Agnes Shanley is senior editor of Pharmaceutical Technology.

Agnes Shanley

	As a result of the ongoing US Congressional impasse over approaches to and funding for US border security, a number of US government agencies officially ran out of funding on Friday, Dec. 21, 2018, with the funding lapse triggering a shutdown on Dec. 22, 2018. 

	This is the third such shutdown to take place in 2018 and the second this year to affect FDA. The first, which took place in January 2018, was resolved within a few days, and the second, in February 2018, within hours.

	At this point, it is not known how long the December 2018 shutdown will remain in force. However, FDA will only be partially affected.  The agency is retaining 59% of staffers and furloughing, or temporarily laying off, the remaining 41% until federal funding issues have been settled (1-3). 

	According to the advocacy group, Alliance for a Stronger FDA, which issued an update (4) on Dec. 21, 2018, furloughs were expected to affect FDA employees who are involved in the development of regulations, and those who focus on administrative and policy-related work. Staff members appointed by the president, as well as members of the agency’s commissioned corps (roughly 1000 staffers in various departments), are among those being retained during the funding lapse period. 

	According to a formal statement (1), FDA is continuing functions that it considers critical to public health, such as emergency inspections, high-risk drug and food recalls, criminal and civil investigations and enforcement, and the screening of imported food and drugs. The agency is also continuing to perform work that was funded by fiscal year 2018 user fees, including the review and approval of new therapies funded by these carryover user fee balances.

	"User fee funds will allow us to continue to review and approve some types of drug and other medicinal product applications, including filings for medical devices, generic drugs, biosimilars and animal drugs, during the lapse in appropriations," noted FDA commissioner 

	During the first week of the shutdown, Gottlieb also tweeted statements and posted 

performing these activities during the shutdown, including sympathetic and encouraging words to those affected by furloughs and those who have been working during scheduled holidays. 

	While work on its fiscal year 2018 applications will continue, the agency will not be able to accept fiscal year 2019 user fees until 2019 funding appropriations have been settled. As a result, FDA cannot accept new drug applications and other submissions that require a fiscal year 2019 fee payment and are submitted during the funding lapse period. 

	As legal experts from the firm Hogan Lovells wrote on the blog, 

on Dec. 27, 2018 (5), “Depending on how long the shutdown lasts, [FDA’s] medical product centers may well be looking at a sizable backlog of applications to triage when the agency is fully operational again ... Thus, if the current shutdown persists, industry should anticipate that certain agency delays will likely continue for some time.” They also noted that it was still unclear how the furlough period would affect the scheduling of US and offshore facility inspections in 2019.

, December 21, 2018.
	4. Alliance for a Stronger FDA, “

What Happens At and After Midnight, Cinderella

, December 21, 2018.
	5. R. Prebula, P. Katz, et al., "

Likely FDA Impact of the Government Shutdown: Regulatory Submission Reviews, Inspections, and Research Projects

Articles

Core functions and those funded by FY 2018 user fees are continuing, and 59% of the Agency’s staffers are being retained.

Critical FDA Functions Continue as US Government Shutdown Hits the One-Week Mark

As niched global markets grow and increase the complexity of pharmaceutical manufacturing, vendor management has become more challenging; the API and excipient supplier base has moved offshore, and more core operations are being outsourced to contract partners. Today, a typical pharmaceutical manufacturer works with 100–200 contract manufacturing organizations (CMOs) (1). A 2013 study found that supply and supplier issues account for 40% of the pharmaceutical industry’s top supply-chain risks (2).

	Adding to the difficulty have been corporate mergers and acquisitions, both on the manufacturer and on the supplier sides. Mergers shift the focus away from manufacturing, as Steve Cottrell, president of Maetrics, wrote in April 2018 in the PharmaPhorum blog (3). This, in turn, limits “the ease with which supply chain gap analyses, supplier assessments, and quality assurance checks (e.g., non-conformance or out-of-stock issues) can be carried out,” he wrote.

