The biopharmaceutical market has seen incredible growth. In your opinion what are the drivers for this growth? Do you see a similar expansion once biosimilars become more prevalent?
Andrew Sandford, Vice President, Global Business Development, Catalent Biologics: The biopharmaceutical market has risen exponentially on the back of innovation, and science will continue to move forward in areas where innovation is more biology related. So, just as the market has shifted from small molecules to large molecules, development eff orts will now focus more on gene- and cell-based therapies.
Biosimilars will address an unmet market segment by providing affordable innovations to populations that today cannot meet the cost of first-to-market treatments. In the US, some of the most innovative biologics are not generally affordable, making it even harder for patients in other parts of the world to access the most cutting-edge innovations. I believe biosimilars will address that segment of the market, which represents a very large unmet need.
In certain markets, biosimilar pricing may not drop as rapidly as some would think, primarily because the cost of developing and manufacturing them is still quite high, and there still needs to be a substantial return on those investments. I think that as more biosimilars are brought to market and innovation is applied in biomanufacturing, especially in countries where the cost may be lower, we will hopefully see patients having access to products that today they do not.
Robert Dream, Managing Director, HDR Company LLC: As the frontier of innovation evolves, the development of safe and eff ective new drug products can expand therapeutic options and address unmet medical needs. Some of the most signifi cant advances are being made using biological products, including monoclonal antibody drugs and other therapeutic proteins. After patents and or other exclusivities expire on these novel drug products, prices will fall once follow-on products such as biosimilars are available, potentially lowering costs for patients expanding access to these innovations.
Generic drugs, for instance, represent 90 percent of all prescriptions in the US. Generic competition facilitated by the 1984 Hatch Waxman Act provided savings of more than $1 trillion to the US health care system over a decade and generated $265 billion in savings in 2017 alone [AAM 2018 Generic Drug Access and Savings in the U.S. Report]. However, until relatively recently, the FDA lacked a statutory pathway to approve follow on versions of biological products.
The approval pathways for biosimilars allows sponsors to leverage FDA’s finding of safety and effectiveness for the reference product to support approval of a biosimilar at a lower cost to sponsors than the development program for the originator reference product, provided the sponsor can demonstrate that the biosimilar meets the statutory standards for biosimilar approval. When it comes to development of a biosimilar, some clinical studies may remain necessary because current analytical technologies, in most cases, may not be sufficient alone to demonstrate that a product meets the standards for biosimilar approval. The reduced need for multiple large clinical outcomes studies as part of biosimilar product development can significantly lower development costs. This could result in lower prices for patients. While the U.S. market for biosimilars is still maturing, FDA research suggests that biosimilars for the same reference product are approved.
Global sales of biosimilars are already expected to reach $100bn in 2025. However, the situation in the US is a bit different as of today.
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Andrew Bulpin, Ph.D., Executive Vice President, Process Solutions, MilliporeSigma: The primary drivers for growth are scientific advancement and shifting demographics.
Over the past 15 years, more and more treatments for underserved indications have become available. In the past, the majority of drugs were small molecules and were prescribed for diseases like high cholesterol, high blood pressure and pain. Today, the pipeline and market are filled with large molecule, biologic drugs for formerly undertreated, serious and/or chronic diseases like Alzheimer’s, rheumatoid arthritis, diabetes and cancer. These new biologic drugs are in high demand.
Additionally, the world population is expanding, the median age is climbing and more nations have garnered enough wealth to focus on health care — all factors that drive the market’s growth.
As for biosimilars, it is difficult to predict how their arrival will affect the market. A few are available, and more are coming. I do believe the availability of biosimilars should make the drugs more affordable and more widely accessible. But it’s unclear what the net effect, if any, on the market will be. It depends on whether more people start buying the drug, and how many people already using it will switch to the biosimilar.
Barrett Fallentine, Director, Product & Process Development, Pharmatech Associates: Since the first biologic drug, Humulin, was approved in 1982, demand for biologic drugs remains high - for several reasons. America’s Baby Boomers are aging, becoming increasingly prone to illnesses or infirmities that require prescription drug treatment. Chronic “poor lifestyle-related” ailments, such as Type-2 diabetes, have also contributed to the demand for biologic drugs. Finally, technological advances in disease treatment, mainly in the field of immunotherapy, have spurred the development of new biologic-based therapies.
