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!
Author: Dr. Suzanne Broussard
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.
Even regulatory authorities like the FDA are promoting the many benefits of 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.
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.
If your organization sells medical devices in multiple participating countries and already maintains a high level of compliance, transitioning to MDSAP is worth considering.
Author: Ashley Self
When you work as a freelance medical writer, it’s easy to feel isolated. You likely work alone, and the nature of your work requires intense focus. And that’s fine…while you are working. But what about when you are looking for your next project? Or, if you are new to the medical writing field? The solitude that serves you so well while you are writing doesn’t foster a great network of colleagues, mentors, and potential employers—and it’s this network that helps push your career forward, expand your knowledge and refer you to new work opportunities.
According to a MarketWatch report, several segments of the global healthcare regulatory affairs outsourcing market are projected to increase on average more than 13% annually between 2017-2025. Use the following networking tips to ensure you have a share of this growing market moving forward.
Building and maintaining your online identity or personal brand may not feel like networking, but it forms the main touchpoint for all your future networking efforts.
With the availability of easy-to-use website building platforms, anyone can have a professional, well-designed website live in a matter of hours. Be sure to use your full name and keywords (like medical writing, CER writing, medical regulatory writing, as well as listing your areas of specialization) on your home page. You can use the other pages to feature links to work samples, testimonials or a list of companies you have worked with, a detailed bio of your experience and education, and even a blog that you update periodically (regular, keyword-optimized updates to your website make it more likely to be found in online search queries). Do an online search and review the websites of other medical writers to see what works.
Simply having a LinkedIn or other professional networking profile isn’t always enough. According to Undercover Recruiter, including a professional headshot; writing a comprehensive, keyword-optimized headline and summary; and including specific keywords in your job history and skills overview may give your profile an edge.
Most employers do a Google search of a prospective candidate’s name before they hire. Have you Googled your name? Now is a good time to find out what hiring managers might see. It is also wise to keep separate social media accounts for your personal and professional endeavors. Check the privacy settings of your personal accounts to make sure you are only sharing that information with trusted friends, not the general public. For your business social media profiles, use a professional profile photo and make sure your posts represent you as a job candidate.
Finding time to write a blog in addition to working full time might sound like a stretch. But blogging can offer benefits that static websites and online profiles don’t—regularly updated content that can be found by search engines. Your weekly blog post doesn’t need to be a four-page research paper about the specifics of a new medical procedure. It can be a short five to ten paragraphs about something new in the industry that you find interesting. Just be sure to include keywords in the blog title and body.
If you’re enjoying this read so far, get some insider tips on getting a hiring manager to pick your resume.
Now that you have a comprehensive online identity, it’s time to start making connections.
Most people find online networking less intimidating than networking in person. That makes it a great place to start. According to a Harvard Business Review article by Doug Camplejohn, VP of Product Management at LinkedIn, the best practices of online networking are:
There are several regional and international associations dedicated to the medical regulatory and writing industry. Most of them boast thousands of members and offer valuable training resources and industry updates. Once you join, try to find members in or near your geographic location. As a freelancer, much of your work may originate in a city far away, however, it’s still nice to have local contacts. Similar to making contacts via social media, you can comment on other users’ posts to introduce yourself, or generate a post of your own. Maybe ask a Word formatting question or initiate a discussion on best quality control practices—something that is relevant to your work but doesn’t cover subject matter people might be uncomfortable discussing publicly online. Alternatively, you can share an article you found interesting. Finding and joining active groups on LinkedIn is also recommended. Below is a list of well-respected organizations:
The above organizations host annual conferences that are attended by most major players in the industry. Now that you have a handful of online contacts, make a plan to attend a conference together or meet up at their booth. A couple of weeks before the conference is also a great time to ping organizations you are interested in working with to see if you can set up a specific time to meet with them during the conference to learn about their needs. Bring several copies of your business card and a short (half or full page) bio that includes a photo and your most relevant experience and training.
Networking is usually a slow process. Think of it as forming a friendship. Friendships offer value to both parties and your networking efforts should do the same. Once a relationship has formed, foster it through regular contact. You can share some wonderful tips that have worked for you. Or maybe reach out for some advice on how to handle a complicated data set. Finally, when you move up the chain and you receive a query from a newbie writer, remember to offer them the same kindness you received all those years ago and give them a hand up.
