Agnes Shanley is senior editor of Pharmaceutical Technology.

Agnes Shanley

	SPI Pharma has expanded its Mannogem mannitol product line for use in oral solid dosage (OSD) forms, offering a new Precious Gem Collection. Its goal is to address challenges that the crystalline sugar alcohol excipient poses for formulators, particularly in patient-centric dosage forms such as orally disintegrating and chewable tablets. 

	Although consumer research has found that use of mannitol can improve perceived aesthetics and taste in pharmaceutical tablets (1), formulations using the excipient can pose technical challenges during formulation and OSD manufacturing. The company extended its line with multifunctional grades of materials designed to offer better binding and disintegration profiles, greater compressibility, and tighter particle size distribution (PSD) ranges. 

	“These new grades align with our core purpose of making a difference in patient adherence. Our customers identified an unmet need in their development efforts. The collection is a response to their needs and provides formulators the ability to develop smaller tablets with faster disintegration times, enhancing patient adherence,” said SPI Pharma president and CEO Jeanne Thoma at the time of the expanded product line launch on March 24, 2020.  

	The company’s Mannogem XL Opal and Ruby products, for example, have been improved to help formulators use mannitol effectively in sophisticated dosage forms, such as multiple unit particle systems (MUPS) and controlled-release (CR) ODTs, so that final products exhibit better hardness, drug-loading capabilities, and friability.  The new grades also require less binder and can be made at lower compression forces. Mannogem XL Opal enables higher production rates by allowing press speeds to be increased. “Formulation is always challenging, and the advantages of mannitol have always been offset by the extra complications that it poses during formulation. These new products provide our customers with a solution that leverages the patient-centric benefits of mannitol while avoiding common formulation problems and simplifying manufacturing,” added Sarath Chandar, chief scientific officer, SPI Pharma’s Applied Innovation Group. SPI Pharma’s expanded line also includes Mannogem Emerald (25-μm diameter PSD) and Onyx (50-μm diameter PSD) product offerings.

	The company, which offers formulary and other formulation development services to pharma clients, established two separate business units three years ago; one focused on excipients and the other on antacids. SPI is currently one of few mannitol suppliers that is focused only on pharmaceutical applications. 

	Reflecting the industry’s move to formulations that are more pleasant and convenient for patients to take, and more likely to induce their adherence with doctor’s prescriptions, SPI has been concentrating efforts on improving products so that they can more readily be used in patient-centric dosage forms, says John McInerney, general manager of excipients and drug delivery at SPI Pharma. 

	“We’re looking closely at dosage forms, and the needs of different patient groups to ensure that our products can enhance formulations by making the finished drug easier for healthcare providers and caregivers to administer and for patients to adhere to, and more pleasant for patients to take,” he says. This has meant creating proprietary technology that improves mannitol’s performance as an excipient, he explains, for name-brand, generic, and over-the-counter formulators.

	Rather than developing novel excipient blends using mannitol, SPI is promoting new blends of pre-approved compendial products. The blends involve materials that are already well understood and can be quickly implemented in existing formulations, particularly newer formulations designed for once daily dosage and more convenient delivery forms, says Coralyn Gonzalez, global head of sales for excipients and drug delivery systems. 

	The company is also promoting its existing services division, which was established over a decade ago to help customers develop formulations based on end-use targets and to get to a full formulary ready for clinical trials, says Bill McCarthy, the company’s global marketing manager for excipients and drug delivery systems.  

	Outcomes-based healthcare and the importance of a B2C focus

	As McInerney explains, SPI Pharma is targeting business to consumer issues in order to strengthen its business to business connection with pharmaceutical formulators.  Patient focus is becoming an important business strategy, given the overall move in healthcare to demonstrating product effectiveness and good patient outcomes.  “Pharmacy benefit managers are already reimbursing providers based on outcomes. The market is heading toward a situation where reimbursement will depend on how well patients comply with physician’s directions,” he says.

	As a result, he says, success in drug delivery, whether on the branded side or with generics and OTCs, is moving far beyond considerations of API efficacy. “In the OTC and nutritionals markets, patient/consumer outcome is being driven by adherence, which, in turn, depends on aesthetics and how pleasing a formulation is to the consumer, says McInerney. Increasingly, brand name, OTC and generic pharmaceutical manufacturers are factoring both API performance and these consumer values into new formulations to drive business, he says. “Companies can now enhance the perceived value of APIs with more aesthetically pleasing dosage forms,” he says.

	SPI designed its materials to balance better performance with better consumer properties. “With the new products, formulators that had been using other grades of mannitol with different PSDs or critical quality attributes, will be able to maintain the same process conditions and achieve higher throughput API loading, better process economics, while maintaining improved mouthfeel patient satisfaction for the same formulation. Manufacturers can produce more tablets per hour and increase the amount of API loading per tablet, which allows them to create new forms without taking risks,” McCarthy says.

