Apr 4, 2016 - compression and coating solutions will meet and exceed · your individual ...... the Board of Apple and Gen
APRIL 2016
Upfront Reducing the manufacturing costs of gene therapies
In My View Why pharma must address environmental discharges
Business Can small biotechs bear the burden of innovation?
Sitting Down With Christian Schneider, Director of NIBSC
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48 – 49
50 – 51
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Online this Month
Controlling Crystallization
Better Bioprocessing The Medicine Maker recently teamed up with GE Healthcare to learn more about the trends and challenges of bioprocessing. You can read a collection of interviews covering topics such as extractables and leachables, vaccine production, bioprocessing bottlenecks and more in the online supplement. https://themedicinemaker.com/ issues/0316/bioprocess-insights/
We all know that crystallization is crucial in the pharma industry when it comes to manufacturing active pharmaceutical ingredients (APIs) – and on page 12 of this issue you can read a snapshot about the fascinating work from Jerry Heng and his team, who hope to be able to give manufacturers greater control over the crystallization process. Heng is a senior
Around the World in 80 Microbes
lecturer in the Department of Chemical Engineering at Imperial College London, UK, and focuses on understanding the role of surface properties in particle engineering. Recently, he has examined the feasibility of establishing templateinduced polymorphic domains for API crystallization. You can read a Q&A with Heng online. http://tmm.txp.to/0416/Heng
Matt Hutchings (University of East Anglia, UK) – who is studying bacteria found on South American leafcutter ants in the hope of discovering new antibiotics – has come up with a list of weird and wonderful places where scientists are seeking new microbes and the drugs they produce. Check out our infographic online. http://tmm.txp.to/0416/Hutchings www.themedicinemaker.com
C o n te n t s
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Online This Month
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Editorial
Battle of the Sexes, by Stephanie Sutton
On The Cover Celebrating the Power List
Upfront
In My View
08 Mega-Merger Not To Be
16 A hepatitis C treatment is a well-deserving winner of the 2015 Drug Discovery of the Year Award, says Ann Hayes
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Bio-Responsive Insulin Delivery
10 Harnessing Adeno-Associated Vectors 11
Parting Shot
12 As Clear as Crystallization
with artwork inspired by the
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Affliction Prediction
(the Beatles).
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Moving from Batch to Continuous
Revolver album cover
17 Johan Bengtsson-Palme and D.G. Joakim Larsson believe it’s time for companies to live up to their ethical responsibilities 18 Will aerosol-based detectors ever meet all the needs of the pharma industry? asks Dorina Kotoni
ISSUE 18 - APRIL 2016 Editor - Stephanie Sutton
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Best Practice 42 Beyond Keeping Up Appearances Is film coating strictly necessary for all tablets? There are many reasons to decide against coating, but there are also many benefits that go beyond optimizing drug release.
Business Features 21 The Power List The Power List is back! It’s time to celebrate the Top 100 inspirational professionals involved in drug development and manufacturing, as nominated by readers.
48 Making Small Biotech Work The industry is increasingly reliant on small biotechs for innovation, but drug development is expensive for anyone, let alone a small company. A sound strategy can go a long way in helping to secure success.
Sitting Down With Reports 38
e Medicine Maker × Catalent Th More Trial, Less Error
50 Christian Schneider, Director of the National Institute for Biological Standards and Control (NIBSC), UK.
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A Battle of the Sexes The Power List is back, but is it a fair representation of the male to female ratio in our industry?
Ed i to r ial
S
References
1. Executive Office of the President,
“Women and Girls in Science, Technology, Engineering, and Math (STEM),” (February, 2013).
http://1.usa.gov/1OLqMFi
2. L. Smith, “Girls in STEM: These figures
show why we need more women in science, tech, engineering and maths,”
The Business Times (January, 2016). http://bit.ly/1TpwnUY
pring (and controversy) is in the air at The Medicine Maker. As well as celebrating longer (and hopefully sunnier) days, we are also celebrating influential professionals in the world of drug development and manufacture. April is the season of The Power List! We’ve been busying ourselves with the 2016 Power List since the inaugural list last year. What is the process? First, we ask you, our readers, to submit nominations and then seek the advice of an expert (but anonymous) judging panel, who whittle the names down to 100 – and rank the Top 20. Not all of you will agree with the list, but at the very least, we hope that it promotes both celebration and discussion. Some of you may be aware that The Medicine Maker has four sister publications across science and medicine, each publishing its own annual Power List. And although the names and faces are clearly different, a common trend runs across all the lists: both the nominees and the final list are heavily dominated by men. In fact, women make up just 18 percent of The Medicine Maker’s 2016 Power List (but more than double the number of women in 2015). So are women simply not being nominated? Or does the List reflect reality? In the US, female employees make up less than 25 percent of the science, technology, engineering and maths (STEM) workforce (1), and in other countries the percentage can be much lower; for example, just over 14 percent of STEM jobs go to women in the UK (2). It’s a recognized problem worldwide, particularly in light of the fact that STEM jobs are considered to pay higher wages. Fortunately, much is being done to encourage more women to take an interest in STEM – a few examples include efforts from organizations such as the European Centre for Women and Technology, the New York Academy of Sciences 1000 Girls – 1000 Futures campaign (US), and the Organization for Women in Science in the Developing World. Although women only make up a small percentage of the 2016 Power List, four of them made it into the Top 20, which is surely testament to the fact that women can certainly do very well in “a man’s world”. Oh – and I should probably mention that the top two spots are also taken by women! Clearly, there’s definitely no lack of female role models in the industry, and with more focus on getting young women interested in science, I can’t help but wonder what The Power Lists will look like in a decade or two… Stephanie Sutton Editor www.themedicinemaker.com
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Up f r o nt
Upfront Reporting on research, personalities, policies and partnerships that are shaping pharmaceutical development and manufacture. We welcome information on any developments in the industry that have really caught your eye, in a good or bad way.
