Joseph Constance 

As clinical trials grow in complexity, clinical operations (ClinOps) professionals are finding it challenging to keep pace and fulfill their oversight responsibilities. Their workloads are increasing like never before, and their resources are not helping them keep pace with a tsunami of data, much of it unstructured. One of the central areas of data requests come from their internal company colleagues in regulatory, for data that regulatory bodies will eventually require, as well as data requests from regulators themselves.

Mike McLaughlin, Associate Director of Clinical Operations at Dermavant Sciences, Inc., says the major ClinOps issue is dealing with large amounts of data and a lack of standardization. “It was much simpler when we dealt with paper files and not electronic data,” he says. “Now we have to sift through and streamline the data and find the data that provides the most value.

“Different companies collect data in different formats. For example, there’s a recommended DIA file structure and format for the TMF, but not all companies file documents using the same file structure,” McLaughlin explains. “It is more difficult to review the TMF if the documents are not structured and formatted correctly. Time-consuming manual labor is needed to correctly structure and format the documents. Software could speed this task.”

Karen Roy, Co-Chair of the DIA-founded Trial Master File (TMF) Reference Model and Chief Strategy Officer at Phlexglobal, a technology and services organization for clinical and regulatory matters, continued: “I think the biggest challenge is that the regulators want to see the detail behind the documentation, including the different systems and audit trails that back up the documentation and (ClinOps) activities. It’s no longer just a matter of providing a few documents to review. This has made the TMF much bigger because people don’t know exactly what they should be collecting or presenting to regulators. They collect way more than they used to, and sometimes more than what’s needed. Mandates have made it harder to keep up from a regulatory perspective.”

“There’s pressure on clinical operations to produce data in a consistent, manageable, and compliant structure for their colleagues in regulatory affairs and operations to streamline submissions. But there are different mandates to follow, such as the Electronic Common Technical Document (eCTD) for the FDA. It’s challenging, especially when you have mandates within mandates creating duplicate work,” adds Jim Nichols, Co-Chair of DIA’s Regulatory Information Management Committee and Chief Product Officer at Phlexglobal. Roy and Nichols add that sometimes the mandates are not clear, leaving ClinOps in the lurch.

Paul Fenton, President and CEO at Montrium believes there has been poor compliance with registering metadata against documents because the process is very labor-intensive and ultimately, “We don’t fully leverage the metadata as an information source. We can scan documents using AI and identify a broader range of metadata that could be extracted from those documents and used to provide a richer base of information about particular types of documents, a particular trial site, or a particular process,” he states.

Several companies are developing AI solutions to recognize documents and metadata, make them more structured, and perform automated extraction on indexing of information. He expects to see these types of systems, which are much more integrated and process driven, with AI and machine learning tools built in, in the next two to three years.

In addition, development of a forms management solution, which would be part of the TMF, would allow companies to collect and add data in a much more structured way directly into a database, according to Fenton. “When you initiate a site, there are many forms that must be completed, which provide basic information about that site, like FDA Form 1572. These forms could be filled out electronically online instead of being uploaded as a document, which would make the data easier to integrate and exploit,” he says.

Fenton chairs a group which has developed a standard for exchange of TMF information between systems, eTMF Exchange Mechanism Standard that is a sub-group of DIA’s TMF Reference Model. They have started to define areas like standard metadata, which is a step toward having more standardized information about operational documentation.

“There’s a lot of variability in terms of the information we have to manage,” Fenton continues. “There are probably around 500 different types of documents collected in a TMF, which all have their own format, and formats can change from one company to the next. Standardization will help, and machine learning could help unlock the gold mine that all of that information represents.”

Jim Reilly, Vice President, Vault R&D, Veeva Systems, a provider of cloud solutions, said, “Why can’t we use AI in the form of natural language processing or machine learning to examine content as it comes into a TMF and automatically classify and attribute metadata to the documents so that we don’t have to spend much resource time reviewing material that’s already been received? This would be a tremendous cost and time saver.”

Although requiring more effort on the part of sponsors and CROs, McLaughlin thinks it’s important that the FDA wants more sponsor oversight and is placing more emphasis on quality. “The current guidance (ICH E6 (R2)) is more specific than in the past. They’re driving home quality and risk assessment to make sure that clinical trials are performed with care.”

In the guidance document, the FDA updates and further outlines responsibilities of institutional review boards (IRBs), investigators, and sponsors based on “evolutions in technology and risk management… to increase efficiency and quality.” The goal is to improve clinical trial design, conduct, oversight, human subject protection, and the reliability of trial results.

