In 2007, the biopharmaceutical market represented ~$71 billion: 10% of the entire pharmaceutical market. Therapeutic proteins and monoclonal antibodies (MAbs) account for 98% of all biotherapeutics in development, the rest being blood proteins and enzymes — all the products of recombinant DNA technology. Before the recession hit full on, growth of this market was estimated by some at ~15%. (Now it’s hard to predict at all.) Making biotech drugs consumes huge amounts of time and money, but they satisfy unmet medical needs, many that cannot be addressed any other way. Now the biotherapeutics industry is being transformed by lean manufacturing, operational excellence, and the FDA’s quality-by-design (QbD) mandate. The emphasis is on cross-functional design and development teams, new approaches to automated processes and technologies, and even ways to integrate upstream and downstream processes. It’s all indicative of a truly maturing industry.

 

Drug Discovery, Innovations, and Product Development

 

Small/virtual biotechnology companies need to design drug/biologic programs that can not only minimize development time, but also convince investors of their value. Achieving regulatory milestones is critical to a product’s success. James Weston (senior vice president of Talaris Advisors LLC) organized a session for the 2010 BIO International Convention’s achieving regulatory approval track called “Development Strategies for Novel Drugs and Biologics: Doing It Right the First Time,” based on the work his consultancy does.

 

“Talaris Advisors helps small/virtual companies get results earlier and faster. We cover the entire development process — manufacturing, preclinical or nonclinical, clinical, and regulatory — but focus on the front end, typically the preclinical early development stage, and designing processes to take clients through major milestones. We look at ways to accelerate getting there and help them make efficient use of their capital, and we look at regulatory strategies and all agencies worldwide. We look at preclinical strategies: what’s needed, when, and why. And we also take a look at manufacturing strategies, at the most efficient process designs. For small companies, it’s key to know what type of process is needed and when. We also incorporate the QbD paradigm into the overall process. Investors want to see the product get developed, not necessarily the company. And we provide the expertise to get that product where it needs to go in a very short time, so an investor doesn’t have to invest in building an infrastructure.”

Weston will be the session chair, and his panel tentatively includes Jean-Yves LeCotonnec (CEO of Trisco Integrated Services in Switzerland); Michael Webb (managing director of Exponential Pharma Ventures); Susan Flint (senior vice president of drug development for Talaris); and Mark Hurt (Talaris’ chief medical officer). “This will be a working interactive session,” he says. “We’ll talk about practical examples in obtaining worldwide regulatory approval of a biologic development program, then how we can implement those programs cost-effectively using a company’s executive team.”

Bioinformatics: What is the current status of computing for biotechnology? What lessons have been learned in applying information technologies to bioindustry? What will be the impact of petascale computing? What does the future hold now that computing power will not be a limiting factor, and how can it transform the nature of industry–academic collaborations? Diana Dummitt (associate director of advancement at the University of Illinois College of Medicine at Urbana–Champagne) organized a session for the convention’s exciting science track called “Petascale Computing, Computational Science, and the Biotechnology Industry,” which aims to answer many of those questions. Her panel of experts will briefly review the status and potential of computational science; describe the capabilities of Blue Waters (the world’s most powerful supercomputer for open scientific research — capable of 1,000-trillion operations/second — 500× faster than today’s most common supercomputers, and expected to go online in 2011); and discuss the potential for supercomputing to address challenges the industry is facing. Among those experts will be Thom Dunning, director of the Institute for Advanced Computing Applications and Technologies and the National Center for Supercomputing Applications at the University of Illinois at Urbana-Champaign.

Dunning told us, “Computing power will continue to increase over the next decade in accordance with Moore’s Law. But there’s been a major change in how this increased computing power is obtained. From the 1970s to 2004, increasing numbers of transistors on each chip was accompanied by frequency increases. It is estimated that 80% of increased computing power came from that increase in frequency, with the number of transistors providing the remaining 20%. From 1993 to 2004, chip frequencies rose from 66 MHz to nearly 4 GHz. In the early 2000s, leakage current raised its ugly head, and it’s preventing further increases in frequency (because of overheating). So chip vendors began to place multiple computer cores on each chip. Quad-core chips are now available, and eight-core chips are being introduced. Increased computing power is now tied to increasing parallelism.”

Computers play three fundamental roles in biology, Dunning said, “First, they enable the modeling of biological systems, from biomolecules to organs to populations. Increased computing power will lead to more accurate computational models of these systems and processes, allowing computational biologists to provide insights into their behavior that would be difficult to obtain otherwise.”

Second, Dunning said, computers enable biologists to manage, analyze, and correlate increasing quantities of data. “This started with the Human Genome Project, which would not have realized its goals without the computing power to assemble and analyze gene sequences.” Thanks to investments in that project, sequencing technology rapidly advanced. “Data from those new technologies offered tremendous opportunities for understanding the relationships between species, the origin of human diseases, and so on.” But all those data and their associated analysis require a lot of computing power. “Some bioinformaticians estimate that petaflops of computing combined with petabytes of data will be required.”

Another application of high-performance computing is in personalized medicine. Its foundation is the correlation of genomic data with the effectiveness of therapeutics and other treatments. “This will require the analysis of massive quantities of data,” said Dunning. “Again, petabytes of data will be needed and teraflops to petaflops of computing power required for the analysis.” Increasing computing power will also continue to affect drug and process development laboratories, Dunning said, providing more functionality and greater automation than in the instruments of today.

Dummitt told BPI contributing editor Lorna McLeod, “There’s often a disconnect between the type of research traditionally conducted in academic laboratories and the biotech industry’s interest in getting things to market quickly. In our conversations with panelist Andrea Hunt (vice president of regenerative medicine at Baxter Healthcare), it became apparent that there is significant controversy about the role computational science might play in the biotech industry. It also seems to me that some attempts might not have been well grounded in research to engage pharmaceutical companies in this science. They didn’t quite fit the problems pharma had.”

According to Hunt, “The power of computational science in biotech and pharma development sounds like a winner. How can you go wrong with so much more data being processed at faster and faster rates? Yet while we continue to have faster processing capabilities, the number of drugs approved per year in the United States is declining, and the time and costs to get them approved has continued to increase. The challenge is in targeting our data analysis to be more useful in screening target compounds or ultimately improving time to development. Perhaps we need to engage in conversations that include earlier and more diverse discussions between pharma/biotech professionals from multiple disciplines and computational scientists to take advantage of these new processing capabilities.”

