Author: Suzanne Broussard
Take the advice of industry experts and AOs—the key to acing the MDSAP audit is to prepare, prepare, prepare.
The MDSAP audit process is intense in that it is designed to provide thorough coverage of QMS and multiple jurisdictions regulations. Remember, your organization already maintains a level of compliance in all countries they sell devices. MDSAP simply rolls all these regulatory requirements into an efficient process. Here are a few tips to keep in mind when preparing for the MDSAP audit.
1. Look closely at the MDSAP Audit Model to determine exactly what the Auditing Organization (AO) will need. The MDSAP Audit Model is the AOs guide. Everything needed for the audit is clearly laid out in this comprehensive guide. Each of the 90 questions the AO will ask is contained in this guide. And, each question is cross-referenced to relevant sections of ISO 13485:2016 and other specific requirements of medical device regulatory authorities participating in the MDSAP program.
2. Use the MDSAP Companion Document to create a gap analysis and perform an internal audit. It is universally agreed by AOs and manufacturers that have been through the MDSAP audit process that the best way to get ready for an MDSAP audit is to use the MDSAP Companion Document as a guideline. The Companion Document further clarifies the Audit Model and provides guidance to the auditors, making this a very handy supplement for manufacturers. MDSAP is very structured, and understanding the specific information that auditors will be focusing on and in which order eliminates any guesswork by the manufacturer.
3. All documents need to be organized and available. The audit is timed. Therefore, the vast volume of documents required need to be organized and quickly accessible—this is critical for a successful audit. The AO will not be able to come back and revisit areas in which documents are not readily available.
4. Organizations must prove control over their suppliers. The way in which you demonstrate control over your suppliers needs to justified, and these details need to be incorporated into procedures and programs. A manufacture cannot simply say their supplier is ISO or MDSAP certified. The AO wants to know how your organization ensures that the supplier is compliant. Here’s why a global medical device manufacturer should consider the MDSAP.
6. Be clear on what is done where. This aspect is especially important for multi-site manufactures. Clearly list the scope of activity at each site and which products are covered by operations. Make sure to define multi-site manufacturing in Stage 1 so the AO can calculate the appropriate time-frame for Stage 2.
7. Employees must be proven competent. Providing objective evidence that employees are competent, not just trained, in regulatory requirements of all pertinent jurisdictions is mandatory. Objective evidence could include testing after training and job function checks to assure competency is practiced—not just learned.
8. Consider the Auditors Perspective. Brian Ludovico, Executive Director at NSF International, suggest organizations keep in mind the AOs perspectives when preparing for the MDSAP Audit. He provided a number of additional tips in recent interviews: auditors cannot read your mind, please justify your work, and regulatory and quality need to be friends in your organization.
9. Learn From Past Mistakes. Marcelo Trevino, Senior VP of Regulatory Affairs and Quality Systems at Applied Medical, provides insights on how to avoid some of the most common mistakes with European regulatory compliance.
If you are ready to bypass the hassle of multiple regulatory inspections and undergo a single, rigorous audit which satisfies the quality regulation of each jurisdiction, consider transitioning to MDSAP.
Author: Suzanne Broussard
When preparing for the MDSAP audit, it is important to understand that the audit focuses heavily on risk-based processes, outsourced processes, and validation activities. MDSAP is based on the international quality systems standard ISO 13485:2016, which requires organizations to consider risk from device conception through its lifetime of use. This Risk Management includes the device manufacturer and the supply chain.
Check out our Resources page for our whitepaper on MedDev 2.7/1 Equivalence and Risk/Benefit Profile.
There are seven “Processes” in the MDSAP audit. FDA’s vision of how all these processes link together is depicted in Figure 2.
The first four “Primary” processes, depicted in the dark blue boxes, and the “Supporting” Purchasing process were all built on a foundation of Risk Management. The other two Supporting processes (note that Device Marketing Authorization and Facility Registration links to two processes), depicted in the light blue boxes, fulfill the requirements of the participating regulatory authorities. There are 90 total tasks.
The MDSAP Audit is designed with the interrelatedness of each process in mind. For example, the manufacturer must identify the linked processes and perform Risk Management in accordance with clause 4.1.2 (c) of ISO 13485:2016. One process naturally links to the next process and the audit is conducted in a logical sequence.