Email: stephanie.sutton@ texerepublishing.com
Mega-Merger Not To Be A newly introduced tax law in the US puts an end to the would-be mega-merger between Pfizer and Allergan Pfizer and Allergan have mutually agreed to terminate their $160-billion merger after the US Department of the Treasury introduced new tax rules at the start of April, specifically aimed at preventing corporate tax inversion deals (1,2). The merger, first announced in November 2015, caused a huge stir within the pharma industry – and also within US government, since the transaction would mean that Pfizer could avoid US taxes by moving its corporate residence to Ireland, where Allergan is located. Prior to April, US tax rules stipulated that, following a merger, if the shareholders of the former US company owned at least 80 percent of the combined firm, the government would subject the business to US taxes, even if the address was abroad. With the proposed merger, Pfizer’s US shareholders would have owned an estimated 56 percent of the combined company – well below the 80 percent threshold, and even below the 60 percent threshold where some restrictions still applied. Under the new rules, however, when the US Treasury calculates the size of the foreign firm (and thus the amount of tax the new company would have to pay) it does not take into account mergers that have taken
place within the previous three years. Much of Allergan’s size is a result of their merger with other companies including Actavis, Forest Laboratories and Warner Chilcott – which when taken together equal around $90 billion dollars, which the US Treasury would not include when estimating the size of Allergan. This would mean that Pfizer’s shareholders would own more than 80 percent of the combined company and would therefore be subjected to US taxes. The US government has also issued regulations against ‘earnings stripping’, whereby recently merged companies – who still have their headquarters in the US – freely lend money to the subsidiary in the foreign country. This allows them to escape the US’s relatively high corporate taxes. The new rules mean the government has more authority to treat those transactions as equity movements – which are taxed. In a statement, Pfizer stated that the merger was terminated because of the “actions announced by the US Department of Treasury on April 4, 2016, which the companies concluded qualified as an ‘Adverse Tax Law Change’ under the merger agreement”. Allergan, however, will not be walking away empty handed – Pfizer has agreed to pay the company $150 million to reimburse expenses from the deal. JS References
1. Pfizer, “Pfizer Announces Termination of
Proposed Combination With Allergan”, April, 2016. www.pfizer.com.
2. US Department of the Treasury, “Treasury
Announces Additional Action to Curb Inversions,
Address Earnings Stripping”, April, 2016. www. treasury.gov
Up f r o n t
Bio-Responsive Insulin Delivery A “smart” synthetic patch uses live pancreatic cells to painlessly deliver insulin through microneedles – on demand Frequently injecting insulin to respond to rises in blood-sugar levels can be both painful and inconvenient. But given that replacing dysfunctional beta cells with healthy donor cells has a number of rejection risks, injections are often seen as the lesser of two evils. Is there a better alternative? Yanqi Ye, PhD research assistant at the University of North Carolina at Chapel Hill, US, and her colleagues have developed a synthetic patch, filled with natural beta cells, that can secrete doses of insulin to control blood sugar levels on demand. The patch is based on a microneedle
platform. “The cells naturally secrete insulin on the patch while the needles act as a bridge between the physiological signals within the body and the therapeutic cells outside the body to keep glucose levels under control,” says Ye, principal author of the study (1). In simple terms, when glucose levels in the blood rise, the beta cells secrete insulin, which is delivered through the microneedle patch. But how do the beta cells sense the rise? In an earlier stage of the work, the researchers only integrated cells with the patch – hoping that, under a hyperglycemic state, glucose could diffuse through the needle and interact with beta cells to promote insulin secretion. However, due to the limited diffusion of glucose, the patch did not effectively respond, and an insignificant increase in insulin secretion was detected. Ye and the team met the challenge: “We have created ‘glucosesignal amplifiers,’ which are synthetic vesicles filled with three components to
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make sure the beta cells can ‘hear’ the call from rising blood-sugar levels and respond accordingly.” The patch has been tested in mice models of type-1 diabetes and was able to help lower blood sugar levels for 10 hours at a time. In the future, Ye believes the therapy could be personalized by using beta cells derived from the patients themselves. The group has also been investigating the potential of the bio-responsive microneedle delivery platform to treat different diseases. “In our latest study, we applied a microneedle patch loaded with anti-PD1 antibody (a cancer immunotherapeutic drug) for treating melanoma,” says Ye. “We have other ongoing projects too.” JS Reference
1. Y. Ye et al, “Microneedles Integrated with
Pancreatic Cells and Synthetic Glucose-Signal Amplifiers for Smart Insulin Delivery,” Adv. Mater (Epub ahead of print, 2016). PMID: 26928976.