	Where excipient suppliers are usually large companies that provide commodity-grade materials for a wide variety of industrial end users, SPI Pharma has found it important to focus on pharmaceutical formulators’ requirements, and to emphasize compliance with current good manufacturing practice (CGMP) requirements first, says McInerney. A crucial requirement is controlling manufacturing processes so that product is consistent from batch to batch, says Gonzalez.  “Having GMP processes in place assures that our processes are in control, and we are providing materials that enable higher API loadings and product form factors,” she adds. 

Pharmaceutical Development and Technology

Articles

Mannitol has been shown to improve patient perceptions of tablet flavor and mouthfeel, but its use can add to tableting challenges. SPI Pharma has developed new grades of material designed to make it easier to manufacture in patient-centered formulations.

Enhancing Mannitol’s Excipient Properties

Since 2017, FDA has approved four gene therapies, and regulators expect the number of gene and cell therapies under development to increase dramatically.

Pharmaceutical Technology’s March 2020 Regulatory Sourcebook


	eBook: Regulatory Sourcebook, March 2020
	March 2020
	Pages: 6–9

	When referring to this article, please cite it as A. Shanley, “Inside FDA’s New Gene and Cell Therapy Guidances," 

Pharmaceutical Technology Regulatory Sourcebook eBook

In January 2020, the agency finalized six clinical development and manufacturing guidance documents and drafted new guidance on what would qualify new gene therapies as orphan drugs.

Inside FDA’s New Gene and Cell Therapy Guidances

		Vineti received an infusion of new investment on February 5, 2020. The company, a spinoff of GE Ventures, focuses exclusively on the supply chain and data management challenges of autologous and allogeneic cell and gene therapies and personalized cancer vaccines. Led by the distributor Cardinal Health, as well as Novartis Pharma AG and Kite, a division of Gilead Sciences, Inc., the funding, $35 million in Series C investments, will be used to improve and expand Vineti’s technology platform, and to aid its global expansion into Europe and the Asia Pacific region, according to a company press release (1). 

		The investment comes in response to rapid growth and the need for a strong technology infrastructure and standardization in the cell and gene therapy space. FDA expects to approve 10-20 cell and gene therapies each year starting in 2025, and to receive up to 200 clinical trial applications for cell and gene therapies per year starting in 2020.  Currently, more than 1050 advanced therapy clinical trials are underway that could involve nearly 60,000 patients, according to data from the Alliance for Regenerative Medicine that were quoted in the press release.

		Novartis and Kite, both customers of Vineti’s, each offer their own CAR-T (chimeric antigen receptor T cell) therapies, and compete in the nascent cell and gene therapy business. Their investment collaboration in Vineti suggests recognition of the need for standardization across the industry. At the same time, the participation of Cardinal Health, a distributor that works with 90% of the hospitals in the US, suggests that the infrastructure required for cell and gene therapies will need to go far beyond the laboratory, facility, and clinic. Under terms of the funding agreement, a Cardinal Health executive will join the company’s board of directors.

		According to Vineti’s management team, the funding will enable a number of enhancements that will improve the configurability of its software, making it easier to add new or updated features or adjust them, allowing for significant savings and faster time to market. The platform will also be improved to facilitate global expansion, including more languages and support for more regional regulations and standards around the world. 

		Of paramount importance will be the inclusion of the standards and integrations needed to scale up and industrialize more therapies. “Even though it’s still early days in cell and gene therapy, some standard approaches are emerging as pre-built integrations that connect critical technology stacks,” CEO Amy DuRoss told 

		So far, the company offers the only independent data management platform that supports commercialized cell and gene therapies in the US and EU. Vineti’s technology has been used in successful regulatory filings, as well as to support early phase clinical programs.  The cloud-based platform features Chain of Identity and Chain of Custody capabilities within what are shaping up to be the most complex supply chain, logistics, reimbursement, and patient-monitoring workflows in the history of biologics. The platform currently supports more than 200 leading medical centers around the world, says DuRoss.

		Vineti’s platform is designed to support a wide range of therapies from clinical to commercial phase, including autologous, allogeneic, and personalized cancer vaccines. In the future, the company plans to expand efforts to support other high-value therapeutics that require precise supply chain coordination, DuRoss says.

		1. Vineti Press Release, February 5, 2020, 

http://www.globenewswire.com/news-release/2020/02/05/1980163/0/en/Vineti-Completes-35-Million-in-Series-C-Financing-to-Industrialize-Personalized-and-High-Value-Therapeutics.html

New funding brings competitors, and a leading healthcare products distributor, into the standardization effort.


