Clinical Researcher—February 2023 (Volume 37, Issue 1)

SCIENCE & SOCIETY

Jim Nichols; Cary Smithson

 

Efforts to improve the regulatory review process through standardization, harmonization, and digitalization have gathered steam in recent years with regulators and industry alike pushing forward with data-driven initiatives. Guest contributors from PharmaLex discuss what these mean for 2023 and beyond.

For the past several years, and particularly since COVID-19, regulators and industry have been on a mission to streamline regulatory reviews, remove redundancy in the submission process, and ultimately bring products to market faster while not compromising on safety.

These objectives have led to several prominent projects and collaborations aimed at leveraging digitalization and data-driven processes to assist both submitters and reviewers. In the year ahead, these initiatives are expected to gain even greater traction as all stakeholders seek to tap into more sources of data, standardize and harmonize regulatory and business processes, and take advantage of new technologies such as automation and artificial intelligence (AI) to make the entire drug development and approval process better, faster, and safer.

There are several prominent global programs overseen by regulatory authorities as well as a number of industry-led initiatives that seek to digitalize and streamline different parts of the product lifecycle—from research and development (R&D) to regulatory submission to manufacturing and beyond.

The FDA and KASA

The first of these efforts is the U.S. Food and Drug Administration’s (FDA’s) pharmaceutical quality initiative dubbed the Knowledge-Aided Assessment and Structured Application (KASA), which was announced in 2019 as part of broader work by the regulatory authority to modernize its regulatory assessments.

KASA “captures and manages information about inherent risk and control approaches for product design, manufacturing, and facilities, in a structured format.”{1} The objective is to take the chemistry, manufacturing, and controls (CMC) information that is included in submission documents and communicate that information to the authorities in the form of structured data. A structured assessment, aided by analytical tools to minimize text-based narratives, gives regulators a better understanding of the entire process and lets them make quality-based assessments in a more efficient, consistent, and objective way. The agency can also make use of KASA to tap into its broad repertoire of historical data to support decision-making.

The KASA review program is already under way, starting with abbreviated new drug applications (ANDAs) for solid oral dosage forms. The agency noted after the November 2022 meeting of the Pharmaceutical Science and Clinical Pharmacology Advisory Committee its intention to seek input on the vision to expand KASA to include all drug substances, new drug and biologic applications, and post-approval changes over the next five years. The agency also is seeking input on stepping up digitalization in KASA through data standardization and utilizing data from cloud-based servers.{2}

A related project is the FDA’s effort to develop structured data standards for pharmaceutical quality (PQ)/CMC information and a structured exchange standard for submitting those data to the agency.{3}

EMA and DADI (PLM Portal)/IDMP

Digitalization is also a high priority for the European Medicines Agency (EMA), which is replacing its PDF electronic application forms (eAFs) for regulatory submissions with digital submissions through its Digital Application Dataset Integration (DADI) project. Now referred to as the Product Lifecycle Management (PLM) Portal, the objective is to have sponsors submit information about their products in a structured fashion.

The portal will enable the EMA to build a large database of product details, all using the same terminology, to match up safety trends and spot signals that might have been missed with unstructured information. The agency has launched the web-based Human Variation eAF for centrally authorized products on the PLM portal and the development team is working on the data and functionalities needed to support decentralized procedure, mutual recognition, and national procedure variation applications. The goal is to introduce these to the eAF during Q2 2023, and to bring in further capabilities to support the transition to variation eAFs during Q2 and Q3.{4}

DADI is aligned with Identification of Medicinal Products (IDMP), since the portal will draw on elements of the SPOR (Substance, Product, Organization, and Referential) data. DADI and IDMP also offer drug and device companies a detailed framework to accelerate their digitalization initiatives. Since the new eAF will include a subset of IDMP data and offer the Fast Healthcare Interoperability Resources (FHIR) data standard, which will in time become mandatory, preparing for DADI is a key step toward IDMP readiness.{5}

Regulatory Consortia

There have also been stronger efforts by regulatory authorities to harmonize processes through several key collaborations, among them the Access Consortium, whose members include Australia (Therapeutic Goods Administration – TGA), Canada (Health Canada), Singapore (Health Sciences Authority – HSA), Switzerland (Swissmedic), and the United Kingdom (Medicines and Healthcare products Regulatory Authority – MHRA).