EX#CITING SCIENCE SESSIONS
Sponsored by Life Technologies

Monday, 3 May 2010
2:00–3:30 PM
From Oligos to Genes to Pathways to Genomes: DNA Construction for Synthetic Biology
4:00–5:30 PM
Hard Science in a Soft World: Engineering in Biology for Regenerative Medicine

Tuesday 4 May 2010
8:00–9:00 AM
Is Biomanufacturing the Next Disruptive Technology Frontier?
9:30–10:30 AM
Induced Pluripotent Stem Cells (iPS Cells): An Embryonic Stem Cell Alternative
2:00–3:30 PM
Clinical Trials in the Genomics Age
4:00–5:00 PM
Therapeutics for Cognitive Aging Organized by the New York Academy of Sciences

Wednesday, 5 May 2010
8:00–9:30 AM
Nanomedicine-Next Generation of Blockbusters
10:00–11:30 AM
RNAi as a New Class of Biological Therapeutics: Progress and Challenges Organized by the New York Academy of Sciences
2:00–3:30 PM
Medical Tourism: New Hope for Patients and New Development Pathways for Biotech
4:00–5:30 PM
Petascale Computing, Computational Science and the Biotechnology Industry

Thursday, 6 May 2010
8:00–9:30 AM
Cutting-Edge Neuroscience: Expanding Role of Neurogenesis for the Treatment of CNS Diseases
10:00–11:30 AM
Novel Therapeutic Approaches for Diabetes: Restoring Pancreatic Beta Cell Function

DRUG DISCOVERY AND DEVELOPMENT SESSIONS
Sponsored by Astellas Pharma US

Monday, 2 May 2010
2:00–3:30 PM
Due Diligence: It’s NOT Just the Science
4:00–5:30 PM
Reengineering the Clinical Trials Contracting Process

Tuesday, 4 May 2010
8:00–9:00 AM
Dual-Specific Antibody Approaches to Cancer Therapy
9:30–10:30 AM
Building Co-discovery Collaborations to Sustain Pipelines: Executive Perspectives on Models That Work
2:00–3:30 PM
Realization of the Promise of Antibody–Drug Conjugates (ADCs)
4:00–5:30 PM
Is Big Pharma Outsourcing Discovery Research to Academia?

Wednesday, 5 May 2010
8:00–9:30 AM
Where Are the Drugs to Stop Bad Bugs?
10:00–11:30 AM
High-Hanging Fruit: Drugging the “Undruggable” Targets
2:00–3:30 PM
Can We Reverse Memory Loss During Aging?
4:00–5:30 PM
Challenging the Conventional Wisdom: Reemergence of Innovative Chemistry for Breakthrough Drugs

Thursday, 6 May 2010
10:00–11:30 AM
Cardiovascular Drug Development: In or Out?

Dummit went on, “So we’ll open this forum where Andrea can pose some of those difficult questions to these computational experts. We hope to start with a dialogue about the reality and then conclude by identifying some areas for future collaboration to further product development.”

Dummitt says this panel will be interactive following brief presentations by speakers who were asked to use layman’s terms for a general audience rather than one specializing in information technology. “Thom Dunning will discuss Blue Waters, which is 100 times more powerful than today’s general purpose supercomputers but dramatically simpler to use. Then Emad Tajkhorshid (professor of medical pharmacology at UL Urbana–Champagne’s college of medicine and the Beckman Institute) will talk about the role of the computational microscope in describing biomolecular behavior and how that will affect the development of new treatments. Rick Stevens (from Argonne National Laboratory and the University of Chicago) will speak on computational tools for genomics and metagenomics, genome annotation and reconstruction, and metabolic modeling. Then Andrea will ask some tough questions about computation and its potential. I think she will represent the biotech industry very well.”

Oncology: Despite some clinical and commercial success, MAbs for cancer treatment often have limited efficacy, and patients can develop immune resistance to them. Combining multiple cancer-fighting agents is becoming an important aspect of cancer therapy. Novel concepts have emerged including antibody fragments, bifunctional MAbs, and T cell–engaging antibodies that redirect cytotoxic lymphocytes to cancer cells. MAbs are also used as vehicles to deliver cytotoxic drugs to tumor cells in so-called conjugate therapies. Recent advances in linker stability, drug potency, and target selection have increased clinical efficacy and safety in several different indications. Antibody–drug conjugates are emerging as a prominent therapeutic modality.

Many researchers have tried to unravel the mechanisms of anticancer immunity, and recent progress has led to significant clinical success for some cancer vaccines. Both patient-individualized approaches and recombinant therapeutic vaccines are in phase 3 clinical trials for diseases such as prostate cancer, breast cancer, and non–small-cell lung cancer. Many industry insiders expect to see therapeutic vaccines approved during the next few years.

Vaccines: In 2004, the World Health Organization (WHO) published a top-10 list of diseases with inadequate near-term therapeutic outlooks, and infection by antibiotic-resistant bacteria topped that list. Every year in the United States alone, methicillin-resistant Staphylococcus aureus (MRSA) infects >94,000 people and kills ~19,000 — more than emphysema (12,551), HIV/AIDS (14,016), Parkinson’s disease (14,593), and homicide (18,573). The drug resistance trend shows no sign of abating. Where will drugs come from to combat these killers?

The avian and swine flus added urgency to a rising demand for effective vaccines worldwide, and WHO is calling for increased capacity to discover, test, manufacture, and deliver such products. Several major infectious diseases also consistently plague developing countries, affecting billions of people. New scientific discoveries and innovative public–private partnerships increase research and investment in vaccines to combat these diseases. Innovative technologies are attacking deadly pathogens as well as cancerous tumors. In addition to various influenzas, MRSA, enteric Escherichia coli (ETEC), shigella, salmonella, and other infections may be treatable using new vaccines. And existing vaccines for anthrax, rabies, and typhoid could be improved. But many technical, business, regulatory, intellectual property, and policy hurdles stand in the way of vaccine development and technology transfer.

Inducing effective immune responses is a key challenge in developing new vaccines. Adjuvants are often used to boost immune response or reduce the amount of antigen needed. Advancing scientific understanding of immune responses has led to new adjuvants, including toll-like receptor agonists, tumor necrosis factor receptor ligands, cytokines, and liposomes — although alum remains the only one widely used and approved for human use. Some others are approved for limited use.

Diseases of Aging: As early as age 20, the mental performance (memory, comprehension, and cognitive speed/function) of normal healthy adults begins to slowly deteriorate. A census report from the National Institute on Aging predicted that the world’s 65-and-older population will hit 1.3 billion by 2040. A major research goal is to develop treatments that promote healthy aging by delaying or mitigating diseases such as Alzheimer’s and Parkinson’s diseases. Cognitive decline similar to human dementia and healthy aging is seen in laboratory rodent models, which provide important insights into brain mechanisms that underlie age-related memory loss. Changes in multiple-organ contributions to brain functions that make and maintain new memories are a recent discovery. Several sessions at the 2010 BIO International Convention will cover these topics.

