Study Clinical Trials of Medical Device by FDA Bioresearch Monitoring (“BIMO”) program

FDA Bioresearch Monitoring (“BIMO”) program are to protect the rights, safety, and welfare of human research subjects and to assure the quality, reliability, and integrity of data collected. It is a good source to learn good clinical practice, responsibilities of sponsors, clinical investigators, contract research organizations, monitors, institutional review boards in clinical trials of medical devices and preparing for FDA inspections. 

FDA Launches Online National Medical Device Curriculum

FDA has launched a new learning tool for academic institutions and science and technology innovators called the National Medical Device Curriculum, to advance their understanding of FDA's medical device regulatory processes. The curriculum offers students FDA-endorsed knowledge about navigating the regulatory process, including how to design, test, and clinically evaluate devices; identify the root causes of adverse events and device malfunctions; and develop iterative device designs. The curriculum includes a series of four fictional case studies based on real-world medical device scenarios in a format similar to Harvard Business School Case Studies. 

By understanding FDA's regulatory process, innovators can accelerate the delivery of innovative medical products to patients.

FDA guidance to nanotechnology products

Nanotechnology is an emerging area which can create many new materials for medical devices, medicine, electronics and energy industries. On the other hand, more and more concerns about nanotechnology are raised about the toxicity and environmental impact of nanomaterials. 

Today, FDA issues three final guidances and one draft guidance to support the responsible development of nanotechnology products (the link).

In guidances, FDA has not established regulatory definitions of “nanotechnology,” “nanomaterial,” “nanoscale,” or other related terms. It aims to help industry when they should consider potential implications for regulatory status, safety, effectiveness, or public health impact that may arise with the application of nanotechnology in FDA-regulated products. FDA advises industry to consult with FDA early in the development process to facilitate a mutual understanding of the specific scientific and regulatory issues for their nanotechnology products.

In "Guidance for Industry Considering Whether an FDA-Regulated Product Involves the Application of Nanotechnology", FDA identifies two Points to Consider that should be used to evaluate whether FDA-regulated products involve the application of nanotechnology.

1. Whether a material or end product is engineered to have at least one external dimension, or an internal or surface structure, in the nanoscale range (approximately 1 nm to 100 nm);
2. Whether a material or end product is engineered to exhibit properties or phenomena, including physical or chemical properties or biological effects, that are attributable to its dimension(s), even if these dimensions fall outside the nanoscale range, up to one micrometer (1,000 nm).

顾客满意-ISO 9001与ISO 13485的区别

对比ISO 9001质量管理体系，ISO 13485医疗器械质量管理体系标准里没有“顾客满意”的要求，代之以“满足顾客要求”。标准中解释：“顾客满意”和“顾客感知度”在法规中作为要求来实施太过于主观。以“满足顾客要求”作为对质量管理体系绩效的测量，与ISO 13485反应当前监管法规和促进世界医疗器械监管法规协调的目标相一致。

所谓“良药苦口”，医疗器械在保证安全、有效的前提下，有时不得不对产品使用的舒适性作出折中甚至舍弃一致降低了顾客满意度。同时，一味地追求顾客满意也会对医疗器械产品的研发、制造产生不利的影响。

虽然现在的标准中未要求＂顾客满意＂，但个人认为在保证医疗器械产品安全、有效的前提下，顾客的使用舒适性应在产品研发阶段给予充分考虑。同时，对顾客使用舒适性的反馈信息的深入分析结果是下一步产品开发和改进的重要的参考。通过考虑结和最新科技成果、仔细分析和评估风险/受益及应用人因工程学原理等，提供产品的使用舒适性，才能更好的开发出顾客满意度高的、具有强大市场竞争力的产品。

Standards of Antimicrobial and Anti-biofilm Assay

In the academic research, different labs and groups have their protocols for evaluating antimicrobial/antibiofilm properties of modified surfaces/materials and antimicrobial agents. In the industrial R&D, adopting international standards is more reliable and trusty. Below is the summary of main standards for antimicrobial/antibiofilm assay used in medical device industry:

• Antimicrobial Effectiveness Tests in United States Pharmacopeia (USP) Chapter 51.
• Zone of Inhibition, MIC, MBC:  refer to standards from the Clinical and Laboratory Standards Institute (CLSI).
• ISO 22196, Measurement of Antibacterial Activity on Plastics and Other non-Porous Surfaces. (based on JIS Z 2801)
• ISO 20743, Determination of Antibacterial Activity of Textile Products.
• ASTM E2149, Standard Test Method for Determining the Antimicrobial Activity of Antimicrobial Agents Under Dynamic Contact Conditions.
• ASTM E2180, Standard Test Method for Determining the Activity of Incorporated Antimicrobial Agent(s) in Polymeric or Hydrophobic Materials.
• ASTM E2315, Standard Guide for Assessment of Antimicrobial Activity Using a Time-Kill Procedure.
• ASTM E1054, Standard Test Methods for Evaluation of Inactivators of Antimicrobial Agents.
• ASTM E1326 Standard Guide for Evaluating Nonconventional Microbiological Tests Used for Enumerating Bacteri.
• JIS (Japan Industrial Standard) Z 2801, Antimicrobial products–Test for Antimicrobial Activity and Efficacy.
• EN 1276, Chemical Disinfectants Bactericidal Activity Testing.
• EN 1040, Basic Bactericidal Activity of Chemical Disinfectant. 
• ASTM E2647, Standard Test Method for Quantification of Pseudomonas aeruginosa Biofilm Grown Using Drip Flow Biofilm Reactor with Low Shear and Continuous Flow.
• ASTM E2196, Standard Test Method for Quantification of Pseudomonas aeruginosa Biofilm Grown with Medium Shear and Continuous Flow Using Rotating Disk Reactor.
• ASTM E2562, Standard Test Method for Quantification of Pseudomonas aeruginosa Biofilm Grown with High Shear and Continuous Flow using CDC Biofilm Reactor.
• Guidances and SOPs by the European Committee on Antimicrobial Susceptibility Testing (EUCAST).

为什么苹果没有在日本出现?

日本的电子、材料、机械制造工业水平很高。我相信苹果ipod、ipad、iphone在日本制造应该没有技术上的问题。但是问什么日本没有开发出这样的颠覆性创新产品。从最近和日本一家著名化学材料公司的合作中，了解了一些日本的产品研发情况，谈谈自己的一些看法。

日本人性格上比较遵守规矩，做事情认真细致，强调团队精神。这是日本人从小就受到的教育。这样会限制了一些个性的发挥，导致缺少颠覆性创新能力。Peter Drucker在90年代指出日本公司喜欢创造性的模仿，满足于把产品作的更好而不是彻底的创新。

日本公司的终身雇佣制、年功序列工资制度对员工的创新能力也有很大的影响。日本公司特别是大公司有点像以前的中国国企，员工基本上在一家公司工作到退休，按部就班地工作、升职。内部晋升是论资排辈，缺乏有效激励机制。跳槽对于日本公司员工不是个人发展的好选项。日本公司的年功序列制度也减少了跳槽的好处。员工跳槽到新公司，资历要从新算起，直接影响到奖金和以后的退休金，而且新公司对跳槽的员工也并不信任。这对稳定员工队伍、增强企业凝聚力、企业持续经营有好处。在日本公司里，拥有突出个人才能，不听上司话的年轻员工会被视为异端。这些因素都在一定程度上削弱了员工的创新能力。

我认为日本公司技术至上的工程师文化，以技术为中心的创新(或者说是创造性的模仿), 而不是以客户为中心的产品开发是其缺少颠覆性创新产品的最重要原因。过于强调技术在产品开发中的重要性，一味准求制造超高质量的产品往往会弱化对市场和客户需求的真正了解。日本公司在技术上不可谓不强，尽管突破性的技术创新不如美国。日本公司将技术研发视为核心，以销售数量而不是市场和客户为导向，过于重视业绩，削弱了其创新能力。我认为：满足和引导客户(包括现有的和新的客户)的现有或未知需求, 为客户创造价值是产品研发和创新的最终目的。技术是实现这个目的的方法和手段之一，有时甚至不是关键的。真正以市场驱动、客户为中心的产品开发是产品在市场成功的前提。客户为中心包括满足现有客户的新需求，甚至客户未知的需求和开发新的客户。开发新客户和满足现有客户的未知需求(有时要主动告诉消费者，他们需要什么) 往往是颠覆性创新的最重要目的。

其他一些感想:
日本公司推行的全面质量管理、改善法、精益生产对于提高产品质量、技术进步、减少浪费、增强企业运营效益具有非常积极的意义。但是正如Michael Porter在他的经典文章"What is strategy"中所说，运营效益并不是企业战略。只提高运营效益不能让企业取得持续性的竞争优势。提高运营效益类似于正确的做事，确定企业战略定位类似于做正确的事，往往做正确的事比正确的做事更关键、更重要。日本企业过度追求运营效益的改善，而忽略战略创新和定位，如果这种情况没有改善，日本企业80年代的辉煌很难再现。

Videos from Nelson Labs

Nice youtube videos from Nelson Labs on biocompatibility, sterilization, packaging validation tests is here. It gives in-depth understanding on related area after reading the International Standards.

