Agnes Shanley is senior editor of Pharmaceutical Technology.

Agnes Shanley

	Few things can strain a sponsor’s relationship with a contract research organization (CRO) more than a missed clinical study deadline.  Missed deadlines often show the true character of the partnership, and even the most cordial professional relationship can quickly degrade into a blame game. As pharmaceutical company sponsors and their CRO partners work to improve drug development efficiency, more are learning the importance of sharing data across organizations.  This article explores how data sharing can strengthen working relationships and improve results.
	
	


	Today, sponsors and CROs work together under various different operating models. On one end of the collaborative spectrum, sponsors develop strategic partnerships with selected CROs, in which they share technology, risk, accountability and decision-making, and even integrate some business processes.  On the opposite end, sponsor and CRO work rather independently, maintaining separate business processes. In this case, the sponsor relies on the CRO to deliver agreed-upon results.
	
	In either case (and in any intermediate model), the collaborative spirit can dissipate the minute something goes awry in the execution of the trial. No matter how much risk sharing is built into the contract, no matter how long-standing the relationship, the two parties are not, and perhaps never can be, equal partners. The sponsor ultimately bears the most risk in the drug development process and depends upon the CRO to perform work according to a contract.

	Regardless of the relationship model employed, it is in a sponsor’s best interest to build a strong and healthy alliance that delivers the performance expected. As information sources solidify and technology advances, there are now ways to shore up the relationship with improved communication and transparency. The following steps are recommended to sponsors intent on making the most of their CRO relationships to improve trial performance:
	
	

Use shared data to discuss study feasibility


	When CROs prepare their bids and present their initial, detailed plans for study enrollment to a sponsor, they have approached the challenge with a certain body of experience, drawing on specific historical data and assumptions. These, in all likelihood, will be different from the sponsor’s own, and the proposed study timeline will reflect these differences.
	
	At this stage, it is understandable that the data from which each party are working would be different, and sponsors should accept that “different data doesn’t automatically equate to better or worse data.” This is the perfect time to begin a dialogue about the nature and causes of the differences that come to light. By comparing experiences and assumptions, the sponsor and CRO can, ideally, “put their heads together” to arrive at a plan that incorporates the best knowledge and experience of both organizations.

	This process takes a bit of patience, as it takes time to vet incoming information, explore differences, and jointly determine what enrollment plan is most realistic. The most advanced sponsors shorten the process by allowing prospective CRO partners to enter their historical information and assumptions into a shared platform that presents them alongside the sponsor’s own. The sponsor can then quickly spot the points of contention and focus conversations on areas of discrepancy (

). Some sponsors open the platform to multiple CROs so that they can make apples-to-apples comparisons across CROs and to their own data.


	Perhaps the single most important piece to ensuring that trials commence, and then proceed, smoothly and according to plan is to establish a mutual understanding of all parties’ expectations. A team with representatives from each organization must come together to agree on the goals and ground rules for each project. While there will be a basic agreement in place governing the overall business relationship (most especially in strategic partnerships), this more detailed level-setting exercise needs to be completed with each research project. Specifically, the project team should agree upon the goals, timeline and interim deadlines, responsibilities, plan for resolving/escalating conflicts, and trigger points for moving to the mitigation plan. The project-specific plan and chosen metrics should, of course, allow the project managers to manage in a way that is respectful of the overall partnership between the sponsor and the CRO.
	
	

Share technology for optimal trial management


	Regardless of the nature of the partnership, sponsors naturally need to monitor study progress closely. Using a shared technology platform can make this process more efficient, because it will give both sponsor and CRO an objective view of key performance indicators and analyze the same performance forecasts. When the performance-monitoring tool is shared, both parties have access to a “single version of the truth” for evaluating operational progress, diagnosing issues, and evaluating “what if” scenarios for corrective actions. In this environment, either party can proactively address any issues that arise.

