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Patrick R. Ayd, BSN, MBA

Advisor: Clinical Sites

Capable Site

What is the difference between a Capable site and a Marketable site? A “Capable” site relies on some skill and some luck. It all starts with your ability to pass a very intense Pre-study Site Selection Visit (PSSV). I tell my clients performing a PSSV without an awarded trial indicates something of significance wrong at their site. The Sponsor will rarely be honest with you and let you know exactly what it is. But trust me when I tell you that this is the case. In an effort to save time and money, many Sponsor’s no longer even conduct PSSV’s (part luck).

Marketable Site

So what is a “Marketable” site? This is a site that relies on a solid foundation of procedures and skill (not luck) and welcomes Sponsors to take a very close look at their facility because they have nothing to hide. The SOPs are in great shape, the correct staff has been trained on those SOPs and the training has been documented. Their Investigational Product (IP)/Drug accountability process is one that can’t be beat or mistakes cannot occur. Their sample handling is also flawless with the right equipment to process PK samples, store the samples, and ship the samples as required, and so much more.

Capable vs Marketable Sites

I believe that the biggest difference between a “Capable” site and a “Marketable” site is that the “Marketable” site has an ongoing independent Quality Assurance program in place where someone unrelated to the organization comes to the site on a regular basis and audits the site to ensure they are following their own SOPs, GCP-ICH guidelines, the CFRs (code of federal regulations) and of course the protocol as written. The “Capable” site that believes they have no issues because a trial monitor has not put it out there acts as if having an FDA audit is of no concern where really they dread the thought of an FDA audit or even a full Sponsor audit. Whereas the “Marketable” site is used to having audits so they tend to have a “bring it on” attitude for both FDA and Sponsor audits.

Setting up and maintaining an independent Quality Assurance program is very affordable and in the long run your bottom line will see positive growth.

Contact BioAlliance Strategies for more information:


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JJL B&W pic slide1The Life Science Entrepreneur: A Practical Guide to Forming, Financing, Building, and Exiting a Life Science Company


Author: Jack J. Luchese, BA, MBA  – Contact Jack J. Luchese

Available on Amazon: Paperback and Kindle

Chapter 1. The Compelling Idea

The The world still loves a great idea! One of the most important things to remember when forming a business is that you must offer something new and special to the marketplace. Sameness is not sexy, nor does it attract capital, the best management talent, or the best advisors and board members.

The “better mousetrap” concept is always useful to consider when deciding upon any business venture. The life sciences business relies on technology, capital, and highly skilled talent to succeed. The newer, better idea or technology draws a crowd, and the other ideas usually struggle and have to settle for less. However, it is the truly disruptive technologies that often get the most attention and capital.

The word disruptive is often misused to mean anything that presents a positive change or better idea. On the contrary, a disruptive technology is a market/business-model game changer that is generally unexpected. Its introduction strategically and materially impacts the current use of products, service providers, distribution channels, and pricing. This creates a situation that is certainly unwanted by established competitive players in the current market. Truly disruptive technologies are few and far between, and they represent the Holy Grail sought by every entrepreneur. If you have one, you will know it because the world will beat a path to your doorway; if you have to convince everyone you meet that your idea is disruptive, it probably is not. Some examples that we all know of include the Internet, e-mail, the iPhone,, and Facebook. Be careful to wisely and appropriately use the word “disruptive” in your communications so as not to lose credibility with your audience.

I cannot overemphasize the importance of selecting a truly exceptional idea to build your business. However, for that idea to develop into a successful business investment, it must be all of these things:

  • Favorably positioned
  • Protected by patents and/or trade secrets
  • Feasible to develop and commercialize
  • Financed by patient third-party investment sources
  • Designed to meet the specific needs of a target market that will readily embrace it

The compelling idea can come in many forms. It could be a biomedical discovery that shows a compelling therapeutic pathway to a cure for a major disease. It could be a new system of distribution to a new sales channel or to all existing channels. Or it could be the merging of several great product concepts into one business model that brings synergy and can command a premium price in the marketplace, to name a few. This compelling idea is something you will present thousands of times to customers, employees, investors, agencies, and service providers. Celebrate your idea, simplify it, communicate it, and make it part of everything you do going forward. Yes, of course you will develop new ideas, but it is imperative that your first idea succeeds, because you may not get a chance to fund a second one.

Contact Jack J. Luchese for support in M&A, Licensing, Financing for your company.

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Patrick R. Ayd, BSN, MBA

Advisor: Clinical Sites

FDA or ICH-GCP Guidelines

I receive many questions regarding whether or not the FDA or ICH-GCP guidelines requires AE or Protocol Deviation logs for a clinical trial. As you all know, what the FDA expects is somewhat vague at best, it is my opinion that creating these logs add a great deal of efficiency, quality and clarity to your clinical trial documentation.