“Sponsors must review documentation on a regular basis, ensuring that CROs are following good clinical practice. As sponsors, we’re responsible for making sure that the obligations that you’ve transferred over to the CRO are being fulfilled,” McLaughlin notes.

“It’s incumbent upon sponsors to be accountable for their trial execution even when they outsource. So, it’s important for them to have a mechanism by which they can accurately receive information from their service providers. Technology can have a significant play here,” explains Reilly.

He thinks that technology needs to “up its game” and provide a consistent mechanism that enables CROs and sponsors to share and exchange information, driving better trial oversight. Part of this involves having better operational data standards and consistent data standards, but he also believes there is a need for technologies that have open connection points, and which are networked so data can flow between CROs and sponsors and be better understood by the receiver.

There is discussion of using artificial intelligence (AI)—as in many areas of pharma—to build quality into unstructured and structured documentation that becomes part of the TMF. “Regulators are increasingly supporting the use of Quality by Design principles (QbD) in clinical trials. Risk-based quality control is a key component of QbD,” Roy explains.

Addressing risk management and taking a risk-based approach pushed by regulators is important for Fenton. But clinical trials contain a lot of information.

“A clinical site might be higher risk because they’re recruiting a lot of patients, or there may be many safety cases at that site, or delays in providing information that can impact risk. We should be able to flag groups of documents or information that should receive additional scrutiny, QC, or verification because they’re considered an inspection risk. Machine learning could improve the risk models over time,” explains Fenton.

While AI can be used to check documentation for quality and to help with risk assessment, there also is a need to collect data from disparate sources more efficiently and to unify the data collection process. “Companies haven’t been the best at building quality into documentation from the beginning and putting processes, such as the ALCOA framework, into their systems,” states Roy. She suggests adding ALCOA and other quality processes to source systems and then using AI to analyze the documents and transfer them to the centralized TMF, which would bemore efficient.

It’s also important to map out what technology can do. Technology can bring things together and indicate knowledge and data gaps. But it won’t tell you which documents are needed, unless it is directed to that need. This is a skilled task that requires the expertise of the ClinOps team, or outside experts, adds Roy. And that subject matter expertise can be built into technology to essentially establish a risk-based approach to a process to check on documentation.

McLaughlin is hopeful that advanced software, such as AI and machine learning, will remove some of the burden from ClinOps personnel, for example by helping to structure any unstructured data, optimizing documentation in the TMF, and by helping trial participants remain compliant with their medications. But he thinks the technology still requires additional commercial exposure before it can fully demonstrate its usefulness in clinical trial settings.

“ClinOps people can do many tasks but they are struggling to keep pace with regulatory requirements,” Nichols explains. “Compliance is taking up more time and effort from trained people to do manual, repetitive tasks. These tasks are tailor-made for AI technologies, such as machine learning.”

To connect the dots of the ins and outs of the trial, including the many different study events, Fenton indicates a standard process model could be established that defines all of the processes that occur in a clinical trial, including the events that trigger them and the data required to describe them. This model would then be used to pull information from different sources.

“Technology can help by leveraging this model. But the model needs to be defined by people who know about clinical processes and by the regulations,” Fenton says. “We can improve the model over time by making connections between different processes and events as well as looking at historical data through machine learning and AI.”

Another related technology trend Alok Tayi PhD, Vice President of Life Sciences at Egnyte, sees is the emergence of natural language processing (NLP) in the clinical trial space. “NLP promises to automate rote tasks and improve data integrity by helping staff extract key data from study reports, CVs, and other documents,” explains Tayi. Recent advancements in NLP enable software to perform cognitive tasks, like document classification, data extraction, and even summarization. Tayi believes that these novel capabilities, integrated into the trial workflow, will allow trials to process quickly new data, check for inaccuracies, and extract insights quickly.

Reilly is encouraged by how the FDA and other regulators are piloting initiatives that can make the review process less difficult. The agency’s Real-Time Oncology Review Pilot Program aims to explore a more efficient review process which includes companies submitting top line results as they occur, speeding the review process.

“In many ways they’re pushing along the data directly to the agency rather than compiling it in a big package. Technology can help with modern submission tools and mechanisms where data can be compiled in a normalized sense and pushed into the regulatory system. A more hardened connection between clinical and regulatory can make a real-time submission process more efficient,” Reilly explains.