Despite advancing scientific understanding of Alzheimer’s disease, a clear path to identifying treatments remains elusive. Patient selection and validating early drug responses or appropriate outcome measures are two difficulties companies need to overcome in working on this difficult therapeutic problem. One session brings together experts from academia and industry to discuss the strategic use of biomarkers in Alzheimer’s disease clinical trials. Another will revisit a recent joint meeting of the New York Academy of Sciences and the Alzheimer’s Drug Discovery Foundation that explored the neurobiology of cognitive aging and how it relates to neurodegenerative disorders.

Practical Matters: Clinical studies present numerous legal challenges across the range of therapeutic areas, and those difficulties become even more complicated when trials are conducted abroad or involve contract research organizations (CROs). Clinical trial delays can cost ≤$35,000/day, with a typical cost overrun costing >$5 million. They also shorten the period during which a product can be commercialized before its patent protection expires. In a recessive economy, biotech companies feel pressured to increase the value obtained from each dollar they spend and maximize returns to their investors. By following big pharma’s lead in reengineering the clinical trials contracting process, the industry should be able to reduce overall costs and increase the value of its products.

Of course, pharmaceutical companies outsource many routine aspects of preclinical drug development, as well. But they have long maintained their grip on the earliest steps of drug discovery, characterized by biological experimentation to identify drug targets. Now they’re looking for help from smaller companies and from academic laboratories. They aim to populate pipelines depleted by patent erosion and competition, and some want to find ways to modulate known drug targets that have been historically intractable: e.g., peptide transmitters, stapled peptides, and glial cell therapies. Featured companies in one convention session believe they may have the tools to reach those targets.

The biotherapeutics industry is evolving from a model of vertical integration and internally developed pipelines to one of distributed resources and externally derived pipelines. This distributive model requires judicious partnering during drug discovery between traditional large pharma/biotech companies and innovative-rich small partners. Joan Lau (CEO of Locus Pharmaceuticals) organized a session for the 2010 BIO International Convention’s drug discovery and development track called “Building Codiscovery Collaborations to Sustain Pipelines: Executive Perspectives on Models that Work” to explore multiple facets of successful codiscovery collaborations and what partners do to nurture scientific innovation while meeting investor and customer expectations. Panelists will provide executive perspectives from both sides and give concrete examples of successes and failures to help attendees understand how partners can best work together in discovery collaborations, what big pharma seeks in discovery partnerships, what small discovery partners can offer — and why they can more effectively deliver drug discovery innovations.

INNOVATIONS IN VACCINES SESSIONS AT THE CONVENTION
Sponsored by sanofi pasteur

Monday, 3 May 2010
2:00–3:30 PM
Therapeutic Cancer Vaccines: From Biological Complexity to Novel Patient Solutions
4:00–5:30 PM
Enhanced Responses: Adjuvants and Immunomodulators for New Vaccines

Tuesday, 4 May 2010
8:00–9:00 AM
Building Vaccine Capacity in Developing Countries
9:30–10:30 AM
Conquering the Diseases of the Developing World
2:00–3:30 PM
Vaccines for the 21st Century

“We’ll have both small biotech CEOs and large pharma representation,” Lau told BPI’s contributing editor, Lorna McLeod. “Malcolm MacCoss is head of chemistry for what was Schering-Plough but now Merck. He’s moderating and will be asking all the panel questions.” Discussion will cover not only discovery, but also preclinical development, and early drug development (phase 1, phase 2).

“In many ways,” Lau went on, “it’s very important for small companies to do the homework of large pharma. They have a lot of complex issues facing them. I would think that there’s a wide range of understanding from small pharma. Some truly understand, and some may not as well.”

Among discovery collaborations, Lau’s own company is involved in a few. “We have an ongoing collaboration with Novartis,” she told Lorna. “And we also have a collaboration ongoing with Ono pharmaceuticals from Japan. Scynexis and Chromocell also have collaborations, and those two CEOs will also be on the panel.”

DELIVERY AND MANUFACTURING OF BIOLOGICS AND DRUGS SESSIONS AT THE CONVENTION
Sponsored by Novozymes

Monday, 3 May 2010
2:00–3:30 PM
New Methods for Bioprocess Modeling and Monitoring: A Multidisciplinary Approach
4:00–5:30 PM
Personalized Medicine: Solutions for GMP Manufacturing of Autologous Cell Products

Tuesday, 4 May 2010
8:00–9:00 AM
Sustainability and Energy Efficiency in Biotech Facilities
9:30–10:30 AM
Quality-by-Design for Biologicals: What’s Next?
2:00–3:30 PM
Build or Buy? Strategic Choices in Biomanufacturing
4:00–5:30 PM
Expression Systems for the Manufacture of Recombinant Proteins

Wednesday, 5 May 2010
8:00–9:30 AM
Handle with Care: Solving the Delivery Challenges of siRNA Therapeutics
2:00–3:30 PM
Biologic Drug Product and Combination Device Manufacturing Considerations
4:00–5:30 PM
Is Your Supply Chain a Blind Spot? Avoiding Common Post-Commercialization Issues

 

Product Innovations, Delivery and Manufacturing

 

Biomanufacturing has seen real growth over the past decade, especially due to the success of MAbs as therapeutic agents. Production of these products for a global market presents many unique challenges in processing, packaging, and combining drug products with delivery devices. For controlling quality and providing QbD as required by the FDA’s process analytical technology (PAT) initiative, knowledge and understanding of complex and highly interactive bioprocesses needs to improve. QbD approaches are already maturing in the industry, and initial global regulatory submissions using QbD development will soon enter review stages. Process optimization through online monitoring, prediction of meaningful parameters, and modeling is subsequently coming into focus. Meanwhile, at least a few autologous cell therapies are moving closer to commercialization, and they face the challenge of ensuring appropriate GMP manufacturing and scale-out (rather than scale-up).

Drugs based on RNAi hold significant promise in treating an array of diseases. Unlike earlier technologies, RNA interference (RNAi) is a catalytic mechanism, so only a few molecules are needed to suppress gene expression. The technology presents its own challenges, of course, and solutions under exploration include synthetic oligonucleotides with functional conjugates or transfection carriers and inverse complementary molecules expressed from plasmid or viral vectors. Those are used in target discovery and validation, but they could also be developed into therapeutics themselves — although systemic delivery of RNAi therapies to target tissues remains a major challenge.

