Interview: Surviving the Paperwork After Clinical Stage Drug Development

The process of drug discovery and development is an extremely complex one – we all know that. It requires highly skilled scientific staff, experienced project managers, and heaps of funding. But a company might have all the money and research it needs, and still fail. Why? Because the paperwork is so hard.

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Mary Mattes, Senior Vice President for Biometrics and Drug Safety at Synteract

During preclinical research and later on in clinical phases, companies need to be in constant communication with the regulatory authorities, resulting in piles of applications at every step of the way. After their early-stage meetings and their initial submissions  – the Initial New Drug (IND) application in the US and the Clinical Trial Application (CTA) in Europe – a company’s drug may have reached its pivotal phase III study.

And now? The dossier submission – a selection of documents and data that sums up the entire story of how a company’s product developed and evolved. Based on the dossier, the product will gain marketing approval – or not. But what goes into such a complex submission? What happens if a submission deadline is missed? How can companies get help? To answer these questions, we have caught up with Mary Mattes, Senior Vice President for Biometrics and Drug Safety at Synteract.

What type of information is included in a dossier submission?

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The dossier submission is used by the regulatory authorities to decide whether to approve a product for public marketing or not

The dossier submission usually happens after a successful phase III, and the dossier is the vehicle the regulatory agency uses to approve the use of a product. Its format is governed by what we refer to as the Common Technical Document (CTD). Basically, the goal of the CTD is to tell the entire story of a company’s product – of their drug, biologic, or device. The CTD is then submitted to the regulatory agencies and they decide whether they will approve it for public marketing or not.

So, the dossier submission includes information about the preclinical work, such as the development of the compound and the various  animal studies. Then it contains data from the clinical side like, how the drug behaves, as well as information about how the drug is produced, which is commonly called the CMC (chemistry, manufacturing, and control) section. And the Integrated Summary of Safety (ISS) and the Integrated Summary of Efficacy (ISE) documents hold information about the safety and efficacy of the product .

Another part of the dossier submission contains commitments as to what a company will do in phase IV. For example, nowadays companies actually have to include a pediatric study plan. There’s been a lot of changes in the laws over the last few years in the US and Europe, requiring companies to actually look at the performance of their drugs in the pediatric population. The pediatric safety study might be carried out after the drug is approved, but with submission, the company commits to completing this kind of study within a certain time frame.

What happens if a company doesn’t stick to the submission timelines?

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The decision of the regulatory authorities is a company’s golden ticket

The sooner a company gets their submission reviewed, the sooner they’re going to be able to  market the product. That’s what drives a company to hit their submission deadline. First, market authorization will bring the drug or product to the patient population, and second, there’s a huge business and financial aspect to be considered.

As a consequence, companies usually have very detailed internal timelines that have to fit into their overall corporate strategy. And there’s a lot of things that happen around these approvals. In addition to getting the drug approved from a safety, regulatory, and efficacy standpoint, they have to start their entire marketing machine, build relationships with providers, and get their drug on the prescribing list in certain countries. So if a company misses their submission deadline, they’ve likely jeopardized their own business strategy.

And once the dossier is submitted, there are some follow-up steps that are required: answering questions from the regulatory agency, providing additional requested data, or attending meetings. Any delay in meeting the timeline of these follow-up steps can further jeopardize the time it takes to market the drug. But also, more importantly, the regulatory agencies have the ability to change the review timeline – which is a company’s golden ticket, right?

So if a company misses a meeting or a certain follow-up submission, regulatory agencies can and in some cases will, put the company’s submission at the bottom of the pile or stop the clock running on their review cycle. That means they might miss the approval date they’ve been promised, or they’ll have to wait until the next set of meetings; ultimately, those things can affect the timing of a product’s launch and cost the company a lot money.

What challenges do companies face during dossier submission?

synteract, dossier submission, marketing authorization, FDA, EMA

“The dossier submission includes information about the preclinical work, such as the development of the compound” – Mary Mattes

I think one of the most challenging parts about the dossier submission is that it requires a number of workstreams to all come together. In a perfect world, a company can begin putting together their dossier as soon as they go into the first clinical phase, because they’ve got all their preclinical data by that time.

But the question of when to begin work on the submission is quite a challenging one: What if I hit my first phase II study and have a serious safety event, and this whole program gets scrapped?

So ideally, a company will have started their dossier creation right at phase I. Some companies are able to do that, but they tend to be the mega companies. At the other end of the spectrum, we have the small pharma and biotech companies, who maybe only have one drug – a drug that is going to decide whether they get to exist as a company. Often, these companies will not begin working on their dossiers that early. They don’t have the money, they don’t have the capacity, and they may have a business strategy in which they’re gambling that a large company will buy them and take over the dossier preparation.

In the end, what this discrepancy creates in the world of dossier submissions is an extremely compressed timeline and multiple workstreams: the creation of the common technical document, all of the different modules that go into it, the different data that needs to be collected and analyzed… It’s a huge job.

How can specialized groups and CROs help overcome these challenges?

When companies start their dossier submission, it is not uncommon that they find themselves in a spot where they don’t have the infrastructure, manpower or expertise. They are lacking the statistical programmers, the biostatisticians, the medical writers, and sometimes even the regulatory know-how.

synteract, dossier submission, marketing authorization, FDA, EMA

The major challenge: A huge number of workstreams have to all come together

Depending on the company, this might be their first dossier submission ever, or because drugs take so long to develop, people may only have had the chance to work on one or two submissions in their career. That is the point at which companies look for support from contract research organizations (CROs) and specialist groups.

Specialized companies and CROs have the luxury of getting to work on a lot of submissions. At Synteract we get to work with a wide range of companies, so we have a lot more experience in the submission process. We can give advice around the requirements, communicate what the document structures have to be, and what the particular rules around the submission timelines and formats are. We have a specialized group that advises companies, but that also provides manpower for some of the larger activities, like programming and biostatistics.  

At the beginning of 2018, we launched our Ready Set Submit services, because we realized that we’d done a lot of regulatory submissions and dossier preparations over the course of our thirty-year history. The Ready Set Submit package is really a way to access all of the services needed in regulatory and dossier submissions: a specialized project management group, regulatory consultation, biostatistical experts, programming prowess, medical writers and so on.

At what point during drug development should companies approach CROs if they need help with their dossier submission?

I think CROs can be most helpful at the end of a company’s phase II-meeting. Phase II-meetings are a common milestone marker with the regulatory agency. By that time, companies should start thinking about the process of their dossier preparation, and it’s also the time when they start making their business plan and building their marketing strategy for their drug.

Another piece of advice: Companies thinking about starting the dossier creation should dedicate a specialized person, like a project manager, who will work together with the partners and CROs. The complexity – the roadblocks, the obstacles, the challenges – that go into dossier submission are very unique. So it’s important to have a project management that understands all the aspects that go into it. Because, in the end, what a dossier submission is, is an extremely complex project management puzzle.

Synteract, an innovative CRO partnering with biotech and pharma companies to bring medicines to market,  was originally founded as a biometrics company doing data management and biostatistics. In the last five years alone, it has completed 12 full dossier submissions, been part of 60 CDISC conversions, and worked on over 20 ISS and ISEs. Click here to learn more and benefit from Synteract’s expertise!


Images via Bakhtiar Zein, Vector A, Joachim Wendler, JuliRose/Shutterstock.com


Author: Larissa Warneck, Science Journalist at Labiotech.eu

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