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Harnessing AdenoAssociated Viruses AAV vectors are a promising tool for gene therapy and regenerative medicine, but only if they can be manufactured efficiently Adeno-associated virus (AAV) is a small, non-enveloped virus with a genome of single-stranded DNA, and for many years nobody paid it much attention because it’s not known to cause disease. But in recent years, researchers have realized that this lack of pathogenicity – in addition to other characteristics – makes AAV vectors perfect for use as a delivery vehicle in gene therapy. However, manufacturing AAV vectors is no easy task, which is likely to make final therapies very expensive. Hurdles include possible contamination with adenovirus or baculovirus, long lead times for cell line production and virus seed generation, low productivity, and high costs. To tackle the challenges, the UK’s Centre for Process Innovation (CPI) has teamed up with Cobra Biologics, a contract development and manufacturing organization, to develop an industrial manufacturing platform. The project is funded through Innovate UK via their competition for the development of regenerative medicines and cell therapies – and is one of five projects in the area. Juliana Haggerty, public/private program manager at CPI’s National Biologics Manufacturing Centre, sheds more light on AAV vectors and the collaboration. What is the potential of AAV vectors? AAV vectors fulfil the basic criteria required
of viral vectors in that they can attach to and enter the target cell, and transfer to and be expressed in the nucleus. Their increased use over other delivery methods for gene therapy stems from the fact that they are non-pathogenic, as well as having the ability to transduce non-dividing cells and provide long-term expression of delivered transgenes. The wide variety of serotypes and long-term stable expression also means they offer great potential for gene correction in a broad range of therapeutic areas. Different AAV serotypes can be exploited to specifically target different tissues types, and also help evade pre-existing immunity to the vector, thus expanding the therapeutic application and commercial potential of AAV-based gene therapies. What progress has been made so far? In terms of gene delivery, viral vectors are now the preferred vehicle for therapy – and they are being used in around 83 percent of the 483 current on-going gene therapy trials. Within these trials, AAV is the most commonly used vector (41 percent, equating to 103 trials). Several AAV gene therapy products are in late-stage clinical development, and one product is approved in the EU as a therapy for Lipoprotein Lipase
deficiency (UniQure’s Glybera). It has been estimated that 20–25 new AAVbased products will start early phase trials each year between 2015 and 2025. What are the aims of your collaboration? The project is being led by Cobra, which has a lot of experience in biotech, including viral manufacturing and gene therapies. They were interested in CPI because of our high-throughput process development and analytical capabilities that allow for in-depth characterization. In addition, we have experience in taking processes developed at small scale and translating them to a commercial or industrial environment. Our aim is to develop a greater understanding of AAV vectors and to develop effective – and scalable – manufacturing methods. In particular, we are looking to develop a toolbox of improved analytical methods that will enable each unit operation to be fully characterized. We’ll be investigating each step of the manufacturing process using design of experiments and highthroughput approaches where possible, with the aim of investigating a range of different manufacturing approaches and technologies.
Gaithersburg Marriott Hotel, Gaithersburg, MD
Parting Shot Sir Andrew Witty seeks to cement his legacy as GSK addresses patents and medicines access in the developing world
Last month, Sir Andrew Witty announced that he would be stepping down as CEO of GlaxoSmithKline after 31 years with the company. Witty’s tenureship hasn’t been without its troubles; large settlements for off-label promotion will be a lasting blemish on his record. And with the company not performing as well as investors had hoped of late – particularly in China – Witty’s resignation will come as no surprise to some. But there have also been highs, and many see Witty as one of pharma’s good guys – increasing access to medicines in the developing world, for example, by capping the price of GSK’s patented medicines in “least developed countries” (LDCs) at no more than 25 percent of developed world prices, and reinvesting 20 percent of any profits made in LDCs back into training community health workers in those countries. In a similar vein, GSK recently announced that it will not file for patent protection in Least Developed and Low Income Countries. They will also seek to grant licenses to generic manufacturers to supply versions of GSK medicines in “lower middle income countries”. “The changes we are setting out aim to make it as clear and simple as possible for generic manufacturers to make and supply
versions of GSK medicines in LDCs, LICs (lower income countries) and most LMICs,” said Witty in a press release (1). “Implementation of these proposals will be subject to local laws… GSK will now consult with its licensing and codevelopment partners on these changes.” Additionally, GSK outlined its intent to commit its future portfolio of cancer treatments to patent pooling and will explore the concept with the Medicines Patent Pool (MPP) to help address the increasing burden of cancer in developing countries. The MPP has been used to accelerate access to HIV, TB and hepatitis C medicines in low and middle income countries through voluntary licensing arrangements. GSK now say they want to expand this approach to oncology – enabling generic versions of GSK’s immuno-oncology and epigenetic therapies, currently in clinical development, to be made available in LDCs, LICs and certain middle income countries, if and when they receive regulatory approval. The move has drawn considerable praise from industry critics, including the head of Knowledge Ecology International, Jamie Love. “Sir Andrew Witty has shown exceptional leadership, and we look forward to the implementation of this ambitious set of initiatives,” he said in a separate press release (2). “Changes to patents and IP systems will not solve the multi-faceted challenges of improving healthcare in developing countries,” said Witty. “However we believe the measures outlined today add to the wider contribution GSK makes to improve access to effective healthcare around the world.” JS
July 18-19, 2016 Emerging Strategies in Drug Product Comparability and Process Validation Forum Co-chairs: Howard Anderson, CDER, FDA Yves Aubin, Health Canada Zahra Shahrokh, STC Biologics Andrew Weiskopf, Biogen
July 20-21, 2016 Change Happens: Technical and Regulatory Considerations for Pharmaceutical Product Lifecycle Management Forum Co-chairs: Julia Edwards, Biogen Joseph Kutza, MedImmune, A member of the AstraZeneca Group Emanuela Lacana, CDER, FDA Ingrid Markovic, CBER, FDA
References
1. GSK, “GSK expands graduated approach to
patents and intellectual property to widen access to medicines in the world’s poorest countries,” (April, 2016). www.gsk.com.
2. Knowledge Ecology International, “KEI statement on GSK’s announcement of policies to expand access to patented medicines,” (March, 2016). www.keionline.com.
