Intertech Engineering Associates, Inc.

Medical Device Validation Series 4 of 4

Part 4, Inadequate requirements usually result in inadequate testing.

This is part four of a four-part series on medical device validation practices.

Here are some telltale signs of inadequate requirements:

  • Software developers need constant access to market and clinical specialists to understand how they want the software to work.
  • Code writing begins before requirements are written or approved.
  • Test authors need frequent access to the software developers to understand how the software should work.
  • Formalized testing finds few if any defects, while “experts” (e.g. developers) with the system find many defects in ad hoc (It could be inadequate testing too, but usually it is a combination of poor requirements and poor testing.)
  • Review of test results is time-consuming and requires “experts” with the software to determine whether tests passed or failed. Note that this does not meet the standard of objective evidence of test results if the results have to be interpreted.
  • A preponderance of tests fail by the testers but are subsequently passed because the “testers didn’t understand how the software works.”

If these red flags fly, you need to go back and rewrite the requirements, making them specific enough so that they can be tested properly. Adequate requirements are the foundation of testing and should be the foundation of software implementation too.  A little extra up-front effort can prevent the whole structure from collapsing later. While testing alone doesn’t amount to validation, proper validation demands testing, and testing depends on testable requirements.

From: Vogel, David A., Ph.D. “Validating Medical Device Software Includes and Goes Beyond Testing.” Medical Product Outsourcing Mar. 2006: n.

Pharma Companies Challenges with Combination Devices and Planning for Variation Part 1 of 3

More and more now Pharma companies are now taking on medical device development as they intend to provide their customers with combination devices. Planning the device development does not always get the attention in project planning as it needs from a project management perspective since the drug development usually takes precedence. Scheduling a drug and a device, in parallel, requires careful management to coordinate the many interactions between drug development and the device development. Planning and scheduling the lifecycle for the product, particularly the development phase, should include integration milestones for the drug and device together. The development long pole is, obviously the drug development and regulatory clearance path, but this does not mean a combination device manufacturer should leave paying attention to the device development for the end. One challenge that is frequently underestimated or overlooked is considering and planning for addressing device variation and its impact on the overall combination devices performance. Combination device developers should plan an iterative device development model as well as integration milestones as a part of the development phase of the lifecycle to also address this. This article series discusses some Pharma company project management approaches as well as some key activities frequently overlooked or underestimated.   


Part 1 of 3: The Combination Device Timeline  

In understanding the development lifecycle for a combination device, the overall milestones to a market release in the US is defined by the regulatory objectives. Developing a pharmaceutical drug requires much in research and testing as it relates to the science we will not cover in this article series, but a high-level explanation of the FDA expected regulatory path is where we will start.  


What is a combinational device? 


The FDA has defined a combination product as:  


“…a combination product is a product composed of two or more different types of medical products (i.e., a combination of a drug, device, and/or biological product with one another). The drugs, devices, and biological products included in combination products are referred to as “constituent parts” of the combination product.”


What are the regulatory pathways for a combination device? 

The development team needs to map out the development process and prepare to develop the product, drug and or the biologic iteratively over a development lifecycle. To do this the developer with regulatory oversite will overlay the device process with the longer drug development timeline.  The timelines for a drug are driven by the regulatory strategy considerations and may be dictated to the manufacturer based on which center has jurisdiction for the product.  The developer can file for an RFD (Request for Designation) and additionally provide a Pre-RFD to get quick feedback on how the FDA will classify the combination product as well as identify the jurisdiction. The jurisdiction is driven by the definition of the primary mode of action (PMOA) and is assigned to one or more of the three possible FDA agency centers by OCP. Additionally, the combination will have one primary jurisdiction center determined based on the PMOA. The FDA centers are: 

  • CDRH – Center for Device and Radiological Health  
  • CDER – Center for Drug Evaluation and Research 
  • CBER – Center for Biologics and Research 
  • OCP – Office of Combination Products 


If the Primary Mode of Action is driven by the drug the primary center of justification will be CDER, if it is the device, it would be CDRH, if it is a biologic then CBER. The FDA can help define the PMOA, as the option to request for a designation RFD is available to manufacturers.  


