Regulatory submissions for clinical trial sponsors and medical device manufacturers are important moments in the journey to market. The process is time-consuming and allows no room for error. Getting anything wrong at this point can be disastrous for product development.
It’s vital then to find the best ways of streamlining the regulatory submission process. In this post, we explore how pharma companies and medical device manufacturers can simplify the process. But first, let’s take a look at how the broader regulatory market is aiming to improve the situation for companies bringing a product to market.
Portal to Simplification
While there are specific strategies trial sponsors can pursue to expedite their submission process, the greater industry framework has also aimed to simplify this process.
Specifically in light of the increased focus on orphan drug development, the European Medicines Agency has created a portal called ‘Iris’ to improve and simplify submission applications, writes Andrea Sisneros at contract research organization Envigo.
The portal allows sponsors to follow their applications in real-time, receiving updates as they progress. Another bonus is that it does not require sponsors to tell the EMA of their intention to submit an application for an orphan drug, instead requiring that orphan designation applications be submitted before published submission deadlines.
This is welcome progress, but Sisneros cautions that simplification does not equate to being simple. Consider that the number of applications for orphan drug development have climbed from 548 between 2000 and 2005, to 1,151 between 2011 and 2015. Yet research shows that between 2000 and 2017, 28 percent of orphan medicinal products failed to reach marketing approval due to a combination of insufficient data, failing to meet quality and safety standards, as well as regulatory and commercial concerns.
Researchers studying gene therapy trials will also enjoy a simpler submission process. Indeed, these will be treated the same as any other clinical trial now that the National Institutes for Health has relaxed its regulations, explains Rikita Patel at BioNews. Of course, the gene therapy trials will still need to meet FDA requirements, but now have one fewer regulatory hurdle to clear.
The change is significant as it removes duplicated efforts for sponsors, which previously had to make submissions to the NIH and FDA. And while welcomed by many, Professor Mildred Cho, a biomedical ethicist at Stanford University, is concerned that the relaxed regulations are premature, and the industry needs first to know more about how gene therapies work.
FDA to Forego Paper Requirement
Another step towards simplification comes from medical device regulators at the FDA, who are set to abandon paper requirements when submitting applications to regulators in favor of a single electronic submission.
This rule will apply to most medical device premarket applications, such as 510(k) premarket submissions, investigational device exemptions, premarket approvals, humanitarian device exemptions, and applications to the Center for Biologics Evaluation and Research, writes senior regulatory analyst Stewart Eisenhart.
The Chinese Model
Last year the Chinese Ministry of Justice also revised regulations concerning medical device developments. The aim is to improve what is required in terms of clinical evidence, approval procedures and post-market surveillance, explain Stephanie (Xing) Huang and Jasmin Hunter at QServe.
To achieve its goal, the ministry wishes to ease clinical evidence requirements by no longer requiring companies launching medical products in the country to file a clinical evaluation report (CER) during the technical file submission phase. Products already require CERs for trials in the US and Europe, but need an additional report for the Chinese market. Huang and Hunter say this shift will drastically speed up, simplify and lower the costs of the submission process.
It’s important to note that the proposed lifting of the CER requirement is for lower-risk devices only; class III devices will still need a China-specific report.
Again, for lower-risk devices, foreign companies looking to launch devices in the Chinese market will be able to forego Chinese-specific test reports and can use their own in-house self-testing reports instead. Higher-risk devices can show a test report from either third-party test labs in China or a foreign test lab.
Huang and Hunter explain that this will likely result in a faster submission and approval process. They also note that the changes to policy means foreign device manufacturers can bring their products to the Chinese market even without market approval in their home country.
New EU Rules and Brexit
With EU regulations changing in 2020 and the UK about to sever ties with the regional body through Brexit, the clinical research industry can breathe easy. There’s a transition period running until the end of 2020, during which time all EU laws governing clinical research will apply to the UK. And as George Underwood at Pharmatimes explains, the EU’s proposed new clinical trial regulations will come into force in 2020, and be binding on the UK.