Novartis, Kite, and Cardinal Health Invest in Cell and Gene Therapy Infrastructure

Successful drug development depends on work done before clinical trials begin. As innovators outsource more of their discovery and  research, contract research organizations (CROs) are taking over more early development activities. Their involvement typically begins by helping sponsors determine the best target therapies to pursue, after which pre-clinical 

 testing evaluate the toxicity and optimal dosage of these therapies. 

	One crucial area is pre-clinical testing, which bridges drug discovery and clinical research stages, and encompasses functions such as pharmacokinetics and toxicology testing, animal research, and cell line and assay optimization. Globally, demand for these services is expected to grow by 6.6% per year to reach $5.2 billion in 2024, according to a 2019 market research report by Market Research Future (1). 

	Geographically, the Asia Pacific market is registering the fastest growth, at 9.4% per year, while demand in North and South America, which account for over 40% of the market, is expected to grow by nearly 7.5%. Pharmacokinetic studies are the fastest growing pre-clinical services sector, increasing by nearly 9% per year, according to the data analysts, while toxicological studies represent the leading market segment and are expected to reach nearly $2.5 billion by 2024.

	Restructuring has reshaped the pre-clinical contract research organization (CRO) market over the past few years, as specialists have merged or been acquired. Most large diversified CROs have expertise, not only in pre-clinical services but also in clinical and discovery. The past three years have seen IMS and Quintiles join to form IQVIA; LabCorp merge with Covance and Chiltern; Icon and MAPI combine; and Eurofins Scientific acquire the pre-clinical specialists Alphora Research, Selcia, and Amatsigroup. 

	Outsourcing is the only way for virtual companies and charities without internal resources (i.e., hospitals and institutes developing therapies for rare diseases) to develop their own pipelines, with projects set up so that sponsors can tap into and manage multidisciplinary teams. But even for larger companies with internal R&D assets, outsourcing has become a way to improve capital efficiency and elasticity, and reduce overall cycle times, says Vicky Steadman, general manager of Eurofins Integrated Discovery. Her division focuses on identifying the best drug candidates for pre-clinical studies, which are then carried out by other divisions of Eurofins. 

	Companies have already reduced cycle times, but abbreviated regulatory approval pathways have made it even more challenging to balance the need for speed with the mandate to meet FDA’s current good laboratory practices (CGLPs) requirements. Illustrating what can go wrong at the pre-clinical research phase, in October 2019, FDA issued a warning letter to Novartis’ subsidiary AveXis, citing problems with data from early animal studies for its new therapy, Zolgensma, a treatment for the rare disease spinal muscular atrophy (2). The company had only alerted regulators to problems with the data after the drug was approved. In addition, regulators found other CGLP issues at the lab, including unexplained discrepancies in potency assays, incomplete records, and failure to follow testing protocols or quality assurance procedures. 

	Paralleling CGMP problems found in recent FDA warning letters for manufacturing, recent CGLP citations for pre-clinical testing often emphasize lack of root cause analysis and corrective action, and failure to follow testing protocols and standard operating procedures (3). 

	One of the most important aspects of any pre-clinical collaboration between a sponsor and CRO is ensuring that work meets CGLPs and other regulatory requirements. That is not necessarily difficult, but can be more challenging than it sounds, says Nancy Catricks, executive director of regulatory compliance at the CRO, Charles River Laboratories. The fundamental requirement is establishing appropriate quality systems at the testing facility, she says. 

	Nonclinical safety studies are legally required to be conducted according to CGLP regulations if they support or are intended to support applications for research or marketing permits for products regulated by FDA, she says. “CGLPs were enacted to assure the quality and integrity of study data and reduce the chances of unreliability and fraud. Following these regulations appropriately assures that studies are reliable and allows FDA to make sound decisions for patient safety.” 

	Ensuring data integrity remains a key challenge, as shown by the AveXis warning letter, and many CROs have established formal methods and teams to make sure that it gets the attention it requires. Charles River, for example, has set up an internal data integrity governance committee made up of key business and regulatory executive leaders, to set goals and assess performance. The company articulates its approach and expectations for data integrity in a global quality policy and has two different plans in place for the business: a global data integrity compliance plan for all its divisions and a CGLP-specific compliance plan. “Extensive CGLP training, with a focus on data integrity throughout, is included in the training program for personnel engaged in pre-clinical work,” Catricks says. All equipment and instruments that are used in CGLP studies are subject to stringent validation and qualification requirements, she says, based on standards that ensure data integrity.

	“The assurance of data integrity is not a new expectation or concept, but over the past few years there has been an increased focus on data integrity within the industry. I think there are times when staff at laboratories that are conducting CGLP work may not have a full understanding of the CGLPs or the quality systems that must be in place to ensure the CGLP regulatory requirements have been met. Unfortunately, this will result in studies that cannot be reproduced and will lead to instances in which FDA rejects studies because the agency cannot confirm data integrity,” Catricks says.  

