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.’
Bassil Akra introducing the panel
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:
1. Always begin with a template
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.
2. Include right amount of details
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.”
3. Create a concept-protocol by mapping out the schedule
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.
4. Keep your background to the point and provide solid rationale for your study
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.
5. Have a clear primary objective
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.
6. Be clear about your endpoints
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.
7. Consider multiple perspectives (FDA vs IRB)
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.
8. Recognize your weaknesses and invest in gaining technical expertise if necessary
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.
9. Get your protocol reviewed independently by experienced peers
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.
10. Get professional writing help if needed
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!
Author: Dr. Suzanne Broussard
MDSAP as a Single Regulatory Audit
The Medical Device Single Audit Program (MDSAP) is now in year three of voluntarily allowing medical device manufacturers to satisfy requirements of multiple regulatory jurisdictions with a single audit. Understanding the basics of MDSAP is the first step to determining if this is right for your organization.
Device manufacturers are starting to accept this more harmonized auditing program, with over 2,700 manufacturers having undergone an MDSAP audit as of December 2018 (Figure 1). The significant increase in audits in 2018 reflects Health Canada’s hard deadline of January 1, 2019 for device manufacturers to comply with MDSAP in order to sell medical devices in Canada. While there were plenty of concerns about the transition, Health Canada received over 3,000 MDSAP certifications or transition submissions accounting for 90% of medical manufacturers operating in Canada. The remaining 10% are companies with very low or no sales, meaning they may likely pull out of the market.
Several early adaptors are lauding the MDSAP program for saving time and limiting company resources needed for auditing agencies. These outcomes are in line with IMDRF’s primary goals for creating MDSAP, which are to “…jointly leverage regulatory resources to manage an efficient, effective, and sustainable single audit program focused on the oversight of medical device manufacturers.”
If you are one of the many medical devices manufacturers that have not yet embraced MDSAP, industry experts suggest it is time to get started! This single audit via MDSAP provides an opportunity for companies to reap the benefits of reduced audits from agencies in multiple jurisdictions if they sell products in participating countries.
Keep in mind that MDSAP does not place a single new requirement on device manufacturers. What MDSAP does is place requirements on the Auditing Organizations (AOs) dictating how to consistently perform an audit. Essentially, AOs are approved by regulatory agencies to perform audits after a rigorous process to prove competency. These AOs are charged with performing the audit in a manner that is consistent and predictable while giving a high degree of confidence that the manufacturer is in complete compliance.
FDA Touts the Benefits of MDSAP
Even regulatory authorities like the FDA are promoting the many benefits of MDSAP.
- MDSAP routine audits are announced in advance by the scheduling AO and have a pre-established duration.
- Manufacturers have one full month to respond to AOs for critical nonconformities (grade 4 and 5) compared to only 15 working days after an FDA inspection.
- MDSAP Certification documents may provide a marketing advantage.
Is Your Organization Ready to Transition to MDSAP?
Some companies that have gone through the process claim that they found the process easier than going through an FDA audit once they embraced MDSAP. Why? Because, the MDSAP audit is performed in a specific order that is predictable and clearly outlined. This approach is very different than an FDA or ISO audit, which are much less predictable. Company testimonials on the FDA MDSAP site claim transition to MDSAP save costs internally with less disruption. This sentiment is shared by other industry leaders who applaud the prescriptive nature of the MDSAP audits.
There are no surprises at MDSAP audits
IMDRF provides device manufacturers with everything required to understand and prepare for MDSAP. A plethora of resources that explain the program in more detail and help prepare for an MDSAP audit are available on FDA’s website. Best of all—they are free!
The most helpful resources are the MDSAP Companion Document and the MDSAP Audit Model.
- Both these forms provide detailed information that directly corresponds with the MDSAP audit.
- There is a section in the documents to explain what should happen at each step of the audit.
- Requirements are asked by auditors in the order presented and the flow does not vary allowing the manufacturer to better plan the audit.
If your organization sells medical devices in multiple participating countries and already maintains a high level of compliance, transitioning to MDSAP is worth considering.