However, even if new CTR legislation isn’t enacted before the end of the transition period, UK laws will remain consistent with EU regulations to ensure researchers in multinational trials can act with certainty.
Too Much Too Soon
With regulators making an effort to simplify regulatory submissions, sponsors must make a concerted effort to get it right. Of course, data is key here. While sponsors need to submit sufficient amounts of data to meet the regulatory requirements, they should be careful of providing too much information. The result of doing so is that sponsors may need to make unwanted changes later on in the process, says Drew Barlow, vice president of regulatory affairs at Syner-G Pharma Consulting.
Essential information in an initial Investigational New Drug submission includes drug dose form and quantities, and notes about the defined study population. However, when trials progress beyond phase I, sponsors will need to submit preliminary efficacy data, and any stability or impurity concerns.
Know Your Format
The Clinical Data Interchange Standards Consortium sets out in its Study Data Tabulation Model (SDTM) the format in which regulatory submissions from sponsors must arrive at the relevant regulatory body. This is to ensure data is submitted in a consistent way so that review times and cross study analyses are improved.
The benefits of standardization include savings in time and resources, better comparisons of studies and submissions, improved data sharing and greater transparency, explains Nicola Tambascia, programming project leader at life sciences company Sanofi.
Regulators demand submissions to meet standards such as the Analysis Data Model (ADaM) for analysis of datasets and the Standard for Exchange of Nonclinical Data (SEND) for non-clinical data.
The SDTM standardizes the way data is submitted so each trial is the same and processes such as data collection, management and reporting can be simplified, Tambasica says. Submitting according to SDTM format ensures that data aggregation and warehousing is easier as are mining and reuse of data.
CTMS for Regulatory Compliance
Of course, there are many different types of CTMS available, but best practice dictates that they should streamline data collection and analysis. When regulatory requirements are fed into a CTMS, sponsors can ensure tasks are not duplicated and human error mitigated.
Regulatory Submissions for Medical Devices
Taking a holistic view when making regulatory submissions is essential. But let’s focus specifically on the market journey for medical device manufacturers.
Medical device manufacturers must deliver a single source of truth in which a submission contains all the necessary information required for approval, according to Alex Butler, medical device solutions manager at software provider MasterControl.
The next consideration is to ensure adequate personnel power, as an organization’s regulatory team is often understaffed. This is when errors happen. A properly staffed regulatory team must then keep track of any product expirations and registration deadlines.
Finally, the team must be ready to adapt to any changes to regulations and standards.
Prepare a Human Factors Report
Again with specific focus on regulatory submissions for medical devices, Marcelo Trevino, SVP of regulatory affairs and quality at Applied Medical, says a human validation test is essential during premarket submission. In it, regulators should see there have been no user errors.
The report should include a description of the people using the device, how and where they will use it, and the training required to operate the device properly. There should also be information provided about user problems and errors, as well as safety risks.
Trevino says the report does not require test data to be included but there should be ample information for regulatory reviewers to see what the user issues were and how they were solved.
Computational Modeling in Regulatory Submissions
Computational modeling in regulatory submissions for medical devices can be used in two main ways. In a study led by Dr. Tina M. Morrison, Chair of the FDA Modeling and Simulation Working Group, it was found that, first, simulation results can provide supporting (digital) evidence in a marketing application. “The second is when simulation is a medical device, such as for clinical decision support; this is ‘software as a medical device.’”
The researchers offer some examples of ‘software as a medical device’ products that used computational modeling and received FDA clearance:
- Heartflow, which simulates blood flow in a personalized 3D model of a patient's coronary arteries.
- CardioInsight Mapping System, which simulates the electrical activity in a personalized model of a patient's heart and torso.
While the research team is pleased to note the successful uses of computational modeling for regulatory submissions, they are quick to say that more needs to be done so that others adopt this practice. Yet reports generated when using computational modeling are an effective means to improve acceptance of submitted digital evidence submitted.
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