By Anna Rose Welch, Director, Cell & Gene Collaborative
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Market access is one of the most commonly spoken “buzz words” and missions of the biosimilar industry. Given that even the most financially powerful nations like the U.S. are struggling to improve market access and drug affordability, you can only imagine the access challenges that exist in nations with fewer resources and less advanced infrastructures. This is why the World Health Organization’s (WHO’s) announcement of its pilot prequalification for rituximab and trastuzumab was met with industry-wide excitement and a hint of intrigue. The pilot program was officially initiated in July 2018, and, come October 2018, the WHO received its first dossier.
Though this is the first time the prequalification program was opened to these (or any) reference biologics and their biosimilars, the program was not a brand-new concept; the WHO has offered this program for small molecule medicines, specifically in the HIV/AIDS, malaria, and tuberculosis indications since 2001. The drugs that are submitted to the WHO via the prequalification program are assessed and, if in line with current GxP and safety, quality, and efficacy standards, they are placed on the WHO’s list of prequalified medicines. This list is then used by United Nations agencies and member states when selecting medicines to purchase and distribute throughout low- and middle-income countries (LMIC).
As Guido Pante, a technical officer of the WHO, shared at the recent DIA Biosimilars conference, WHO’s decision to launch the prequalification program for biologics came following the World Health Assembly’s adoption of a resolution in 2014 to improve access to biologics and similar biotherapeutic products (SBPs). Given the challenges LMIC have procuring or producing quality products and regulating them locally, the prequalification program would ensure the entrance of safe and quality treatments to a wider array of countries.
Following the introduction of this pilot, however, news has been scarce on the program’s progress. That’s why I was particularly excited to hear Pante’s presentation at the DIA conference, during which he outlined the current requirements for the two prequalification pathways and the progresses and pitfalls for companies seeking a spot on the WHO’s list of prequalified medicines.
Building The Prequalification Assessment Program
While prequalification, generally speaking, was a familiar procedure overall to the WHO and to many small molecule manufacturers, Pante acknowledged that the WHO team had to “build everything from scratch” for the biosimilar prequalification pilot. This was one of what Pante said was a series of reasons as to why the WHO selected rituximab and trastuzumab as the first two products. “There are established WHO technical guidances on evaluation of biotherapeutic products [BTPs] and the SRAs have extensive experience in evaluating and assessing mAbs,” he said.
A big portion of the work in building this program was laying the groundwork for the submission process and creating the necessary documentation. The WHO established a series of documents to guide companies which can be found on the website, including a list of frequently asked questions, guidelines on how to prepare, format, and submit the appropriate documentation screening checklists, and screening checklists, to name a few. Seeing as there are two separate prequalification pathways — the full assessment pathway and the abridged assessment pathway — these guidelines needed to provide instructions for two separate submission strategies.
For those of you who may be less familiar with the workings of the WHO, it’s important to note that the organization is not a regulator. It does not approve treatments for the market as the FDA or European Medicines Agency (EMA) do; rather, as Pante explained, it is a critical support system for member state regulators working to establish, implement, and maintain critical quality standards. The WHO establishes these standards, provides the necessary guidelines, and encourages harmonization efforts among member countries. Since the WHO isn’t a regulatory agency, Pante made sure to stress that prequalification does not equate to local approval within each member state. Following a product’s acceptance to the list of prequalified medicines, the company must then submit the drug for approval from local regulators prior to being distributed on each market. To ease this process, the WHO urges companies to pursue a collaborative registration procedure, which would allow LMIC nations to access the WHO assessment report and, in turn, accelerate local approval.
Expanding Upon The Two Pathways And Current Progress
As you may have guessed from the name, the full assessment pathway is for biosimilars that have not yet been approved by an SRA. However, in order to qualify for prequalification, it must be a biosimilar to a reference product that has been approved and sourced from an SRA market. The biosimilar must also be marketed in the country of registration.
For products undergoing the full assessment pathway, WHO requires that drugmakers demonstrate advanced production processes and quality control. WHO also requires an inspection of the applicant’s clinical testing or contract research organizations and manufacturing facilities to ensure they are GCP- and GMP-compliant and, if needed, will carry out random sampling of the drug substance/product. Pante stressed that the experts from stringent regulatory authorities (SRAs) which comprise the board of WHO prequalification assessors rely upon the familiar concept of “totality of the evidence” in reviewing the submitted biosimilar dossiers.
“Totality of evidence is applied for the full assessment pathway in a step-wise approach, starting from the quality data, analytical similarity, and comparability exercises for the reduction of non-clinical and clinical data,” said Pante.
The regulatory landscape is currently full of debate surrounding the importance of large-scale clinical equivalence trials in biosimilar development. Given ongoing discussions about the important role pharmacokinetics (PK) and pharmacodynamics (PD) data can play in reducing the clinical package of a biosimilar application, Pante did say that prequalification could also be granted based on PK/PD data, depending on the complexity of the molecule. However, since the pilot is only considering two mAbs for the time-being, which are not a walk in the park to develop, the WHO is asking to assess a comparative equivalence trial.
