The mantra for a while has been that it's not good enough to get your drug approved, you've got to get it payed for, too. For gene therapy treatments, the payment is more complex, and you can add manufacturing and supply chain logistics to the list of challenges.

The complexity of manufacturing and supply chain logistics comes from autologous therapies needing to be produced individually for a single patient. "These personalized therapies require scaling out – ensuring patient-specific processes are established and can meet patient needs quickly – not scaling up," a report from PwC Health Research Institute (HRI) notes. "Companies should consider how to scale in a manner that is consistent with long-term sustainability, such as through contract manufacturing agreements."

There appears to be a "war for manufacturing capacity" brewing, according to the PwC report, as the FDA expects to receive more than 200 IND applications per year starting in 2020. "Greater competition for existing manufacturing capacity likely will result in higher costs or scarcer supplies for customers, and companies may need to make investments into manufacturing technologies – or purchases of companies for their manufacturing expertise – to ensure they are able to compete or gain an edge over other players," the report notes.

In addition to manufacturing issues and bottlenecks, companies also need to focus on being able to reach patients at the sites of care. Autologous treatments require removal of cells at the start of the process and infusing the cells back into patients after the manufacturing process.

"In the U.S., as of July 2019, 13 states lacked facilities offering any approved gene therapies, according to the HRI analysis. Just five ZIP codes in the country can boast health systems that offer all four gene therapies with FDA approval," the PwC report notes.

Supply chain logistics

Trakcel, of Cardiff, U.K., has developed an end-to-end supply chain management system for companies developing genetically modified autologous cell products. The software includes dynamic scheduling, allowing doctors to reserve manufacturing space based on how far a patient is from the manufacturing facility. The system tracks the cells from the patient, through the manufacturing process and back to the patient, keeping track of who handled the cells and when they were handled, which allows for real-time updates and satisfies regulators that the correct treatment will get to the right patient.

"It looks like it's becoming a de facto standard that electronic traceability is required in order to have your autologous therapy approved," Matthew Lakelin, Trakcel's vice president of scientific affairs, told BioWorld Insight.

Over the last few months, Trakcel has set up a series of partnerships to make it easier for companies to use third-party providers during the manufacturing process. In June, Trakcel paired up with Be The Match Biotherapies, integrating its software with Be The Match Biotherapies' cell procurement services. Last month, Trakcel and McKesson Corp., of Irving, Texas, announced a collaboration to integrate their supply chain logistics. And earlier this month, Trakcel expanded its relationship with contract manufacturer Wuxi Apptec Co. Ltd., of Shanghai, so its software can work seamlessly with Wuxi's manufacturing facilities for their mutual clients.

Lakelin recommends that companies set up their supply chain management system while in clinical trials. "Commercial launch can put a lot of strain on systems and processes and so it's always better to test them in pivotal trials, so you can take any learning that you acquire and modify your supply chain in time for commercial launch," he advised.

Cell therapy manufacturing in a box

Orgenesis Inc., of Germantown, Md., is a contract manufacturer for autologous and allogeneic cell therapies that has also partnered with researchers to in-license therapies, such as its Autologous Insulin Producing (AIP) cell technology that uses transdifferentiation to convert liver cells into AIP cells.

"We quickly realized that actually doing this in a biotech fashion in a centralized facility is not really solving the problem because you can do thousands or 5,000 [treatments] but what happens when you get into the millions?" Vered Caplan, CEO of Orgenesis, pointed out.

So Orgenesis started working with researchers to develop systems to produce products in the hospitals at the point of care. The company is piecing together components, some of which are off the shelf, some that were licensed and some developed by Orgenesis to create a closed system to manufacture autologous cell therapies.

"It's a clean room in a box, leaving the technician outside," Caplan told BioWorld Insight.

Orgenesis is working on multiple systems with different configurations that account for different manufacturing processes for the products. It expects to have several closed systems in clinical trials next year.

To keep from slowing down the development process, Caplan said she envisions companies developing automated processes in clean rooms in centralized facilities. Once the process is optimized and validated, the box can be closed up to allow manufacturing at the point of care.

Costs and reimbursement

An analysis of the manufacturing of CAR T gene therapies by Harrison et. al. in Cryotherapy estimates the cost of manufacturing an autologous CAR T is $95,780 per dose.

Trakcel's Lakelin said he thinks supply chain management can help lower the costs of manufacturing by maximizing capacity, "If you can optimize the use of a clean room, it means you can manufacture more of these products and reduce the number of clean rooms you need to meet the capacity for your patient population."

Likewise Caplan said she thinks Orgenesis' new systems can help lower the cost. "Our hope is that by utilizing automation, closed systems and localized manufacturing, we can actually bring down the cost so it's much less prohibitive."

While reducing manufacturing costs would help bring down the price, companies will still need to charge substantially more for the one-time therapies than they do for ongoing treatments for chronic diseases.

PwC notes that gene therapy companies are currently using outcomes-based pricing and multiyear payments to help gain coverage for their therapies. They also provide financing for health care providers so they don't have to pay for the therapy until after being reimbursed.

"Outcomes-based contracts may be especially important to insurers worried about paying six- or seven-figure prices for a therapy that might not work. This is especially true just after approval, when there is a relative lack of real-world use data," the report notes.

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