As the U.S. is experiencing peak demand for innovator-developed biotherapeutics, certain impediments to biosimilar production, such as proprietary licensing and patent restrictions, are falling away. A number of patents affecting widely used biologic drugs will expire by 2022 (National Pharmaceutical Services), paving the way for increased production of biosimilar alternatives to those biologic drugs.
This combination of increased demand, coupled with the elimination of impediments to production has created a perfect storm for continued growth and expansion in the biopharmaceutical industry. I predict that we will see a similar expansion of the biosimilar industry with this space evolving similarly as the generics space. Once they are accepted as interchangeable, low-cost biosimilars will start showing up in the pharmacy.
While the industry has seen incredible interest in developing biopharma products, are there any limiting factors to this growth?
Sandford: The first biologic drugs developed, and their biosimilar counterparts, treated indications with large patient populations. Those “blockbuster drugs” have driven explosive growth for the biopharma industry. We are now seeing a shift from predominantly blockbusters to developments aimed at more orphan drugs and personalized (or precision) medicines. Because the target markets are smaller, this may require more molecules to be developed in order to achieve the same growth trajectory. Although new modalities, such as gene and cell therapies, may offset any lag in growth.
Additionally, the global healthcare industry needs to stay healthy. There need to be commensurate returns for drug development across both small and large molecule. But right now, I think the market is managing it appropriately.
We at Catalent are expanding our offering in the biologics area because we see the potential that biologics have to address unmet patient needs, and we have the resources and expertise to support this growing industry. We are investing in both companies and technologies that help to save time, for example by more precisely selecting high performing cell lines, reduce complexity and increase the flexibility of manufacturing.
Dream: Biological drug products play a central role in combating human diseases; however, developing new successful biological drug products present many challenges, including labor intensive production processes, tighter regulatory controls, and increased market competition.
Few of the limiting factors that affect the biological drug products as it matures from research and development through an approval stage and product launch are as follows:
- The fear of the unknown, not every molecule discovered reaches the market. Usually, developers start with 2000 to 5000 molecules and only 2-3 molecules after 7 to 8 years timeline make it to product launch
- Biological drug products development is costly and time consuming. The Tufts Center for the Study of Drug Development (CSDD) pegs a bellwether figure in the drug industry, is based on an average out-of-pocket cost of $1.4 billion and an estimate of $1.2 billion in returns that investors forego on that money during the 10-plus years a drug candidate spends in development.
These factors create a limitation on who will afford the time and the cost to develop such products with no warranty on the outcome.
Bulpin: I see two main factors that might limit growth. The first is unpredictability. Biopharmaceutical development and manufacturing are global ventures, and a degree of uncertainty is inevitable: natural disasters, political events.
The second factor challenging growth is always present: pushing the limits of science. Yes, we continue to make advances, but there is always more to be done. The first Nobel Prize for immuno-oncology was just awarded for the discovery of immune checkpoint inhibitors. While this represents progress, science has a long way to go to develop safe and effective treatments for all cancers and other life-altering diseases. That said, current progress offers hope and inspiration to all of us engaged in pharmaceutical innovation - especially to a patient waiting for a cure.
Bikash Chatterjee, President and Chief Science Officer, Pharmatech Associates: The evolution of a regulatory pathway has been the most arduous factor in the growth of biopharma. ADCs, CAR-T, NGS and companion diagnostics/targeted therapy all represent regulatory paradigm shifts to conventional small and large molecule drug development: the same can be said for biosimilars. It was not until the FDA’s clarifying guidances described the pathway for biosimilars and bio-betters did industry activity markedly increase. However, the level of characterization required by the FDA is substantial for biosimilars, and it is even greater when seeking formal interchangeability approval: as a result the promised cost reduction for biosimilars versus the innovator drug has not materialized. Looking ahead, the clinical trials framework is the next impediment to be addressed, and the potential effectiveness and industry willingness to participate in basket studies or umbrella programs may well dictate how quickly novel drug therapies make it through the regulatory framework.
As the pharmaceutical industry has become more global – what are some concerns pharma companies have in developing and marketing biopharmaceutical and biosimilar products worldwide?
Sandford: Regulatory approval is one area of focus. US companies are looking to obtain approvals in the EU and other markets. Additionally, companies are increasingly building development and manufacturing facilities overseas due to supply chain and cost considerations. Sponsor companies are evaluating the regulatory requirements and intellectual property/patent laws of various governing bodies in order to ensure that they meet the different standards for approval and protection in a global market.