Quality Assurance vs Quality Control

Quality assurance and quality control are two important aspects in quality management system. They often confuse R&D staffs especially scientists at the university who are not familar with the industry and manufacturing. Generally speaking, Quality Assurance (QA) is process oriented and focuses on defect prevention, while Quality Control (QC) is product oriented and focuses on defect identification. Good summary can be found: Difference of QA and QC. In my opinion, QA is to make sure do the thing right then naturally it lead to do the right thing. While QC focuses on investigate if we are doing the right thing.

Smith&Nephew Global Wound Academy

Smith&Nephew is a top company in wound management and surgery materials. They have a very good online study source of wound knowledge: Global Wounda Academy.

Online Resource for Formulation, Raw Materials and Ingredients

• Prospector® search engine from U: Prospector

Good online formulation database including main chemical and cosmetic raw materials companies. So needn't search the companies one by one.

• Household Products Database, the United States

Detailed chemical composition in household products.

• Cosmetic substances and ingredients database in the European Commission

Chemicals used in Cosmetic in EC. can learn cosmetic ingredients according to their functions and cosmetic directive.

• Preservatives from Lonza: FormulaProtect
• Preservatives from Ashland: Preservatives Selector

Marketing in Customer-focused Product Development

Product is the total package of benefits (not just features of products) the customer receives when they buy. It is important for R&D staffs to understand that an industry is a customer-satisfying process instead of a goods-producing process. New product development should be market-driven and customer-focused. It will meet customer needs or creat new customers and markets. 

Marketing is about satisfying customer needs and wants. According to its definition, marketing is the activity, set of institutions, and processes for creating, capturing, communicating, delivering, and exchanging offerings that have value for customers, clients, partners, and society at large. It normally includes assessing the market (marketing strategy and marketing plan, SWOT analysis), understanding the market (consumer behavior), and targeting the market (segmentation, targeting, and positioning); creating value (product and service), capturing value (price), delivering value (place and supply chain and channel), and communicating value (promotion, advertising, public relations, customer relationship management). Developing new products is usually a charpter in marketing-related books.

Marketing plays a major role in developing a successful product. So marketing knowledge is very necessary to be learned for a R&D staff when starting a product development. Basic principles of marketing can be studied with the classic book Marketing Management by Philip Kotler. There is a good youtube playlist for marketing.

Medical Device Exhibitions

Although company website, online searching, and FDA database can provide a lot of information on the medical device company, exhibitions are still traditional and rich sources to learn medical device industry. Main exhibitions of medical devices are:

• Medica and Compamed
• FIME 
• Medtec
• China International Medical Equipment Fair
• Arab Health

More exhibition information can be found: http://10times.com/top100/medical-pharma

Summary on Format of 510(k) Premarket Notification Submission

After reading the FDA guidance for Industry and FDA staff: Format for Traditional and Abbreviated 510(k)s, a good summary on the format of an original 510(k) submission including sections and related regualtions, guidance documents, internet links which can be found in Chapter III of the guidance.

510(k) is a type of premarket submission that is intended to demonstrate that the device to be marketed is at least as safe and effective as a legally marketed device that does not require PMA. A legally marketed device is a device that was legally marketed prior to May 28, 1976, for which a PMA is not required, or a device which has been reclassified from class III to class II or I, or a device which has been found substantially equivalent through the 510(k) process. A legally marketed device is commonly known as the "predicate" device in 510(k).

FDA recommends that 510(k) submission includes the 21 sections preferaly in the sequence below:

1. Medical Device User Fee Cover Sheet (Form FDA 3601)
2. CDRH Premarket Review Submission Cover Sheet 
3. 510(k) Cover Letter
   
4. Indications for Use Statement
5. 510(k) Summary or 510(k) Statement
6. Truthful and Accuracy Statement
7. Class III Summary and Certification
8. Financial Certification or Disclosure Statement
9. Declarations of Conformity and Summary Reports
10. Executive Summary
11. Device Description
12. Substantial Equivalence Discussion
13. Proposed Labeling
14. Sterilization and Shelf Life
15. Biocompatibility
16. Software
17. Electromagnetic Compatibility and Electrical Safety
18. Performance Testing – Bench
19. Performance Testing – Animal
20. Performance Testing – Clinical
21. Othe

The U.S. Food and Drug Administration (FDA) Medical Devices Information

FDA website is a rich resourse for learning industry medical devices. Warning letter to related companis can be studied to  sum up experience. Warning Letters. 

Establishment Registration & Device Listing in Medical Device Database provides detailed information of the company in a medical device which is same with your product.

Production Classification provides medical device classifications, product codes, FDA premarket review organizations, and other regulatory information.

Recognized Consensus Standards, 510(k) Premarket Notification, and Premarket Approval databases are very useful as well.

Identify Opportunities in New Product Development from Errors

We can learn and identify new opportunities from our mistakes as the famous saying "Failure is the mother of success."