Several companies are developing unique delivery technologies, ranging from lipid-based formulations to polymer engineering and novel nanofabrication techniques. Nanotechnology, imaging, and other technologies are also expected to play a key role in the future of health care delivery and management. Rapid and multiplexed detection modalities for clinics, hospital bedsides, laboratory settings, and even homes could be pivotal in rapid monitoring of genomic, proteomic, metabolic, and other types of markers and indicators. Novel therapeutic delivery technologies (e.g., nanoparticles) are poised to significantly change the treatment of disease. But discovery, identification, and development of new receptors will be critical to the successful use and deployment of nanotech-based sensor systems.

Some companies are researching multifunctional nanoparticles for additive or synergistic effects in addition to useful first-generation nanoparticles that offer prolonged circulation in blood, passive or active target specificity, and increased cell penetration. For instance, certain nanomaterials respond to physiological stimuli such as pH, temperature, or dissolved oxygen and can increase selectivity in drug delivery to target tissues. Multifunctional nanosystems offer a single carrier platform to incorporate multiple therapeutic agents for simultaneous or sequential delivery, using energy (e.g., heat, light, or sound) to enhance therapeutic effects, and combining drug(s) with imaging agents for real-time monitoring of therapeutic efficacy.

Bioprocessing Decisions: A major hurdle in taking vaccines and other biologics to market is developing an economically viable process to make them at industrial scale. Some advances have provided manufacturers with more choices among production systems than were available even five years ago. They span the range of prokaryotic and eukaryotic organisms and include bacterial, yeast, fungal, plant, and insect- or mammalian-cell systems. Many systems are based on cell lines that have been specifically engineered for improved production characteristics, such as defined post-translational modifications or localization/secretion of expressed proteins. Several products made using nontraditional systems are now in mid- to late-stage development, and some have even made it to market.

Biologics and vaccines are facing global competition and political cost pressures, so biomanufacturing has become a critical component in development and commercial strategy. Issues such as geographic manufacturing capacity imbalances, potentially game-changing technologies, biosecurity and supply-chain worries, and emerging countries’ desire to serve their own markets, are driving interest in smaller, more widely distributed production approaches. Drug developers both large and small face hard choices (with trade-offs on costs, timing, location, and control) in deciding whether to build (or reengineer) in-house facilities or outsource their drug production.

Robert Gottlieb (principal of RMG Associates) and Ellen M. Martin (a partner in Kureczka∣Martin Associates) organized a session for the 2010 BIO International Convention’s delivery and manufacturing track called “Build or Buy? Strategic Choices in Biomanufacturing” as well as a second panel for the exciting science track called “Is Biomanufacturing the Next Disruptive Technology Frontier?” Martin described them this way: “Build-or-Buy is about faster, cheaper, better, and safer, where you put it, and who’s in control. And Disruptive Tech is about what’s new, exciting, and different.”

She went on: “When genetic engineering started 30-some years ago, it was a totally hot technology, and it still is a miracle. But I think people have gotten used to it, and it’s lost some of that miraculous charm. It’s still an extremely cool technology to take living organisms or pieces of them and harness those to do much more exotic things than make beer or wine or bread, which is how biotech got started. There’s a rule of thumb in engineering that 20–30 years is about the time it takes for a technology to mature. Transistors are a great example. The time between Bardeen’s Nobel prize and the personal computer was about that. So what we’re seeing here is an industry that has really matured. From the build-or-buy perspective, with consolidation and big pharma buying biotech capacity, it’s ended up very much concentrated worldwide. Howard Levine (of BioProcess Technology Consultants, chair of the ‘Disruptive’ panel) used a figure in a panel last year showing that some 80–90% of the capacity is controlled by the top 10 companies. That’s very concentrated geographically in North America and Europe.”

But China and India are working hard to come up to speed. Martin said they’re motivated “not only to establish their own industries but also to establish their own markets. Who’s going to sell to emerging markets is becoming a big creative decision issue for many companies, from big ones to start-ups.” And not just China and India. A-Bio Pharma, a pioneering biologics contract manufacturer in Singapore, will be represented by a speaker on the Build-or-Buy panel.

How have the economics of biomanufacturing changed over the past couple of decades? Martin says there’s probably overcapacity now, “but it’s not in optimal locations for growing markets or for small companies. Big companies control it, and it’s not always easy to get access to that — especially since most of those companies don’t think of themselves as being in the contract manufacturing business.”

Gottlieb pointed out that building manufacturing capacity is “an enormous capital investment, certainly for emerging companies. It’s investment that often has to take place early on, before you even know you have a viable product — and that has not changed, although potentially it’s starting to with some of the newer technologies such as disposables and flexible facilities. They take much less time to construct and scale, so companies can delay a major investment decision until they’re hopefully a little more ‘derisked’ on the development side.”

So disposables and outsourcing provide some means for companies to advance until they can afford to build a facility. Gottlieb said the Build-or-Buy panel includes case studies involving two companies, Itero Biopharmaceuticals and Crucell, who are partnering with Xcellerex. “For clinical-scale material, Crucell is acquiring a complete manufacturing train from Xcellerex. If you look at improvements that have been made in process development and culture/yield,” Gottlieb said, “fewer facilities will need 20,000-L fermentors. Instead, they’re looking at much smaller scales.”

 

Martin added, “That undercuts the need and value of big brick-and-mortar facilities. In theory, you could use a building that’s no bigger than a pilot plant to produce enough for clinical trials and into product launch. Especially with the blockbuster model breaking down in pharmaceuticals, I think biologicals are generally going to be made with smaller production runs. We’re looking at a very different balance of trade-offs in cost and location, who owns the building and what’s inside it.”

Gottlieb said, “One challenge (particularly in vaccines) when you’ve got a tremendous amount of capacity tied up in one facility is if there’s a problem, then the disruption is huge. It happened in the flu business a couple years ago. If you’re in a pandemic or biosecurity situation, there’s a lot to be said for distributed manufacturing to deal with capacity in multiple locations.”

Outsourcing could have a big impact as well. “Some companies — such as Itero Biopharmaceuticals — can leverage the geography by doing R&D in the United States and then manufacturing elsewhere. I think the ability to make those kinds of decisions is going to provide a lot of small companies with new technologies and approaches.”

Automation is also part of the industry’s maturity. Gottlieb said “If you include electronic data capture and QA/QC information, then you can improve your quality.” And Martin pointed out, “Consultants on our panel — Eric Langer and Howard Levine — will speak to the fact that some years ago everybody talked about physical capacity as the big constraint. Expert people and automation may provide the solution. If you can automate some parts of the process, then your engineers can focus on either doing things better or doing new things.”