Author: Ashley Self
As a medical writer you juggle huge, complicated data sets from hundreds of source studies, analyze that data to draw conclusions and ensure all your processes meet regulatory guidelines. You simply remember all that information, right? Also, you’re perfect. You’ve never pasted a series of data into the wrong cell or misplaced a decimal point. Especially not after working ten hours straight to meet a deadline.
What’s that? You’re human?
Join the club. It’s only reasonable to anticipate an occasional error from a medical writer who is tasked with researching, analyzing, processing, and inputting large volumes of data and information. That’s why the best medical writing teams have built quality control protocols into their processes, starting from the beginning.
That’s right. Good quality control isn’t just proofing the final document before it’s submitted. It’s an ongoing process. Implementing the following best practices is the first step in a robust quality control plan.
Working from document templates is a great way to save time and ensure formatting, naming conventions and document style guidelines remain uniform in a large document. (Have MS Word do the work for you) Templates allow you, the writer, to stick to content rather than constantly having to pull up formatting tools to make adjustments as you write. When the time comes for a final quality control proof, documents created from a template typically have fewer formatting corrections and also take much less time to review. As an added bonus, working from a template can also ensure that the document will translate into the final submission format without errors.
Medical writing teams should also practice a “review as you go” approach to data extraction and writing. When adding a new data set to the document, comparing that data to the source data before moving on to the next section doesn’t take much time and can catch costly mistakes early.
To make these early interventions run smoothly, new writers should be trained on how to properly use document templates and how to run mini quality control checks throughout the writing process.
The Final Step
Even with the above protocols, in the end, a comprehensive quality control review by an independent quality control specialist is mandatory. This quality control specialist should have specific training on how to effectively review the final document based on general best practices and internal guidelines. During this final review, the reviewer will check all data against the data source; confirm that conclusions and findings are supported by the data; check for formatting, grammatical and style errors; verify all internal and external links and references; and confirm the content and structure meets regulatory guidelines.
At this critical stage, it is important to maintain an audit trail of all changes and corrections recommended by the quality control reviewer. In addition to noting these changes through a tracking feature in the software, the reviewer should note major content issues in a separate report. As the original writer, you must then go through the final document and make the changes. If there is a major error you think was noted by mistake, you can explain your reasoning in the quality control report. When any major changes are made, you must also remember to review the related conclusions to confirm the data still verifies. At this point, any dynamic links within the document should also be broken.
While a quality control reviewer’s job may seem small compared to the medical writer’s, reviewing a document that is several hundred pages long and full of thousands of data points is a painstaking process. This is not something that can be dropped in their inbox a few hours before your deadline. Quality control review should be scheduled in your original project scope. After all, the quality control review ultimately upholds your stellar reputation and keeps all your hard work from being invalidated because of a small error.
Worried you may miss something? Download our Free Quality Control Checklist.
Author: Katherine Lalicker, Editor: Ashley Self
Managing your figures, tables, references, and so much more on a lengthy, complex regulatory document can seem impossible. Even seasoned medical writers struggle when trying to make changes or add content without breaking a document. Chances are, the tools you need already exist. Read on to find out how some of the simplest Microsoft Word tools can allow for smooth changes to maintain an organized, uniform document.
CER documents need to be clear and uniform, which can make it difficult to pull content from one document to another without disturbing the style of the document. There are multiple paste options that allow you to either match the formatting of your document or paste text without any formatting. All options can be found under the Home tab on the toolbar in the copy and paste section. Two important functions for CER writing are Match Formatting and Keep Text Only.
A well-designed template functions as a formatting blueprint for your document. While some companies may provide their own template, it is important to be able to create and establish a template to ensure uniformity through your work. With a good template, writers just need to insert the information.
Preset styles found in the Styles section of the Home tab help writers focus on content and quality. Found under the Styles Pane, styles can be quickly modified to match the formatting guidelines for your document. Once a style has been added, it will appear on the styles pane where you can select them when needed.
Additional features such as an automatic table of contents and cross-referencing can also be added to a template.
Useful Tip: You can save your formatting as a template by selecting File – Save As Template.
Useful Tip: Formatting is a meticulous aspect of any complex document. To reveal formatting, click on the paragraph mark located on the Home tab and all formatting marks appear. This tool makes it easier to edit the formatting without losing content.