		When sponsors and CROs are open about sharing information during both the feasibility phase and study execution, the benefits accrue to all parties, and most especially to the smooth conduct of the trial. Sponsors that apply the approaches recommended here report that they:

		Uncover misalignment in the early stage of trial planning-before it is allowed to create serious problems with the quality of study data or the adherence to timelines

		Shift the conversation about feasibility from one riding on anecdotal evidence to one based on quantitative evidence

		Develop a mutual understanding of, and appreciation for, the risk involved in the project

		Foster a greater sense of accountability and investment in the results

		Develop stronger alliances that benefit from shared ideas and decision making.

	However, the most significant value in having a global planning and tracking platform and common data model between the sponsor and CRO is that it increases study predictability. This, in turn, improves performance and reduces costs.

	Prior to adopting such an approach, one global pharmaceutical company was struggling with the fact that fewer than 40% of its trials were executing according to plan. As seen in 

, performance began improving immediately upon implementation of a shared platform.

	Over approximately three years, the company saw a 100% increase in the number of studies recruiting to plan (exceeding the goal to achieve a 50% increase). Given that daily operational costs for trials average $37,000, (1) this improvement saved the sponsor an estimated tens of millions of dollars across its trial portfolio.

	Through a commitment to communication, sharing data and sharing technology platforms, sponsors and CROs can change the dynamics of their relationship to become more collaborative, efficient, and productive. By combining joint histories to build inputs and assumptions from the outset, they can devise the most realistic plan for trial execution together, with a shared understanding of expectations.

	As the trial progresses, it is crucial that both parties share the same trial management platform and derive forecasts through the same methodology, giving access to the same milestones and data points for decision-making. Through this approach, global teams, once isolated, can be in alliance from beginning to end, leading not only to stronger collaboration, but also to the successful achievement of trial milestones.

	Imagine if the industry as a whole could achieve gains like those realized by the company in the example cited. This model of sharing has the potential to impact the entire drug development process dramatically, bringing drugs to market on time and on budget.


	1. “Boosting the Predictability of Clinical Trial Performance,” Gartner case study, 2007.


	April Lewis is the Head of Product Education for IMS Health’s Clinical Trial Optimization Solutions division.


	Vol. 39, (2) Supplement
	Pages: s49–s51
	

: When referring to this article, please cite it as A. Lewis, “Time to Share,” supplement to

Articles

Data sharing and a common data model can improve CRO partnerships and trial results.

Time to Share

There was a lot of speculation when FUJIFILM Corporation entered the biopharmaceutical business in 2011, acquiring Diosynth and MSD Biologics from Merck & Co. and partnering with Mitsubishi Pharmaceuticals, which now owns 20% of the company.  Many in the industry asked, in op-eds and on social media sites, what impact an Asian electronics company would have on the industry. 

	Over the last two years, FUJIFILM Diosynth Biotechnologies U.S.A. Inc., has made a number of strategic moves:

		Developing and manufacturing antibody drug conjugates (ADCs), through a strategic alliance with India’s Piramal.

		Introducing the Apollo mammalian cell platform last quarter

		Acquiring Kalon Biotherapeutics in December, and with it, modern, rapidly deployable vaccine manufacturing technology, capabilities in new cell lines, new closed cleanroom technology, and the operation of the National Center for Therapeutics Manufacturing, an advanced vaccine manufacturing facility built by Texas A&M, with funding from the U.S. Department of Health and Human Services’ (HHS’) Biomedical Advanced Research and Development Authority (BARDA). FUJIFILM currently owns 49% of Kalon, but plans to increase its stake to 100% pending achievements of key milestones.


	In three years, Kalon has gained key clients, such as GlaxoSmithKline (GSK) and MD Anderson, and grown to more than 100 employees. This is FUJIFILM Diosynth Biotechnologies’ first acquisition, but the company had been looking for ways to expand, either through new capabilities or more capacity, says John Foy, President and CEO of its new subsidiary, Texas-based FUJIFILM Diosynth Biotechnologies Texas, LLC.  “Kalon expands our capabilities into core classical vaccine manufacturing using cell-based technologies, and in viral expression, and high-containment systems.” 
	Kalon’s modular technology was another attraction. As Foy notes, it has only been in use for a few years. “We want to see the facilities that exist prove that technology, which goes very well with single-use systems.” FUJIFILM Diosynth has installed 2000-L single-use cell culture equipment at both its North Carolina and its United Kingdom sites. “Today, we are capable of running processes 100% in single-use equipment,” Foy says.
	 