SHARING SCIENCE SOLUTIONS
Please browse the Forum Web site for program updates: www.casss.org
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Up f r o nt
As Clear as Crystallization Functionalized glass is shown to trigger nucleation of specific crystal forms Over the past few decades, immeasurable resources have been spent trying to understand the crystallization process. But despite research efforts, a delicate balance of several influencing factors continues to make crystallization a difficult problem for medicine makers to dea l w ith. Crystallization is crucial in t he pha r maceut ica l industry as a separation process for intermediates and as the final step in t he ma nu fac t u re of active pharmaceutical i n g r e d i e n t s ( A P I s) – precise cont rol of crystallization is vital to ensure polymorphic p u r it y a n d b a t c h-t o batch product consistency. Because different cr ystal forms (polymorphs) of APIs exhibit different physicochemical proper ties and can behave ver y differently once inside the body, understanding the factors affecting crystallization is vital to manufacturers hoping to control the process. Studies have revealed that the outcome of a crystallization process is dependent on a crystallization triangle of solvent conditions, nucleation initiators, and process conditions (including stirring, geometry of vessel, flow pattern, etc.) of the system. Many researchers have reported that special glass surfaces have the potentia l to nucleate cr ysta ls of therapeutic proteins. However, in
a recent study, Jerry Heng and his colleagues at the Department of Chemical Engineering, Imperial College London, have demonstrated that even a normal glass surface – when modified through surface treatments – can trigger nucleation of specific crystal forms of a small-molecule API (1). Polymorph control in pharmaceutical crystallization
is typically ensured by seeding the solution with the desired crystal form and by operating the process at a preset solute concentration. “However, variations in the properties of seed crystals and solution conditions, at times, result in crystallization of unwanted polymorphs,” says Heng. “The current work is important for the understanding of selective nucleation of polymorphic forms on different chemically-modified surfaces.”
The researchers used computational molecular modeling methodology to understand how the glass interacts with the API crystal. “Contrary to conventional wisdom, this study has shown that intermolecu la r interactions bet ween the t e mp l a t e surface and the crystalline phase impact the polymorphic outc ome ,” s ay s Heng. He suggests that the molecular model ing ca lcu lations outlined in the study could be used to predict the propensity for preferential nucleation on new engineered surfaces. With further de velopment of t he results, Heng hopes the approach could be used by manufacturers to have additional control over the crystallization process by improving predictability of the outcome and to ensuring product consistency. Moving forward, Heng hopes to develop design rules to engineer new templates for other crystallization systems, making his approach easily acceptable and applicable for newer drugs, and to explore means of applying his findings to large scale production processes, and to next generation therapeutics – such as biomacromolecules. JS Reference
1. J. Heng et al., “Establishing template
-induced polymorphic domains for API crystallization: the case of carb
amazepine,” CrystEngComm17, 6384-6392, 2016.
Up f r o n t
Affliction Prediction Could drug development be guided by a new algorithm that predicts the side effects of potential medicines?
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small subset of similar drugs to build prediction models for specific drugs, which makes it more robust for those hard-to-predict, rare side effect cases,” says Jianhua Ruan, group leader of the project. The model developed by Ruan and his team uses a technique called “ensemble classification”. The researchers identified a set of similar drugs for each drug based on their chemical substructures and then constructed a number of base classifiers – these can be any machine learning classifiers, such as a decision tree, support vector machine or a random forest. “Our method could also be used to identify chemical substructures related to different side effects, which means that pharma companies may be able to investigate the underlying mechanism that causes the side effect. This potential could make predictive models like ours crucial in guiding the development of new drugs,” says Ruan. JS Reference
1. M.J.Jahid and J. Ruan, “Structure-based prediction of drug side effects
using a novel classification algorithm,” Int. J. Comput. Biol. Drug Des., 9, 1/2, 87 (2016).
Side effects are inherently unpredictable, often first detected in clinical trials or even by patients after approval. What if drug developers could predict side effects before the drug goes to trial? Researchers at the University of Texas San Antonio have developed an ensemble-based classification algorithm to predict side effects associated with different drugs – and so far it has outperformed previous methods and standard classifiers (based on evaluation results of 1385 side effects for 888 FDAapproved drugs). The team have also applied their method to a number of uncharacterized drug molecules in the DrugBank database to predict their side effects, which have subsequently been validated using literature mining. The software works by assessing the chemical structure of a drug molecule and then determining whether there are any key sub-structures that are known to cause side effects in other drugs. “Some previous studies used ordinary canonical correlation analysis (OCCA) and sparse canonical correlation analysis (SCCA) to predict side effects,” says Jamiul Jahid one of the authors on the research paper (1). “We compared our results thoroughly with the SSCA method in our manuscript and found that our method significantly outperformed SCCA.” “One unique feature of our new approach is that it identifies hard to predict rare side effects which can be easily ignored by other approaches. Our model uses chemical sub-structure to identify a
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Up f r o nt
Moving from Batch to Continuous The first switch from batch to continuous manufacturing has been made – and approved by the FDA. Will pharma’s future be continuous? There has been encouragement from many industry stakeholders, including the FDA, to switch from batch to continuous manufacturing. Implementing this change for already approved products is considered to be easier said than done, but it’s not impossible; in mid-April, the FDA for the first time approved a pharma manufacturer (Janssen) to