	She suggests process mapping as a useful tool for laboratory managers who want to improve or enhance their pre-clinical research programs. This approach requires staff to take a critical look at all the steps involved in a particular process to determine whether there are any that are unnecessary or do not add value, and then remove those steps. It also calls for a close examination of areas where there may be gaps in data integrity.

	Laboratories interested in establishing a CGLP program should engage with partners that understand CGLPs, including the preambles, and have expertise working in an established CGLP environment. “Simply reading the CGLPs is not sufficient,” Catricks says. 

	Both sponsors and CROs are using or developing new tools to improve pre-clinical testing efficiency. A number are working with machine learning. One such tool is the pre-clinical data integration and capture tool, PreDICT, developed by AstraZeneca and Tessella to access, share, and analyze different types of pre-clinical data. The software can predict optimal doses and scheduling. So far, AstraZeneca reports using it for more than 150 projects, and notes that it has saved 30% of the time usually required for pharmacokinetic/pharmacodynamic models. In addition, the company claims that use of the software has saved 1.5 to 2 days of study time for drug, metabolism, and pharmacokinetics as well as bioscience studies (4).

	Also leveraging machine learning is Riffyn, a company that started up six years ago, which offers a cloud-based platform, SDE, short for Scientific Development Environment, for pre-clinical and other development work. The software incorporates principles from Six Sigma’s define, measure, analyze, improve, and control (DMAIC), quality by design, and measurement systems analysis, says CEO Tim Gardner. Riffyn’s initial experience was in industrial biotechnology, where SDE was used by the enzyme manufacturer Novozymes to increase capacity by an order of magnitude and cut time to mmarket by a factor of two, Gardner says. The company is now working with a number of pharmaceutical and biopharmaceutical companies on pre-clinical and other development programs, including bioassays, formulations development, and bioprocess development.  

	As Gardner explains, SDE is really a digitized Process Lifecycle Management environment. “It’s built around mapping production and analytical process designs and specifications and then accelerating the improvement cycles of those processes until they are ready for transfer to manufacturing.” In bioassay development for one pharmaceutical client, Gardner explains, the tool allowed users to cut 2400 hours per year out of the lab time required for assays, halving workload for a group of four.

	Clearly, machine learning and artificial intelligence, which are already playing a more dominant role in drug discovery, promise to be used in more pre-clinical work, and beyond, in the future. Not only sponsors, but a growing number of CROs and contract development and manufacturing organizations are actively exploring the technology’s potential. 

	1. Market Research Futures, The Global Pre-Clinical CRO Market, 2019. 
	2. J. Wechsler, “Data Integrity Scandal Prompts FDA Probe,” 

, 39 (10) (2019). 
	3.  FDA, “Warning Letter to American Pre-Clinical Services,”

, February 12, 2019.
	4. Tessella Ltd., Rethinking Pre-Clinical Data Collection, 

â¨
	Vol. 44, No. 2
	â¨February 2020 â¨
	Pages: 54-55

	When citing this article, please cite it as A. Shanley, "Pre-Clinical: Laying the Right Foundation,"

Quick approval pathways challenge teams to balance compliance with the need for speed. 

Pre-Clinical: Laying the Right Foundation

The past few years have seen dramatic growth in cell and gene therapy research and commercialization. As questions of access and cost continue to come up, developers are adding new capacity to help keep up with explosive demand for new therapies. Over the past few months, Kite Pharma and Novartis have both built new facilities in the United States and Europe, while Lonza, WuXi Biologics, and other contract development and manufacturing organizations (CDMOs) have been expanding manufacturing capacity.

	Established ways of gathering, transferring, and storing data and materials for traditional biopharmaceuticals will not work in the evolving supply chain for autologous and allogeneic therapies. For one thing, manufacturing and transport involve many more diverse stakeholders and patient groups than traditional programs, while, for autologous therapies, there is a need to closely coordinate raw material extraction and final product production, and transport to and from collection centers and from manufacturing to clinic. 

	Over the past six months, alliances have started up to streamline data management and access to improve the transmission of data from raw material collection points to manufacturing, and to patients at the point of use. In one such collaboration, the CDMO Lonza, IT company Vineti, and logistics specialist Cryoport are working to optimize logistics for cell and gene therapies. 

	Lonza’s formal collaboration with Vineti had begun in July 2019, to integrate the CDMO’s MES and electronic batch record (EBR) execution solution with Vineti’s supply chain orchestration  platform, designed to connect manufacturers and healthcare providers at point of care, in real time. 

