Highly regulated industries like biomedical engineering, life science, and pharmaceutical development are always at risk of an audit by a regulatory agency like the United States Food and Drug Administration (FDA). The last thing you want to worry about is the FDA or related regulatory body finding an issue with your compliance with regulations. Documentation, moreover, detailed, accurate documentation is critical to avoid these pitfalls common to these industries. 

Keeping an organized and updated system that keeps your documents in order and ready when you need them can be challenging. This is especially true if you are a small startup and perhaps lack the capability to keep regulatory documentation paperless. Most of all, keeping these documents in order while also adhering to regulations with stellar compliance is a massive concern.

That’s why an effective document control system can make all the difference. 

The best way to reduce a risk of an audit or inspection by a regulatory agency is to obtain a consultation by a regulatory expert to ensure that you are doing everything correctly.

What is the Document Control System?

A document control system allows for easy arrangement and organization of files that comply with the quality assurance and regulatory standards set by governing bodies like the FDA. An effective document control system will typically be paperless, and their graphical user interface should make navigation and reporting compliance easy. 

Document control signals to regulatory bodies that your group follows good practice in the manufacturing and management of products. It assures that your group can access all documentation and track changes made to crucial compliance in standard operating procedures. 

Types of Documents Required for Creating Regulated Products

Clinical trials, for example, have massive documentation needs as they produce a lot of case report forms (CRFs) as well as protocol management copy that must be organized properly for the FDA and sponsors. Things like standard operating procedures (SOPs), CRFs, investigational review board (IRB) correspondence, plans and reports, checklists, adverse event logging, and protocol deviations all need to be handled carefully, and this can be challenging. 

Document control involves tracking different information related to the document, like the name of the person who created it, who approved the document, its status (valid, draft, in revision, awaiting approval), and authorization status (controlled/registered copy or authorized printout with signatures). Controlling for this information is usually a standard requirement for reporting to most agencies. With so many moving parts, a paper-based document control system is prone to errors and thus, nonconformances. A digitized document control system can eliminate these errors if implemented consistently across the organization.

Related: Ways to Collect Clinical Data

Document Control Is Not Just About Checking Boxes

The process of documenting information, and keeping that documentation controlled, is not just a system of checking boxes. While running through a basic checklist is how you meet minimum standards, you need to think about how best to organize things in relation to your company’s needs and structure. Document control is not a one size fits all process, and tailoring the process to your individual pipeline is critical for success. 

For example, hybrid paper and paperless models of document control technically meet minimum requirements for most agencies. However, doing so can hurt your company if it is not employed properly. Mismatched information between electronic forms and hard copies are common in this model and can spell disaster for the life cycle of your product. 

Related: Mythical Medical and The Unsolvable Equation: Benefit-to-risk analyses

Why You Need a Document Control System

If you are in the market for a better document control system than the one you are currently using (if you have one, at all), there are a few things you need to consider. Compliance will always be a primary concern. A good document control system will not only reduce the regulatory risks of compliance, but also increase transparency, improve security, and reduce the dissonance between hard copies of documents. There are other potential benefits.

Better Access Control

With electronic documentation controls, you can set user permissions. This ensures that only the correct people have access to the right documents. Say, for instance, you are an administrator, and you only want to share documents with either other admins like yourself or approvers. A quality document control system will allow you to do this, share and distribute and modify relevant documents without looping in the wrong team members. 

Improve Compliance

Electronic document control simplifies meeting compliance, and a particularly great control system will make obtaining authorization signatures or sharing passwords securely a breeze. These systems will minimize the risks of incomplete authorizations, incorrect forms, or drop-off in the audit process.

Learn ways that you can improve compliance with our services and solutions.

Transparency

Document control systems allow for seamless access to documents needed across many teams within your company. Increasing transparency improves data flow and prevents chokes in the pipeline of your product or service. When your team is taking too long to retrieve archived documents, you have an issue, especially during an audit or inspection. A good document control system will be able to handle many different file types, possess an accessible keyword query system, and control and modify user permissions accordingly.

Global Collaboration

If your workforce is spread across many different facilities over the nation, or even the world, a cloud-based electronic document control system will improve the speed at which collaboration can happen. A common holdup for large operations is the slow courier system across these office locations; electronic documentation controls eliminate this lag. 