Device manufacturers currently selling in these markets should already be in compliance with each country’s quality regulations, but allocating time and resources for each country’s audit can be challenging. Thankfully, MDSAP’s fruition offers the opportunity to simplify this challenge. Keep in mind that companies only need to be compliant in markets they are currently selling, and organizations are not allowed to opt out of participating nations in which they sell once they adopt MDSAP (no “cherry-picking”).
Read more about how device manufacturers can benefit from the MDSAP.
The audit is very scripted and starts with the Management Process working through each subsequent task straight through to the Purchasing Process. There is no deviation in flow and every “task” is timed. Tasks sections are broken down into Clause and Regulations, Additional Country-specific Requirements, and Links to Other Processes.
The Initial Certification Audit is conducted in two separate stages, typically several weeks apart.
Stage 1 is designed to determine if the Quality Management System (QMS) and other MDSAP documentation requirements are adequate, evaluate the readiness of the manufacturer, and facilitate the planning of the Stage 2 audit. Stage 1, sometimes referred to as a desk-audit, occurs in real-time, typically via virtual communications between the organization and auditor.
Here is an example of what MDSAP is looking for in Stage 1. “Whenever a MDSAP Audit Task requires an auditor to verify the identification and documentation of a requirement in QMS documentation, this verification should be performed as part of the pre-audit preparation and documentation review, as practical, to minimize on-site audit time and to increase the auditor’s familiarity with the manufacturer’s QMS.“
A deficiency letter is sent out after the Stage 1 audit informing manufacturers of deficiencies. Corrective action can then be taken to avoid getting findings during the physical audit.
The Stage 2 audit activities determine the manufacturer’s actual compliance with ISO 13485:2016 and all the regulatory requirements of the participating jurisdiction in which they market. There are two onsite auditors that split up assignments, typically in individual conference rooms.
The flow and timing of the Stage 2 audit are based on the specific tasks that need to be performed as assessed from the information supplied in Stage 1. The duration is calculated using the MDSAP P0008 algorithm based on the number of tasks and the time allotted for each. Variables like the number of employees and the specific process activities performed by the organization are used in this calculation. MDSAP provides two tools to help determine audit time, both of which are available on the FDA website.
Author: Douglas McGarvey
Criterion Edge chats with regulatory authorities and other medical device and pharmaceutical industry experts to share their viewpoints on topics that impact our industry. With this expert advice, we aim to keep you informed about current developments and encourage discussion among those of us who work in large and small medical device, pharmaceutical, or biologic companies, CROs and other industry groups. Our goal is to offer up-to-date and reliable information to help you navigate the regulatory landscape and gain a better understanding of critical issues that affect our industry.
NOTE: This forum is not meant to provide legal advice or official policy for any participant. It is simply provided as a discussion between Criterion Edge and various experts for the purpose of sharing the thoughts and opinions of participants.
We spoke with an expert from a major European notified body about how companies can prepare for revision 4 of MedDev 2.7/1 and upcoming changes in MDR rules. We discussed how these new regulations affect both new and existing products. Our expert says that the new MDR regulations pose serious implications for clinical evaluation reports based on literature review.
In the future, it will not be acceptable to build a clinical evaluation report (CER) based on literature instruction. This is a significant change! To put this in context, some 80% of products placed on the European market today are based on literature research. Industry experts think that that number will shrink to about 10% following the new MDR requirements.
For a new product, a literature review will no longer be sufficient to establish equivalency with an existing product. Manufacturers must establish equivalence between the medical device and its equivalent comparator. This requires comparison of devices for clinical application, biological compatibility features and technical parameters. In order to prove that these features are the same for the two products, companies will need to have access to the technical documentation of the equivalent product. It’s not sufficient to simply bring the other product to the laboratory and test it. Manufacturers will need to have two sets of technical documentation. Otherwise, the product equivalency will not be accepted.
For ongoing/annual updates, clinical literature will continue to be important. However, since there is no grandfathering of certificates, every new product will basically get to the European market in the first place based on MDR.
Once the MDR changes are in effect, the certification of many existing products will no longer be valid. Even if an organization certifies today, the certification will not be grandfathered into the new system. Every organization will need to go through the new certification process based on the new rules that go into effect in May 2020. It’s important to note the limited timeframe for the new certification process, so companies need to plan ahead.
With regard to current CERs, companies will need to revise and update all clinical reviews. First, they will need to update all of the initial CERs to meet Rev 4 of the guidance document, which is actually very close to the MDR requirements.