	Vineti, which focuses on supply chain management for cell and gene therapies, has been in business for approximately four years, and grew out of GE Ventures, says cofounder and CEO Amy DuRoss. Back around 2012, a leading biopharmaceutical company with a chimeric antigen receptor T cell (CAR-T) product in Phase III had approached GE to help with unprecedented manufacturing and supply-chain issues. The product, which is now commercially available, was being produced almost entirely manually, says DuRoss, and presented the most complex supply chain and logistics workflow requirements ever seen in the history of biologics. “They were using brute force against the production and delivery of each therapeutic. Once they saw that they were likely to commercialize, they realized that there was no way to scale production and delivery on a manual basis,” she says. 

	For roughly two years, GE Ventures evaluated the challenges involved, and Vineti was set up in 2015 as an independent company to automate those specific supply chain and logistic workflow requirements.  The company uses an enterprise platform developed inhouse, and an integration layer driven by application programming interfaces (APIs).

	With CDMOs, the connection point depends on what the partner wishes to emphasize.  With Lonza, for example, the emphasis is on the MES and EBR system. “Vineti is managing chain of identity and chain of custody externally, and providing data as a feed internally into Lonza’s shop floor,” DuRoss says. 

	The two partners plan a number of other integration efforts that will deepen the capacity for data sharing and integration to improve capacity optimization. “CDMO customers no longer have to handle data integration themselves, since the system will already be built for them to link into,” she says. Cryoport’s Chief Commercial Officer Mark Sawicki discussed its work in cell and gene therapy logistics and supply chain management with Lonza and Vineti with Pharmaceutical Technology.

 What is one of the most challenging aspects of working in cell- and gene-therapy logistics today? 

: The supply chain is far more complex than it is for monoclonal antibodies or small molecules. Regenerative medicines are patient-specific materials. You cannot simply order bulk materials and manufacture lots of product and just push those out to market. In addition, there is a lot of variability in procuring the materials (i.e., you’re typically dealing with severely immunocompromised patients, so scheduling to get them in to pull materials, to transport or manufacture them, can be an issue). In some cases, patients can get sick or there can be weather issues. 

	As a result, scheduling is extremely challenging, especially for autologous materials. It is a bit easier for allogenics, but, at this point, networks for transporting donor materials have not yet been fully vetted. 

	Complicating the picture is the fact that the manufacturing processes associated with autologous therapies are not mature. This means that developers often have to extend instrumentation and processes that have been used for single-patient production to large-scale manufacturing in a commercial manufacturing environment. The interconnectivity and optimization of workflow isn’t there yet. Companies such as Lonza are trying to identify automation competencies to make the process move faster and more smoothly, but, as an industry, we aren’t there yet. 

	Finally, the manufactured materials themselves are extremely fragile and irreplaceable, but they have to be pushed back out under very rigorous timelines and exacting conditions. You don’t have the latitude for deviations because they might destroy the product or even kill the patient. All of these elements create significant complexity that the industry hasn’t had to deal with before.

  What do these challenges mean for CDMO and sponsor data management and IT systems?

 IT is a huge consideration. We are now working to integrate our individual IT systems so that information flows from one system to the next. The goal is to eliminate the need for manual intervention and reduce the risk of human error. At Cryoport, we have also begun to use artificial intelligence (AI)-based tools to examine product workflow, the risk elements associated with moving material in, manufacturing, and moving product back out. The only way that these AI systems can be effective is by gaining access to large amounts of data, and we’re now able to pull that data through our partnerships. 

  What is required for interconnectivity, and did you develop the AI systems in-house or with a partner?

 Systems must be nimble enough to talk to each other, so that if there is a delay during one phase of the process (e.g., during transportation, manufacturing, or administration) the information can be pushed out through the entire system so that everyone understands the ramifications of what is going on. 

	We hired our own data scientists to develop the AI systems, although Vinetti is working on AI systems of its own. Our use of AI is focusing on all around risk management for materials, and how we can use existing data more effectively to manage risk and improve operations, whether for storage or distribution. By the third quarter of next year, we expect to roll out a new version of our software that will include several of the AI features that we’re working on now.  

 How do you connect to CDMOs and to the clinical side? What elements are needed? 

 We typically connect through electronic data interchange or APIs using either a pull or push, bidirectional, or unidirectional process from conduits that have been designed to transition or share data with clients’ enterprise resource planning systems and portals, as well as Vineti’s IT platform. In some cases, elements of our IT system are being replicated inside a partner’s site. 

	If a Lonza client, for example, wants to schedule distribution of an autologous product, they can go into Lonza’s system, find an interface to our system, and get whatever help they need. Solutions providers such as Vineti are designing systems that are as flexible as possible to enable data to flow more easily between systems.

	Specialized containers and cleaning validation 

 What led Cryoport to develop the customized containers?

