09 April 2019
Globally accepted products are becoming increasingly in demand, leading to more need for regulatory harmonization, particularly for biosimilars.
The biopharmaceutical regulatory landscape is continually shifting and adapting, mirroring the innovative nature of the industry and ultimately ensuring the safety of all stakeholders. With increasing demands for globally accepted solutions to mitigate the rising development costs, further regulatory harmonization would undoubtedly be beneficial to patients and manufacturers.
Currently, however, there remain some key differences between national regulatory requirements within the biopharmaceutical space. “Arguably, the most significant difference between national/regional regulatory bodies is in the way that follow-on biologics are developed and assessed,” says David Deere, chief commercialization officer for PaizaBio.
There is generally a good level of understanding about medicines evaluations within the classic innovator countries/regions (such as the United States and Europe). Within the US, any biological product is submitted for assessment to FDA, and in Europe, human medicines derived from biotechnological processes are evaluated by the European Medicines Agency (EMA).
“In Australia, biologicals refer only to human cells and tissues,” confirms Alexandra Isabel Rosa, regulatory affairs associate at ELS Solutions. “Hence, vaccines (that do not contain viable human cells), recombinant products, and blood-derived products are not considered biologics and are treated by the national authority (the Therapeutic Goods Administration) as medicines or medical devices.”
Registration of new biological entities in South Africa usually occurs following the registration by at least one international regulatory authority the South African regulatory authority is aligned with, usually EMA or FDA, Rosa continues.
“In Switzerland and New Zealand, the biological application may happen after approval in a reference jurisdiction (such as Europe) or in parallel with the European Union and US submissions,” she adds. “This approach generates a reduction of submission fees.”
There is an understandable recognition by the regulatory bodies, however, that biologics require a different knowledge and skillset than traditional pharmaceuticals (small molecules), emphasizes Deere. “This presents a problem of obtaining trained staff among domestic experts in many markets,” he adds.
In China, which has vast market potential, particularly compared with other emerging markets, there is an expansion of regulatory review staff within the National Medical Products Administration (NMPA, formerly CFDA) underway. “The staff levels have been expanded by five times since 2015, and the NMPA has plans to double the number of staff again by 2020,” Deere notes. “Through a variety of avenues including the Gates Foundation, the NMPA has secured access to highly experienced professionals from FDA/EMA that have helped train their new staff as they ramp-up oversight of the burgeoning Chinese biomanufacturing sector.”
Biosimilar products are biologicals that have similar structure, biological activity, efficacy, safety, and immunogenicity to an approved biological medicine, which is referred to as the innovator or reference medicine. “However,” Rosa adds, “Biosimilar products are not considered generics of biological products because of the manufacturing process, which is complex and implies some intrinsic variability.”
According to Patricia Hurley, senior director, PPD Consulting, it should be noted that several biologics (in particular some interesting monoclonal antibody products) are coming ‘off patent,’ which will undoubtedly lead to an upswing in biosimilar development. “For biosimilar medicinal products, the ‘regulatory bar’ remains at a higher level, with regulators expecting to see a stepwise approach throughout the development program,” she adds.
John Watkins, associate director, regulatory affairs, PPD, concurs. “This high regulatory requirement is a result of the natural variability and more complicated manufacturing process for biopharmaceuticals by cell culture in a bioreactor, which preclude an exact replication of microheterogeneity (1). Therefore, more studies are required for regulatory authority approval of biosimilars than for a generic version of small molecule products.”
When addressing the regulatory body required information, the dossier for a biosimilar will not only differ from that of the reference medicine but may also vary depending upon the approving region/country. “While both EMA and FDA require similar clinical development standards from sponsor companies including full pharmacokinetic/pharmacodynamic bioequivalence comparisons to the innovator/reference biologic as well as limited phased clinical development to establish comparative safety and efficacy, EMA does not address the issue of ‘interchangeability,’ which is predominately a US legislative artefact,” Deere reveals.
“Biosimilar designations for both FDA and EMA require that the biosimilar demonstrates no ‘clinically meaningful differences’ between the sponsored biosimilar being evaluated when compared with the reference innovator biologic,” he adds. “But, FDA has an ‘additional’ category for interchangeability, which requires additional clinical trials that evaluate ‘switching’ patients from branded reference to the biosimilar instead of the standard naïve head-to-head comparisons.”