In large, information-dense documents, it is counterproductive to scroll endlessly to find sections of interest. A well-done table of contents in MS Word makes finding specific content simple. This creates a link between corresponding titles in a table of contents instead of requiring a user to manually insert a cross-reference for each section. A table of contents is easy to insert, but users make some common mistakes that can affect the efficiency of the automated tool.
Formatting styles are critical to creating a table of contents. Word provides preset automated table of contents options that require you to pick a style for each of your title types. You will notice that “Heading 1,” “Heading 2,” and “Heading 3” are located where the chapter titles and sections will be. Applying the corresponding styles, located in the Styles section, will determine the format of your table and which titles are linked.
Decide what text you want to be included on the Table of Contents and use either Heading 1, 2, or 3 – Go to References – Table of Contentson the left side of the ribbon – Choose from the Automated Table of Contents options that are previewed
As a good practice, the table of contents must always be updated at the end of the writing process. Updating the entire table will revise heading changes along with page numbers.
You can modify your table of contents by selecting the Custom Table of Contents option. Changes can be made to the table format and what you want to be included on the table in the dialogue box.
Cross-referencing connects items within a document, similar to a hyperlink, for smooth navigation, which is useful in lengthy documents. You want to use this to ensure the reader can access information quickly without needing to manually search for it. The cross-reference tool can be used to link headings, footnotes, captions, figures, and tables to where they are in the text. Did you know that cross-references can be updated just like the table of contents? Updating is crucial because content is constantly moving around the document from page to page.
To insert a cross-reference, go under the Insert or Reference tabs, and choose the type and caption.
Insert tab: Insert – Link – Cross-reference
References tab: References –Cross-reference
An added benefit to using cross-reference is that it will actively change based on the output. If a document is printed, the cross-reference will change to tell the reader where the content is in printed form.
Some writers recommend this book, Microsoft Word for Medical and Technical Writers, as a good read to familiarize yourself with all that MS Word can do for complex medical writing needs.
When pulling tables from PDF documents onto a Word file, a simple copy and paste doesn’t always do the job, requiring the writer to recreate the table. These tables can include important information on instructions, uses of the product, and complex clinical data.
Once you insert a table, use the table Design and Layout tabs to quickly customize a table. The preset styles are a good place to start and can be altered by selecting the menu under Modify Table Style. A modified style can then be saved so it is available anytime you need it.
A split table can cause confusion, especially when a large amount of information is being presented. To resolve this, we can go under the Table Properties and select Repeat as header row at the top of each page to make sure the headings of the table show up if a large table splits across pages. Additionally, by unchecking the box for Allow row to break across pages, you can also prevent a row from splitting up.
It is common for a company to want their logo and additional information included on the top and/or bottom of a document’s pages. Headers and footers are integral to any document for this reason and include features that can make editing them easy.
Once you have opened the header and footer edit option, either by double clicking one or choosing the option to insert one, the Design tab appears. Here you can choose style, formatting, and content you want to be included in your header and footer.
Headers and footers, like page numbers, can be excluded from the first page.
Including page numbers is critical in any long document, but there are other benefits to using them in technical writing. Page numbers can be used in cross-referencing when the text is referring to information found on a specific page. Page numbers can also be modified to fit the needs, and style, of your document.
By default, a number will always appear. However, you can unmark the box that reads Show number on first page when you are first inserting page numbers. This will turn the second page into “page one” of the document, a useful tool for when you have a cover page.
Many people will likely be reviewing your document, which is why the ability to track each user’s activity on a long document is so important. Word provides tools for tracking changes, edits, and comments. These tools are useful when one or more people are reviewing/editing a document. All of this can be done under the Review tab.
Changes can be tracked by clicking the Tracking menu – turn on Track Changes. Comments can be inserted by selecting New Comment.
All changes and comments will appear on the side of the page and indicate what has been changed in the document and comments that have been made.
Useful Tip: The Navigation Pane makes it easy to view changes and comments. In addition, it includes a tab where you can view your table of contents and click through it without needing to scroll back the top of the document. The Navigation Pane can be made visible under the View tab.
Clinical Evaluation Reports (CERs) often include figures and tables that do not always fit on a regular, portrait-oriented page. Page orientations can be found in the Layout tab. If you have a table or figure that is too wide for one page, it is possible to change the orientation of that single page to Landscape.
Adjusting the orientation to fit specific content saves time and ensures you do not need to alter or potentially lose important information.
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