Crucially, it will not be acceptable to just focus on safety in order to update the report. It will be necessary to go back and prove the clinical safety of the product in the first place and then to provide updates. This is a major issue for both small and large companies.
Many companies will need to perform clinical studies and, in many cases, retrospective clinical studies. They’ll need robust programs for post-market clinical surveillance (PMCS) and post-market clinical follow-up (PMCF). With the changing rules, manufacturers will need to take a proactive, not a reactive approach, to stay compliant. Companies will need to have a very strong PMCF plan, which is different from requirements in MedDev revision 3.
Significantly, companies will need to proactively collect PMCF data. Then, depending on the product classification, they will need to produce two yearly reports with clinical data – a Product Safety Update Report (PSUR) and a Summary of Safety and Clinical Performance (SSCP). The data posted in those reports will come from the company’s post-market follow-up activities.
The Commission is creating guidance documents to clarify what it wants to see in these reports. But this reporting is not the same as a regular CER update. The two efforts must be done in conjunction with each another.
But writing the annual reports is just the beginning – evaluation of the reports is also necessary. Companies must upload the annual reports to Eudamed, the European Databank on Medical Devices, and the manufacturer’s notified body will review those reports each year.
Current discussions among notified bodies suggest that the Eudamed databank will be available by the end of the transition period or the month prior to the implementation in May 2020.
For further guidance, the Notified Body Operations Group (NBOG), a membership organization of European notified bodies, may be publishing papers with their interpretation of the regulations.
‘Ask the Expert’ is published by Criterion Edge, Inc. Criterion Edge, Inc. is a regulatory writing company that provides outsourced writing services to the pharmaceutical and medical device industries. The company’s expertise in regulatory writing best practices, honed over decades, produces superior deliverables and provides budget, resource and timeline flexibility for regulatory managers. We empower companies to deliver superior health care solutions. To learn more about how we do this, click here to contact us.
Some of our team members attended the MedTech Summit in Brussels a few weeks ago. Our President Laurie Mitchell presented on a panel with Bassil Akra from TÜV SÜD, Peter O’Blenis from Evidence Partners, and Caroline Byrd from Leica Biosystems. The topic: ‘Examining the Implications of the MDR on Data Management: Collection, Triage, Management and Reuse of Data for Regulatory Purposes.’
Author: Aarti Urs
Once your team receives the long-awaited approval to conduct a clinical study on your favorite compound or device, it is time to turn the wheels full speed. But before you begin with your study, you will need to write a detailed clinical study protocol (CSP). A CSP is the single most vital document outlining these questions: Why is the trial being conducted? How should it be executed? And what are the contingency plans? It is a crucial communication document between the investigators conducting the study, IRB, and federal regulatory agencies. According to International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) E3 , CSP is a document that describes the objective(s), design, methodology, statistical considerations, and organization of the trial. In order to write a solid, error proof protocol here are a few tips:
While writing the CSP it is crucial to keep the “audience” in mind. You will be communicating with physicians, nurses, IRB members, and scientific reviewers. Before you begin writing, read ICH E3 guidelines for the topics which are necessary to include in a fully integrated protocol. Consolidate the list of documents provided in ICH appendix 1 needed for your protocol so that you do not accidentally omit any item. These guidelines are meant to be as a guidance document which can be modified or adapted to better communicate the information if necessary.
To avoid any ambiguity and present a complete, well organized and easy to read report, many NIH programs encourage or require the use of protocol templates. There are many different templates available on the internet. Most of these templates include a detailed list of items that should be incorporated into the protocol.
The rule of thumb is to include the right amount of details to effectively communicate the study requirements to the reader of each section.
Thus, the protocol must inform the study staff about how the study treatments will be assigned, how the subjects are to be treated, and what assessments are to be performed when, with what equipment, and by whom.
It should inform pharmacy staff about how the study medication will be packed and when to dispense, return and track. It will also specify whether special storage facilities are required. There should be enough detail for the lab staff on how to obtain biological samples together with the allocation of responsibilities for their analysis.
Even at the protocol writing stage, there should be a clear idea of the data to be collected and the analysis to be performed.
ICH E3 Guideline provides guidance on the amount of detail expected from the data reporting: “The report with its appendices should also provide enough individual patient data, including the demographic and baseline data, and details of analytical methods, to allow replication of the critical analyses when authorities wish to do so. It is also particularly important that all analyses, tables, and figures carry, in text or as part of the table, clear identification of the set of patients from which they were generated.”