	The results have been clearly seen in an increase in drug shortages, recalls, and regulatory citations for insufficient quality management and vendor oversight. Overall, supply reliability issues cost biopharmaceutical companies $2 billion in revenue each year, according to the Boston Consulting Group (4). Pharmaceutical manufacturers still have limited visibility into their supply chains, and fairly loose, ad hoc connections with many of their vendors, in sharp contrast to the close supplier-manufacturer partnerships and data exchange programs that exist in the automotive, aerospace, and electronics industries.

	Manufacturers have been working individually and in concert to address these issues, through initiatives such as the Pharmaceutical Supply Chain Initiative (PSCI), a group of 33 manufacturers that has developed best practices, self-assessment guidelines, and an audit protocol based on the principles of sustainable sourcing and traceability, transparency, business resilience, and management capability and systems.

	The organization, which started up in 2005 with five members, has trained 190 auditors and 150 staffers at pharmaceutical industry suppliers in best practices and principles and is promoting the concept of shared supplier audits to reduce costs for manufacturers and their suppliers. The number of shared PSCI audits more than doubled from 61 in 2016 to 152 in 2017, according to Enric Bosch Radó, a manager in Boehringer-Ingelheim’s environmental health and safety department, who presented a progress report at Salon International de la Logistique (SIL), the international logistics meeting in Barcelona on June 5, 2018 (5).

	BioPhorum, a collaborative industry effort, is working on a blueprint for 21st century supply chain management as part of its Technology Roadmap program. Newer technologies, such as single-use systems for cell culture, Protein A, and chromatographic resins, require a significant investment from biopharmaceutical manufacturers, according to the group’s latest report (6), while the cost of poor quality (evident in raw material variability and lack of understanding and control of the supply chain) is high and must be driven out. Close collaboration between manufacturers and vendors will be increasingly important for ensuring supplies of single-use technologies, and as more companies evaluate continuous bioprocessing, said Jonathan Haigh, head of downstream processing at FujiFilm Diosynth, a company that is both a manufacturer and a contract manufacturer, in a video (7) discussing roadmapping efforts.  BioPhorum has called for changing the way manufacturers and vendors interact, and to promote harmonized methods using electronic data exchange. The group is also working on improving forecasting and planning software.

	One method that suppliers and their customers are using to attempt to balance rapid growth in demand and the need for careful planning is the sales and operational planning process, which examines inventory replenishment and distribution needs, and assesses manufacturing, including manufacturing and quality equipment and warehousing and how well it can support customer requirements, said Aida Tsouroukdissian, head of demand planning at MilliporeSigma in a 2018 video (8). Other methods being used include supply chain business continuity planning and supply chain mapping as well as change management.

	There is a need to go beyond the superficial level, noted Roger Estrella, senior risk manager for supplier business continuity at Genentech, in an Rx-360 workshop addressing challenges in the pharmaceutical raw material supplier chain (9). Estrella’s business continuity group works closely with Roche’s corporate quality risk organization, which handles audits, recalls and customer complaints, and process capability to be able to respond to and find the root cause of quality issues. Roche analyzes suppliers based on their potential impact on the business and the patient. The first question is what would happen to patients if there were a problem with the supply of this particular product? What impact would a supply interruption have on revenues and on patients? Materials are classified based on level of risk (e.g., oncology products would be placed in a higher category of risk than treatments for rheumatology), he said.

	Manufacturers must identify hazardous conditions, assess risks and develop contingency plans, get them approved and then implement them. Challenges to asserting full control over supply chains include cognitive bias, supply chain complexity, and business change management, Estrella said. Too often, employees may tend to discount risks, especially those that may occur in the future, he said, adding that strengthening supplier risk assessment requires a top-down approach and senior-level management support if it is to succeed. He said that, wherever possible, Roche avoids being dependent on overseas suppliers.

	It is no longer enough for manufacturers to have transparency from most important suppliers; they now need insights into how these suppliers manage their supply chains, Estrella said. Roche asks that suppliers give them some idea of their business continuity management by conducting manufacturing risk assessments at each relevant manufacturing site; developing mitigation plans for each risk; determining worst-case scenarios for the most likely site risks; and estimating the time that it would take for them to return to normal after a supply upset. If suppliers aren’t already doing this, the company helps them with the process and uses results to develop its risk mitigation inventory levels for the particular material, he said.