switch from batch to continuous – and the agency hopes that more will follow suit. Janssen pursued the change for the production of Prezista (darunavir) via the FDA’s recently-released draft guidance to industry, Advancement of Emerging Technology Applications to Modernize the Pharmaceutical Manufacturing Base, which was introduced in 2015 with the specif ic aim of helping pharma manufacturers to implement new technology. The reason for the FDA’s focus on new technologies is a desire to update the industry and its processes. In a recent blog post (1), Larence Yu, Deputy Director at the FDA Office of Pharmaceutical Quality, Center for Drug Evaluation, suggested that a timetraveling pharmaceutical scientist from the 1960s would be very much home in today’s industry. “They would already be very familiar with most of the processes
and production techniques being used. That’s because not much has changed in pharmaceutical production over the last 50 or so years,” he wrote (3). “Today, a new and exciting technology — continuous manufacturing — enables much faster production and more reliable products through an uninterrupted process.” For time-traveling scientists from the 1960s then, will familiar batch processes soon be a thing of the past? Several manufacturers are beginning to adopt continuous manufacturing, but announcements to date have been for new products; for example, Vertex Pharmaceutica ls has been using continuous manufacturing for its cystic fibrosis drug Orkamvi since its approval date in July 2015. Janssen is the first company to make the switch for an already approved drug – and the company is likely planning for more in the future. Last year, Janssen expanded its collaboration with Rutgers School of Engineering, with the hopes of transitioning “several” products to continuous manufacturing (2). Other big pharma giants are also jumping on the continuous processing bandwagon. GlaxoSmithKline, for example, is in the process of building a continuous manufacturing plant in Singapore. “Although it is not easy for drug manufacturers to transition from batch to continuous manufacturing, there are significant rewards. FDA encourages others in the pharmaceutical industry to consider similar efforts,” says Yu. JS References
1. L. Yu, “Continuous Manufacturing has a
Strong Impact on Drug Quality”, April, 2016. www.blogs.fda.gov
2. Rutgers School of Engineering, “Janssen
Supply Chain Expands Collaboration with
Rutgers School of Engineering with $6 Million Funding Arrangement to Implement
Continuous Manufacturing Initiative,” (May, 2015). http://soe.rutgers.edu
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I n M y V iew
In My View In this opinion section, experts from across the world share a single strongly held view or key idea. Submissions are welcome. Articles should be short, focused, personal and passionate, and may deal with any aspect of pharmaceutical development or manufacture. They can be up to 600 words in length and written in the first person. Contact the editor at: stephanie.sutton @texerepublishing.com
What Price Glory? The pharmaceutical industry receives its fair share of both praise and scorn. Behind the politics, the hard work and impressive achievements of legions of industry researchers often go unnoticed.
By Ann Hayes, Pharmaceutical Consultant, The Ann Hayes Consultancy, UK. The British Pharmacological Society’s Industry Committee, of which I was chair until the end of 2015, launched the Drug Discovery of the Year award in 2012 to recognize the hard work of scientists in research and drug discovery. By the time a new drug is launched, the commercial team often receives the majority of the feedback on the new drug from doctors and patients. You rarely hear about the individuals involved in the early stages of the drug’s development, which is why our award is given to the R&D team, rather than the company as a whole. This year’s winners – a team of scientists who worked on Gilead’s sofosbuvir (Sovaldi) – were easily the top choice for the Industry Committee, for two reasons. The first is the drug’s significant impact on an obvious unmet medical need – hepatitis C – and the second is that it is a great example of pharmacological
principles being applied to move the drug from discovery, through development, and into the clinic. Sovaldi is highly effective in 90 to 100 percent of patients, and brings about a complete cure in many. It is very well tolerated, with an excellent safet y profile, and a high barrier to resistance. The drug is so effective that a number of companies have abandoned their hepatitis C research programs altogether in favor of hepatitis B; they have been advised that Solvaldi has effectively removed the medical need for further hepatitis C therapies. In terms of the pharmacology, the researchers have been very clever. They’ve made a pro-drug that facilitates entry of the molecule into hepatocytes (where the hepatitis C virus resides) at which point it is metabolized into the active drug, which means that it only works at the site of disease and is thus very effective and has a good side effect profile. It acts against all six genotypes of hepatitis C, it’s a once-a-day tablet, and there are no food effects or drug interactions – it’s simply a really good drug. Fifteen years ago when I left GlaxoSmithKline, there was no good treatment for hepatitis C, so
“The drug is so effective that a number of companies have abandoned their hepatitis C research programs altogether.”
I n M y V iew
this has been a remarkable step change. In my view, these positive stories are not given enough attention. Hepatitis C is not the only disease to witness a revolution over the past decade; we have made huge strides in multiple sclerosis and rheumatoid arthritis, for example. I spoke with a doctor who told me he regularly walks through the rheumatoid arthritis clinic on his way to oncology. Ten years ago, he was constantly tripping over wheelchairs, but now almost none of the patients are wheelchair-bound, thanks to diseasemodifying therapies like anti-TNF drugs. And yet few people sit down and write about those successes. The
pharma industry itself can often be cautious, failing to communicate just how amazing some of these advances are – and that leaves the media to concentrate on negative stories rather than celebrating success. I think there is an element of that negativity in the controversy over the pricing of Sovaldi. The drug is expensive; there is no disputing that. But compared with the direct medical and economic cost associated with ongoing hepatitis C infection – the lost days of work, the drug treatments, the risk of liver cirrhosis or cancer – Sovaldi represents large savings for healthcare systems. Factor in the huge improvements to
Time to Limit Antibiotic Pollution The use and misuse of antibiotics is a major driver behind the drugresistance problem, but large environmental discharges of antibiotics from pharma manufacturing can also contribute. It’s time for companies to live up to their ethical responsibilities. By Johan Bengtsson-Palme, doctoral student at the Department of Infectious Diseases, The Sahlgrenska Academy, and D. G. Joakim Larsson, Director of the Centre for Antibiotic Resistance Research (CARe) at the University of Gothenburg, and Professor in environmental pharmacology at the Department of Infectious Diseases, the Sahlgrenska Academy, University of Gothenburg, Sweden.