An AE log allows the clinical research coordinator (CRC) and the Principal Investigator (PI) the ability to take a quick look to see how the AE’s might be trending for a trial. If the CRC hands an AE form to the PI to assess and sign once every three weeks the PI could rate each AE is “unrelated”. If there had been an AE log the PI might see a pattern of AE’s and begin to rate them differently.  For the CRC the AE log is a great tool to look at when doing a participant’s last visit. The CRC can take a quick look to make sure that all of the participant’s AE’s are closed or reassessed to end that portion of the documentation for the clinical trial.

A Protocol Deviation log holds a similar purpose. The site’s PI or clinical management team can take a quick look to see the types of protocol deviations that are occurring and assess if there are trends they need to address. This could include retraining staff, working with the sponsor, changing source documents, etc. A Protocol Deviation log also ensures that the IRB has been notified as appropriate for any protocol deviations that were made.

So even though there is no FDA guidance or ICH-GCP verbiage that requires these types of logs, these logs remain important tools. The logs go a long way in helping a clinical site stay on track and keep up with efficient quality operations which is key to each site’s success.  Contact Us

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Imen Jelassi BW picImen Jelassi, PharmD, MSc

Advisor: EU Director Strategic Partnerships

Contact Us For More Information

Imen Jelassi, PharmD, MSc, is building relationships between EU life science companies and the US. Her activities create opportunities for EU CROs, Pharma and Biotechs to align with US companies for strategic relationships in Business and Corporate Development, Web Design, Branding, Video Production and Ad Hoc Scientific Leadership. Imen states “Our effort to connect EU based companies to US sponsors and CROs has enabled our EU clients to earn bidding opportunities not otherwise available to them.”

Targeted Messages to Targeted Contacts

Targeted messages to targeted life science contacts increases BD-ROI through our model of Fractionalized BD. By creating content in a newsletter format and distributing to targeted individuals, our clients educate their audience with information and links back to their Website, Twitter and Slideshare accounts. Then reports are generated for BD teams for follow up activities keeping them client facing instead of performing time consuming daily grunt work.

Contact us to learn more.

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The Changing Landscape of European Medical Device Regulations

Patrick D. Mize, Ph.D.  linkedin small logo
Contact Dr. Mize

Advisor: Product Development / Regulatory Services

Part 3 of 3

Pre-clinical and Performance Studies

Pre-clinical and verification performance studies are usually summarized in the Technical File and a summary can be presented in the CER or the studies can be referenced here. Preclinical and performance studies are specific to the type of device and its intended use. A detailed list of the device’s Design Characteristics / Critical Features should be available from design documents and risk analysis.

These essential features for performance and safety make up part of the design input-output matrix and are the features that need to be verified and validated in these studies. These studies are, by definition, pre-clinical, and as such are studies with defined objectives, acceptance criteria, protocol and conclusions. Deviations from protocol should be few, well-documented, and explained. Final device prototypes or manufactured and internally approved devices are needed for these studies.

Many standards exist that delineate how these studies are to be performed and give suggested protocols and rationales for statistical sampling and analysis. Use of specific standards and protocols and having safety testing performed independently by a certified third party vendor helps insure impartial data. One cannot emphasize enough that a thorough review of the standards that are applicable for the evaluation of the device should be done early in the design process of the device.

For example, surgical devices require both biocompatibility and sterility validation studies as well as preclinical animal studies to show both safety of the new surgical devices and the efficacy in use of the instruments. Biocompatibility(13) and Sterility studies(14) are required when the device comes in contact with the intended use population and can be performed by many certified 3rd-party vendors. Safety studies are a key part of this section and are of a major focus of regulatory and notified bodies due to increasing reports of devices that do not meet the long term needs of the user. The literature report and pre-clinical studies can in certain instances be sufficient to show safety, efficacy and clinical utility; therefore, an argument can be made that human trials are not necessary.

Clinical Data

The European Commission Guidance MEDDEV 2.7.1 rev. 3 Clinical Evaluation: Guide for Manufacturers and Notified Bodies(15) provides details on the process of conducting clinical evaluations such as, but not limited to, starting with either a Standard Operating Procedure (SOP) or a Clinical Evaluation Plan (CEP) describing the literature search, objectives, methods, and endpoints. The document also provides a list of references that can be useful. Also MEDDEV 2.7.4 contains further guidelines for manufacturers and notified bodies for clinical investigations of medical devices(16).