The expectations of FDA and EMA are clear in terms of biosimilar development, and are laid out in the relevant guidance documents, Watkins stresses. “Several countries have adopted the overarching principles of these ICH jurisdictions, such as Australia, India, and Saudi Arabia, to name but a few,” Hurley adds. “Biosimilar developers should be aware that even though EMA and FDA biosimilar guidelines refer to the ‘totality of evidence’ regarding the quality, nonclinical, and clinical data packages, EMA and FDA will require the applicant to demonstrate similarity with the reference medicinal product at the quality level (1). Having very comprehensive and robust clinical and nonclinical data packages will not compensate for having a limited quality data package.”
For Deere, regulatory requirement variances can be more pronounced in emerging countries, where many follow-on biologics are simple biological ‘copies’ of an innovator product. “These ‘biogenerics’ are standard in India and predominate in China,” he adds. “While a biological copy may have similar characterization and varying standards of established bioavailability, they do not have established comparable safety and efficacy based on comparative clinical trials.” Although, Deere notes that China’s NMPA has now adopted a biosimilar approval pathway that features similar requirements to those of the US and Europe, with the country’s regulatory body approving its first biosimilar in February 2019 (2).
Even within the European Union, there are differences, particularly relating to the issue of interchangeability. “EU member states treat the issue of interchangeability differently, with some countries allowing biosimilars carte blanche formulary interchangeability while others leave it up to subscribing physician discretion,” Deere adds. “As a result, this ‘issue’ has been exploited by innovator companies in defense of branded products, sowing doubt within the medical community, which has negatively impacted adoption of cost-saving biosimilars; especially in the US. Studies are confirming interchangeability of approved biosimilars (3) leading to rapid adoption of biosimilars over branded biologics because of cost savings.”
However, Deere specifies that to date, while there have been 18 biosimilars approved by FDA, only seven are on the market. “Three are recent approvals, the rest face a thicket of process patent litigation and have been voluntarily delayed in exchange for a licensing grant to market the drug in other regions, namely the EU, by the innovator company,” he says. “The remaining companies are involved in on-going ligation and have chosen to delay their biosimilar launch. None of the biosimilars in the US have been approved as interchangeable.”
Regulatory harmonization ensures that common compliance standards are met and sustained, ultimately protecting the consumer’s safety and health, explains Rosa. “Relevantly, harmonization also facilitates market access, making new drugs available for patients that otherwise would not have therapeutic alternatives,” she says.
Through a synchronized system, regulatory bodies could also benefit as duplicated inspections are avoided, which allows for greater focus on sites that could have a higher risk and could broaden the inspection coverage of the global supply chain, Rosa continues. Additionally, for manufacturers, the reduction in the number of inspections that they will be subjected to implies that there will be a reduction in cost.
“Harmonization efforts have mainly assumed the form of mutual recognition agreements (MRAs), which require regulatory agencies to recognize each other’s competence and equivalence,” says Rosa. “For example, FDA and EMA entered into one such MRA in November 2017, although this is transitional and is not expected to be completed until July 2019 (4). The EU has other MRAs in place with Australia, Canada, Israel, Japan, New Zealand, and Switzerland.”
An important aspect of the MRAs for Deere is that they relate to ‘foreign’ manufacturing inspections, which he notes is particularly prudent for emerging countries, such as China and India, as through these agreements there will be better exchange of reports. “Of course, the International Council for Harmonization (ICH) is also constantly attempting to harmonize regulations,” he adds. “China’s membership in June 2017 and subsequent Management Committee ship in June 2018, further, serves to ‘obligate’ China to ICH global standards.”
A frequent approach taken by most developers is to file for marketing authorization in Europe or the US prior to targeting other markets. “The reason for this approach is that applicants may take advantage of the scientific advice and pre-submission meetings provided by these authorities on quality, non-clinical, and clinical aspects of applications, which will allow the development of more complete dossiers, that meet regulations and expectations, and contribute to the decrease of time for revision and approval,” notes Rosa. “It is not essential to ask for scientific advice with authorities of other markets as advice received from FDA or EMA will typically cover global requirements.”
In Deere’s opinion, the product type will have an important part to play in the marketing approach. “For truly innovative, first-in-class, products which offer substantial therapeutic value, the higher price-points of the developed markets (US/EU, Japan) will likely remain the targeted launch markets, with China also included, assuming there are no major risks to the molecule,” he says. “For biosimilars and novel but non-first-in-class products, regional strategies might be appropriate dependent upon market environment. Of course, national or regional disease population demographics might warrant local/regional therapeutic need, such as malaria and other infectious diseases.”