Over the last decade, antibiotic resistance has put increasing pressure on human healthcare and is estimated to account for 700,000 deaths every year (1). The use (and misuse) of antibiotics in both human medicine and agriculture is a well-known cause of resistance; a muchless discussed driver is the environmental discharge of pharmaceuticals (2). Both the development and spread of resistant bacteria in the environment can be promoted by antibiotic selection, and so release of antibiotics into the environment can accelerate the problem. Importantly, in contrast to the use of antibiotics, environmental discharges are not associated with any benefits – only risks. For a long time, the subject of environmental pollution with antibiotics
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quality of life, which are harder to put a price on, and Sovaldi starts to look like pretty good value. What the public often don’t realize is the enormous costs of bringing a drug to market, taking into account just how few drugs make it into the clinic, and how few of these make a substantial profit. It’s a difficult argument – healthcare systems are being stretched and need to keep costs down, but pharma companies are also facing tough times. If the industry stops investing in drug discovery and development, who will fund these activities? Ultimately, the key factor is the value that the drug brings to patients – and Sovaldi brings huge value to patients.
“Companies with foresight can benefit by making early efforts to reform their production chains towards green manufacturing.” has been neglected – presumably because the potential impact of the problem has not been recognized. Slowly, awareness is growing, but we need improved national and international regulation – and established limits for environmental releases, if we are to make a difference. At the moment, there is little public information about where and how medicines are produced, because of a lack of transparency in the production www.themedicinemaker.com
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I n M y V iew
“Demands for the sustainable, ‘green’ production of pharmaceuticals have already been raised and this is likely to accelerate.” chain. This also means that it is difficult to know which companies are making an effort. In our view, companies producing and formulating antibiotics have an ethical responsibility to minimize the discharge of antibiotics into the environment. With available treatment options for bacterial infections deteriorating rapidly, we need to act fast. Unfortunately, the current systems for assessing risks associated with pharmaceutical pollution do not account for resistance promotion (3). Ecotoxicological data for antibiotics is scarce and, even when such data exist, the identified effect concentrations are often higher than those that kill many bacterial species, and hence do not protect against resistance selection. Recently, we broadly estimated the concentrations that promote resistance based on the EUCAST (European Commit tee on A nt imicrobia l Susceptibility Testing) database on the antibiotic susceptibility of clinical isolates (4). We based our estimates on the fact that a given antibiotic concentration that kills or inhibits growth of some bacterial species will, by consequence, be selective under at least some conditions. Thus, the lowest inhibitory concentrations reported are
also the upper boundaries for selective concentrations. The actual selective concentrations are likely to be even lower – but exactly how much lower is still not known. By accounting for limited sampling of species and the extent of available data, we used the upper boundary concentrations to predict no effect concentrations (PNECs) for each antibiotic. These PNECs for resistance selection can be applied in regulatory contexts, and may eventually be ref ined or supplemented with experimental data as they become available (5). The recent O’Neill report on antimicrobial resistance, commissioned by the British Government, specifically highlights the urgent need for enforceable regulations on antibiotic discharges (6). The concentrations we report can be used by local authorities to define emission limits for antibiotic-producing factories, or for pharma companies to assess and manage risks for resistance selection associated with their own discharges. They also fill an important knowledge gap to make the proposed environmental certificates within the good manufacturing practice framework for antibiotics concrete. Similarly, further development of environmental criteria as part of public procurement processes for antibiotics, as implemented by Sweden and considered by the WHO, will eventually require defined discharge limits. There are also strong incentives to introduce evaluations based on scientific data in the environmental risk assessment of antibiotics within the guidelines of, for example, the European Medicines Agency. Demands for the sustainable, ‘green’ production of pharmaceuticals have already been raised and this is likely to accelerate, which means that pharma companies should be prepared for increased pressure in the future in the form of sharpened procurement criteria
and new legislation. Companies with foresight can benefit by making early efforts to reform their production chains towards green manufacturing to get ahead of the enactments to come. A transformation to documented sustainable production may have other benefits for pharmaceutical producers too, by providing environmentally friendly products to conscious customers, which could set responsible companies apar t from the negligent. Most companies will want to avoid distrust associated with not taking action (see the “Bad Medicine” report by Sum Of Us (7) for an example of this). With a large number of proposed discharge limits now at hand (4), we think the time is ripe to take action. References
1. Review on Antimicrobial Resistance,
“Antimicrobial Resistance: Tackling a crisis for the health and wealth of nations” report
(December, 2014). http://bit.ly/1yCt7re
2. R.L. Finley et al. “The scourge of antibiotic resistance: the important role of the
environment,” Clin. Infect. Dis., 57, 704–710 (2013).
3. M. Ågerstrand et al. 2015. “Improving
environmental risk assessment of human
pharmaceuticals,” Environ Sci Tech, 49(9), 5336-5345 (2015).
4. J. Bengtsson-Palme and D.G.J. Larsson,
“Concentrations of antibiotics predicted to
select for resistant bacteria: Proposed limits for environmental regulation,” Environ Int., 86, 140–149 (2016).
5. S.V Lundström et al., “Minimal selective concentrations of tetracycline in complex
aquatic bacterial biofilms,” Science of the Total Environment, 553, 587-595 (2016).
6. Review on Antimicrobial Resistance,
“Antimicrobials in agriculture and the
environment: Reducing unnecessary use and waste,” report (December, 2015). http://bit. ly/1SLeZYn
7. Sum Of Us, “Bad Medicine” report (June, 2015). http://bit.ly/1FS6Adq
I n M y V iew
The Search for the Ideal Detector Will aerosol-based detectors ever meet all the needs of the pharmaceutical industry?