	FUJIFILM Diosynth has also been investing in mammalian cell culture technology at its North Carolina and UK facilities, says Foy, who has spent the past 14.5 years in a number of different management and engineering roles in North Carolina, and who worked at Diosynth before joining FUJIFILM Diosynth. The Apollo platform is one result of this new focus. “It allows us to take a gene from a customer and put it into our platform, media and process technologies to accelerate the time from tech transfer to clinical supplies,” Foy says. 

	FUJIFILM’s new Texas-based company will be focusing first on its core contract with GSK for operating a new $91-million vaccine manufacturing facility for pandemic flu response, Foy says. Texas A&M is now building the facility, which will be the foundation for Texas A&M’s Center for Innovation in Advanced Development and Manufacturing (CIADM), an R&D program that aims to prepare the nation for disease pandemics by speeding up vaccine development times.

	It will use GSK’s own proprietary cell-based technology and should come online in the next 15 months, Foy says.  It will be capable of producing 50 million doses in four months.
	Also underway are projects with other programs with HHS’ Biomedical Advanced Research and Development Authority (BARDA) and CIADM.  (Box)

	The acquisition takes Texas’ growing biocorridor one step closer to realizing the state’s goal of becoming the nation’s third coast for biopharmaceutical manufacturing. “There’s a lot of motivation within the local community, and a very strong commitment for Texas to grow,” Foy says. “A number of interesting programs are in place to help support growth, create a critical mass of opportunities and job growth,” says Foy. “Over the coming months, we want to take 20 years of experience from FUJIFILM Diosynth and accelerate development of the Texas company into a more mature business,” Foy says.

	An important part of this plan is integrating diverse manufacturing and quality cultures, as FUJIFILM Diosynth did when it combined Lean Six Sigma programs from Merck and Schering Plough with the FUJIFILM Way culture.  “We have brought these robust quality and manufacturing practices into all our facilities and will quickly bring them to Texas,” Foy says.  “What we’ll look at are operational efficiency opportunities and how to grow flexibly in a lean environment. We also bring robust overall quality systems, taking these systems to accelerate development of new systems in Texas.” 

From Years to Months: The Incredible Shrinking Vaccine Timeline


					
					Under contract to Biomedical Advanced Research and Development Authority (BARDA) and the Defense Advanced Research Projects Agency (DARPA) bioterrorism preparedness projects, Texas A&M has been a key developer of technologies designed to reduce the timeframes required to produce vaccines. The idea is to be able to mobilize resources immediately when a pandemic strikes.Texas A&M has also played a role in developing disposable process equipment for personalized medicines, through Gradalis Construction, a company that has worked in clinical and R&D areas, and collaborated with the Mary Crowley Cancer Center.  This work has resulted in technologies that enable the kind of personalized, product-centered manufacturing and small batch sizes that biopharma will require as the industry moves to personalized medicine. 

					Much of its work has focused on vaccines, and the university’s collaborations include projects that involve plant, insect, and mammalian cell culture. But its innovation and partnerships have also helped develop the manufacturing infrastructure required for fast processing. 
					Under the traditional NIH timeline, as defined in 2004, it could take up to 16 years between the time that a pathogen is identified to the time when vaccines are manufactured. Plans call for shrinking that time scale down to 16 months.  

					Enabling these timelines is what engineer Robert Dream, who helped design these facilities, has called the “mobile bioprocessing unit,” self-contained mobile units featuring inherent air quality and other controls.  In a talk at INTERPHEX 2013, Dream discussed these modules and how they would be employed, one per type of technology (e.g., for mammalian vs. insect or plant cells), to avoid cross-contamination. He also discussed how they would simplify scale up, as “stockpile pods” would allow a facility to increase capacity by ten fold within 24 hours. 