: The advanced therapy shipper line is a segregated, specially engineered fleet to support the distribution of clinical and commercial cell and gene products. We rolled it out to get ahead of what we anticipate future FDA regulations to look like, and to focus on what we expect to become most important feature of any shipment and packaging product in this space: traceability. 

	Currently, two third-party foundations, the Foundation for the Accreditation of Cell Therapies and the Standards Coordinating Body for the Alliance for Regenerative Medicine, are putting together recommendations for FDA in conjunction with ISO [International Organization for Standardization] TC 276, which will establish a long-term regulatory framework for the cell and gene space. 

	Our goal is to use the same standards that you would see in a GMP manufacturing environment for the equipment that is used to transport these materials to end users. Some standards are data related (e.g., for data loggers, track and trace, and geo-fencing), but the most important aspect is establishing traceability for equipment performance. 

	We can verify and confirm the historical utilization of every piece of equipment, who used it, and where and for what. That’s one of the most important elements that is being introduced in the program. 

	We’re also introducing a validated cleaning process for the industry that demonstrates a 99.9999% reduction in all contaminants, which brings it as close to product sterilization as possible (since it would be physically impossible to sterilize shippers and tanks out in the field). This will eliminate the risk of cross-contamination.

  What are you expecting in terms of standards (e.g., for good distribution practices for the new therapies)? Are there existing standards, and what are you expecting FDA and the European Medicines Agency to do?

 Existing standards are based around International Safe Transit Association (ISTA) protocols that have been used for the past 30 years. One liability is that these protocols incorporate a tolerance for deviation that is fine for small molecules or many biologics but could potentially render regenerative medicines unuseable.

	With many cell and gene therapies, deviations from prescribed environmental conditions, even those that last for a few milliseconds, half a second, or a second, can destroy product completely. There is no visible way to tell whether the cells are still useable after an upset. You won’t be able to tell if the viability of the cells has gone from 90% to 10% without doing extensive testing.

	This is why full traceability is so important, so that you know how a given piece of packaging will perform each time it leaves or returns to the manufacturing facility. Traceability looks at the risk of cross contamination, at equipment performance, and at the traceability of each shipment and whether it has been subjected to any shocks or condition deviations. 

	These data will eventually be connected to outcomes research. Say, for example, a sample has been shipped at the correct temperature, but affected by shear events along the way. It will eventually be possible to determine whether these incidents had any impact on product efficacy. If a client has dosed 13,000 patients during this time period, they would be able to examine the data and see any patterns that come up. We maintain every bit of data generated by our systems and can currently go back nine years and provide regulators with any information they request.

  Is there currently a bottleneck in the services available for cell and gene therapy development? 

 As more products come to market, there are issues with scale. Some producers haven’t had the bandwidth to keep up with demand, and this has held back their growth. Then there is the issue of viral vector manufacturing capacity and the risk of having a single supplier for the required materials. 

	Currently, many of the materials required for GMP manufacturing of cell and gene therapies are single sourced, which is extremely risky, and manufacturers are typically smaller providers because this is a niche industry. The 800-pound gorillas aren’t yet supplying reagents and other necessities because there was no market for them five years ago. However, today there is still a pipeline of 1000 clinical products, all of which use GMP starting materials from single, small provider sources. That poses a major risk.

 This is easier to manage for autologous treatments. As you move to allogeneic products, instead of 2000 or 3000, you will be dealing with two or three million, and fleets will move from 1000 to 100,000. There’s only so much existing capacity for liquid nitrogen shippers. This is also true for storage and distribution. For example, how will pharmacies do the visual inspection required when releasing allogeneic product from a liquid nitrogen tank when performing visual inspection can potentially render product unuseable? The industry must resolve many of these questions. 


	Vol. 44, No. 2
	February 2020
	Pages: 48-50

	When referring to this article, please cite it as A. Shanley, "Managing Risk for Cell and Gene Therapies," 

Vein-to-vein programs are focusing on data access and traceability. 

Managing Risk for Cell and Gene Therapy Logistics

As prices for key therapies continue to increase, the pharmaceutical industry faces a public opinion crisis in the United States, with few prospects for improvement (1). According to IQVIA, high costs prevent 70% of the patients who need medicines from filling, or refilling prescriptions (2). People are demanding that the industry define its mission. Is it helping patients or generating profits?  CEOs might argue that they are doing both, but the public and legislators aren’t buying it. 

	US legislators and public interest groups are focusing on price caps and the use of a global index to rein in drug prices, but this approach “has never led to a system that simultaneously incents innovation and promotes widespread affordability,” writes Wayne Winegarden, senior fellow at the Pacific Research Institute in a recent analysis of drug pricing (3). 

	Industry groups such as the Pharmaceutical Research and Manufacturers of America (PhRMA) and BIO have taken a mainly defensive posture, arguing that price controls will kill innovation, without outlining any clear alternatives for reducing prices. 