By Dorina Kotoni, Analytical Expert Principal Scientist, Novartis, Basel, Switzerland. When developing impurity-profiling methods for pharma applications, detection and sensitivity can be challenging. On one hand, the high variability of physicochemical properties of the analytes requires that we use universal detection systems, while on the other hand the expectations of regulators drive the need for higher sensitivity and detectability (for trace analysis, degradation by-products, and so on). The pharmaceutical industry has been basing most of its release methods on liquid chromatography (LC) with UV detectors and gas chromatography with flame ionization detectors, with the occasional use of fluorescence and mass spectrometry. There is still a reluctance to introduce other “universal detectors”. Moreover, pharma’s “ideal” detector should be sensitive and robust, ideally showing a universal response independently of the properties of the sample. It should be able to detect and quantify all components, including unknowns for which no reference standards are available (which is typically the case for early phase projects). Ease-of-use, the ability to interface with high-performance liquid chromatography (HPLC) and ultra
HPLC instruments, cost effectiveness, as well as a good understanding of the response curves, are fundamental for the purchase and implementation of a new detector. The truth is, although we are promised great things, we are still waiting for a commercially available and truly universal detector!
“Pharma’s ‘ideal’ detector should be sensitive and robust.” The next best thing to a universal detector, according to instrument manufacturers, is an aerosol-based detector, but, in reality, this only delivers what it promises for detecting non-volatile components under isocratic elution conditions. While there have been significant advances in this field, there is still a lot to be understood in the responses obtained with light scattering and charged aerosol detectors – for example, gradient effects, detector settings, influence of compound properties on the detection. Interestingly, a few recent studies highlight that volatility of a compound is not sufficient to explain differences observed in detection. For nonvolatiles and semi-volatiles, parameters such as molar volume and diffusivity, as well as net charge of the compound seem to play a role in detection. These new aspects still need further investigation and explanation by theoreticians and instrument manufacturers. Understanding the response model of aerosol-based detectors under hydrophilic interaction LC (HILIC) conditions can
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frequently prove even more challenging. Analytes eluted in HILIC often require an alternative detection technique due to low UV absorption (sugars, aliphatic amines, lipids, amino acids). There is ongoing research in the field but so far, most publications describe work done under mainly isocratic elution conditions. In my opinion, we still have a long way to go in understanding aerosol-based detection under HILIC conditions. A HILIC expert once told me “we never use gradients in HILIC, they are too complex”, showing that there is still a big gap to cover, model and understand, both in terms of separation and of detection. A universal response model for non-volatile molecules in HILIC is inherently more complex and needs to consider not only the gradient effects, but also the detector settings, the mobile phase interference, and the polarity of the analytes. Manufacturers need to investigate the fundamentals of nebulization and particle formation further to design detectors with increased sensitivity and greater uniformity in their response. In some cases, it might not be enough to widen the dynamic range of the detector by data interpolation through algorithms introduced between the analog and the digital output of the signal. We need to detect more and better – and I don’t think that, in the case of aerosol-based detection, an algorithm (as refined as it may be) will save the day. I am convinced, however, that when there is a better understanding of the response model for aerosol-based detection under a variety of analytical conditions, the pharma industry will be very happy to introduce them routinely. The need is there. In the meantime, we are still looking for that ideal detector... This article was originally published in The Analytical Scientist (www. theanalyticalscientist.com), a sister publication to The Medicine Maker. www.themedicinemaker.com
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The nominations are in and after considerable debate and analysis from our judging panel, we present The Power List 2016 – our second foray into the Top 100 most influential people in the world of drug development and manufacture. Though we realize our list can (and should) never be definitive, who can argue that the faces within – both familiar and new – do not beautifully highlight the brilliance and diversity found within our field? www.themedicinemaker.com
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The Power List
James Agalloco President, Agalloco & Associates James is a past president of the Parenteral Drug Association and frequent author on the subjects of sterilization, aseptic processing, and process validation. “I am very grateful for the opportunities I’ve been given to share my personal and professional experiences with others through publications, presentations and training,” says James. “It’s brought me lifelong friends, colleagues and more throughout my career.”
Phil S. Baran Darlene Shiley Professor, The Scripps Research Institute Phil has racked up a number of impressive natural product syntheses, and won dozens of chemistry’s highest accolades. He says he is most proud of “educating the next generation of chemists and inventing reactions and strategies that can be rapidly translated to aid medicinal chemists in their efforts to discover new life saving medicines.”
Jonathan Bones Principal Investigator, NIBRT Characterization and Comparability Laboratory, NIBRT – The National Institute for Bioprocessing Research and Training “I’m delighted to be a part of NIBRT; it’s fantastic to work with a group of talented and dedicated people, to see the Institute continually grow and develop to fulfil its mandate of becoming a global center for excellence in research and training in all aspects of biopharmaceutical production,” says Jonathan.
María José Alonso Professor of Biopharmaceutics and Pharmaceutical Technology, University of Santiago de Compostela
Stéphane Bancel
Maria has pioneered the design and development of novel nanostructures for the targeted delivery of drugs and vaccines. She has also made critical contributions to the understanding of the interaction and transport of biodegradable nanoparticles through biological barriers. Maria has published over 200 scientific papers and has 11 licensed patents to her name.
Prior to Moderna, Stéphane was CEO of bioMérieux and he has also held leadership positions at Eli Lilly. He was elected a 2009 Young Global Leader by the World Economic Forum in France, and was chosen as the Best CEO in the Biotechnology Sector, according to the 2011 Thomson Reuters Pan European EXTEL Study.
Mary C. Beckerle Chief Executive Officer and Director of Huntsman Cancer Institute, University of Utah Mary is well-known for her research into cancer and has defined a novel molecular pathway for cell motility; her lab is currently working to understand the effect of this pathway on tumor progression. She is also Associate Vice President for Cancer Affairs at the University of Utah.