Enhance Quality Management

Document control will make modifications to quality assurance protocols like SOPs, as well as updating in accordance with quality control testing far faster. It also ensures adherence to regulations and internal company procedures.

Create a Document Control Governance Board

A best practice would be to create a cross-functional document control governance board. It would include those within quality systems, information technology, and process owners. Their collaboration facilitates creating, implementing, monitoring, and adjusting the infrastructure. They can take a risk-based approach as they actively oversee and evaluate the current state and then develop strategies for improvement and growth as business needs change. Finally, the board and create metrics and present to important internal cross-functional stakeholders (reviewers, approvers, process owners) and senior leaders.

Recover from Disaster

When problems arise, such as a data breach, cloud-based document control systems can ensure your group will be able to land on its feet. Losing data can be disastrous for many business sectors, but good control systems can mitigate this risk effectively. 

Related: Metrics for Notified Bodies, Manufacturers, and Regulators

Bottom Line

Document controls are some of the most crucial components of running a company in a highly regulated field. The tools you need to adhere to compliance standards while also maintaining the flow of operations can be accessed through these document control systems.

Having trouble with the compliance standards? Contact us today for more information!

Clinical evaluations and clinical investigations are two of the most critical parts of a medical device’s journey to mass marketing. Despite this being the case, there are frequent, widespread misconceptions of what each means.

In this article, clinical evaluations, clinical investigations, and the processes, along with the requirements for each, will be discussed.

What is Clinical Evaluation?

When discussing clinical evaluation, we are not referring to the type where a patient is evaluated for medical reasons, though the two references do often get mixed up. Instead, we are referring to the clinical evaluation of a medical device. Clinical Evaluations are mandatory and were required starting with the early Active Implantable Medical Device Directive (90/385/EEC 20 JUN1990) and the Medical Device Directive (93/42/EEC 14 JUN1993). It was later incorporated into the first ISO 13485 quality management standard (see the current standard ISO 13485:2016 – Medical Device Quality Management System clause 7.3.7).  Now it appears in the European Union (EU) Medical Device Regulation (MDR) 2017/745 May 2017.

Clinical evaluation is the term used to describe a process plan where all of the relevant data regarding a device is collected and then assessed. The review determines whether there’s enough evidence to show that the device conforms to the necessary regulatory requirements and when a clinical investigation might be needed. The EU MDR 2017/745 Article 2 (Definitions) defines clinical evaluation as a systematic and planned process to continuously generate, collect, analyze and assess the clinical data pertaining to a device to verify the safety and performance, including clinical benefits, of the device when used as intended by the manufacturer. In other words, the clinical evaluation is a methodologically sound, ongoing (living) planned procedure to collect, appraise, and analyze ‘clinical data’ relating to a medical device. The manufacturer must answer the question, “Is there sufficient clinical evidence to confirm compliance with the relevant requirements for safety and performance when using the device according to the Instructions For Use (IFU)?”  

A document called a Clinical Evaluation Report is where the results of the process plan and analysis are recorded and documented. 

Related: Mythical Medical and the Unbuilt Team: A hiring process that works even when regulatory requirements change, or global health pandemics occur

How to obtain the clinical data?

There is more than one way to obtain the clinical data needed for the initial clinical evaluation. First, is the relevant scientific literature relating the design, intended purpose, safety, and performance. Here the manufacturer can either use the equivalence pathway or collect new clinical data on their device. If the equivalence route is chosen, the data must demonstrate compliance to or the spirit of the relevant regulatory requirements, e.g., Essential Requirements under the medical device directives or the General Safety and Performance Requirements (Annex I) under the newer medical device regulations. If equivalence is not demonstrated or established, other methods have to be used to collect new clinical data, e.g., surveys, clinical investigations, or if approved in other countries, large, “big data” hospital networks or registries. Some manufacturers may choose a combination of both equivalence and new clinical data for their initial submission.

The whole point of the clinical evaluation is to assess the clinical data to ensure that it conforms to the national requirements and standards. Once this data has been acquired, the clinical evaluation report can written and finalized. The clinical evaluation report is not just a paper exercise to meet requirements. It is an ongoing process of becoming compliant and then staying up-to-date on products being placed on the market.