	Manufacturers must also look at each supplier’s business portfolio and ask how each particular product fits into that vendor’s big picture. “Consolidations have complicated the supplier-manufacturer picture. Every time that a merger and acquisition takes place, a rising star product can become a dog, and the new owners may decide not to invest in quality and delivery performance initiatives,” he said. In some cases, the new business owners may even stop making a product that has always been important to the manufacturer’s business, and biopharmaceutical manufacturers must be prepared and develop alternatives. He also noted that a supplier may be critical to an individual biopharmaceutical company’s business, yet biopharmaceutical manufacturing may not be a major market focus for them, so manufacturers should be prepared.  In general, he said, manufacturers must know suppliers, and must work to minimize the number of intermediates in the supply chain. “The more handoffs you have, the more potential points of failure,” he said. So if there are handoffs it is essential for manufacturers to know who is involved and how they will handle any situations that may come up.

	Stressing the importance of supply chain mapping and risk management, he noted that it is straightforward to identify risk, but challenging to mitigate it. Biopharmaceutical manufacturers must be prepared to understand and communicate more closely with suppliers to prevent quality and supply problems from affecting patients and their bottom line.

,” July 2018.
	2. M. Jaberidoost et al., 

 21, 69 (2013).
	3. S. Cottrell, “Gaining a Clear View of Supply Chain Visibility,” pharmaphorum.com, April 20, 2018, www.pharmaphorum.com/views-analysis-market-access/gaining-clear-view-supply-chain-visibility/.
	4. A. Merchant et al., “

How to Break the Vicious Cycle in Biopharma Supply

,” bcg.com, March 16, 2017.
	5. E.B. Radó, “Creating a Better Supply Chain in the Pharmaceutical Industry: The Pharmaceutical Supply Chain Initiative,” a presentation made at Salon International de la Logistique (SIL) (Barcelona, Spain, 2018).
	6. BioPhorum, “Biopharmaceutical Manufacturing Technology Roadmap: Supply Partnership Management,” biophorum.org, December 2017.
	7. BioPhorum, “

The Importance of Supply Partners in the Technology Roadmap

,” biophorum.com.
	8. A. Tsouroukdissian, “

,” emdmillipore.com, Nov. 30, 2017.
	9. R. Estrella, “Challenges to Raw Material and Supplier Risk Management,” Rx-360 Workshop, “Addressing Challenges in the Pharmaceutical Raw Material Supply Chain Through Industry Collaboration,” rx360.org, March 13, 2014.

Vol. 42, No. 12
	December 2018
	Pages: 16–17

	When referring to this article, please cite it as A. Shanley, “Going Beyond the Surface to Ensure Supplier Quality," 

Success depends on supplier communication and transparency, but it’s up to buyers to demand the right information and to look at the vendor’s overall business goals.

Going Beyond the Surface to Ensure Supplier Quality

Technology transfer is a difficult process, whether it occurs between R&D and manufacturing within a single company, between an academic lab and a corporation, or between a manufacturer and a contract development and manufacturing organization (CDMO). Pharma’s folklore is full of stories about tech transfer failures: analytical techniques or processes that worked perfectly in the lab, yet failed on the plant floor, costing partners significant time and money, and derailing promising development programs.

	Where a few decades ago, research department staffers might speak glibly of throwing a process “over the wall” from R&D to scaleup and manufacturing, today most organizations realize how wasteful that approach has been and are approaching tech transfer in a much more systematic and collaborative way. Crossfunctional teams are usually the rule, with representatives from each major operational group (e.g., quality, business, research, and operations) at the sponsor group taking an active role in moving projects forward.