Dream: As biopharma moves from the scientific frontier to the business mainstream, the industry will increasingly be forced to confront the same challenges faced by other businesses: maintaining competitiveness by ensuring affordability, quality, and delivery performance.
Bulpin: A chief concern in developing and marketing biopharmaceuticals and biosimilars globally is regulatory uncertainty. When a drug is approved by the FDA, will it be accepted in Europe, Japan and China? There has long been a desire to share clinical trial data and streamline international approval processes to get drugs to patients faster. In recent years, progress has been made on implementing a mutual recognition agreement between the FDA and the European Union. The agreement creates efficiency by allowing the U.S. and Europe to recognize each other’s clinical trial data. This kind of cooperation helps to address concerns and partially de-risk some regulatory aspects of drug development.
Another issue with worldwide pharmaceutical manufacturing is finding, training and retaining local talent to produce biologic drugs using Good Manufacturing Practices (GMP). Since 1995, MilliporeSigma has built non-GMP laboratories that offer more than 80 hands-on courses to help customers produce reliable, high-quality products. Each year, more than 1,500 customers visit one of nine M Lab™ Collaboration Centers on four continents, where pharma manufacturers can explore ideas, learn innovative techniques and work side by side with technical experts to solve critical bioprocessing challenges.
Chatterjee: The ability to characterize and control the materials and process steps that impact the safety and efficacy of the drug product is the biggest concern. We have seen many examples of marketplaces struggling with data integrity, material suitability, and process control issues. These challenges are magnified with large and complex molecule drug therapies.
As biopharmaceutical products become more prevalent do you see their acceptance from patients growing? Do developers of biopharma products have an obligation to consider “patientcentricity” as a key element in their drug development scale-up?
Sandford: I see the acceptance increasing, especially for biosimilars, which I believe is a very good thing for patients as well as for the market, because it enables those who need these innovations to gain access.
I do believe there is an obligation to consider patient-centricity, but I think it depends on how patient-centricity is defined - I think it can be interpreted in a number of different ways. From my perspective, if industry can support patients who are suffering from cancer in Nigeria in the same way as patients who are suffering from cancer in Norway, and they can gain access within the terms of the economic structure in their particular geography, I think that is a fair approach.
Dream: If anything, the emerging long-term picture is even more exciting, with disruptive innovations such as immunotherapies, antibody drug conjugates, and gene and cell therapies all making progress toward commercial launch in the next few years. Biopharma looks poised to transform the industry once more, as increasing understanding of the interaction between drugs and the genetic makeup of patients helps to improve the targeting of therapies. Combined with robust, low-cost genetic profiling, this knowledge will improve treatment outcomes and serve to accelerate and improve the outcomes of clinical trials, helping to reduce the cost of drug development.
The patient and developer being entwined in the creation of innovative and or in pursuing follow-on biologics brings the patient into the fold of the development and discovery of the product. As a result creates a kinder atmosphere between patient and manufacturer.
Bulpin: The biopharmaceutical industry has an obligation to patients for their health, safety and well-being. Today’s genome-directed diagnostics and therapeutics entail patient-centricity by design. By developing these techniques and products that allow practitioners to find the mix of drugs most likely to impact each individual’s illness, we are advancing patient-centricity and treating diseases as never before.
All these rapidly advancing modalities - such as cell and gene therapy and immuno-oncology - raise new manufacturing, supply and regulatory challenges. Manufacturers and other suppliers have a responsibility to provide solutions that build in precision and efficiency for the increasingly complex, exacting, multi-step processes required to deliver high-quality biopharmaceuticals to patients.
The irony is that patients may not distinguish between biopharmaceuticals and other drugs; they just want a treatment that works well without intolerable side effects. It’s our job to provide the wherewithal for these new, effective therapies to become reality. To make patient-centric medicine a reality, MilliporeSigma is pioneering efforts in CRISPR and helping customers advance Cell & Gene Therapy. For example, our Carlsbad, California, facility is a key manufacturer of viral vectors – a critical component to develop personalized cell and gene therapy treatments.
Chatterjee: We have seen new drug therapies that are both disease modifying and actually curing disease. The barriers to adoption will certainly be aided if IV delivery can be avoided in a clinical setting. In terms of patient-centricity, there is no doubt that patient centric data resources are here to stay and will become more a component of drug design as well as clinical trial endpoint design, because of their ability to provide insight into the treatment of the disease state.