	Venture capitalists have stepped into the breach, starting off the new year by advancing solutions to the pricing dilemma that consider the industry’s obligation to individual patients, as well as the need to support innovation. January 13, 2020 saw the public introduction of EQRx, an innovator company based in Cambridge, MA. The company was established in late 2019 by investor Alexis Borisey, formerly managing director of Third Rock Ventures, who has led 15 different biopharma companies, five of which have gone public, and biopharma executive Melanie Nallicheri, who was most recently the chief business officer of Foundation Medicine (now part of Roche), and is now EQRx’s president and chief operating officer. 

	EQRx aims to leverage best practices and new targeted approaches and to focus on known biologies to establish an “innovation engine” that will allow successful development to be replicated, faster and more cost effectively, between different classes of drugs (e.g., from oncology to neurological treatments), Nallicheri says. Using this approach would reduce development failure from the industry’s current 90% level to 40–50%, she says, and would allow the company to offer the therapies at drastically reduced prices. 

	Plans call for EQRx to introduce its first product to patients and healthcare providers within the next five years, Nallicheri says, with 10 additional therapies to follow over the next 10 years. The primary focus is most likely to be on oncology treatments, she says, but would broaden over time. “We’re trying to democratize biopharmaceutical innovation, disrupt the status quo and break the mold,” she says.

	On a more theoretical front, January 20, 2020 saw the publication of 

The Great American Drug Deal: A New Prescription for Innovation and Affordable Medicines

, written by PhD virologist Peter Kolchinsky, founding partner and portfolio manager at RA Capital. Addressing issues that affect all stakeholders (i.e., healthcare systems, providers, patients, payers, and developers), the book outlines approaches that could make drugs more accessible while rewarding innovators for persevering with the cost and challenges of drug development. 

	Both Borisey and Kolchinsky have built their careers on evaluating the degree of innovation, and potential impact, of new companies and therapies. Kolchinsky sees the current state of antibiotic and antimicrobial therapies as a warning to industry and the public of what can happen when the incentive to innovate is lost. 

	Although headquartered in Cambridge, EQRx will be a global company operating from more than one site, and is currently pursuing partnerships with contract development and manufacturing organizations and technology vendors, says Nallicheri. Rather than launching biosimilars or generics, its products will be “equivalars,” therapies that target the same disease and systemic problems as existing drugs, but without violating any intellectual property (IP). EQRx's equivilars represent an intermediate route of “pseudo-genericizing” novel drug classes, says Kolchinsky.  Myovant and Obseva are developing fast-followers to Neurocrine’s gonadotropin-releasing hormone (GDRH) antagonists for treating endometriosis, and multiple companies have developed their own versions of CGRP (calcitonin gene-related peptide) inhibitors for migraine and CAR (chimeric antibody receptor) T cell therapies for cancer, he says. 

	“Prices for hepatitis C virus treatments came down precisely because Abbvie launched a second drug and offered payers a discount.  And even in cases where the list prices in a category are going up, the net prices may be going down due to competition among what the public and Congress often dismiss as me-toos,” he says. Kolchinsky points to IQVIA data showing that net prices in general aren't growing even though list prices are increasing, with pharmacy benefit managers (PBMs) just taking a great and greater cut of the difference.  "Whether they are called equivilars, me-too drugs, or fast-followers, having similar drugs compete on price is a proven model that saves society money, although, in the end, nothing will beat the value of all those drugs just going generic," he says.

	There won’t be any patent violation problems, says Nallicheri.  “IP restrictions are narrower than one might think, and there are ways to avoid running afoul of other patents, either with new products or those created via licensing,” she says. 

Leveraging best practices and new technologies 

	EQRx will combine novel approaches that its management team members have worked with, including precision medicine methods that would allow the company to target the patients most likely to benefit from a specific medicine, to match them up to potential therapies and optimize clinical trial results. Additional technologies center around novel ways to use data, she says, as well as approaches to simplifying the overall supply chain. “These approaches have never before been combined with the goal of improving efficiency and establishing a lower unit cost for each individual medicine,” she says. 

	It would be difficult to apply this approach in an established biopharmaceutical company, she says, given the need to mitigate risks at each step in the value chain.  Having a new company and business model will allow EQRx to take a different mindset going into development, she says, although the risks remain significant.

	One way EQRX will reduce these risks is by starting with disease targets that can be readily identified and are reasonably well understood. Target-based drug development was made possible by results from the Human Genome Project, as well as sophisticated modeling of target structures, says Kevin Noonan, partner at McDonnell Boehnen Hulbert & Berghoff LLP and chair of the firm’s Biotechnology & Pharmaceuticals Practice Group. “Modeling provided an 

analogue to traditional methods such as wet chemistry binding assays and high-throughput screening,” he says. 