When looking at regulatory affairs, however, Deere states there is a simple correlation that if a company is global then its approach to regulatory affairs should be global. “In addition to uniform product safety monitoring, all development teams and product teams should have international regulatory affairs as a component,” he says. “What is ultimately going to happen is that, with minimal exception, corporate development portfolios will be developed by global project teams, simultaneous in the three regions: US, EU, and China.”
Rosa highlights the need for regulatory affairs departments to perform regular literature searches to keep pace with regional, local, and global regulation changes. “Global companies should have locally specialized regulatory teams, whose qualified members should be allowed to circulate within global departments to give and receive training, mitigating both regulatory risks and costs,” she adds.
Alternatively, companies can outsource regulatory services. “Smaller contract research organizations and specialist regulatory consultancies certainly can offer most regulatory services, while the larger providers can offer them on a full global basis,” explains Alistair Davidson, executive director, regulatory affairs, PPD. “With the evolution of the global regulatory landscape and pressure on pharma companies to control costs, many companies are looking for effective outsourcing to ease costs while continuing to deliver quality outputs.”
Davidson continues to explain that for companies that have medium-to-large global product portfolios the majority of regulatory work occurs in the post-approval phase—mainly relating to the maintenance of marketing authorizations. “Such activities lend themselves well to outsourcing as a lot of them are predictable and relatively routine, although they do have key time- and quality-related compliance criteria,” he says. “A significant proportion of such work, including work traditionally done by local regulatory teams at the company/country/affiliate level, can be delivered from dedicated remote or virtual centers conferring greater consistency, efficiency, and effectiveness.”
Although Deere agrees that mid-sized companies seeking geographic expansion, particularly into emerging markets, can benefit from outsourcing regulatory processes for filing purposes, he cautions that once a product is on the market in-house responsibilities are key. “Once a product reaches market, safety and continued compliance, as well as future products should be ‘in-house’ and directly reportable to global regulatory affairs,” he states. “Scientists, clinicians, and certainly commercial teams too often forget that the first ‘customer’ for their product is regulatory agencies, which do not like being ‘ignored’ before/during new drug application/marketing authorization review/approval, or afterwards. ‘Relationships’ cannot be outsourced, and as any lawyer or regulatory affairs professional will advise, corporate liability is inherent in the product sold regardless of geography.”
There is a current wave of digital solutions impacting the bio/pharma industry. For Rosa, artificial intelligence (AI) is of particular note as it is influencing drug discovery as well as disease diagnosis and monitorization. “However, in my opinion, AI will also enable the management of regulatory challenges that manufacturers presently face,” she says.
Rosa explains that the advantage of AI-powered customer relationship management (CRM) software in addressing and solving innovation and pipeline problems is twofold. “Firstly, this software will provide the desired product for the health platform sought, pre-qualified in terms of regulatory status, lead time, and supply price pre-negotiated to fall in target-net present value bandwidth,” she adds. “Secondly, these systems will map out processes that entail the innovation effort from all relevant departments in tangible and pre-negotiated workflow and service-level agreements.”
“To me, the most pressing technical issue is what role continuous manufacturing will play,” emphasizes Deere. “If the logarithmic increase in yield over large-scale bioreactors can be successfully scaled, a lot of manufacturing space/capacity could be made redundant, very quickly! And, of course, downstream purification offers lots of opportunity for improvement, which represents huge regulatory challenges.”
Technical advances may also usher in significant cost savings, particularly considering biosimilars, notes Deere. “These cost implications could be proportionally similar to those witnessed in the small-molecule generic field 30 years ago,” he adds.
Additionally, the ability of developers to demonstrate comparable safety and efficacy of biosimilars with the innovator product will become the industry standard, Deere continues. “The ‘rubric’ of interchangeability will drop from the vocabulary as sponsor companies include switching arms in clinical efficacy trials and data confirm that biosimilars equal interchangeability in all patients both in safety and efficacy,” he summarizes. “As the ‘comfort-level’ rises among regulators that large biologics can be successfully manufactured via standardized biomanufacturing procedures and that these ‘copies’ truly translate as clinically comparable to the innovator/reference product in patients, clinical development requirements for biosimilars will likely be reduced accordingly.”
1. J. Watkins and C. Ryder, Regulatory Rapporteur, 14 (10) 26–32 (2017).
2. Biocentury, “China Approves First Biosimilar, Shanghai Henlius’ HLX01,” Press Release, Feb. 25, 2019.
3. D. Deere, “Biosimilars and Healthcare Policy: What China Can Learn from the EU and US,” Biopharm. Int., Sep. 28, 2019.
4. EMA, “Mutual Recognition Agreements (MRA),” Human Regulatory, Research and Development.
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