October Spotlight October 2016

BPI Staff

October 14, 2016

7 Min Read

Adaptive Pathways Pilot Program Results

A final report became available this past summer about the European Medicines Agency’s (EMA) pilot project on developing medicines for unmet needs. The project showed that adaptive pathways can bring multiple stakeholders together — including regulators, health-technology assessment (HTA) bodies, healthcare professionals, and patients — to evaluate drug development and data gathering.

Adaptive pathways allow for a planned, progressive approach to bringing medicines to patients. The concept makes use of existing approval tools (e.g., conditional market authorization) used in the European Union since 2006. It also builds on experience gained with strengthened postmarket monitoring introduced by the European Union’s 2012 pharmacovigilance legislation. Under this paradigm, drugs are authorized for small groups of patients who benefit most from them. Then as additional evidence is gathered on each drug’s performance, progressive licensing adaptations will extend or restrict their previously authorized indications. Adaptive pathways can support development in difficult indications for generating evidence (e.g., infectious diseases, Alzheimer’s and degenerative diseases, and rare cancers).

In March 2014, the EMA launched its pilot project to explore practical use of the adaptive pathways concept with drugs already in the works. The agency invited companies to submit ongoing development programs that could meet the following requirements: a staggered approval from very small, restricted patient populations to increasingly wider populations; a binding plan of postlicense evidence gathering; and involvement of key stakeholders in the process. The same principles and legal tools apply as for any other new medicine.

During this project, EMA received 62 applications, 18 of which were selected for consideration. At the end of the pilot, six applications had progressed to receiving formal advice by the EMA and HTA bodies and one received simple scientific advice. Most proposals were considered unsuitable for adaptive pathways, and the companies involved were advised to pursue traditional development routes.

This program helped the EMA to identify a number of aspects for further consideration: a need for increased patient involvement in selecting candidates for adaptive pathways, the importance of defining strategies for real-world evidence collection to assess drug efficacy and effectiveness, and the potential for payers to provide input on pricing strategies. Adaptive pathways is still a developing concept that will be refined as more medicines are considered.

A strong pharmacovigilance system and cooperation among stakeholders will provide for systematic monitoring of the safety and overall performance of a drug in clinical practice. Those are the two key elements underpinning the adaptive pathways concept. It is particularly important for all involved stakeholders to agree before market authorization on a plan of postlicense knowledge gathering and that the drug developer commits to carrying out that plan. Once authorization is granted, the plan becomes a legally binding regulatory obligation.

Drug developers who are interested in following the adaptive pathways approach for Europe should submit a proposal to the EMA. An updated guidance document outlines steps to follow. To gather the views and proposals from stakeholders on the adaptive pathways approach, the agency is organizing a workshop on 8 December 2016.

A Ballooning Global Biosimilars Market

In a 2015 report, Allied Market Research forecasts the global biosimilars market to grow rapidly through 2020 — from an overall revenue of US$2.55 billion in 2014 to approximately $26.55 billion by 2020 (a compound annual growth rate, CAGR, of 49.1%). Key driving factors fostering that market growth should be low pricing, ease of development, and reliable and timely regulations with quick biosimilar approvals.

The market for follow-on biologics originated primarily from expiration of patent protection for many blockbuster biopharmaceuticals with high annual revenues. Their high prices, coupled with rising healthcare costs around the world, have led to an increased demand for biosimilars. To gain approval from the European Medicines Agency (EMA), the US Food and Drug Administration (FDA), and the World Health Organization (WHO), biosimilars must meet one of two criteria: Either be interchangeable with reference biologics in terms of efficacy or function, or demonstrate a lack of meaningful clinical difference from the originals. Favorable regulatory environments with pathways for approval across major regions such as Europe and the United States would persuade more developers and companies to invest in the market.