Are more biotech companies outsourcing than 10–20 years ago? Gottlieb recommended Eric Langer’s “excellent survey about this every year” (1). And Martin said he’s focused very much on how individual companies view the mix. “A small company has to plan how much product to make and when (to get through clinical trials), and how to do that when venture capitalists keep them on a very short monetary leash. And there are companies that want to take their excess capacity and find somebody who will help them cover their overhead. The real issue is matching those folks up. I suspect plenty of companies have excess capacity but aren’t doing a very good job of marketing it to those who might want to use it.”

Gottlieb reminded us, “A current mantra for VCs is capital efficiency, and at early stage companies there’s not a lot of appetite for brick-and-mortar investment. When you look at the economics of building or buying, outsourcing becomes very attractive. What should come out of this panel is how to weigh those pluses and minuses for each option. Xcellerex also functions as a CMO, so if someone’s interested in that kind of relationship they can do that and still own their process, then can make a choice later in development. That’s sort of a hybrid option.”

Martin noted, “It’s not necessarily just two parties involved. There are also the venture capitalists. For example, Itero Biopharmaceuticals is thinking about their manufacturing economics up front, as part of their business plan. It used to be a lot of companies got to phase 2 before they really thought about the economics of biomanufacturing. But it’s become absolutely essential for any company wanting to get a biologic onto the market to think about all aspects of biomanufacturing — from what process to use to where to do it — much earlier than before.”

Also emerging in importance are biosecurity and supply chain security issues. “Those kinds of worries are obviously much more of an issue if you’re talking about a world stage for biomanufacturing,” Martin said, “than if you’re talking about a single country like the United States.” And it’s a lot more complex that simply asking a vendor where something comes from. “Consider the potential disruption if there’s a pandemic and China shuts down,” she cautioned. Sole-sourced ingredients are particularly problematic.

In ~30 years since the harnessing of genetic engineering for making human proteins, production methods for therapeutic proteins have evolved dramatically. The accelerating growth of marketed protein therapies and the need for new vaccines worldwide has spotlighted manufacturing as either a potential bottleneck or a powerful enabler of next-generation drugs. New biotechnologies such as transgenic animals and plants, single-use and flexible expression systems, designer antibodies and nonnative proteins, as well as new vaccine platforms (e.g., insect cell culture using recombinant baculovirus), may not only transform the development timelines and commercial economics of the biologicals and vaccine industries, but also enable development of previously impractical products.

Gottlieb predicted that “shifting from eggs to cell culture could transform the vaccine industry in dramatic ways.” Even dozens of fermentors are relatively small compared with an assembly line using millions of eggs. “Also in terms of speed: Part of the vaccine industry challenge is knowing how much to make and match capacity to demand. We saw that problem with H1N1. First everybody was scared, and companies were ramping up like crazy. We didn’t quite have enough, then we had too much, now we’ve got excess supply. Being able to ramp up more quickly is key. On our ‘disruptive’ panel, Novavax will talk about their cell-based virus-like particle technology. They can scale quickly, and they also have a deal with Xcellerex. With disposable technologies and all these new strategies, products that maybe didn’t economically make sense before can start doing so. So there may be other molecules out there that haven’t seen the light of day but now become commercially attractive.”

Martin considered, “That’s sort of the flip side of the notion of disruptive technology. Some think transformative might be a better term because disruptive implies destruction. But it can be creative destruction, and that can be a good thing. If new technologies become standard, then all the companies that have invested in the old egg-based vaccine production methods are threatened. But the transformation is that technology enables drugs that weren’t possible before. For example, a cell-free production system like Sutro Biopharma’s would be as disruptive as disposables: With no cells, downstream processing becomes potentially much more efficient because you don’t have to remove as much junk.”

Of course, it can take time for new technologies to be accepted, much less take over, especially in a highly regulated industry. Martin said, “I think disposables are already there. Even three years ago it was barely on people’s radar screens. By last year everybody was talking about single-use technology and looking for ways to use it.” Gottlieb said transgenic animal systems are finally starting to live up to their promise, too, after many years of talk and development. “Now there’s one out there with an approved drug.”

Martin added, “And some of the plant systems are coming on stream. Biolex and their duckweed, that’s no longer just an eyebrow-raising approach; they’re making antibodies. The idea of transgenic plants and animals goes back to the very beginning of biotechnology. There were tobacco-based systems in the 1990s that didn’t really go anywhere, but now those technologies have matured to the point where they’re really making progress.”

Gottlieb agreed. “In fact, one of the panelists is from a Canadian company that’s using safflower seeds: SemBioSys Genetics. One of their programs involves a promising cardiovascular drug that had issues with excessive manufacturing cost. They have a plant-based approach that may solve the economics. SemBioSys is getting expression only in the seed oil, not the whole plant. So you basically crush the seeds and get it out of the oil. You don’t have to grind up the plants like you did for some of the earlier transgenics.”

Martin said, “That points to another kind of long-term pattern we’ve seen time and again in biologicals. Some things start out with immense promise — monoclonal antibodies are probably the best example. Everybody thought they were dead after some 15 years of development, and then they came roaring back and now represent an absolutely established technology platform.”

Gottlieb said that’s “almost the encapsulated story of biotechnology: potentially transformative technologies and small companies with not much cash and short timelines trying to move it forward. A lot of people give up on it, but others keep working at it.”

“Hyperbolic promises,” Martin put in, “followed by massive disappointment.” And then the phoenix rises from the ashes.

 

Biomarkers, Devices, and Predictive Diagnostics

 

Advances in biotechnology have revolutionized molecular tools for genome-level investigation of human transcriptome, proteome, and metabolome changes during disease. The wealth of data generated by such tools brings a need to sort the trash from the treasure. Integrated computational models would apply genome-level data to biomarker discovery and drug development. In the context of drug development, a biomarker is a molecule or parameter that can be monitored as an indicator of disease/progression or pharmacological response to a therapy.

Genetic biomarkers such as single-nucleotide polymorphisms (SNPs) have been used to sub-type patient populations for determining proper therapeutic dosages, assessing disease risk, identifying patients with more rapid disease progression, and predicting disease severity. Use of such biomarkers in cancer research is well established but outside that field their application remains limited. Drug developers in other disease areas also need to predict patient response, increase efficacy outcomes, and improve risk–benefit ratios. Biomarker combinations (e.g., genetic, protein, and imaging) present an exciting option. Integrating these test panels into drug development begins with an understanding that chronic disease phenotypes are polygenic, so a “one-molecule-fits-all” approach to drug development may no longer be a viable model.

Academic, government, and industry partners are collaborating in developing software tools and case studies to assess the opportunities for biomarkers in drug development, how they can alleviate complexity and cost, and the economic viability of stratified medicines and companion diagnostics. Such tools and case studies are intended to support personalized medicine decision making, and one panel focusing on them was developed for the convention involving a cooperative research and development agreement (CRADA) among the FDA, Adaptive Pharmacogenomics, and GlaxoSmithKline, recently expanding to include the Massachusetts Institute of Technology.