It is mandated that the clinical evaluation and all of its documentation be updated continuously with any post-market surveillance information that becomes available. If for any reason, the post-market surveillance is found not to be necessary regarding the medical device follow up, there must be an acceptable justification and it must be documented. Current thinking, unlike in the past, among Notified Bodies and regulators is that those justifications for not performing surveillance would be rare. In regards to high-risk medical devices, the final report must include a clinical follow-up report.

Get expert guidance through the medical device approval process with Global Strategic Solutions. Learn more here!

What is Clinical Investigation?

Not to be confused with clinical evaluations, clinical investigations are clinical trials (studies) in at least one human subject, which are performed to assess the performance and, most importantly, the safety of a specific medical device. Recently, an international standard, ISO 14155:2020, was updated. This standard addresses the good clinical practice that is expected for the design, conduct, recording, and reporting of clinical investigations carried out in human subjects to assess the clinical performance or effectiveness as well as the safety of medical devices. Another international standard that also has relevance to performing a clinical investigation is ISO 14971:2019. All medical devices have risks. This standard is intended to help manufacturers of medical devices to:

• Identify the hazards associated with medical devices
• Estimate and evaluate the associated risks
• Control those risks
• Monitor the effectiveness of those controls

As clinical investigations are usually performed on higher risk devices, ISO 14971:2019 highlights three principles that should guide the manufacturer to mitigate or alleviate risks along the approval (and post-approval) pathway. First, they should design medical devices that are inherently safe. Next, protective measures or controls in the actual medical and/or the manufacturing process should be identified and implemented. Finally, safety information, such as found on the product labeling or within the IFU, should be communicated to either:

• those using the device
• coming in contact with the device, or 
• caregivers of those requiring the device.
  

These two international standards, along with the EU MDR, provide confidence that manufacturers are designing safe and effective medical products. Regulators and Notified Bodies will independently confirm this as well.

Clinical Investigation for Class III and Implantable Devices

Clinical investigations were first required in 1990 for all active implantable medical devices, virtually the highest risk medical devices at that time. That thinking has evolved, and authorities are taking a risk-based approach EU MDR 2017.745, Article 61(4). The current thinking is that for implantable devices and class III devices, clinical investigations shall be performed. There are some exceptions, three are described here although others exist:

• The device has been designed by modifications of a device already marketed by the same manufacturer, 
• The modified device has been demonstrated by the manufacturer to be equivalent to the marketed device, in accordance with Section 3 of Annex XIV and this demonstration has been endorsed by the notified body, and
• The clinical evaluation of the marketed device is sufficient to demonstrate conformity of the modified device with the relevant safety and performance requirements. 

In these cases, the notified body shall check that the Post-Market Clinical Follow-up plan is appropriate and includes post-market studies to demonstrate or confirm the safety and performance of the device.

Decisions to perform a clinical investigation under the EU MDR can be complicated and complex, but distill down to an active interaction between data obtained during the risk management and clinical evaluation processes and whether that data allows conformity to Annex I, “General Safety and Performance Requirements” (GSPR). The figure below illustrates this interaction.

In general, a medical device requiring a clinical investigation is ready to enter the market once a successful clinical investigation has taken place. It’s the results from the clinical investigation that will be included within the clinical evaluation which will be used, in part, for product approval.  The results (assuming satisfactory) show that the medical device complies with the regulatory requirements of performance and safety. Thus, clinical investigations hold considerable weight.

Related: Mythical Medical and the Unbuilt Team: A hiring process that works even when regulatory requirements change, or global health pandemics occur 

What is The Clinical Investigation plan?

There are many plans created to bring a medical device to the market. There is even a plan for clinical investigations. The clinical investigation plan involves, among other things:   

• Statistical power

• Patient population

• Clear and measurable objectives

• Criteria for stopping the trial

• Ethical consideration and informed consent   

‘What is The Manufacturer’s Responsibility?

In a situation where the sponsor of a clinical investigation is outside the EU or is not Union-established, it’s the manufacturer’s or sponsor’s responsibility to make sure that a legal or natural person is Union-established and acting as their legal representative.

