof, Next step recommendation and prediction based on process mining in adaptive case management, ACM International Conference Proceeding Series 23-24-April-2015 (2015). [22] A. R. Hevner, S. T. March, J. Park, S. Ram, Design science in information systems research,
MIS Quarterly 28 (2004) 75–79.
Characteristics Description
ATMP Development Processes Characteristics of KiPs Knowledge-driven
The status and availability of data In many cases, emerging knowland knowledge objects drive hu- edge/data together with scientists’ man decision making and directly interpretation determine flow of influence the flow of process ac- process actions.
tions and events.
Unpredictable The exact activity, event and knowl- ATMP development is an exedge flow depends on situation- ploratory process. Neither the and context-specific elements that process nor the knowledge related may not be known a priori, may to the product being developed can change during process execution, be fully prescribed a priori. and may vary over diferent process cases.
Emergent The actual course of actions gradu- It is a search process where realizaally emerges during process execu- tions throughout the process and tion and is determined step by step, availability of certain data/knowlwhen more information is available edge shape the process step by step.
Constraint- and rule- Process participants may be influ- Compliance regulations and related driven enced by or may have to com- guidelines should be taken into conply with constraints and rules that sideration throughout the process. drive actions performance and decision making.
Non-repeatable The process instance undertaken to deal with a specific case or situation is hardly repeatable, i.e., diferent executions of the process vary from one another.
Collaborationoriented Goal-oriented Event Driven
Process creation, management and execution occurs in a collaborative multi-user environment, where human centred and process-related knowledge is co-created, shared and transferred by and among process participants with diferent roles.
The process evolves through a series of intermediate goals or milestones to be achieved.
Process progression is afected by the occurrence of diferent kinds of events that influence knowledge workers’ decision making.
Development processes are hardly repeatable since in every case, scientific approach, materials used and/or aim of the study and hence related process requirements are diferent.
ATMP development process involves many partners with diferent roles: scientists from diferent fields, project managers, regulators, companies etc. Each stakeholder contributes to the process.