Biobanks have great potential for biomarker discovery, but they come in many shapes and sizes — ranging from highly stratified, single-disease cohorts to large, population-based biobanks collected over years. Another session at the BIO International Convention will describe possible benefits of using population biobanks, in particular the HUNT study in central Norway, which stores genotypic/phenotypic information on >100,000 people — including data that predate the onset of disease. The main challenge with such repositories are in biomarker validation, but potential applications in asthma, diabetes, and cancer make them worth the trouble.

BIOMARKERS SESSIONS
Monday, 3 May 2010
2:00–3:30 PM
IP Issues Affecting Biomarker-Based Diagnostics
4:00–5:30 PM
Commercialization of Biomarkers: From Discovery to Medical Diagnostics

Tuesday, 4 May 2010
8:00–9:00 AM
Development of Translational Biomarkers to Accelerate Clinical Treatments for Alzheimer’s Disease
2:00–3:30 PM
Impact of Biomarkers on Drug Development Complexity and Cost
4:00–5:30 PM
Population Biobanks: A Suitable and Fast Route to Biomarker Discovery and Validation?

Wednesday, 5 May 2010
8:00–9:30 AM
Effective Use of Biomarkers in Early to Late-Stage Drug Development: How to Improve Efficacy and Commercial Success
2:00–3:30 PM
The Computational and Validation Challenges of Biomarker Discovery
4:00–5:30 PM
Role of Biomarkers in Clinical Development of Novel Cancer Therapies

Diagnostics: The market for molecular diagnostics is growing fast (expected by some to reach $7 billion by 2011), and they are influencing many treatment decisions (60–70%, according to one Research and Markets report). Biodiagnostics are applying new technologies and newly validated genes and biomarkers in tests for a range of conditions — from infectious disease to cancer, inherited disorders, and prenatal diagnosis. Breakthrough technologies are producing a new generation of sensitive and accessible diagnostics that could revolutionize how patients are diagnosed and even treated. New diagnostics must demonstrate their real value to replace currently marketed products.

DEVICES AND PREDICTIVE DIAGNOSTICS SESSIONS
Sponsored by Abbott

Tuesday, 4 May 2010
8:00–9:00 AM
Widely Accessible Diagnostic Technologies
9:30–10:30 AM
Point-of-Care Diagnostics: Decentralizing the Health Care Paradigm
4:00–5:30 PM
It’s Personal: Transforming Health Care Through Personalized Medicine

Wednesday, 5 May 2010
8:00–9:30 AM
Functional Biomarkers: The Next Phase of Personalized Medicine?
10:00–11:30 AM
Companion Diagnostics: The Regulatory Hurdles
2:00–3:00 PM
The Artificial Pancreas: Closing the Loop on Insulin Delivery in the Treatment of Diabetes
4:00–5:30 PM
Diagnostics and Therapeutics for Individualized Nanomedicine

Thursday, 6 May 2010
8:00–9:30 AM
Leading the Way in Health Care: Molecular Diagnostics Coming of Age
10:00–11:30 AM
New Diagnostics for a New Health Care System

Resource-limited countries account for a major portion of the global disease burden, which translates to an earnest need for widely accessible diagnostic technologies. People in low-income economies have a significantly lower life expectancy than those in advanced nations. But their mortality rates can be brought down with the help of cost-effective and reliable diagnostic technologies. Regions such as South Africa and Southeast Asia urgently need diagnostic platforms that would make cost-effective, evidence-based treatment a reality for them.

In the developed world, personalized medicine is already becoming a reality. It can improve health outcomes and could save billions of dollars every year. Advances rely on close coordination in the development of therapies and their companion diagnostics. But getting therapies and diagnostic devices through FDA agency review and market approval creates complex logistic hurdles in coordinating simultaneous review of these combination products. It has been difficult to bring a complete understanding of those differences to all the stakeholders, from industry to the regulatory agencies. The Companion Diagnostics Working Group was established by the Association of Medical Diagnostics Manufacturers to address this issue, and one panel at the convention will present their successes in closing the gap so far.

Medical research is evolving toward identifying biological variations that determine individual disease susceptibility, prognosis, and treatment outcomes. Dramatic increase in biomarker discovery is indicated by patent filings and publications, which continue to outpace clinical validation and market introduction of related products. From assay development and analytical method validation to development of protocols for tissue acquisition, storage, and processing — and ultimately to clinical studies for determining sensitivity and specificity — commercialization of biomarkers is resource-intensive. Before making such substantial investment, diagnostic test developers want candidate biomarkers to meet a range of technical, clinical, regulatory, and commercial criteria. Tim Clark (a partner in intellectual property and technology at Piper Alderman) and Christopher Boyer (executive director Bio-Link Australia) organized a session for the 2010 BIO International Convention’s biomarkers track called “Commercialization of Biomarkers: Moving from Discovery to the Medical Diagnostics Market.” Boyer told BPI contributing editor Lorna McLeod that the clinical diagnostic market is the main place biomarkers can make a difference.

“There are some important applications,” he said, “in which drug developers use these markers as surrogate endpoints or to help with their preclinical drug development, even in drug discovery. But the larger market is in clinical diagnostics, including a variety of applications and indications. Basically, one might develop a diagnostic that a doctor could use to provide some actionable information. That seems to be a key to commercially viable biomarkers: They need to give doctors information they can use to make treatment decisions, either in diagnosing particular disease or assessing predisposition for disease and looking at treatment options. The increasing body of knowledge in the field of genetic biomarkers can help doctors select medications — when they know certain drugs won’t work with certain mutations in cancer genes, for example. The range of uses generally falls into three main categories: diagnosis, prognosis, and treatment response.”

Clark added, “An issue with biomarkers in clinical trials, for example, is how surrogate endpoints are often developed ad hoc to suit particular clinical development programs of individual companies doing individual trials. It’s often about reducing the cost or time frame of a clinical development program. But there are bigger commercial opportunities in looking at things that have wider application. The exciting area is pharmacogenomics, looking at particular biomarkers for genes involved in diseases such as cancer, and making treatment decisions based on that information.”

Are patenting issues with biomarkers similar to those of patenting genes and proteins? Does a patent essentially cover a particular application of a given biomarker, for example? Clark says, “To satisfy patentability requirements, many jurisdictions will require showing some obvious use or application for isolated genes. With biomarkers, patents are more likely to be for method of use in a particular diagnostic or treatment application. So in broad terms, the types are slightly different.”