The health authorities from these countries collaborate to promote greater regulatory alignment, promote international cooperation, reduce duplicative efforts, and improve each agency’s capacity to review and approve products. Stated objectives for 2021 to 2024 include expanding work-sharing initiatives and sharing best practices, as well as finding ways to collaborate throughout a product’s lifecycle. One key area of focus is using real-world data and real-world evidence to inform clinical trial design, craft regulatory approaches, and support early access to emergency products, such as for COVID-19.{6}

Another regulatory consortium is Project Orbis, which brings together the FDA, the TGA, Brazil’s National Health Surveillance Agency (ANVISA), Health Canada, Israel Ministry of Health (IMOH) Pharmaceutical Administration, the HSA, Swissmedic, and the MHRA. Project Orbis was established by the FDA’s Oncology Center of Excellence to support collaborative review of new cancer treatments to speed up access for patients in need.

Industry-Based Collaborations

Several prominent industry collaborations have formed in recent years to improve the product application process, address common industry problems, and establish best practices.

Accumulus Synergy is a nonprofit organization that is working with health authorities globally to come up with a central global mechanism for submitting application information through a multi-tenant, cloud-based environment accessible by all regulatory bodies. The objective is to achieve a single product, process, dataset, and submission platform. To date, 12 pharmaceutical companies are members of Accumulus. The organization will be rolling out pilots through 2023 and plans to have the platform broadly available in 2024. One of the first pilots will involve Project Orbis, initially testing submissions of synthetic data and carrying out full data pilots over the next year to 18 months.{7}

Another industry-led, nonprofit organization is the Pistoia Alliance, which has more than 200 life sciences members, including 18 of the top 20 pharmaceutical companies. The organization has more than 25 projects under way, aimed at addressing common industry barriers to innovation, including working with regulators to adopt new standards and supporting the implementation of AI. One key Pistoia Alliance project is an Identification of Medicinal Product (IDMP) Common Core Ontology to help bridge “regional and functional perspectives on common substance-related data objects and global and scientifically objective representations by a semantically defined integration layer of the IDMP standard.”{8} The goal is to ensure data usability across organizational boundaries and regulatory jurisdictions and counter any inconsistencies in interpretation of the standards.

In a similar vein, the DIA RIM Working Group proposed the Regulatory Information Management (RIM) Reference Model to address the problem of a divergent understanding of the scope, terminology, processes, and data requirements of RIM. It is hoped that the RIM Reference Model will become a globally accepted standard, just as the trial master file (TMF) model has. This too started out as a DIA-led program and has since become integrated into Clinical Data Interchange Standards Consortium (CDISC) standards.

Streamlining R&D and Regulatory Processes

These different programs all come at a time when data have indeed become the new currency for the industry. Companies are seeking to tap into the vast amount of data they have and the ability to use data analytics to support their R&D and business goals—whether using real-world data to support clinical trials or gaining insights for a line extension or to analyze their marketing channels.

In 2023 and beyond, we are likely to see more companies make use of tools and technologies to assist them with processes such as intelligent automation, including natural language processing/generation as well as structured content management and authoring. Indeed, companies have already seen success in applying robotic process automation (RPA) to clinical and regulatory realms. In the near future, they are likely to look for further efficiencies by leveraging these tools to mine data and make decisions based on broader sources of information, as well as to tools such as natural language process to streamline authoring.

Other areas that will likely gain traction in the year ahead include the Internet of Things and RPA in manufacturing and packaging, for example, intelligent blister packs for clinical study supplies or post-market to monitor compliance with treatment protocols—innovations some leading companies are already trialling. With the trend toward decentralized clinical trials, wearables are likely to be more widely used during studies to monitor patients, and potentially even predict a safety signal.

In the area of CMC where manufacturing changes take place throughout the lifecycle of a product, companies often have to deal with different requirements globally. Here AI and other tools could prove helpful to allow companies to bundle submissions across multiple countries to optimize processes and limit redundancies.

Many of these digital innovations came to the fore during the COVID-19 pandemic as companies and regulators turned to digitalization to prevent too much disruption. They have proved that many processes can be handled better, faster, and more safely than seen from the use of previous methods. As an example, in the past, oversight of the TMF was a very manual process that involved site check-in and document collection. With more trials becoming decentralized, site visits have become unnecessary and all the information that previously was collected in-person can be accessed remotely.