	In addition, best practices often call for minimizing the number of tech transfers required involved in the development of a drug, says James Bernstein, principal of Live Oak Pharmaceutical Services. This approach depends on careful contract partner selection, he says, to ensure that the CDMO’s strengths are fully leveraged at each stage. Typically, he says, a sponsoring drug company will opt to work with a smaller contract partner for the initial development and formulation, then design the process so that only one tech transfer is required, he says, so the project can move straight from development to Phase III. “If we plan the process well, we can get away with only one tech transfer, but you’ll always have at least one,” he says.

	Tech transfer is also the best time to consider scale-up type issues, and to take stock of risks based on the technologies and equipment that are available, says James Blackwell, principal of the Windshire Consulting Group. “By understanding the sensitivities and behaviors of your system, you can start to predict behavior,” he says.

	Currently, a growing number of companies are starting to use novel technology to help improve and speed tech transfer. Merck, for example, tested the use of augmented reality to move an analytical process between sites, and found that it improved efficiency by 10% (1). By allowing partners in the transfer to interact directly, to troubleshoot and share “tribal knowledge” (i.e., expertise gained by people experienced in operating the equipment or working with the technology that cannot be written into a training manual or other typical documentation), the technology can help improve communication and eliminate travel time and expenses (2).

	Joseph Szczesiul, director of technical services for UPM Pharmaceuticals, recently shared best practices for tech transfer with 

: What are the crucial elements to doing tech transfer correctly, and when should their foundations be established?

: The best foundation for tech transfer success is complete formulation and process development. You cannot correct formulation deficiencies during tech transfer, and process optimization can only provide limited improvement. An inadequate enteric coating, for example, or a wet granulation with insufficient binder, can only be improved incrementally by process changes. The big fix comes from formulation change, which needs to be done early in the development process.

	To step back even further, a development project needs clear and complete goals, which then lead to a strategy, and then to a plan of work. The obvious goals are to succeed in the clinic, to file your application, get approval, and start selling product. But a product also needs to pass validation. It must also be physically and chemically stable, and will need to succeed in routine manufacturing and to meet regulatory requirements.

	A good practice is to maintain a development narrative over the life of the project. This becomes a reference, but it is also a tool for periodic review. It should include the goals for each stage of development. It should list the batches made, their purpose, and their outcome, and also list all issues and problems encountered with each one. 

	All issues should be resolved before proceeding to the next development phase. At the end of each phase, call a team meeting, review the development against the goals for that phase, and determine whether the project is ready to move further down the path. In that way, you keep returning to your overall strategy, and your idea of big-picture success.

	A little knowledge (transfer) is a dangerous thing

: What are the biggest mistakes that pharmaceutical companies and inventors most often make when approaching tech transfer? What do they often appear to overlook or leave out?

: Incomplete knowledge transfer to the CDMO is a consistent problem with tech transfer projects, and projects are often delayed due to incomplete information being provided. Effective technology transfer requires access to relevant information about the process that is being transferred.

	Client companies must provide as much information as possible to their CDMO, since the client possesses all of the documented and undocumented product and process knowledge at that phase of the project. Ideally, knowledge transfer takes place through the provision of a technology transfer document package, as well as through routine ongoing communication.

	In addition to the ‘hard’ data transfer, it is important for client companies to transfer their peripheral and soft, experiential knowledge. The client’s experts that know manufacturing, analytical, and safety aspects of the product should be on the project team so they can provide continued review and input. 

: What should client companies ideally focus on, and how should they be staffing and managing these projects?

: Client companies should focus on information transfer, on having a clear regulatory strategy, and on developing an appropriate plan of work in conjunction with their CDMO. A tech transfer plan of work establishes the steps to be implemented to generate all of the information and data necessary for successful regulatory filing. It must meet regulatory agency expectations for the application and answer questions specific to the product being transferred.

: Can you share any tech transfer war stories?

: Years ago, I worked on a project where nearly, but not quite all, of the required information was communicated by a sponsor. This project involved the site transfer of an approved Wurster-coated product. It was sustained-release, with the polymer dissolved in a flammable solvent. 

	Our fluid bed was from the same equipment manufacturer, it was explosion-proof, and it matched the bowl size of the fluid bed at the originating site, so it was assumed when the development contract was signed that no process development work would be needed, just a confirmation batch to verify a successful run using the parameters in the original batch record. 

