President/founder of RQMIS Inc. a consulting company with experience in the Medical Device/Biotechnology Industry focused on Regulatory/Clinical/Quality Affairs and Product Management. RQMIS Inc. provides support in the areas of regulatory submissions (510k, IDE, PMA, HUD/HDE, Design Dossiers), Clinical Study Design/Management, Risk Management, Quality System Design/Audits (FDA QSR and ISO 13485) and FDA Negotiation and Communication (QSR Audits, 483s, Warning Letters, Bioresearch Monitoring, Medical Device Reports, Recalls).
Seven years experience as a Biomedical Engineer and Sr. Scientific Reviewer at FDA/CDRH/ODE and FDA’s Boston District. This government experience was followed with seventeen (17) years in midlevel and executive management positions in small start-up and large multinational medical device companies. Market responsibilities included United States (including Puerto Rico), European Union, South America, Canada, Japan and South Korea.
Provides companies with regulatory and clinical strategic advice on bringing novel technologies to the United States and EU markets in the clinical fields of orthopaedics/neurosurgery/diabetic care (spine, restorative/reconstructive, sports medicine and wound healing), gastroenterology/urology/gynecology/pulmonology/cardiology/plastic surgery (endoscopy/laparoscopy/minimally invasive/biliary stents). The devices involved have included active implantables, long term implants, electromechanical, ultrasonic imaging and PACS products.
As a former scientific reviewer within ODE I was not at all surprised to see the internal survey results of how “intended use” and “indication for use” were inconsistently interpreted and applied. This issue has been around and debated internally since the mid to late 80’s and has never truly been addressed directly by the Agency. This inconsistency of interpretation can either cause a major surprise during a 510(k) review or can render a marketed device misbranded and adulterated for being promoted for an unapproved use. This inconsistency deserves the Agency’s highest attention since it can create a major problem for the manufacturer. At one end of the spectrum a finding of not substantially equivalent during a 510(k) review can end a product or a company. At the postmarketing phase of the product lifecycle, a misbranding/adulteration violation of the FD&C act can cause a suspension of sales of the medical device and litigation as a result of a serious injury/death due to use of the medical device for unapproved uses.
So we all understand that internal audits and supplier audits are required by regulation. We also understand that if a company does not have an audit schedule or has one but is not able to fulfill the schedule an observation or noncompliance is likely from the FDA or Notified Body. However, for the moment, let’s get past the obvious and focus on the real benefit of audits.
If a company manages the audit program in a productive manner (i.e., not as a punitive weapon against employees or suppliers) they will quickly determine the “real” benefits of a solid, productive audit program. The challenge often is that a company does not utilize qualified auditors. Not simply qualified in auditing techniques but an auditor that is familiar with the regulations and most importantly the subject material they are auditing. In this blog, let’s discuss the internal audit program.
Design Control or as the Europeans like to refer to it, Product Realization, is clearly the most critical phase in the product lifecycle. It requires critical input from Research and Development, Marketing, Manufacturing, Quality, Regulatory, and Clinical (not listed based on importance). If managed well it will feed off of critical information gathered/created during the Product Idea phase (i.e., Research/Prototyping phase) and create as its first step a clear set of objective design input requirements. These design input requirements will ultimately evolve into design specifications or outputs. The ultimate objective evidence that must be produced to satisfy the developer (the medical product company) and 3rd Parties (FDA, Notified Bodies, Competent Authorities, Insurance Companies) is the objective evidence produced during design verification and design validation. However, it is often the case that the Medical Product Developer and the 3rd Party don’t always think alike. Even more challenging is the fact that the 3rd Parties themselves often don’t agree what the objective evidence should be (i.e., FDA doesn’t always agree with Notified Bodies/Competent Authorities or vice versa). Thus the critical need to integrate Regulatory, Clinical, Quality and Insurance Reimbursement demands into the design control/product realization process. To do this a medical product developer/manufacturer must have integrated operational processes and the current Regulatory, Clinical, Quality and Insurance Reimbursement information/knowledge/experience to assure the creation of the required objective evidence to achieve regulatory approvals and insurance reimbursement coverage.