Tayi expects AI algorithms will help the industry address key data privacy issues. AI can help sponsors, sites, and CROs monitor their data for sensitive information and ensure compliance in an automated fashion. For example, technology can ensure that consent documents are properly classified, or that data managers are alerted to personally identifiable information (PII) embedded within the metadata of CT imaging. “But we need clarity on how to train the models to help identify data as well as very specific regulations to which we can tie the data,” Tayi notes. He also sees AI helping structure data and metadata for one’s TMF.

In addition, as sponsors and CROs consider running new types of trials, such as virtual clinical trials, data privacy risks are heightened. According to Tayi, institutions will need automation and AI software that ensures that the right people have access to the right data, without the overhead and burden to the team.

Articles

Clinical operations professionals, burdened by lack of data standardization, turn to technology in hopes of streamlining regulatory processes for the future.

Regulatory Data: How Technology Can Help ClinOps Survive

Many emerging biopharmaceutical companies are highly dependent on the success of one product—usually their lead compound. Because of limited staffing and regulatory experience, many hire contract research organizations (CROs) to help them navigate the regulatory pathway, leaning on their expertise, foresight, and knowledge of the complex landscape.

Some emerging biopharma aren’t completely satisfied with their CRO relationships, and believe the CRO partners could be more responsive to their needs, particularly in light of the increasing role these smaller companies are playing in driving drug innovation—responsible for much of the life sciences industry’s R&D pipeline in recent years.

Emerging biopharma companies developed about 65% of the new drugs approved in 2018 in the U.S., according to IQVIA. In addition, of all companies sponsoring one or more clinical development program, 61% are not among the top 50 largest pharma. Moreover, 60% of FDA approvals in 2018 went to firms that had never before received an approval.

These small biotechs are under pressure to get CRO and vendor partnerships right from the start, much more so than for big pharma, because they cannot afford missteps that cost them time and money. The smaller operations simply don’t have the financial resources that larger pharmaceutical companies have, making the smaller biopharma more sensitive to such problems as clinical trial timeline delays, out-of-scope change orders, and cost overruns. For many, one poorly-designed clinical trial could end their existence.

The relationship between emerging biopharma and CROs continues to evolve, but are CROs, especially the larger ones, tailoring their service offerings enough for these fledgling, important players, given their unique operating constraints compared to big pharma?

It’s helpful to have all of the bells and whistles that new technologies can bring to a clinical trial, but small companies also need a high-touch relationship with CROs. Many are looking for close contact and good oversight on the part of the CRO. They want a service provider that’s mindful of their small-client needs. They don’t want to feel like they’re just a drop in the bucket of a large CRO’s business.

“With worries about cost overruns, financial issues, and paying enough attention to detail, I’m looking for a smaller CRO that I can connect with, who would be very responsive, and a contact there who takes on responsibility,” Audrey Rossow, senior director of clinical operations at Pulmatrix, Inc., a developer of pulmonary-delivered therapeutics, tells 

. While partnering with a CRO with pulmonary or rare disease expertise would be beneficial, Rossow adds, “We need, above all else, transparency, flexibility, and problem-solving skills from a CRO.”

As a small company running clinical trials, Rossow’s concerns include avoiding cost overruns and timeline delays, and executing properly designed trials with little deviation as possible from the trial protocol. Essentially, what’s important to her is a CRO partner that pays attention to detail and meets timelines, which in Rossow’s experience has not always been the case.

“For small biotechs, a week for us is like a month or two in terms of making decisions and getting things done. I don’t need the Titanic, I need a speedboat,” says Rossow, who has a deep background in clinical operations and project management; before joining Pulmatrix last fall, she was a consultant for 10years.

When interviewing CRO project manager candidates, Rossow notes that it’s the answers to the soft questions that are most telling. “What would a CRO’s tactical and financial plan be if they are 10 months behind in activating trial sites, or months behind their enrollment timelines?” she says. “I want a project manager at a CRO that I can completely connect with. In my career I’ve had to change projects managers at CROs, and it was the best decision I ever made because someone else came on board and got what I was talking about, and got things back on the rails.”

Mike McLaughlin, associate director of clinical operations at Dermavant Sciences, Inc., says the company is seeking a CRO partner with a mindset and culture similar to its own. “It’s important to find a CRO that’s a right fit from a culture standpoint, with a culture similar to ours, which is to be nimble, quick, and flexible, and offer a quick turnaround,” he says.