	However, two significant issues arose after we finally received a copy of the batch record. First, the originating site used the same size bowl as our fluid bed, but it was connected to a different expansion chamber to a model that was two sizes larger than ours.  This meant that our filter chamber was several feet shorter than theirs, so we had to reduce airflow, to avoid driving product up into the filter. 

	Second, we learned that the other site had a sealed air system with solvent recovery, and purged their system with nitrogen to prevent combustion of the solvent. We did not have either capability, and for safety and insurance reasons, our maximum spray rate could not exceed 40% of the original spray rate. A new coating process had to be developed.  So the project exceeded its original scope, required unexpected process development work, and caused an unexpected delay for the client. 

: For virtual companies, and even nonvirtual companies that outsource most key functions, what is essential to coordinating efforts and ensuring success?

: The first step is to understand and analyze your own company’s limitations in terms of specific knowledge and experience for the project at hand. Then fill in your knowledge gaps with the appropriate consultants and the CDMO. A key component of your relationship with the right CDMO should be education: their technical leads should be able to explain not just what they are doing, but why, in the same way that that they should be able to explain to an auditor or FDA investigator what they have done, and why. 

	There should be a continual feedback loop of review and information to the client as the project progresses. Your knowledge and understanding of your product should grow throughout its development life. Look for a CDMO that can communicate technical and scientific information, and consider this an important part of the contract partner selection process.

	Beyond that, evaluate the progress of your project against its development strategy. Work completed needs to be considered in the context of your overall goals. It is important to conduct gate-keeping reviews before starting significant steps, such as the manufacture of registration batches or validation batches, to verify that the project is ready to advance.

, 106 (12) 3438–3441 (2017).
	2. A. Shanley, “Mixed Reality Gains a Foothold in the Pharma Lab,” 

Pharmaceutical Technology Bio/Pharma Laboratory Best Practices eBook

Vol. 42, No. 12
	December 2018
	Pages: 24–25, 48

	When referring to this article, please cite it as A. Shanley, “Tech Transfer: Tearing Down the Wall," 

Once described as “throwing processes over the wall,” tech transfer is evolving into close collaboration and communication, as potential problems are considered sooner, and new technology is applied. Joseph Szczesiul, director of technical services for UPM Pharmaceuticals, shares best practices.

Tech Transfer: Tearing Down the Wall

Interest is growing in a new approach that allows the monitoring of critical quality attributes in real time for complex biologics such as monoclonal antibodies, opening up new possibilities in biopharmaceutical development and quality control. A consortium of biopharmaceutical companies, analytical instrumentation vendors, FDA and NIST is exploring capabilities and promoting this approach. 

Bio/Pharma Laboratory Best Practices 2018 

	When referring to this article, please cite it as A. Shanley, "Multiple Attributes Monitoring: A New Phase in PAT for Biopharmaceuticals," 

Pharmaceutical Technology Bio/Pharma Laboratory Best Practices 

By reducing the number of assays needed and allowing product quality attributes to be measured end to end, MAM promises to allow users to gain product and process understanding much sooner than they could in the past, and to ensure quality and safety in a more efficient, streamlined way, throughout the product life cycle.

Multiple Attributes Monitoring: A New Phase in PAT for Biopharmaceuticals

Augmented or mixed reality offers benefits in tech transfer, general batch recordkeeping and SOPs, and training, especially the transmission of “tribal knowledge” that cannot be put in a training manual.  Now that augmented reality hardware has sufficiently advanced, use of the technology is starting to take off in pharma.  Apprentice.io is focusing on pharma and biotech applications.  The company’s CEO and cofounder Anthony Stracquatanio discusses trends.

	When referring to this article, please cite it as A. Shanley, "Mixed Reality Gains a Foothold in the Lab," 

Rather than isolating the user in a virtual world, mixed reality allows contextualized data to be shared in real time, improving assays, standard
operating procedures, workflows, and overall tech transfer.