Through the development phase you have planned, designed, verified/validated your product and then carefully designed and implemented your manufacturing processes. Your product begins commercial use and nothing should go wrong………right? I think we have all heard the classic phrase "the best laid plans of mice and men often go astray". This applies equally in the medical product world. Either you don’t anticipate everything that may occur in the real life application of your product (e.g., user training, human factors, drug interactions, off-label use, short-term vs long-term use, larger patient population demographics, etc.) or at a minimum you find ways (designs/manufacturing) to improve upon your product. If a company has a robust Customer Feedback/Post Market Surveillance Process, a strong Corrective and Preventative Action (CAPA) Process and a responsive Design Control Process, they can respond efficiently and effectively while gaining customer loyalty.
On February 11, 2011, the company doors of Anulex Technologies, Inc. began to close. On this day, they were informed by FDA via a Anulex Warning Letter that there regulatory strategy/execution was severely defective. The company decided early in their history that they could obtain a 510(k) clearance for soft tissue approximation (suture) for procedures such as general and orthopedic surgery. After such a clearance they could proceed and conduct prospective phase III clinical studies for spinal annular repair (as part of a spinal discectomy procedure. This was the real marketing objective) without FDA approval (Investigational Device Exemption). It is clearly understood by most that this is a more specific patient population with a very different goal; to repair a spinal disc to allow continued functioning of that anatomical structure (an anatomical part that is avascular and doesn’t have a significant repair mechanism like skin). In addition, the adverse event profile for such an indication is much more significant (proximity to the cauda equina) than closing a surgical incision. All of these differences should have clearly identified their regulatory strategy as fraught with problems.
On November 22, 2013, 23andMe received a Warning Letter from FDA confirming that it had pursued the incorrect regulatory strategy regarding their Saliva Collection Kit and Personal Genome Service. This letter was not simply an order to stop its practice of selling a product that they believed at one time not to be a medical device, a risk some companies might take, but a letter that communicated to the world that an independent 3rd Party, FDA, believed their product had no merit in diagnosing the potential disease state of patients. This was a clear indictment as to the basic scientific integrity of their product.
This letter should not have been a surprise to the company. It had been in clear communication with FDA for over four years. In addition, in the previous 14 months they had submitted 510(k)s that were clearly being challenged as to the adequacy of the company’s verification/validation testing to support indications for use that had been expanding in the midst of this ongoing regulatory negotiation.
A Regulatory Strategic Plan (RSP) used to bring a medical product to market requires solid regulatory knowledge married with scientific/engineering/clinical expertise using critical thinking skills. An RSP does not focus solely on the path to obtain regulatory approval or clearance but also links the approval/clearance to how the product is manufactured, promoted and how future product revisions or line extensions are introduced to the market. If done properly and maintained over the course of a medical product’s lifecycle a company will have a more predictable product development timeline that can be adjusted as new information becomes available and a product regulatory risk profile that can be actively managed during post market release. If implemented effectively, the RSP will result in improved operational process efficiency, reduced operational costs, and a reduction in time to market. If the results of product development or the experience after commercialization is not as predicted, the RSP will better position you to make adjustments and, unfortunately, make the difficult decision to cancel a development project or recall/remove a product from the market.
An idea for a new medical product can arise from a breakthrough in technology (smart phone technology/the cloud, a new biomaterial, nanotechnology, etc.), the identification of a new compound that can interact with a biological process, the ability to manufacture a biological molecule (e.g, peptides, the ability to process human tissue to derive active biological substances (e.g., stem cells) or combining medical devices with biologics or drugs. However, none of these intriguing or exciting breakthroughs will achieve commercial success without a clear connection with an unmet patient or clinical need. These needs can already be in demand by clinicians (a product to monitor patients remotely) and surgeons (an artificial spinal disc that restores motion to the spine). Or the need that may not be appreciated until the technology presents the opportunity (nanotechnology that allows selective uptake of drugs based upon cell type).
These breakthroughs in technology may create new medical products or they may allow existing products to be modified to improve performance, including safety and/or effectiveness. Regulatory bodies dictate the pathway to first human use and ultimately commercial use of these medical products. Insurance reimbursement entities influence the development of products due to reimbursement decisions. Every country has its own pathway, but the medical products indication for use/intended use and its mechanism of action or mode of action play the primary variables in defining the regulatory pathway’s complexity.