In any regard, this said sponsor/manufacturer is responsible for taking care of a large part of this operation. They are responsible for:

• Insurance
• Design of the study
• Principal investigator designation
• Applications with the ethical committee
• Keeping documentation available and up-to-date. Also, incorporating the clinical investigation reports (data) into the technical documentation that’s legally mandated to be kept available by the manufacturer
• Incident reporting

What is The Role of The Competent Authority?

Once clinical investigation registration has taken place, competent authorities and saddled with the responsibility of providing the authorization for a clinical investigation to begin. According to the Medical Device Regulation (MDR), approval could take less than a month. The commission may engage in delegated acts to fine-tune the procedure. Each clinical investigation receives one single registration number or SRN for short. This is to maintain a more efficient and reliable exchange of data between member-states, the Commission, the public, and others.

Related:  Mythical Medical and The Unsolvable Equation: Benefit-to-risk analyses   

What is The Role of The Notified Body?

The Notified Body is a conformity assessment organization. They review the clinical evaluation and, if required, the clinical investigation. These documents, and others, are part of the technical documentation review that occurs before granting a CE certificate. There are many processes, reports, and personnel that undergo inspection or scrutiny prior to approval which includes, in part: 

• A benefit-to-risk analysis
• An inspection or discussion of how the device fits into current clinical practice by evaluating state-of-the-art information
• An assessment of the clinical safety and performance
• Auditing the manufacturer and its personnel
• Evaluation of post-marketing or post-approval processes and plans

Conclusion

Due to the massively impactful nature of medical devices, it is of the utmost ethical and business importance to carefully consider which aspects of safety and performance can be supported by not only pre-clinical evidence, but also clinical evidence from evaluation in humans. It is only through a thorough clinical evaluation of all the available data that regulators and Notified Bodies approve medical devices. There are other requirements, such as post-market surveillance, once a device is on the market. That will be the topic of a future article.

The EU MDR is basically a fascinating and highly intriguing story about redemption within the medical device sector or business. It’s about having a final chance to make a change before it’s too late. If done correctly, clinical evaluations, along with clinical investigations, are steps being taken now to ensure a bright, innovative future for medical device development that meets unmet medical needs. 

Get expert guidance through the medical device approval process with Global Strategic Solutions. Learn more here!

There exists vast amount of creative solutions to leverage real-world, state-of-the-art clinical data. It actually can be fun but has potential to create new workaholics if you have this passion. Patients, healthcare practitioners, patient advocacy groups, Notified Bodies (NBs), competent authorities, and the European Commission do not want your device to miserably be left behind. Real challenges exist for the medical device industry to transform from those old directives to the new European Union (EU) Medical Device Regulation (MDR).

Here is the problem. Manufacturers (and other stakeholders) recognize they don’t have enough current clinical data to either re-license their devices under the existing regulations or to license them under the upcoming EU MDR. They are running out of time. The industry is far behind in recognizing what is possible. Few are looking forward to 2020, but you can.

Until there is further guidance, there exist six proven methodologies or ways to actively and systematically gather, in a scientifically and valid manner, post-marketing evidence that can be used to update technical documentation files. This method can be applied to all classes of devices, but a risk-based, decision tree approach is suggested. In fact, using multiple approaches could be relevant for many devices. It depends, in part, on the scientific question being asked and how much existing, relevant clinical data the manufacture possesses. These assume relevant local and national regulations are followed, e.g., patient privacy laws, good clinical practice, safety reporting, etc.

These are ranked from least costly and lowest level of evidence to the more expensive, but highest level of evidence. A draft financial starting point is provided for each column in US dollars with one “M” representing $000. For example, $200 M would represent $200, 000. Please adapt these values to represent your business model and currency.

1.    Surveys 

Although this may be the lowest level and least costly option, real value can be obtained if scientifically and statistically created correctly and you get information from the right group. This could be a business opportunity to visit and engage customers, users, etc. directly (versus a mass mailing) using the appropriate manufacturer personnel, of course. Feedback is usually rapid and depending on the method used, can be either dialog-based or they just check the box.