Mixed Reality Gains a Foothold in the Lab

	Now that the first gene therapies have been approved and have become 

commercial products, innovative therapies have reached a crucial threshold and proven what can be achieved. Spark Therapeutics, for example, received “breakthrough therapy” status for its retinal dystrophy treatment, Luxturna, which was approved by FDA in 2017 and has been viewed favorably by the European Medicine Agency’s Committee for Medicinal Products for Human Use (CHMP). The company is also working on treatÂ­ments for hemophilia B, and is currently collaborating with Pfizer on Phase III clinical trials. 

	At this point, better manufacturing processes will be crucial. “Sustained, reliable manufacturing will be required to bring gene therapy to patients worldwide,” Mikael Dolsten, president of worldwide R&D at Pfizer, told attendees at a panel discussion of gene therapy at the 2018 Galien Forum on October 25, 2018 in New York City.

	As one audience member whose relative suffers from a genetic rare disease put it, “You’d better hurry up.” Currently, FDA has approved one directly-administered and two cell-based gene therapies, but has received over 700 investigational new drug (IND) applications in the gene therapy field, said Peter Marks, director of FDA’s Center for Biologics Evaluation and Research. 

	“We will need a one-to-two orders of magnitude improvement in our ability to manufacture quantities of gene therapy vectors and a one-to-two orders of magnitude reduction in costs in order to do this,” said Marks, who cited the development of Apple’s iPhone as an example of why this won’t be impossible. 

	Agreed Brian Kaspar, scientific founder and chief scientific officer of AveXis, Inc., which was recently acquired by Novartis, “We need to think about global regulatory strategies and the cost of goods and manufacturing so that batch 1 acts like batch 3 and batch 303,” he said.  

	AveXis, which was acquired by Novartis in April 2018, is focusing on the rare pediatric disease spinal muscular atrophy, a condition that affects 500 children born in the United States each year, and normally ends their lives before their second birthday. In Phase I clinical trials of AveXis’ one-time gene therapy treatment, Kaspar said, all participants survived, and many are now over five years old and thriving, enjoying a greatly improved quality of life. The company has grown to more than 500 employees and is now moving into other research areas such as Rett syndrome, a condition on the autistic spectrum, as well as a genetic form of amyotrophic lateral sclerosis (ALS), said Kasper.

	Kathy High, president, cofounder, and head of R&D at Spark Therapeutics and Philip Gregory, chief science officer at Bluebird Bio, discussed their companies’ histories, their different approaches to one-time gene therapy treatments, and the work that they are doing to improve vector yield.

adeno-associated viral vectors (AVV) and is focusing on diseases that involve tissues of the retina, the liver, and the central nervous system, Bluebird uses an 

approach involving Lentivirus vectors, which carry genetic payloads that modify cells that have been removed from a patient, adding them to stem cells and then injecting them back into the patient.  The company is focusing on severe genetic diseases that include sickle cell anemia and thalassemia.  Bluebird’s approach can also be used to treat cancer, with vectors carrying redirection technologies that teach chimeric antigen receptor (CAR) T cells to see specific targets on the surface of tumor cells, said Gregory.

	Progress only demonstrates the inextricable link between good clinical work and good process development, said High. “We’re already up by logs from where we were when we started our research,” she said. 

	Bluebird, meanwhile, has recently made some major 

 to its manufacturing processes for the vectors, Gregory said. “The latest generation of our thalassemia therapy features a different 

 that massively improves transduction efficiency and the amount of vector we need to use,” he said. 

	In addition, on the CAR-T side, Bluebird has developed a new process that greatly improves cell durability, said Gregory, noting “Generation 1.0 processes need to be updated if we are to get these treatments to more patients.” 

	Gene therapy: quiet childhood, stormy adolescence

	High sketched the history of clinical gene therapy research, which began in the 1990s at the National InstituteS of Health (NIH).  The research that was to drive Spark began during that decade at Children’s Hospital in Philadelphia. The field was considered controversial and some companies that had begun research programs, including a partner that had worked with Spark’s founders at Children’s Hospital, left the field later, noted High. “Gene therapy has had a quiet childhood but a difficult adolescence,” she said.