“In principle, these are the same standards required by SRAs,” added Pante. “Prequalification is not a waiver of quality and efficacy but aims to ensure availability of the highest quality possible biosimilars and biologics for LMIC.”
The abridged assessment pathway on the other hand, is for the biosimilars that have already been approved in an SRA. Because the SRA has already carried out a detailed review of the data and approved these products and inspected the necessary facilities, Pante said the WHO’s role is to ensure two things: that the product submitted for prequalification is the same that underwent the SRA approval, and that the manufacturer has fully considered the needs and infrastructure limitations of LMIC. The WHO does not wish to repeat any inspections or full assessments that have already been carried out by the SRA.
There are only a few prequalification requirements manufacturers must meet separately from the review and approval by an SRA. “We ask that shipping and packaging plans for the product be in compliance with WHO international guidelines for vaccines, given that delivery timing and cold chain stability can be problematic in LMIC,” said Pante. “We also ask to see unique risk minimization measures and adverse event reporting and recall plans because these will all likely need to be different compared to those of SRAs.”
So far, the WHO has received 23 dossiers in total for both assessment pathways: 14 for trastuzumab and nine for rituximab. Nine of these dossiers have been for the full assessment pathway, though, as you might expect, it hasn’t been an easy journey for a number of the submitters. As Pante shared, there were four dossiers retracted following the pre-submission meetings, and another five were considered “significantly deficient” following the pre-submission meeting. There are five additional dossiers expected, however it’s unclear when they’ll be submitted.
The abridged pathway has received 14 submissions — six rituxumabs and 8 trastuzumabs. According to Pante, the assessment of these dossiers has been moving forward quickly, and he anticipates we’ll be celebrating the prequalification of several products in the near future.
What Have Been The Biggest Challenges Thus Far?
In the past few years, I’ve spent a little time writing about the emerging markets, as well as a handful of articles on LMIC and the unique challenges they pose for drugmakers. Back in 2018, I wrote several articles featuring the insights of the Access to Medicines Foundation on how biosimilar companies can establish strategies to enter LMICs. Many of these nations do not have the proper manufacturing capabilities or logistics established. Similarly, some countries may have uneven distributions of wealth, making it difficult to understand treatment patterns and sites of care. This can affect everything from the drug’s presentation, shelf-life, stability, reporting and risk management systems, and overall stakeholder education. In other nations, such as the Middle East North Africa (MENA) region, the presence of copy biologics adds another dimension of complexity.
Given these unique considerations that aren’t present in SRA markets, it’s likely not a surprise that one of the biggest oversights via the abridged pathway is ensuring that the product is appropriately geared toward entering these healthcare systems. As Pante outlined, many dossiers were submitted without adjusting pharmacovigilance and adverse event reporting protocol to local clinical practice and the overall infrastructure in LMIC. Similarly, a number of submitters did not follow the WHO’s international packaging and shipping guidelines. Moving forward, it’s critical for companies considering the abridged prequalification pathway to ensure they are adapting their products to a completely different set of risks.
When it comes to the full assessment pathway, many of the submissions showed a lack of experience or familiarity with more stringent regulatory procedures, particularly in the analytical and comparability exercises. Indeed, one of the benefits of the full assessment pathway the WHO touts is that it introduces companies with little to no experience with SRA-level requirements to more stringent development protocol. The learnings from the WHO assessment can then be used, not only to improve the company’s biosimilar development process, but also process development and manufacturing across the company’s pipeline.
There were a number of issues that stood out as the most difficult for companies to meet. Pante continued to reiterate the importance of companies purchasing their reference product comparators from an SRA market. One of the most problematic issues for dossiers on this pathway was that companies sourced the reference product from non-SRA nations, which renders the application invalid for prequalification. Comparability, as well, was often performed insufficiently; rather than comparing three batches of the reference product with 3 batches of the biosimilar, for example, the exercise was carried out using only one batch of each product. In fact, in some instances, the reference product proved problematic because it had expired or it had not been stored at the appropriate temperature. Companies also struggled to derive appropriate similarity range/acceptance criteria; characterize both the reference product and biosimilar according to accepted standards; justify and appropriately document biological potency assay selection and process development; and properly design (and/or perform) clinical pivotal PK/PD studies and sufficiently powered safety and efficacy studies.
Though challenges abound for companies embarking on the prequalification opportunity, Pante remained optimistic that we’re close to seeing products prequalified via the abridged pathway. And this progress can’t come at a better time, considering the United Nations’ 2030 sustainable development goals — the third goal in particular being achieving universal health coverage. Certain diseases, including malaria and tuberculosis remain critical pain points for certain populations, while affordability remains an issue for patients that have greater access to basic healthcare needs. The WHO prequalification process may only be one part of this large, multistakeholder effort, but it can go a long way to ensuring access to affordable, quality treatments in nations that, to date, have been lacking essential health services and the benefits of biologic treatment.