Boyer agreed. “Most biomarker patents are method-of-use patents that don’t necessarily cover any composition of matter. If you talk about a gene or protein, it is possible to obtain composition-of-matter coverage as a drug target or antigen. Lots of applications can be covered under composition of matter, which is very broad coverage. But in many cases particular gene mutations are indicative of certain phenotypes, and those may be covered independently and would not be dependent on broader composition-of-matter patents. Most diagnostics are based on method-of-use patents.”

Clark added, “Often with biomarkers you’re looking at either multiple polymorphisms or gene mutations. And there may be separate patents for different polymorphisms, or you may be looking at a number of different genes that together form a test. Multiple biomarker assays look at a range of different genes and then allow a physician to make a clinical decision based on their results. It can raise a practical issue in managing intellectual property. It may well be that different entities own the patents to different polymorphisms or genes, and that could raise some complexity: One may need to cross-license perhaps different patents from different entities to get a complete product on the market.”

Boyer added, “Some new proteins and peptides are being discovered as biomarkers, and that’s coming with the advent of advanced mass spectrometry, so scientists can detect very small quantities of particular analytes in blood or fecal samples. That might involve both composition-of-matter and method-of-use patents.”

It’s been suggested that personalized medicine and biomarker-based diagnostics could help resurrect some previously disappointing drugs, such as the Xigris sepsis drug from Eli Lilly (2). Boyer agrees. “That’s an important application. Some companies perceive a significant patent risk associated with biomarkers as a result of some high-profile court cases. They’re saying, ‘Well, maybe we don’t really want to be in that business of developing biomarkers for clinical diagnostics. We feel it’s a safer business model with a bigger reward if we go after only those biomarkers that can be used to reposition or resurrect failed drugs.’ And that’s a good strategy. You’ve got a drug with an otherwise great safety profile, a great preclinical package, and in phase 2 for whatever reason (maybe you didn’t select the right patients) you didn’t get the efficacy you wanted. If you can use some genetic biomarker or protein to stratify patients so you know who will respond to the drug, that’s increasingly appealing to the FDA and regulatory agencies across the world. It’s an attractive business model for several companies who are either resurrecting a failed drug or seeking approval for a new drug in a very targeted patient population.”

Clark pointed out, “I supposed it can be seen as a two-edged sword. For new drug development, it may offer the benefit of decreasing the risk of a clinical trial program, but this strategy may limit your patient population from the outset. Stratifying the patient population may allow you to obtain approval for a drug that otherwise would be difficult or impossible to market.”

There are other challenges to the biomarker business model. Companies such as 23andMe and Navigenics are in the personal genome business. “Customers send a cheek swab into the company,” Boyer explained, “and they’ll analyze 300–500 genes to produce a profile risks for certain diseases or conditions. There’s some controversy about that because of the potential impact that information could have on people. In most cases a test is ordered by a physician, and the results are delivered to that physician or a genetic counselor. But we’re getting very close to the $1,000 genome. There are also Internet programs that will analyze the information, so you can almost become your own genetic analyst — and there doesn’t seem to be any way to stop this other than regulation.”

Clark suggested that there are two types of concerns here. “From a health perspective, there’s the risk of whether it’s being properly analyzed. But the other side is from a commercial perspective: With the advent of direct-to-consumer models and the possibility of personal genomes at an affordable cost, it becomes a risk to the traditional diagnostics business model.”

In relation to the regulatory issues related to biomarkers, Clark said, “I’m not aware of any particular broad general regulations around access to personal genome information by individuals. It will be interesting to see how these ethical and legal issues are managed in the future.”

Tissue engineering and regenerative medicine could solve some major unmet medical needs. Developers of these products face two challenges: developing conditions for robust and reliable cell growth to ensure that the cells act as intended and developing nanostructured materials that are biocompatible and integrate with both host and donor cells. Marrying the two disciplines of material science and cell biology will ensure that final products perform correctly.

Mike Fisher (business development director at Bio Nano Consulting) organized a session for the 2010 BIO International Convention’s exciting science track to address these issues called “Hard Science in a Soft World: The Challenges of Engineering in Biology for Regenerative Medicine.” Most of these products, he says, are still in development. “Companies are trying to produce artificial tissues or autologous cells that mimic tissues. You have two problems with these products. First, you have to make sure the cell biology’s going to do what you want it to do. So you have, for example, stem cells or a patient’s own cells that you then grow up. Once they’re reimplanted, you want to make sure that they do what you want them to do and don’t become cancerous or go off and do other unexpected things. The second issue is that you have to put some sort of structure in there to hold the cells in place, some cell matrix they like. And that will remain in a patient’s body or maybe break down as cells take over. For example, you can have bone-type structures that are reabsorbed as real bone is created. These two types of products come together, with material science on one side and biology on the other, and that’s what makes tissue engineering and regenerative medicine so complex.”

A range of polymeric materials are used, including hydroxyapatite for bone-like structures. Fisher also mentioned, “BioCeramic Therapeutics in London has a ceramic that’s flexible enough that you can grow cells in it to produce a bone-like structure. Some others break down over time and are designed to do that, but you want them to remain long enough to function. If a patient’s body is still growing, you want it to be able to grow too — rather than to have to go in and remove a tissue graft and put another one in. So there’s a fine line to be drawn.”

This is very new science, and associated regulations are developing alongside, just as with early recombinant therapies. “Companies struggle over exactly how they can get through the regulatory hurdles,” Fisher says, “and do the right kinds of studies and provide the right types of information to regulatory agencies when nobody knows what the regulations will be or what the agencies need. Everybody’s learning in parallel. If you go down the wrong route, then your company’s in trouble. And there are few standards out there for companies to adopt in producing these materials. When protein drugs came in originally, the pharmaceutical industry said, ‘Look, these are great products, but we don’t know how to handle them. We don’t know how they’re going to be regulated. We don’t know how to manufacture them. We’re used to small molecules.’ Now 20 years on, all the pharmaceutical companies are ‘biopharma’ companies. Once that regulatory pathway is created, these products get adopted. It’s just finding that way through and getting the pathway clear so people can see that the products will be approved if X, Y, and Z steps are followed in their development.”

Further complicating matters are differences in how regenerative medicine is approached from Europe to the United States. Fisher pointed out, “The way the FDA handles combination products and certain devices can be different from the way the EMEA handles them. For example, the FDA has a nanotechnology task force, which applies to the material side of regenerative medicine. In the United Kingdom and the European Union, they don’t really have a distinct nanotech strategy, but they try to fit these products into categories within the standard regulations. If your product has a cell in it, then it’s classed as a biologic; if it doesn’t, and it’s just a material, then it’s a device. You’ve got to know exactly where you’re going, and that’s a problem too. It’s not standardized across the world, but there are discussions to try and standardize the regulations. Again, because it’s so new, that’s actually quite difficult to do.”