	After its collaborator left the field, the research group had to manufacture its own clinical-grade vector in order to do regulatory work, said High. As more programs succeeded, the company had to determine how to move its retinal dystrophy product, Luxturna, through Phase III and approval. The company decided to spin off the Children’s Hospital research group’s activities as a separate company, founding Spark in 2013. The company currently has 350 employees, and its research is focusing on diseases that affect tissues within the retina, liver, and central nervous system.

	As High explained, Spark’s two lead programs represent different challenges with gene therapy. Luxturna treats a condition that has not had any successful cures so far, so it involved developing and validating a novel primary endpoint.  The company worked very closely on this with FDA, she said. The company’s work in hemophilia, meanwhile, has highlighted the difficulties of understanding and managing the human immune system’s response to a recombinant that has been engineered from a virus. 

	FDA has also developed programs designed to help speed the development of gene therapies, said Marks. The agency offers expedited programs such as Breakthrough Therapy, priority review, which can reduce review period by four months, and accelerated approval provisions.

	“We have also started to help de-risk development by allowing innovator companies to talk with reviewers in early non-binding regulatory meetings through the Interact program, which provides an informal opportunity to talk about preclinical and clinical issues and plans,” he said.

	“From our vantage point, the next step in development of these therapies will require a quantum leap in manufacturing. Gene therapy also has the potential to address issues, not only in high income but in low- and middle-income countries, which don’t currently have the infrastructure required,” he said.

	Don’t make the perfect the enemy of the good

	Focus has been a crucial enabler of gene therapy innovation so far, and the process of focusing on areas where improvements have been shown and refining them. At some point, for example, High says, Spark researchers found that enough problems had been solved to enable AAV delivery to a few target tissue types that would allow development work to proceed.  “Have we solved everything we need to solve? No, but I do believe that good clinical results drive better process development, which expands manufacturing capability and allows you to approach clinical areas that you could not approach before,” she says.  High predicts that the industry will continue to see an expansion of feasible targets in gene therapies. “Do not make the perfect the enemy of the good,” she advised. 

	Marks emphasized the importance of regulatory harmonization in speeding development of gene therapies, noting that dialogue has been ongoing. “High-income countries and the E[uropean] U[nion] understand that it is really challenging for developers to follow different global standards,” he said.  “We are starting to encourage people very early on to come to us, and even to invite E[uropean] M[edicines] A[gency] to listen to their discussions,” he said. This approach will be very important in dealing with surrogate endpoints. 

	Marks noted that FDA is currently very comfortable with the use of surrogate endpoints in some areas, and believes that the agency can help drive acceptance throughout the global regulatory community. 

	During a question and answer session, an audience member asked about treatments for polygenic diseases. Getting there will take time, panelists noted. “The field has progressed in thinking about very advanced targets, and in how to establish safety and dosing parameters and to design clinical trials,”said Kaspar. Developers will now need to take that knowledge and use those tools to start working on therapies for larger diseases such as Alzheimer’s and congestive heart failure, he said.

	There will be challenges in developing treatments for conditions such as cystic fibrosis and Huntingtons. “For 

delivery of AAV, every target tissue is essentially a different problem, and part of this has to do with the immune response, which is also tissue-specific,” said High. With cystic fibrosis, she explained, there is a need to reach the basal respiratory epithelium, but the cells above it continually turn over. “AAV is not an integrating vector, so it would be lost from cells at the top of the respiratory tract that are sloughed off. There are many complexities that have to be dealt with as you branch out to all the different types of target tissues,” she said.

	Dolsten suggests that focus continue to guide development work. “Once you branch into polygenic diseases, in which environmental influences are also at work, it will be hard to tease apart technology shortcomings and delivery issues.  It is better to approach the problem stepwise and gain confidence with monogenic diseases first,” he said.

Improving the manufacturing of gene therapy vectors will be crucial to making advanced treatments accessible to more patients who need them, agreed panelists at the 2018 Galien Forum.