ISO 14155-1:2011 addresses good clinical practice for the design, conduct, recording and reporting of clinical investigations carried out on human subjects to assess the safety or performance of medical devices for regulatory and other purposes. This International Standard specifies general requirements intended to:

  • Protect the rights, safety and well-being of human subjects
  • Ensure the scientific conduct of the clinical investigation and the credibility of the clinical investigation results
  • Define the responsibilities of the sponsor and principal investigator
  • Assist sponsors, investigators, ethics committees, regulatory authorities and other bodies involved in the conformity assessment of medical devices.(17)

Discussion and Analysis of Device Design, Safety and Efficacy (Conformance)

This section of the report pulls together the elements of each of the previous sections of the report: design objectives and input statements; risk analysis and mitigation; regulatory and standards review; literature review; performance and preclinical studies; and clinical studies, if any.

This section should discuss the testing data related to the design inputs and show the objective evidence that the design meets both performance and safety objectives. There is a story to tell here. Your medical device’s story; complete with beginning, middle, and an [initial] end. The immediate end is showing that your device conforms to the MDD and can be marketed in the EU.

Post-Marketing Surveillance and CAPA Reviews

The manufacturer has the responsibly for maintaining a Post Marketing Surveillance [PMS] system and notifying the Competent Authorities [CA] of incidents immediately upon learning of them per MEDDEV 2.12-1.18 The notification may be done through the manufacturer’s EC Representative. Vigilance (reports) must be forwarded in standardized format per MEDDEV 2.12/1/Rev. 6. The CA has the responsible for monitoring vigilance reports19 and taking appropriate action. Post Market Surveillance allows the manufacturer to not miss signals of field failures that could result in unnecessary patient injuries. The failure to act increases the possible liability/punitive damages that the company may face.

A good PMS system facilitates development of improved and safer products and reduces loss and damage to a manufacturer’s brand. The international Medical Device Regulators Forum [IMDRF] lists a series of GHTF documents concerning Post Market Surveillance20 and best practices.

Post-Marketing surveillance data make up one part of the information that is regularly reviewed by the Corrective and Preventative Action [CAPA] Team. Regularly reviewing PMS and internal tracking data on product release, significant manufacturing issues or changes in critical components allow the manufacturer to both document occurrences and outcomes. A summary of these data are included in the regular update to the CER and allows easy review by the NB. These data comprise the second [follow-up] end of the medical devices’ story.







18 Part of ISO 13485

19 Vigilance Contact Points within CAs


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The Changing Landscape of European Medical Device Regulations

Patrick D. Mize, Ph.D.  linkedin small logo
Contact Dr. Mize

Advisor: Product Development / Regulatory Services


The Clinical Evaluation Report [CER]

The CER, which is included in your Technical File or Design Dossier, is required when bringing a medical device to market and helps demonstrate that the device achieves the intended purposes while minimizing any anticipated risks and foreseeable adverse events and conforms to the relevant Essential Requirements of the Medical Directives. The CER summarizes design characteristics, risk evaluation and mitigation, performance and pre-clinical testing of the device, literature reviews / references, clinical trial results, internal CAPA information and post-launch surveillance data. This compilation provides objective evidence that the device conforms to the relevant Medical Device Directive both at launch and during post-market clinical follow up.

Clinical evaluation is the assessment and analysis of pre-clinical and clinical data needed to verify the clinical safety and performance of a medical device. A Clinical Evaluation Report (CER) outlines the scope and context of the clinical evaluation of your device and includes these parts:

  • Overview, scope, plan, essential design characteristics
  • Risk assessment and mitigation
  • Literature review and report
  • Pre-clinical and performance studies
  • Clinical data
  • Appraisal and analysis stages of the evaluation
  • Post-marketing surveillance and CAPA reviews
  • Conclusions about device safety and performance

Clinical evaluation is an ongoing process that is first conducted during the conformity assessment process leading to initial EC labeling and marketing and is repeated periodically during the life cycle of the device. Post Market Surveillance [PMS] continues throughout the time the device is marketed and beyond for implantable devices. These surveillance programs monitor ongoing performance and safety. PMS can include adverse event reports, results from published literature on the device, clinical investigations, and formal post-marketing surveillance, including Post-Market Clinical Follow-Up Studies. This continued evaluation is essential for identifying further risks that occur with use of the device and, if necessary, may result in design or labeling changes.

Plan and Essential Design Characteristics

In my experience, the overall plan, design of the device, and determination of the essential design characteristics or “critical attributes” are crucial for the successful development of the device. Clearly defining the design characteristics and critical attributes related to the intended use and users allows the team to focus on the risks of the design and performance necessary for the desired clinical efficacy. Development and validation needs can then be assessed and a pathway (plan) for development can be finalized. A full knowledge of the regulatory hurdles necessary for approval is essential at this step. Many of the Essential Requirements have ISO standards or standards from other organizations which both dictate and guide the manufacturer in the necessary design and testing of the medical device.

Risk assessment and mitigation

ISO 14971 is the risk management standard for medical devices. Its purpose is to help manufacturers establish a medical device risk management process they can use to identify hazards, to estimate and evaluate risks, and to develop, implement, and monitor the effectiveness of risk control measures.