					This technology is at the heart of the Center for National Center for Therapeutics Manufacturing, which Kalon, now FUJIFILM Diosynth Biotechnologies Texas LLC, will operate. Whether or not Texas becomes biopharma’s third US focal point, companies in its biocorridor are creating manufacturing and technology platforms that should enable shorter timeframes and better, more consistent product quality.


	Vol. 39, (2) Supplement
	Pages: s44–s45
	

: When referring to this article, please cite it as A. Shanley, “FUJIFILM's New Biopharm Game Plan,” supplement to

After launching a new mammalian cell platform, FUJIFILM Diosynth Biotechnologies U.S.A., has acquired fast-track vaccine manufacturing knowhow and a major presence in Texas’ emerging biocorridor with Kalon, its first acquisition.

FUJIFILM's New Biopharm Game Plan

	At one time, cell therapies, whether immunotherapies, stem cell therapies or tissue regeneration therapies, were the stuff of science fiction.  Today, they have become a reality, and some cell therapies have already been commercialized.  All Big Pharma and Big Bio companies are working in this area.

	However, the industry faces significant challenges in getting more of these therapies to market.  As a number of contract services companies explore this niche, there is a greater need for technologies---for instance, 3-D, rather than planar, bioreactors, capable of processing trillions rather than billions of cells.  In addition, better instrumentation and automation will be required to reduce the extremely high cost of treating individual patients.

	In addition, companies that choose to outsource any of the development and scaleup work will need to approach these projects in the right spirit, and asking the right questions.

 asked Eytan Abraham, head of cell therapy research and technology at Lonza, who also worked at Pluristem Technologies, for his views on what is needed to bring the technology forward. Here is some of what he had to say. 

:  What are the major hurdles for developing robust and reliable processes for cell therapy?

: One major hurdle that we are facing is the planar culture technologies that are currently being used.  These traditional planar culture technologies will not be able to meet cell number demand for larger indications. Hence, the move to 3-D bioreactor-based culture processes and technologies will be pivotal and is recommended.

	The use of bioreactors may also enable the development of more robust and reliable processes, which would be optimized, fully controlled, and far less manual. Another major hurdle that we face is the pairing of these processes with adequate upstream and downstream technologies. 

	The last hurdle, which occurs during the final step of the process, is the delivery of the cells at point-of-care. Much needs to be done to streamline cell therapy product shipping, storage and delivery. Lastly, good and relevant analytical assays need to be in place to confirm that process changes have not changed the product.

: What unique challenges are posed by autologous products?  Do you see the industry focusing on allogeneic products first, or will the two be developed and commercialized in parallel?

: Autologous cell therapies indeed pose unique challenges. The central challenge, from a manufacturing perspective, is the fact that these therapies will have to be out-scaled rather then up-scaled. Conducting this out-scale process -- while using automated, robust and cost-effective manufacturing methods -- will be a significant challenge. 

	Additionally, each lot, representing one patient, will have to be segregated.  Technologies to meet these challenges are currently being developed.  However, it is a fact that autologous cell therapies are the only viable option for certain indications.  Therefore, it is believed that allogeneic and autologous therapies will be developed and commercialized in parallel, despite these hurdles.

: What should sponsor companies (used to thinking in terms of Mabs and traditional biopharmaceuticals) think about first, when they decide to develop a cell therapy program?

: I believe that cell therapy will play a central role in future medicine, and will, together with pharmaceuticals, biologics and medical devices, become the fourth pillar of healthcare. Pharma companies that realize this and invest early in this area, whether through R&D or acquisitions, can greatly benefit.

	However, it is clear that significant investment will be needed and that failures will be a part of the progress. There are several key elements to minimizing the chances of failure:

		Cell therapies are mechanistically complex – a solid understanding of the mechanisms of action is critical.

		Have good analytical methods and animal models that truly mirror the viability and potency of the cells.

		Have a manufacturing process that can produce cells at the required quantity, quality and cost. Work hard to implement these processes early and perfect them.

		Be vigilant in assuring that up-scaling or changes to the process are not changing the cell therapy product.

		Design intelligent and sufficiently powered clinical trials which also look at dosing effect.

		Be prepared to invest the significant time and money that it takes.

: What should company managers think about when they decide to work with a CMO to develop a cell therapy?