The next step will be for companies to figure out how to govern these digital processes and technologies without stifling innovation to speed time to market. Already, the clinical realm has made huge leaps forward with digitalization. In 2023, we’re likely to see more digital advances to improve quality and drive greater efficiencies across organizations.

Certainly, regulatory requirements from the likes of EMA and FDA are driving change. Equally, however, companies are looking for opportunities to break down some of the functional data silos that have long plagued the industry. They’re looking to optimize their processes and streamline the handoffs between clinical and regulatory teams as well as between manufacturing and quality functions.

Meeting the Challenges Ahead

While the move to digitalization and data-driven processes creates many synergies, there are obstacles for companies to overcome. For example, companies with multiple national registrations in the European Union will need to manage thousands of entries to the PLM Portal and will also need to find a way to maintain connectivity between their internal stores of data and what ends up at the health authority.

Managing these processes will mean some internal juggling as well as putting pressure on the health authorities that are implementing digital solutions that don’t enable direct machine-to-machine information transfer, as is the case with the PLM Portal. The best way forward will be to get involved in some of the consortia that are working to bring about greater harmonization, such as the Pistoia Alliance and Accumulus Synergy.

Change management will also become more important in order to help employees adopt new processes, such as structured content management. The business will need to invest more heavily in training efforts to help people adopt new technologies. Also, as with any change, it’s likely that the early adopters will lead the charge and, as their successes become apparent, others will follow suit.

From the regulatory authority side, there will need to be consistency and follow-through. Companies have invested time and money in preparing for IDMP only to see the EMA announce a change of plan and instead adopt the PLM Portal, at least for the time being. Having spent millions on new systems and processes, master data management, and new terminologies and ontologies, companies rightfully felt the rug had been pulled from under their feet. These sudden changes of direction will dissuade industry from investing time and money in any new regulatory initiative until it becomes mandatory.

With concerns over national or global recessions or downturns persisting, companies will likely want proof that an investment will provide clear business benefit—as many automation and AI innovations undoubtedly do provide—or certainty from the health authorities.

Nevertheless, 2023 will bring more investment in digital innovations that will help to move the needle for companies—whether in R&D, regulatory submissions, manufacturing, or commercial.

References

1. Yu LX, Raw A, Wu L, Capacci-Daniel C, Zhang Y, Rosencrance S. 2019. FDA’s new pharmaceutical quality initiative: Knowledge-aided assessment & structured applications. International Journal of Pharmaceutics: X (Volume 1). https://www.sciencedirect.com/science/article/pii/S2590156719300246
2. U.S. Food and Drug Administration. 2022. Knowledge-aided Assessment and Structured Application (KASA): A New Approach that Modernizes FDA’s Quality Assessment of Regulatory Drug Applications. https://www.fda.gov/media/162865/download
3. U.S. Food and Drug Administration. Pharmaceutical Quality/Chemistry, Manufacturing & Controls (PQ/CMC). https://www.fda.gov/industry/fda-data-standards-advisory-board/pharmaceutical-qualitychemistry-manufacturing-controls-pqcmc
4. European Medicines Agency. 2022. PLM Portal eAF (DADI). https://esubmission.ema.europa.eu/cessp/cessp.htm
5. Smithson C, Nichols J. 2021. What is the EMA DADI Project – and Why is it Critical to IDMP, eCTD, RIM, and More? Phlexglobal. https://www.phlexglobal.com/blog/what-is-the-ema-dadi-project-and-why-is-it-critical-to-idmp-ectd-rim-and-more
6. Access Consortium Strategic Plan 2021–2024. https://www.canada.ca/en/health-canada/services/drugs-health-products/international-activities/access-consortium/strategic-plan-2021-2024.html
7. Usdin S. 2022. Accumulus Synergy: modernizing interactions with and among regulators. BioCentury. https://www.biocentury.com/article/645608/accumulus-synergy-modernizing-interactions-with-and-among-regulators
8. Pistoia Alliance. IDMP Ontology. https://www.pistoiaalliance.org/projects/current-projects/idmp-ontology/

Jim Nichols is Chief Product Officer at Phlexglobal, a PharmaLex company, where he has been instrumental in overseeing the product roadmap and strategies for the company’s business applications, including its eTMF and regulatory platforms.

Cary Smithson is Director of Regulatory Solutions at Phlexglobal, drawing on more than 30 years of experience in life sciences focused on leading strategic initiatives to drive increased business productivity, enhance regulatory compliance, and simplify information management and the use of technology.