In addition to surgical needs and market analysis, problems、adverse events, and errors of existing products is an effective way to find the opportunities for new product development. They also provide important information for risk management of medical device. The following online resources can be used as references.

• FDA Total Product Life Cycle
• FDA MedSun Reports database
• FDA's MAUDE database
• FDA's Medical Device Recalls database
• Safety Communications
• ECRI institute's Medical Device Safety Reports database
• Sentinel Events from the Joint Commission
• UK MHRA alerts

Business-Driven Research and Development

As a R&D scientist and engineer in industrial area, although I think they share some common parts in problem-solving skills and applying knowledge people have mastered, business or market-driven R&D has many different points with interest, paper or even funding-oriented research. 

The book "Business-Driven Research and Development:Managing Knowledge to Create Wealth" by Ashok S. Ganguly, who was the Unilever R&D manager, enhance my understanding about industrial R&D. The author grew from a researcher to a R&D manager. This experience makes the author to be more closer real world of industrial R&D, which is not impossible for professors in businees schools. The book states that the primary role of industrial R&D is to fulfill strategic objectives of the company within a framework of time and cost targets. The author tries to give the means to improve competitive advantage of the company through overcoming the gap between R&D and the market place.

Innovation- beyond Technology and Product Innovation

The medical device industry is a hotbed of innovation. In today's intense competitive and fast-changing markets, innovative products or services have paramount importance for organizations to obtain sustainable competitive advantage either in lower costs or differentiation or both.

R&D staff or manager with technology background is easy to think the technology is the first consideration in innovation. Science and technology is No 1 factor, which may work in the university but often fails in the industry.

According Peter F. Drucker's article "The Discipline of Innovation", innovation starts with a conscious, purposeful search and analysis of new opportunities. The sources of innovation opportunities can be from without a company or industry:

• unexpected occurrences
• incongruities between expectations and results
• process needs
• industry and market changes

Three additional sources are from outside of a company:

• demographic changes
• changes in perception
• new knowledge

Product, process, market, organization, management, service, logistics, business mode, technology innovations can result from these opportunities. These sources will have different importance at different times, areas and firms such as the established and the start-up. New knowledge-whether science, technology or society - is just one in seven sources of innovation. Drucker emphasizes that knowledge-based innovations are superstars of entrepreneurship, demand many kinds of knowledge and long lead times, and is more market dependent than any other kind of innovation.

Product innovation can get idea from above opportunities. For example, aging (demographic changes) is a serious problem for society but it is an opportunity for medical device industry. I believe that the successful product innovation should be customer-oriented, i.e. meet current customers requirement (incremental and sustaining innovation) or create new customers and markets (great breakthrough or disruptive innovation). For medical device industry, customers may include patients, doctors and nurses.

Final Year Projects

When I was in NUS, as a mentor, I directed more than 40 undergraduates for their final year projects which are applied or exploratory researches in medical  device, biointerface and funcational material aeras. The projects are listed as follows:

1. Liposomes for drug delivery in bladder cancer
2. Nanoparticle-based intravesical therapy for bladder cancer
3. Interaction of stem cells with nanotopography
4. Anti-biofilm nano composites of graphene oxide
5. Initial interaction of human bone marrow stem cells and staphylococcus epidermidis bacteria with microtopography
6. Interactions of human bone marrow stem cells and bacteria with multilayers of chitosan derivatives on titanium
7. Nanostructure surface interaction with bone marrow stem cells
8. Injectable chitosan-based hydrogels/membranes for biomedical applications
9. Magnetic nanoparticles for hyperthermia treatment of cancer
10. Stability of peptides and growth factors immobilized on orthopedic implants
11. Polymer-magnetite nanoparticles for cell labeling
12. Cell-metal interactions in orthopaedic applications
13. Bacterial attachment to superhydrophobic and hydrophilic surfaces
14. Functionalized materials for antibiofilm applications
15. Antibacterial properties of calcium phosphate bone cement with incorporation of chitosan nanoparticle
16. Polyelectrolyte multilayers on metal for inhibiting biocorrosion
17. Polyelectrolyte multilayers of chitosan and heparin on titanium for biomedical applications

Seven Basic Tools of Quality

I often utilize flow chart, check sheet in the project management in the academic research to improve the work efficiency, they are also used widely in quality management, so called Seven Basic Tools of Quality. Quality management is a field which is less involved in the academic research in universities. Total quality management needs to be considered in the initial stage in prodcut development to ensure excellent final products.

National Medal of Technology and Innovation

Innovation product development plays a major role for supporting companies to obtain sustainable competitive advantage.

National Medal of Technology and Innovation is a good resource for industrial R&D-related staffs to know the big names in technical innovations and further learn from their experience.