	But EQRx’s products will undergo the same regulatory scrutiny and have the same relatively short exclusivity periods that conventional drugs have. “Unless there are additional strategies in play, it is hard to see how the proposed competing drugs will be economically viable,” Noonan says.

	Nallicheri anticipates a great deal of competition. “We’re not naïve about the degree of difficulty involved. Making things simpler is very different from saying something is easy,” she says. Risk will still be there, particularly idiosyncratic risk. 

	However, the company sees major opportunities. Despite the number of therapies available, the industry has not even come close to exhausting the possibilities for addressing potential targets for new treatments, says Nallicheri.  “More than 90% of the medicines available today are not curative, and most new therapies only provide marginal survival benefits over existing treatments,” she says, offering huge potential for developing curative products at a much lower price.

	Questions remain about how readily insurance companies might work with a drug developer that has a novel business model.  At this point, Nallicheri is optimistic. “Payers are looking for solutions, and disruptive solutions that are market-based and that create tighter alignment between supply and demand have a much better chance of succeeding than crude, mandated solutions,” she says. “Besides, as an industry, do we really want that kind of approach?” she asks.

	Also arguing for market-based approaches is Peter Kolchinsky, whose new book aims to clarify misunderstandings about innovation and to start discussion and debate about the role that insurance companies and other payers, patients, healthcare systems, and drug developers and manufacturers should play in reducing drug prices.  Kolchinsy believes that innovation should be clearly separated from mere patent extension and that industry funding be limited to the first 10-15 years after a new drug is developed.  “If we don’t sacrifice the excessively long revenue tails some companies have figured out how to append to old drugs, society will simply squash all revenues down with indiscriminate price controls,” he says.

	The patent system was designed to give finite rewards, like a mortgage, for innovation, he says. “If companies exploit the patent system to achieve infinite monopolies, it might be legal, but it’s at odds with the spirit of competitive, free-market economics (i.e., capitalism) and laws can be changed to block such exploitation of the patent system,” he says.  Kolchinsky proposes a mechanism called “contractual genericization” 

	With contractual genericization, all companies that develop a new drug would have to enter into a contract with a government agency (structured along the lines of the US Biomedical Advanced Research and Development Authority [BARDA]) when they file for approval of their drug. This would ensure that the drug becomes inexpensive once the initial patent period has expired. Using this approach, Kolchinsky says, if the company made a legitimate, useful upgrade to the drug after it launched, it could receive a six-month deferral of the contractual genericization date, just as FDA awards companies six more months of patent exclusivity in exchange for running pediatric trials. 

	“An invention is meant to become inexpensive in the long run. That’s why patents expire. Contractual genericization is just a fall-back for those cases when things don’t play out the way they were meant to because of the complexities of drug development, regulation, and the patent system,” says Kolchinsky. 

	“When I’m funding the development of a new drug, I don’t count on revenues 20 years after approval. I have to discount anything that’s that far away and, because my discount rate is high (i.e., 8–12%), factors that are more than 10-15 years away are essentially irrelevant to my decision. So if you tell me ‘my company’s drug will become very inexpensive after 15 years on the market’, that won’t prevent me from investing in its development. I wasn’t counting on those revenues anyway,” he says. 

	“It’s now time to guide Congress to reaffirm the pro-innovation price control we’ve long had: drugs going generic. That keeps big companies hunting for new drugs to launch to replace their aging ones, which keeps them engaged with small companies, partnering and acquiring them. If big companies are allowed to just kick back and harvest extended revenues from old drugs, they may lose their eagerness to fund innovation, and that’s no good for patients,” he says. 


	Kolchinsky is critical of insurance companies and the role that they have played in creating the drug pricing and access problem. “The drugs that cost hundreds of thousands of dollars are needed by fewer patients than those that cost less. So we should not focus on one drug’s cost and assume that drugs are unaffordable to insurance companies,” he says. “Curing a patient of Hepatitis C for $80,000 is way cheaper than treating patients in hospitals with surgeries and transplants as they gradually die from their infection. So we mustn’t look at the price of any one drug in isolation from all the costs they avert. We spend tens of billions on vaccines each year that spare us much more pain and cost,” Kolchinsky says.  

	Having drugs go generic is in society’s best interests, he says. “If we don’t ensure that high drug costs are a finite mortgage instead of an infinite rent, then Congress will be right to regulate those rents down,” he says.

Public Opinion: Can Pharma Chart a New Course?”

Improving Market Efficiencies Will Promote Greater Drug Affordability

,” Pacific Research Institute, January 2020. 

While the US public and law makers push for price controls, pharma’s venture capitalists have other ideas for balancing innovation and affordability.