The CER should reference or contain the Risk Management Report. Risk management is the systematic application of management policies, procedures and practices to the tasks of analyzing, evaluating and controlling risk. Risk evaluation and mitigation differentiates most critical product features related to safety or harm, quantifies and determines the acceptability of risk, and provides focus and priority for product development and life cycle activities.

Risk management is required in the development process and should continue during the full life cycle for marketed medical devices in the EU.

The risk management process defines:

  • a hazard as a potential source of harm
  • harm as physical injury or damage to the health of people, or damage to property or the environment
  • a risk as a combination of the probability of occurrence of harm and the severity of that harm
  • severity as a measure of the possible consequences of a hazard

Risk mitigation occurs through modification of the design and procedures for use of the medical device in the intended population. Any residual risk, risk remaining after risk control measures have been taken must be acceptable when weighed against the clinical benefit in the intended use population. Identified risks should be evaluated and quantified during pre-clinical, validation and clinical studies to determine if the identified hazard has been mitigated through design and procedural modifications.

Literature Review and Report

A literature review should include investigations published on other similar devices and characteristics of the intended use population. The literature review for established devices investigates, in a systematic and thorough manner, the clinical literature and includes clinical outcomes and adverse event data. The CER may serve as the primary source of clinical evidence to support commercialization and may justify no new clinical investigations.

The literature review should not only cover your device and comparable devices but also alternative treatments for the intended use. For example, the literature review for a new device to treat atrial fibrillation would include any published pre-clinical or clinical studies of the new device, published clinical studies of similar devices used for the same intended use, and medical / drug treatments for atrial fibrillation. The true safety and effectiveness of the new treatment can then be compared to all alternatives.

The literature review is composed of the following parts:

The Review Plan:

  • Identifies the purpose and scope of the review;
  • Includes the intended use of the medical device and its classification;
  • Defines a search strategy [terms to include, other comparator medical devices, and the approach to captures the safety and efficacy of current clinical treatment];
  • Defines search restriction and limitations; years included and excluded, number of articles, type of article (pre-clinical studies, clinical trials, meta-analysis of trials, reviews, etc.), and a rationale for each;
  • Identifies the sources to use to identify useful citations [e.g., Medline, EMBASE, Google, Cochrane Clinical Reviews, etc.12].

Although Medline includes over 19 million citations, there are about 2000 global medical journals that aren’t included. EMBASE gives access to MedLine citations and to the other 2000 journals that Medline doesn’t abstract. EMBASE is required for a literature review compliant with the Directives.

  • Gather and list articles selected from initial literature search
  • Read the articles, excluded articles about the same study, state the reason for exclusion in the table
  • Read the remaining articles again and exclude the articles that are redundant or irrelevant or unusable for other reasons, state the reason for exclusion in the table
  • Weight each article according to relevant criteria
  • Same or similar device: Actual device, Similar Device, Other device
  • Indication: Same indication, Minor difference, Major difference
  • Subject population: Same population, Similar population, Different population
  • Compile the data with regard to the study design, number of patients, success or failure of device, adverse events, etc.
  • Recommend that safety and performance data be put into tables for ease of comparison
  • Data Analysis
  • Conclusions based on purpose and scope of the literature review and intended use of the reviewed medical device
  1. Although Medline includes over 19 million citations, there are about 2000 global medical journals that aren’t included. EMBASE gives access to MedLine citations and to the other 2000 journals that Medline doesn’t abstract. EMBASE is required for a literature review compliant with the Directives.

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Ayd pic copyThe Critical Nature of SOP’s

It is critical that every clinical research facility have SOPs or Standard Operating Procedures. An SOP is a document that clearly defines/describes how a procedure or process is performed at your research facility. Standardizing procedures and processes is key to collecting correct, timely, and consistent data which is a goal in every clinical research trial.

SOP’s for Training

SOPs are an excellent source for training permanent staff and temporary staff members how to conduct a procedure or process so the procedures or processes are consistently conducted regardless of who performs them. SOPs need to be as detailed as the process or procedure calls for to create consistent results. The documentation of training of your staff is critical so as to show external regulators and Sponsors that your staff does have the tools necessary to collect accurate and timely clinical research data in a consistent manner.

Mirror Process and Procedures

SOPs should mirror the process or procedure to ensure consistent data collection and documentation. SOPs should be created internally with staff participation and be specific to your facility so be wary of “buying” a set of SOPs. You are much better served by consulting an industry expert to help establish your SOPs. SOPs are critical to the success and prosperity of your clinical research site. Let us help you create an SOP “system” that will meet the expectations of Sponsors and the FDA. SOPs that are done correctly the first time will be a timeless asset to your organization.

Contact Us for additional information