: The complexity of cell therapy means that significant know-how and manufacturing capabilities are essential to producing and testing these products. As this is an emerging field, the expertise and infrastructure needed to do this properly are rare. 

	One of the biggest advantages of using a CMO that is well versed in producing cell therapies is that you get the vast know-how and facilities that will give you much better chances for a successful launch of your product to the market. 

	However, there is also an argument to be made for maintaining process development and manufacturing in-house so that you have a better control and understanding of the process and product. This approach also comes at a significant cost in time and money, and has a steep learning curve.

	Lastly, while tapping into the know-how of a CDO/CMO is priceless, they cannot supply all the answers; so you must go to them with a fair understanding of your cell therapy product, at least from a scientific mode-of-action perspective.

: Where do you see the greatest need for regulatory clarity? For both sponsors and contract partners?

: As in any emerging field, there are many regulatory uncertainties. The critical point is that the regulators work closely with anyone involved in this arena-small companies, pharma, CROs and CMOs to get the best and most relevant regulatory guidelines in place as soon as possible.


	Vol. 39, (2) Supplement
	Pages: s34–s36
	

: When referring to this article, please cite it as A. Shanley, “Commercializing Cell Therapies: Lonza’s Eytan Abraham on Challenges and Rewards,” supplement to

Better equipment and automated processes will be key. So, too, will the right way of approaching outsourcing relationships.

Commercializing Cell Therapies: Lonza’s Eytan Abraham on Challenges and Rewards

	Sandoz announced on Dec. 8, 2014 that its PIONEER Phase III study demonstrated the similarity of its investigational biosimilar, filgrastim, with Amgen’s Neupogen. The drug is designed to prevent severe neutropenia in breast cancer patients who are receiving chemotherapy.  Studies reportedly showed that repeated switching between the investigational biosimilar and the original drug had no impact on efficacy, safety or immunogenicity.

	The study was a randomized, double-blind, four-group trial conducted at 27 centers, Nasdaq reported, and evaluated 218 breast cancer patients receiving neoadjuvant myelosuppressive chemotherapy.

	FDA accepted Sandoz’s application for filgrastim on July 24, marking the first time that a filing was accepted under the US Biologics Price Competition and Innovation Act of 2009.

	"We are pleased by these clinical study results, as they confirm the similarity of our investigational biosimilar filgrastim compared to the reference product in terms of safety and efficacy," said Dr. Mark McCamish, head of global biopharmaceutical and oncology injectables development at Sandoz. "The data from this important study also reinforce the results we have seen in earlier stages of development including multiple Phase I, pre-clinical and analytical studies. We look forward to making this product available to patients and healthcare providers in the United States."

	Sandoz currently markets three biosimilars outside the U.S.and sells biosimilars in over 60 countries.

Sandoz announces their version of filgrastim, a follow-on biologic for the treatment of neutropenia, is as safe and effective as Amgen's Neupogen.

Sandoz's Biosimilar Shows Similarity to Amgen's Neupogen

According to a recent Bain Research Study, the pharma companies that delivered most value to their shareholders have been the ones that lead a single category.  The last several years have been marked by significant merger and acquisition activity. Recent mergers in the US, dominated by “inversions” and often driven by the desire to reduce taxes, sometimes seemed a bit random, as companies merged with partners with whom they seemed to have little in common.

  Studying those companies that have consistently delivered the greatest value to shareholders over the past 20 years, “New Paths to Value Creation in Pharma,” by Nils Benhnke, partner in Bain’s San Francisco office, and his colleagues in New York and Boston, draws some simple conclusions that might be useful for any company in any industry to consider.   At a time when big pharma companies are starting to resemble each other, the report suggests that those companies have built leadership in a single category and targeted acquisitions to match core strengths. The study points to Roche in oncology, Novo Nordisk in diabetes, Biogen Idec in neurology, Celgene in oncology, and Gilead in HIV and AIDS, extended by Hepatitis C.  At the paper’s conclusions, the authors ask the following simple questions of pharma leaders:

•	What are the core categories in which you can maintain or develop a leadership position? 
  •	How will you win in these categories? 
  •	What is your repeatable business model? Does it set you up for success for the future? 
  •	What moves can you make to preempt emerging competition in your core business?
  •	What M&A moves are necessary to build and defend category leadership positions?