The guidelines also including the detailed discussion of adverse events: “The full integrated report of the individual study should include the most detailed discussion of individual adverse events or laboratory abnormalities, but these should usually be reexamined as part of an overall safety analysis of all available data in any application.”
An excellent way to simplify protocol writing is to create a concept-protocol by laying out the study schedule. This concept-protocol is an initial map showing the visit timings, study phases (e.g. screening, run-in, dose titration, wash-out, treatment, follow-on etc), inclusion/exclusion criteria and assessments, including relevant notes on how specific assessments are to be performed and what time points should be used for analysis. Mapping out the study timeline upfront reduces the likelihood of any changes during protocol writing, which in turn streamlines the production of the protocol. This is not a regulatory document so there is no standard format. It can be in a tabular form, a flow diagram or just bullet points. This is a condensed version of a protocol which can outline the “big picture” in a small, succinct format.
All protocols require a section detailing the scientific rationale for a protocol, and the justification in medical and scientific literature for the hypothesis being proposed.
The Introductory section should be as succinct as possible and should be organized in a logical, sequential manner. Background and rationale should not be more than 3-5 pages and can be referenced back to the investigator’s brochure, full grant or key literature references, if necessary.
Instead of trying to answer too many questions at the same time, it is necessary to get one primary objective right. However tempting it maybe to try to answer multiple questions at the same time, it will unnecessarily complicate the study by adding potentially confounding variables that may impede the interpretation of data. The objective should be (SMART objective): Specific, Measurable, Achievable, Relevant and Time based.The primary objective must be well-defined with a well-founded rationale that is logically explained in the introduction of the protocol. This will also help to convince ethics committees that the question needs to be answered, and that it is being addressed by the trial in an ethical way with the best interest and safety of subjects in mind.
The primary objective of the CSR dictates the primary endpoint. Primary endpoint is sometimes called primary outcome measure or primary variable. Primary endpoint also requires clarity of thought in order to justify the choice of endpoint, which needs to align with the expectations in your field. Try to keep your endpoints quantitative/ objective (e.g. Blood pressure, laboratory values etc), as opposed to qualitative/ subjective (Pain, discomfort etc). In case of subjective endpoints, try to back up these measurements with surrogate markers (e.g. laboratory value) that correlates with disease or symptoms. Alternatively, a validated scoring system can be considered.
Primary endpoints will also determine sample size. If the subject numbers run to be too large and impractical with respect to funds, it is important to consult statisticians.
Since the protocol has to be approved by both IRB and FDA, it is important to consider their complementary but distinct perspectives. IRB protects participants of the study by ensuring that risks to the participants is minimal and reasonable in relation to the anticipated benefits of the study. IRB also ensures that no specific gender, race, ethnicity or socioeconomic status of participants is disproportionately bearing burden or reaping benefits of the study.
FDA on the other hand, focuses on how the safety and efficacy of the drug or device affects the overall population. Hence the study results must provide rigorous evidence that the drug or device is for the welfare of people. Most investigators are well aware of FDA requirements but are less familiar with IRB requirements. Less invasive study designs and optimal use of all data points is the key to protect subjects and achieve IRB approval. Robust study design with validated safety and efficacy endpoints is the key for FDA approval. If a study protocol requires more than minimal risks, include a compelling rationale for the need of these procedures.
It is crucial to critically analyze yours’ and your organization’s strengths and weaknesses that would reflect in the protocol. Once you identify any weaknesses, fill those gaps by seeking outside expertise or by investing in training internal staff. Early investments to strengthen your study design will reap long term benefits.
Do not hesitate to take outside help on reviewing your protocol. Ask an outside member of the scientific community or a colleague to review your protocol. This will provide you invaluable feedback on the clarity of your writing, and whether your protocol has enough details for an outside member to understand your study and rationale behind the study.
If you lack the necessary writing expertise to generate a robust CSP, it would be prudent to seek professional writing help.
We are a team of full service medical writers with expertise in regulatory know-how and focus on flawless execution, thereby maximizing your chances of success. Contact Criterion Edge to learn more about our writing services and follow us on Twitter and LinkedIn.
As Antoine de Saint said “A goal without a plan is just a wish.” Writing down a robust plan, investing in proper resources and seeking outside expertise to bridge any internal gaps in knowledge is the key to successful execution of clinical study. Good luck with your CSP!
September 21-24, 2019
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