The US market for biosimilars gained momentum after the launch of its first approval: Sandoz/Novartis’ Zarxio (filgrastim, follow-on to Amgen’s Neupogen) in September 2015. Sandoz claims that the biosimilar has gradually eroded the original’s US market share by 13%. In March 2016, the FDA approved its second biosimilar product: Hospira/Pfizer’s Inflectra (infliximab, follow-on to Janssen Biotech’s Remicade). Already approved in Canada, Mexico, Australia, and much of Europe, it is the first biosimilar monoclonal antibody (MAb) to be approved in the United States. Similar developments would unlock new opportunities for drug developers on the global market.

Many European countries have commissioned studies that focus on Celltrion’s biosimilar Remsina (infliximab). That also would foster biosimilar market growth across Europe. Furthermore, the product is being sold in many Nordic countries at a huge discount rate (~75%), further boosting its adoption.

Erythropoietin and MAbs, both glycosylated proteins, together accounted for about a third of the total global biosimilars market revenue in 2014. Among leading indications, blood disorders and oncology combined accounted for about 61% of products in development. Interferon is the fastest growing biosimilar, estimated to grow at a CAGR of 51.1% during the forecast period.

Emerging trends suggest that Europe is attracting major investors interested in the biosimilars industry. Its growth prospects are driven by streamlined regulatory guidelines and high adoption rates by physicians, payers, and patients.

But Incentives for Physicians to Prescribe Biosimilars Would Improve Affordability: According to an April 2016 report — Payor Strategies to Promote Biosimilar Utilization — from Matrix Global Advisors (MGA) and released by the Pharmaceutical Care Management Association (PCMA), incentives for doctors to prescribe biosimilars could increase their use and further reduce costs for healthcare payers. PCMA is the national association representing America’s pharmacy-benefit managers. The report states that biologics are some of the most expensive drugs on the world market and represent a large share of US drug spending. Biosimilars could reduce the price of treatment and benefit both patients and the healthcare system as a whole. But more doctors need to prescribe them.

The report notes that in addition to improving physician education around biosimilars, policy makers and payers could encourage physicians to use biosimilars by rewarding them for doing so, just as some payers promote increased generic use. “Biosimilars offer the potential to improve cost-effectiveness of medicines by driving competition,” says MGA’s CEO Alex Brill, author of the report. “But to facilitate a robust US biosimilars marketplace, additional tools may be necessary for payers to consider.” He cites a recent IMS Health report stating that drug spending expected to be subject biosimilar competition between 2016 and 2020 could be $182 billion.

“Each day that providers delay prescribing FDA-approved biosimilars means higher costs and fewer options for patients,” says PCMA president and CEO Mark Merritt. The report concludes that more biosimilar prescriptions will drive competition in the market, so incentivizing biosimilars use will increase the robustness of their market, further benefiting both patients and the healthcare system in the United States.

Manufacturing Crystal MAbs

Contract development and manufacturing organization Ajinomoto Althea Inc. has patented a method of crystallizing monoclonal antibodies (MAbs) for stabilization, storage, and delivery in scale-up and GMP manufacturing. Jennifer Cannon (commercial vice president) says that “Typical crystallization methods involve slow diffusion processes that can take weeks, whereas Althea’s batch process for antibody crystallization can be complete within one day.”

So-called Crystalomics formulation technology addresses unique challenges that arise during MAb development. Issues with viscosity, aggregation, and instability are common. The Crystalomics group will work with Althea’s clients to produce highly concentrated crystalline formulations with low viscosity, low-volume administration, and increased stability. Crystalline suspensions could enable alternative routes of delivery that are more patient friendly.

Cannon says MAb products are “among the fastest growing drug classes in the world.” They make up >75% of biologics development pipelines. “We anticipate this trend to continue.” But Crystalomics technology should be applicable across a broad range of biomolecules including recombinant proteins, peptides, nucleic acids, and antibiotics.


Transcription errors in the July–August 2016 BPI Theater supplement’s BIO 2016 summaries section (Greg Adams’s presentation, “The Portrait of a Protein”) have been corrected in our online archive: Moles is now MALS (multiangle light scattering); aggregates start as dimers (not monomers); and Delta G trending detects free energy required to unfold a biomolecule (rather than the change in entropy as a protein unfolds).

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