We have already seen the benefits of a more patient-centric focus in drug development scale-up and design. If you look back on Enbrel, one of the first blockbuster biologics, a key component of its rapid adoption rate, beyond the pure effectiveness of the drug, was the integrated packaging design which assisted the patient in delivering the drug.
What do you see as the major industry critical issues over the next five years in regards to biopharmaceutical/biosimilar product development?
Sandford: I think the industry is strong today, and I believe innovation is driving breakthrough treatments that will help the global healthcare system reduce costs while enabling people to live longer, healthier lives.
Next generation modalities, such as antibody-drug conjugates and bi/multi-specific antibodies, are promising in the near term for their ability to provide targeted treatment for many indications. Other approaches, such as gene and cell therapy, have the potential to address illnesses and conditions that lack desirable treatment options today. However, challenges may exist around regulatory and market acceptance of these new approaches.
I truly believe there is great promise in the healthcare market as we continue to innovate around new classes of molecules and new ways to develop and manufacture them. I think it is a really exciting time to be in the biopharmaceutical space.
Dream: Downward cost pressure will intensify as healthcare systems struggle to balance rising demand with flat or declining budgets. In this environment, payors may find it difficult to justify the annual treatment costs of $50K to $100K that some biopharma products currently demand. It is hard to imagine that these price premiums will be sustainable for any but the most innovative drugs. Furthermore, governments in emerging markets understand the critical role that biopharma will play in boosting healthcare outcomes, and they are aggressively supporting alternative ways to fulfill demand for these products.
The result of these pressures will be the inevitable development of the biosimilars industry. The availability of biosimilar versions of human growth hormones and interferons has already opened access to these products to a far larger number of patients. As patent protection on more complex biopharmaceuticals expires, biosimilars will surely follow the same path.
The increase in approvals over the past few years will encourage more biopharmaceutical manufacturers to develop and apply to market drug products, including both innovator and biosimilar products.
Bulpin: Biopharmaceutical manufacturing is challenging. The critical question for us at MilliporeSigma is how can we make manufacturing faster, more affordable and more flexible without sacrificing quality?
Our goal - the manufacturing plant of the future - will be different. It will combine biology, data science and chemical engineering to streamline production through connected and continuous, rather than batch, production.
In continuous bioprocessing, the production and purification steps are merged into a single ecosystem so that raw materials flow uninterrupted into the production bioreactor through product harvest, purification and testing. Previous stand-alone equipment will be interconnected and integrated digitally, with built-in sensors for monitoring and quality control.
MilliporeSigma estimates that by 2025, approximately 30% of molecules within commercial manufacturing will utilize process intensification technologies leading toward continuous processing. The conversion of batch processes to continuous manufacturing is the future of the pharmaceutical industry, employing continuousflow, end-to-end integration of manufacturing sub-processes with a significant level of control strategies.
Still, biologics are perhaps the most complex product people consume; minute process variations can readily diminish effectiveness, safety and supply. Manufacturers will need the right forward-looking technologies and expert guidance to succeed in simplifying their processes while reducing cost and risk.
MilliporeSigma recently launched the BioContinuum™ Platform for next generation improvements. This platform provides incremental benefits now, with a mind to continuous process of the future and will transform drug manufacturing, setting the standard for improvements in process efficiency, simplified plant operations and consistency in manufacturing.
Chatterjee: I see two critical industry issues for biosimilars: interchangeability, and pricing.
Interchangeability - Biosimilars are products that are highly similar, not identical: this is a subtle but important distinction for physicians who prescribe the drug treatment. Physicians understand the risk profile of prescribing a generic drug, because it has the same active pharmaceutical ingredients as the innovator drug and, for all practical purposes, is interchangeable with it. A biosimilar does not have the same drug substance as the innovator drug although it is intended to be clinically equivalent. In fact a biosimilar cannot be prescribed as an interchangeable option with a branded biologic unless it meets additional clinical and characterization requirements defined by the FDA. Understanding the consequences of prescribing a highly similar but non-interchangeable drug therapy is potentially a more complex decision for a physician to make. The motivation to prescribe may come down to simple cost, and if the cost is not appreciably less then it becomes harder to justify recommending the biosimilar.
Pricing - Unlike generic drugs that offer the possibility of a clinically effective alternative at 70-80% less cost than the innovator drug, so far biosimilars have not demonstrated the same magnitude of cost savings to the consumer. A larger price reduction could be realized if multiple biosimilars enter the market for the same indication - competition could spur greater adoption.