Fisher says his session will be all about bringing together engineering and biology, even on the most basic of levels. “If you say substrate to an engineer, he or she will think of a silicon wafer or something like that — something material. But a biologist thinks of a molecule that gets broken down by an enzyme. So the same word has two completely different meanings. How do we bring those two together?”

 

Achieving Regulatory Approval

 

Several sessions at the convention are exploring the regulatory pathways for biotherapeutic products in the United States and Europe. One reports on the results of a 2009 survey by PricewaterhouseCoopers of the life sciences industry’s working relationship with the FDA (3). Lessons learned can help companies improve their relationships with all regulatory authorities. Recognizing the two-way nature of such relationships, survey updates in 2006 and 2009 examined long-term dialogue between the FDA and bioindustry. The 2009 survey added new questions relating to the FDA’s Sentinel System for monitoring adverse events as well as renewal of user fees, incentives for the development of personalized medicine, and guidance on data management.

Many federal programs foster development of agents against biological threats to US public health and security. Some such products will treat medical conditions without significant commercial value. And associated regulations, guidances, and review paradigms are unfamiliar to most in the industry. A panel will cover strategies related to prevention and treatment of pandemic threats and emergent exposures. Another will explore business models under consideration for biosimilar product development. As well as the capabilities and environmental conditions needed for a company to be successful in the development, manufacture, and marketing of biosimilar products, panelists will review how to work within a new regulatory environment and describe the role of new technology platforms in realizing the promise of biosimilars.

Meanwhile, China’s growing middle class is high on many priority lists for marketing drug products. Some companies already have a presence in China, but full exploitation of the market requires negotiating several obstacles, one being effective interaction with the Chinese drug administration. So another panel explores the nuances of the Chinese drug approval process as it pertains to introducing new drugs in China from abroad. There may be ways to maximize exclusivity, and harmonization proposals could improve approval times and provide for more new-drug introductions.

Combination Products: The FDA’s Office of Combination Products (OCP) was established on 24 December 2002, as required by Section 204 of the Medical Device User Fee and Modernization Act of 2002 (MDUFMA). That law gave the OCP broad responsibilities covering the regulatory life cycle of drug–device, drug–biologic, and device–biologic combination products. A combination product may include two or more regulated components: e.g., a drug, device, or biologic. In 2004, the FDA released a draft guidance for combination products (4), and it has since proposed some rules regarding combination products. Some 510(k) submissions for medical devices include antimicrobial agents, there are new contrast imaging indication considerations for devices and approved drug and biological products, and technical aspects must be considered for pen, jet, and related injectors intended for use with biotherapeutics. Attorneys Alice Martin and Julie Dykstra of Barnes & Thornburg, LLP organized a session for the 2010 BIO International Convention’s achieving regulatory approval track called “Sailing Through Regulatory Waters: Approval of Combination Products,” which is planned to cover all the above.

Martin told BPI contributing editor Lorna McLeod, “We are trying to explain in this panel ways companies can incorporate intellectual property protection with their FDA requirements. That means maximizing terms and minimizing cost and hurdles. A message is to think ahead, plan ahead. Of course, we’re focusing on combination products, but I think the general principles will work for other categories as well. I’ll be moderating and addressing some intellectual property issues. Julie will talk about regulatory hurdles. We have an FDA speaker, who will be addressing what’s going on in the OCP. And we have a speaker from Roche Diagnostics who will be addressing from a diagnostic standpoint what issues companies like Roche face. We have a speaker from Baxter Healthcare, who is going to address how companies like Baxter consider aspects of therapeutic applications of combination products. We have a Purdue professor who will talk about regulation of nanomedicine and other policy issues from a more academic standpoint. Combination products are a newer area that people aren’t as familiar with. Some of my clients are using stem cells with scaffolding, for example, that might be combination products.”

Dykstra put in, “Some examples can be very technical, such as drug-eluting stents, but they can also be very simple, such as condoms with spermicides. We decided it probably would be best from my regulatory perspective to ask someone high-level from the OCP to assist our panel, so we asked John Weiner to join us. He’s associate director for policy and product classification, which seems to be the main hurdle for a lot of companies. For a drug-eluting stent, what is the primary mode of action: the drug or the stent itself holding an artery open? You would have the Office of Medical Devices working in conjunction with CDER, and in one case it was the medical device office that took primary jurisdiction. One thing I’m going to talk about is what primary mode of action means. It’s any mode of action for a combo product that provides the most important therapeutic action. I’m going to give examples and show which center they would go to and legally why. I’ll also talk about the OCP, which in my opinion is one of the most well run machines at the FDA. They’re extremely helpful both formally and informally helping companies assess, ‘Is this a combination product to begin with? Is it a combination product, and if so, what’s the primary mode of action? Which center will have primary jurisdiction, and why?’ They’re also good at helping companies make sure they have the appropriate clinical substantiation. And they coordinate the two or more centers together that need to have scientific input into the final review and decision. It’s wonderful to have representatives from Baxter and Roche who have jumped those hurdles, and me to describe what the hurdles are, then Weiner to say ‘This is how we handle the hurdles and why.’”

Regarding the FDA’s current approach, Martin pointed out that “the whole plan is get everybody to move faster and more accurately so we get better products out on the market with the least amount of hassle and cost. With our session, my overall goal is to explain how the combination of intellectual property protection and regulatory issues of combination products are facilitated so products can get to the market with minimal hassle, best accuracy, and the lowest cost.”

ACHIEVING REGULATORY APPROVAL SESSIONS
Monday, 3 May 2010
2:00–3:30 PM
How to Improve the Working Relationship Between the Life Sciences Industry and FDA
4:00–5:30 PM
The Evolution of Oncology Drug Development: Opportunities and Challenges

Tuesday, 4 May 2010
8:00–9:00 AM
Sailing Through Regulatory Waters: Approval of Combination Products
9:30–10:30 AM
The Regulatory Landscape for Products Against Pandemic and Emerging Threats

Wednesday, 5 May 2010
8:00–9:30 AM
Risk Evaluation and Mitigation Strategies (REMS): So Far Still to Go
10:00–11:30 AM
FDA Town Hall
2:00–3:30 PM
EMEA/FDA Town Hall
4:00–5:30 PM
Benefits of Biosimilars: What Are the Possibilities?

Thursday, 6 May 2010
8:00–9:30 AM
Development Strategies for Novel Drugs and Biologics: Doing It Right the First Time
10:00–11:30 AM
Drug Approval in China: What You Need to Know to Succeed

REFERENCES