“We’re concerned that we’re just a drop in the bucket in a large CRO’s financial portfolio. So then how much attention are we going to get?” adds McLaughlin. “We need a CRO team that’s high quality, high performing, and offers overall support.”

Dermavant, a clinical-stage biopharma company focused on the development and commercialization of in immuno-dermatology treatments, has five candidates in various phases of clinical trials. McLaughlin says that for fairly small Phase I or II studies, he prefers to link up with a smaller CRO that’s more sensitive about costs and meeting deadlines. In addition, the contact person at the sponsor would likely be easier to reach to discuss any concerns, McLaughlin notes. In his experience, a smaller CRO can often provide an experienced, flexible, and responsive team with low staff turnover.

McLaughlin says it’s important for an emerging biopharma not to be “shoehorned” into a larger CRO’s system, where it’s more difficult to pick and choose the services and support the sponsor needs. The alternative can often be service offerings that are redundant to a biopharma’s internal capabilities.

When considering CRO partnerships, McLaughlin looks for quality and thoroughness in CRO proposals, which help quantify capabilities. He’ll also discuss the candidates with colleagues, but sometimes the decision ultimately comes down to gut instincts, he indicates.

“All sponsors are looking for quality, timeliness, and staying within budget from their CROs,” he says. “I want to keep changes and costs to a minimum.”

Among specific deliverables from CROs that emerging biopharma’s are looking for, according to McLaughlin, include:

Starting the study on time and meeting enrollment deadlines.

Establishing trial sites of high quality.

Delivering a properly formatted clinical study report shell and statistical analysis plan.

“It’s important to calculate and track your interactions and activities along the established timeline,” he notes.

Possessing certain intangibles are key as well, says McLaughlin, such as trust, good communication, and being proactive. “A CRO team of high performers and experts will make it easier for us to develop a good relationship,” he explains. “It’s like dating. We’re trying to develop a good relationship. It’s an engagement that you’re about to go through, for better or worse, for the next six months, year, or longer. The clinical trial needs to have a good start for the relationship to work.”

Jim Barlow, CEO at ImmunoGenesis, Inc., which designs therapies targeting immune resistance in immunologically cold tumors, is planning for the company’s main trial to get underway in 2021. “As for a CRO partner, we’d be looking to link up with a company that has oncology experience, although it would not necessarily have to be exclusively oncology,” he says. “It’s important that they have some experience with oncology trials, and that they know the pitfalls and challenges in the area.”

Barlow notes that small biopharma companies have fewer resources, and thus are “laser-focused” on a single clinical trial most of the time. “The company team will know the ins and outs of that study, and will work on it every day. It will typically handle budget negotiations with the trial site partner, and most of the logistics around training and site initiation,” he says. “But if you’re running several trials, you’ll need a CRO that can take command and coordinate all of the trial work.”

Barlow would like to be able to pick from a menu of services and support offered by a CRO. For him, adverse event reporting, the statistical analysis plan, project management, and addressing regulatory issues would be very important.

“Being able to have a modular approach where you could pick only the services you need would help bring fixed costs down and would be a huge advantage,” Barlow tells 

. “We might have a trial operating at only two sites, so it’s not the same amount of legwork needed as if we had 50 sites. But we’re still going to need some of the key systems the CRO will offer, so I would like to negotiate on these.”

Another option for the smaller-sized sponsor, Barlow suggests, is considering hiring CROs on a consulting basis for specialty tasks, and still gain access, for example, to their statistical analysis group, adverse event reporting, or their knowledge of local markets and regulatory requirements.

Executives note that sponsors will sometimes encounter a serious design issue in the middle of their study that they didn’t plan for when initiating. “While a challenge for big pharmas, the impact can be significantly greater for smaller companies who already have much more limited budgets and resources to consider,” says Tanya du Plessis, vice president of data strategies and solutions at the Bioforum Group, which describes itself as a data-driven CRO, offering expertise in clinical data management and biostatistical analysis, among other services.

Essentially, big pharma organizations have large, cross-functional teams with an array of specialists in-house, unlike many smaller companies who do not have the budgets or scale to staff their teams as comprehensively—and with people who have deep experience addressing all the issues that can come up and disrupt a clinical trial.

“We try to understand how emerging biopharma companies operate,” du Plessis says. “We help them by offering smart solutions. We try to be nimble because we realize the limited options that small biopharma may have.”

CROs recognize the importance for sponsors in getting the right advice and guidance early on so that they can design the study properly and collect the appropriate data from the onset. “It all comes down to thoughtfully mapping out a data collection and management strategy that builds in flexibility from the start,” says Amir Malka, president and co-founder of Bioforum. “You need to put a lot of effort and accuracy into designing the study and at the same time be aware of the budgetary restraints.”