Challenges exist. Potential downsides would be limited experience with surveys, low survey return rates, and potentially non-representative sample. Finally, “This could be a trap!” Many financial officers or budget owners will want all their devices to use surveys. Although it really depends on the question, generally it would be difficult to convince NBs and their medical reviewers that this is the right risk-based model for class III, implantables, or active devices. I have had those conversations and would love to hear your experiences in an “off the clock” setting, of course.

2.    Hospital Databases

If you need clinical data quickly, you will love this. As the healthcare industry is booming electronically, this represents a forgotten, clever, and shrewd decision tree method. If done correctly, many regulatory agencies or bodies have found value in reviewing this type of real-world device experience. Especially where several large hospitals are contributing. If you desire a new, exciting professional challenge, this opportunity is for you. I can personally attest that this was a viable pathway for re-licensure with the United States Food and Drug Administration, several NBs, and brilliant, thoughtful competent authorities, e.g., Australia, Argentina, Brazil, Canada, China, India, Israel, Japan, Mexico, Portugal, Saudi Arabia, Taiwan, Thailand, etc. Although the barrier was lower for acceptance from acute use products, it was also successfully applied with implantable devices.

With volumes of clinical information available within large, geographically based hospital networks, it is very difficult for regulators to dismiss what this valuable evidence represents.

Challenges exist. First, you need to identify both a local physician/user advocate because they know how to interpret what their data means (and what it does not mean) and their database manager who knows not only how to extract data elements, but also the validity and limitations of the system. Second, there are challenges with maintaining hospital contracts to obtain data long-term. Of course, in the real-world, users practice medicine. Thus, the information may not be representative of on-label or as intended in the approved population. This is actually good news. Manufacturers are expected to have processes in place to assist with identifying possible systematic misuse or off-label use of the device, with a view to verifying that the intended purpose is correct.

3.    Investigator-Sponsored Studies (ISS) aka Investigator-Initiated Trials/Studies/Research

These clinical investigations are submitted for funding to a manufacturer. The lead or principal investigator (PI) assumes regulatory responsibilities. These are usually orders of magnitude cheaper than industry-sponsored studies. They can provide important clinical evidence on device safety and performance. Contracting is usually with the institution, rather than the PI and remains in effect if the PI leaves; thus, allowing the investigation to continue by promoting a qualified, sub-investigator to that vacated role. This approach can help manufacturers with public procurement or tender processes. If aligned with clinical development plans, this approach could generate important, initial clinical data in other populations to assist with future product development.

Challenges exist. PIs may not be interested in core products (just not exciting to them) and prefer studying what’s new. Second, once the primary endpoint is reached, many are not excited to follow-up on research subjects year-over-year, for example. Research grants always have funding at significantly lower levels for follow-up visits. It’s a business or revenue stream, so it’s common for PIs to move to the next big project. Data quality may not be as high, usually because of lower levels of monitoring and limited audits. Next, some manufacturers have restrictions on “directing” the investigation. They are required to be more hands off. For those experienced with clinical investigations, it takes longer lead times to initiate a site(s) compared to the previous two methods mentioned above. Data may not be aligned with the product label. Seasoned PIs are typically more interested in pushing the product into risky populations versus overseeing a surveillance investigation. However, this would be an opportunity for newer PIs that are interested in working with the industry. The perception is it’s not real science and the results may be difficult to publish in major medical/scientific, peer-reviewed journals.

4.    National Registries

Where these exist, they are known within the industry because, in part, they may be required by law or supported by medical associations. Data is published on a regular basis in the medical literature or as publicly available annual reports since many countries are financially supporting these. It is predicted that the industry will be seeing more of these in the future. Manufacturers are encouraged to find ways to empower these national registries.

Challenges exist. First, there is limited ability to alter or change the database quickly. Not all device components are included. There is less flexibility to create downloads from the database “off schedule.” Additionally, data lag exists in terms of when data is uploaded from sites. This could be 6 to 9 months which is painful if a safety signal needs to be evaluated quickly. Finally, there is usually limited ability to go back and investigate a specific data point.

5.    Small Product Registries

Many manufacturers have experience running product registries. It’s becoming a core competency. The industry finds manufacture-friendly (and competent) PIs and sites, many of which desire to better understand technologies when used in their hands. Typically practice standards are different in various geographies and many have a desire to understand safety and performance in those environments. These registries can also assist with tender processes and complement product development activities.