A Bain research study on shareholder value draws conclusions about pharma leaders.

Pharma M&As: Can Focus Cut Through the Clutter?

The Access to Medicine Foundation, an independent nonprofit group based in the Netherlands, released its 

, designed to show how effective name-brand pharma companies are in making their products accessible to the world’s people. This year, GSK topped the list of 18 Big Pharma companies for the fourth time since the Index (released every other year) was introduced. Novo Nordisk made the greatest improvement, moving from sixth place in 2012’s Index to second place in 2014.

The Foundation is funded by the Bill & Melinda Gates Foundation, the Dutch Ministry of Foreign Affairs, and the UK’s Department for International Development. Its goal is to use transparent metrics to show how effective pharmaceutical companies are in making their products accessible to more of the world’s people. These methods are refined continuously, with help from stakeholders that include the World Health Organization, non-government organizations, governments, universities, and institutional investors.The Foundation plans to introduce its Index to the generic pharma world in the future. 

“After sharpening what and how we measure, we are now able to draw a much clearer picture of the industry’s strengths, weaknesses, progress and struggles, and what it takes to be a leader in access to medicine,” said Wim Leereveld, founder and CEO of the Access to Medicine Index, in a 

. “Top performers innovate constantly, and usually have to innovate in several areas to maintain their position,” he added. 

And innovation needn’t require heft. “Companies that have the biggest market presence are not necessarily at the top of the Index. We found that four companies currently produce 50 percent of all the relevant products. However, they are scattered across the Index,” said Jayasree K. Iyer, head of research at the Access to Medicine Index, in a press release. “This means that what defines where companies rank has less to do with how many relevant products they have, than with what they do with their products and expertise.”

This year’s Index shows that the industry has stepped up its efforts on several fronts. For instance, it is paying more attention to socioeconomic factors, increasingly tailoring prices within countries. Since 2012, the number of products in the pipeline appropriate for developing countries has grown by 47, the Foundation reports. 

More companies are experimenting with innovative access-oriented business models. Companies are granting more licenses to developing-country companies to make and distribute generic versions of their medicines. Meanwhile, policies and activities to improve access to medicine continue to get better organized.

However, progress is uneven in two important areas: ethical marketing and transparency of communications. Nearly all the 18 companies participating in this year’s Index have been the subject of settlements or judgments regarding breaches in ethical marketing, bribery or corruption standards, or competition laws in the last two years. During the period of analysis there were high-profile allegations of corrupt practices against several companies operating in China. The case against GSK, one of those companies, was settled after the period of analysis, and therefore did not affect its score in the 2014 Index.

Pharmaceutical company R&D is a crucial element of enhancing access to medicine. The 2014 Index shows that five companies are developing 54% of the 327 products in the industry’s pipeline. All disease classes are being targeted, but more than half of the products under development target just five diseases.

About 36% of the pipeline targets non-communicable diseases, which are becoming increasingly important in developing countries. However, plans to make these products available in developing countries are limited. Pricing strategies for them are also limited and lag behind those for many communicable diseases.

More than half of the companies are developing “child-size” medicines, as liquids, chewable tablets, child-appropriate doses, or new formulations.
  Since the 2012 Index, at least 30 products from the pipeline, for 11 diseases relevant to developing countries, have come to the market. These include:

A new type of pill for multi-drug resistant tuberculosis that is the first new drug for the disease in 40 years (Johnson & Johnson)

A pill that can cure hepatitis C, which is a high-burden disease in developing countries. The company has issued licenses allowing distribution of generic versions of the drug in more than 91 developing countries (Gilead).

“Our company report cards identify a tailored path for each company to follow in order to maximize its opportunities for improving access to medicine. They all address access issues in different ways, but our analysis shows that all companies can do more,” Leereveld said. 

An index from the Access to Medicine Foundation ranks GSK as most effective in making products accessible.