The next consideration is for the developer to plot out the regulatory submission types once the drug is far enough and ready for controlled laboratory and animal testing. Submission application types can include:  

  • an investigational device exemption application (IDE);  
  • an investigational new drug application (IND);  
  • biologics license application (BLA);  
  • new drug application (NDA); or  
  • premarket approval application (PMA).  
  • Other types of applications that might pertain to a combinational device include (premarket notification 510(k) or abbreviated new drug application ANDA). 


A manufacturer of a combinational device will likely be required to undergo clinical trials under a new drug application (NDA), investigational device exemption (IDE) or an investigational new drug (IND) application. Once the submission pathway is known the clinical trial strategy can be defined identifying the clinical trials as being key milestones for the development process which drives the first stages of the product lifecycle.  


What are important considerations that drive pharmaceutical and device development? 


Drug development requires preclinical evaluation, screening formulation, toxicology testing, pharmacology and biochemistry testing, just to name a few. All of these testing components represent many person-hours of effort that make up the first part of drug development. This is the basic careful science necessary before a manufacturer is even close to clearing a drug or thinking about a combinational product, to deliver the drug.  Once a drug enters the phased clinical step there is a more defined framework to schedule things around. These clinical studies are completed in three premarket clinical phases. 


As mentioned already, that just getting to the clinical phase of drug development is one significant effort, but getting through the three clinical phases, is also a no easy task. There are three key clinical phases and trials for a drug, each having a particular objective necessary to support FDA clearance.  The phase 1 clinical trial is intended to support primary safety. The phase 2 clinical trial will support short-term safety, but it is mainly intended to support effectiveness. Finally, the phase 3 clinical trial is intended to demonstrate safety, dosage, and effectiveness. According to a BIO report looking at clinical phase transition success and likelihood of approval (over a period from 2005 – 2015), drug manufacturers only have a 9.6% chance of successfully getting from phase 1 clinical to drug approval (through all 3 phases).  When a manufacturer decides that they wish to market the drug with a device, most frequently facilitating a delivery system, they really should decide this during the early clinical phases so the device development can occur early enough to support the clinical trials.  


For a combination device, the clinical submission and trials will serve to support the drug approval, but it will often support the device safety and effectiveness as well. Understanding this basic framework of the clearance establishes a timeline where some key device activities and milestones can be mapped. For a combination device, aligning the timelines between the drug and the device becomes critical. 


Developing a drug, from the molecule, through approval takes 10 to 15 years and can cost developers over $1 billion. Device development, from concept to approval can take 2 to 5 years and can cost developers tens of millions of dollars. Because of the cost and risks in both the device and drug development many companies developing combination devices will attempt to choose a drug and or a device that has been cleared for other similar uses and therefore proven to a degree that is possible, for the combined effort. The below example timeline is scaled to an aggressive overall timeframe and is intended to demonstrate relative time periods and some key milestones of the device development over the drug timeline. 



(Timeline  Figure 1) 

The example timeline figure above shows the drug regulatory phases with the device development lifecycle represented on the bottom. The device lifecycle represented reflects the design control elements expected in a common sequential waterfall development lifecycle. This does not suggest that a waterfall lifecycle is explicitly required but intends to represent the primary goals for the first baseline during this time period. It is expected and practical to expect that planning and requirements change, as well as the design, throughout the whole lifecycle. Good design control process should be established to ensure each of the sequential elements of design controls is applied for iterations, as the product evolves and the design output matures. 


At this point, we can discuss three important device development activities that are frequently overlooked or underestimated by drug manufacturers in a combination device project. These activities drive some of the milestones we should establish in our development lifecycle planning.  Three important key device activities are:  

  • Key activity 1: the sourcing or manufacture of devices to support the development lifecycle (particularly for phase 2 and 3 clinical and device verification). What is important about these devices is maintaining an understanding of the configuration of these devices, so interactions and impact on the clinical studies is understood;  
  • Key activity 2: the planning and coordination of usability studies. What is important about usability is that the results drive requirements, design as well evaluation and managing of particular safety risks; and 
  • Key activity 3: the coordination and the application of the appropriate design controls during development to address sources of variability and optimize the device design. What is important about managing the design process is that doing so adds assurance to the maturing of the actual product as well as demonstrating through documentation of the inputs and outputs the developer can establish confidence in the results testing and performance.  


The three keys will be further discussed in the next section of this article series.  We would be interested in your own experiences with these or based on your experiences what other areas are just as or more important.