Challenges exist. Few device registries exist on lower profit margin products. Similar to ISSs mentioned above, there is a long lead time to set up registries, recruit subjects, and then follow them until the primary endpoint is reached. The PI’s enthusiasm decreases if they are required to follow subjects year-over-year. Many PIs, in general, believe it’s not science after the primary endpoint is reached.

6.    Large Manufacturer Registries

The thought here is to set up an infrastructure and follow all products in one large registry. This is more common in smaller companies. Many times, there are limited exclusion criteria (all comers or more comers design). The manufacturer has more control over the database, monitors more frequently and performs scheduled audits to ensure higher integrity of the clinical data.

Challenges exist. This approach impacts R&D pipelines because of limited financial resources. The profitability of products may lead to a reassessment of lower-margin products. As mentioned for ISSs and small product registries, there exist lead times to start the registry, get to the endpoint and PIs find year-over-year follow-up boring.

Don’t let your device be left behind. These creative, strategic solutions can assist manufacturers to plan their evidence creation strategy, in order to improve the approval process. Get the right people involved to help with planning to identify or confirm safety, performance, or effectiveness, e.g., physicians, statisticians, users, NBs, database managers, regulators, advocacy groups, etc. Others could be involved too, e.g., consultants, advisors, clinical research organizations, and other relevant partners. These six strategies are all great sources of clinical data that can be included in clinical evaluations and post-market surveillance plans. There is no need to create new workaholics.

The thirst for data is hard to satisfy. It’s been my experience that data leads to data. Questions lead to answers, then more questions and the creation of more data. This aligns with EU MDR commitments to life-cycle or lifetime management of medical devices.

Predictability in product approvals is a competitive advantage. Implementing proven approaches like these increases this predictability. Pay attention to upcoming Common Specifications. Factor this in as you go through your decision tree. Once an infrastructure like this is set up, performing large-scale meta-analyses, or an analysis of an analysis, is the next logical, innovative step to better understand device safety, performance, and effectiveness.

Strategies like these can provide manufacturers with a platform for those discussions, which usually occur following gap analyses. It also will empower you to have fun now as you look forward to 2020 to celebrate the beginning of a new, EU MDR-focused year.

If you have success stories implementing strategies like these, I’d love to hear from you.

David R Rutledge, Pharm.D., FCCP, FAHA 
david.rutledge@globalstrategicsolutions.com
+1 (630) 846-0350 cell

Although the bar was set high in an environment where scrutiny had never been more intense, Notified Bodies stepped up and succeeded with their new designation. The European Commission (EC) on Thursday added one additional Notified Body designated under the new Medical Devices Regulation (MDR). This brings the new total to five. Congratulations!

BSI-UK (0086) www.bsigroup.com 19JAN2019

TÜV SÜD (0123) www.tuev-sued.de/ps 27MAY2019

DEKRA (0124) www.dekra-certification.de 14AUG2019

IMQ ITALY (0051) www.imq.it 20AUG2019

TÜV Rheinland (0197) www.tuv.com/safety 26SEPT2019

For those manufacturers that have received or are about to receive notices that their Notified Body is withdrawing from MDD (or IVDD) and not pursuing MDR certification, huge challenges exist. Your hopes of relying on them to support the soft transition (2020-2024 under MDD or 2022-2024 under IVDD) have disappeared. Manufacturers are given 90 days to find a new Notified Body. How is that going?

The days of “like-to-like” transfers are gone; now it could take up to a year. A potential gap is likely to occur and there are consequences to your device certificates.

The MDR has prescriptive procedures for “Changes to designations and notifications” (see Article 46). Until then, manufacturers today should contact and petition the authority responsible for the Notified Body to identify the legal pathway forward. Procedures will vary by authority and should be considered emergency, temporary measures which will have some restrictions. In some cases, you will be requested to contact the authority where the authorized representative is located or where the manufacturer is located.

What’s been your biggest challenge? Although there are only 243 days left until 26MAY2020, there are still strategies that can be implemented to save your device.

David R Rutledge, Pharm.D., FCCP, FAHA, President & CEO, Global Strategic Solutions, LLC, david.rutledge@globalstrategicsolutions.com