It’s critical for CRO executives, according to Malka, to understand a small biotech’s level of clinical trial expertise; its data strategy, plans, and assumptions, which may require modifications; the size and complexity of the study; and how to integrate all of the technologies involved.

The significance of correctly written and designed clinical trial protocols—targeting the correct data—is greater for emerging biopharma, executives emphasize. Bioforum, for example, works with sponsors throughout the clinical trial process to FDA submission, involving itself in developing the overall strategy for a new drug candidate, as well as addressing safety and efficacy issues that arise.

Hence, data must be properly integrated from all studies before regulatory filing, a complicated process that smaller companies often partner with CROs to support. Bioforum, for instance, has experience in several therapeutic areas, but its specialty is working with smaller biotechs as a full partner, du Plessis says. The company prides itself in its flat organizational structure, which eliminates layers of management between a customer and the Bioforum leadership team.

“Even though we are a global company, we can come down to a smaller company’s scale, and develop a good understanding of their specific needs” says Du Plessis.

This involves partnering from the beginning of a clinical development program and recognizing where the potential risk spots are, Malka adds. “Our goal is to build a strong, long-term relationship with sponsors that grows as they do; so building trust is a top priority for us,” he says.

According to du Plessis, Bioforum generally encounters three types of clients: those who do not know the specifics of how to collect and manage clinical trial data; those who have predefined concepts but who require more specific guidance; and those who are in the middle of conducting a trial and encounter significant issues.

“They need to think about which technologies they want to use to collect their data. And it must be the correct data in the correct format. This takes time, and if they don’t have a background in data, they don’t have a really solid understanding of what has to be done,” she says. “We’re not going to force them in any direction, but will give them an array of options. It’s about doing their homework for them and making their lives easier. At the end of the day, we want them to feel good about the data, and they should feel confident.”

“Our client base looks for us to supplement their capabilities,” Tara Franks, chief operating officer, Translational Drug Development (TD2), tells 

. TD2 is an oncology-focused CRO that also specializes in working with biotechs.

“Some biotech companies don’t have the resources of a larger pharma. They look to our team to fill in the gaps in their internal infrastructure,” adds Franks. “This may be the first time a client is developing a drug together as a team, whereas the large pharma companies do it on a regular basis and have an infrastructure and process in place. When we engage with smaller biotech companies, we help them develop their plan and process.”

CROs specializing in offering this type of tactical and strategic support along the path to potential regulatory approval is a big appeal to the smaller, clinical-stage biopharma.

“Scientists will publish in a high-impact journal, get some venture capital funding, and form a company,” says Stephen Gately, PhD, president and CEO, TD2. “But there’s a fairly significant gap between writing a paper and actually getting a drug approved. Companies are typically technology-heavy but not development-heavy.”

Emerging biopharmas need partners that can provide a vision and context of the regulatory realities inherent in drug development— and ones not distracted by “cool science.” Their audience now is the FDA and not a scientific publication,” says Gately. “They need a pathway to approval.”

TD2’s service focus in this area includes aligning the science of a client’s molecule with the regulatory requirements for clinical testing and potential marketability.

The company has a staff of experts who assist with and write the sections of an investigational new drug (IND) application related to the chemistry involved.

TD2 and others can solicit requests for proposals from institutions that manufacture drugs, select those vendors, and support and audit those companies. CROs focused on the emerging biopharma space often have expert toxicologists who can establish the requests for proposal, can identify the clinical studies absolutely necessary, the minimum number of trials required, conduct the studies, audit the sites, and generate output of all study results in a format suitable for FDA submission, says Gately.

“We’ve had the responsibility for 30 full oncology INDs where our team managed every single aspect and presented the technology to the regulatory authorities,” he says. “Some companies come with data from perhaps a single academic center, where they evaluated the technology against one particular tumor type. And they conclude that the therapy can be developed against that same tumor type. Those companies have access to capital. But they don’t always bring with that access a tactical and strategic approach.”

is an independent writer and analyst based in New Jersey. He can be reached at jacpub@gmail.com

Stakes are high for emerging biopharmaceutical companies to get their relationships with CRO partners right from the outset.

Joseph Constance

Articles

Regulatory Data: How Technology Can Help ClinOps Survive

Small Biopharma and CROs: Seeking Stronger Synergies