Chief Executive Officer, Moderna Therapeutics
David Bentley Vice President and Chief Scientist, Illumina David was a founding member of the Sanger Centre (now the Wellcome Trust Sanger Institute) and led the Centre in their contributions to the Human Genome Project. He and his team have been involved in the 100,000 Genomes Project in partnership with Genomics England and the UK National Health Service.
Olivier Brandicourt Chief Executive Officer, Sanofi Olivier has 28 years of global experience in the pharmaceutical industry, most recently as Chairman of the Board of Management of Bayer HealthCare AG and a member of the Executive Council of Bayer AG. He started his career as a physician working primarily on malaria. He practiced medicine in the Republic of the Congo for two years.
The Power List
Pierre Chambon Carsten Brockmeyer
Chair of Molecular Genetics and Biology, University of Strasbourg Institute for Advanced Study
Chief Executive Officer, Formycon Carsten has been working with the biosimilars industry from the very beginning; he was involved in the development of Binocrit (epoetin alfa), the world’s first complex biosimilar anemia drug. He was headhunted for the role at Formycon after holding a one-day workshop on biosimilars at the company.
Pierre’s scientific achievements are numerous; the discovery of multiple RNA polymerases (1969); the discovery of animal split genes (1977); and a marked contribution to the discovery of the superfamily of nuclear receptors (1987). He is also the founder of the Institute for Genetics and Cellular and Molecular Biology in Strasbourg.
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John Chiminski President and Chief Executive Officer, Catalent John joined Catalent after more than 20 years’ of experience at GE Healthcare and was featured on last year’s Power List. He says, “Over the past year, alongside our expansions in consumer health and biologics, we introduced our new platform which matches the best drug delivery technologies to developmental molecules.”
William Chin Chief Medical Officer and Executive Vice President, Scientific and Regulatory Advocacy, Pharmaceutical Research and Manufacturers of America (PhRMA) “While it is gratifying personally to be recognized in this way, I hope that it reflects an appreciation of the paramount importance of science and medicine in the biopharmaceutical industry. This is critical to sustain a pipeline of drugs that have the potential to help future patients live better lives and even to cure diseases,” says William.
Stephen T. Colgan Senior Director, Global CMC, Pfizer Worldwide Research and Development Dr. Colgan has advocated lean stability strategies for more than a decade. These strategies provide a focus on the highest risk attributes and time points and facilitate rapid introduction of medicines into clinical trials. Regulatory filings are more science and riskbased without impacting safety, efficacy, or quality of the product.
Jean-Paul Clozel Founder and Chief Executive Officer, Actelion After eleven years as a clinician, Jean-Paul decided to move to applied research – spending 12 years at F. Hoffmann-La Roche, during which time he was responsible for the selection of the first T-channel blocker. He has built Actelion from a start-up to a multi-billion market capitalization company.
Meindert Danhof Professor of Pharmacology, Leiden University
Francis S. Collins
Meindert Danhof’s research focuses on novel concepts of systems pharmacology, interfacing theories from systems biology with quantitative pharmacology. He is former scientific director of the Leiden Academic Center for Drug research, and he is also a Past President of the European Federation of Pharmaceutical Sciences.
Francis is the Director of the US National Institutes of Health, the largest supporter of biomedical research in the world. He is a physician–geneticist noted for his landmark discoveries of disease genes and his leadership of the international Human Genome Project.
Director, US National Institutes of Health
www.themedicinemaker.com
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The Power List
Wendel Doubleday
Sir Andrew Dillon
Founder, and Chief Executive Officer, Blue Sphere Health
Director, Process Research & Development, Seattle Genetics
Chief Executive, UK National Institute for Health and Care Excellence (NICE)
Mark Davison is considered an expert on anticounterfeiting, drug traceability (serialization) and patient engagement. “I enjoy helping pharmaceutical companies, NGOs and governments to keep patients safe from fake drugs,” he says. “With imagination, the same systems can also improve adherence and drive better clinical outcomes.”
Wendel leads Seattle Genetics’ process chemistry department, which focuses on the development of novel chemical processes for highly potent drug-linkers. He is currently responsible for defining how processes for cytotoxic agents can be safely and efficiently developed within a biotech environment, and transferred to external manufacturing.
After a successful career in hospital management Sir Andrew joined NICE – the body which determines the cost-effectiveness of new drugs for the UK National Health Service – as its founding Chief Executive in 1999. He has held this position ever since and was awarded a knighthood in 2009 for services to UK healthcare.
Mark Davison
Suzanne Farid Professor of Bioprocess Systems Engineering, University College London
Frances D. Fergusson President Emeritus, Vassar College
Suzanne’s research centers on computer-based, decision-support tools – particularly those that help with the design of cost-effective bioprocesses, such as tools that can analyze economic drivers and trade-offs in antibody production, or tools that help with capacity planning and portfolio management. She has received funding for her work from a number of large pharma companies.
Frances has a degree in art history and between 1986 and 2006, she served as President of Vassar College. But she has also put her administrative skills to use in the pharma industry. She has served on the Mayo Clinic Board and been a director at Wyeth. Today, in addition to teaching, she sits on Pfizer’s board of directors.
Miguel Forte Chief Operating Officer, TxCell After several clinical, academic and regulatory positions in the public sector in Portugal and at the European Medicines Agency, Miguel moved into the private sector, and became Vice President of Global Medical Affairs Inflammation Worldwide at UCB. Miguel currently juggles positions at the Lisbon and Aveiro Universities, the Commercialization Committee of the International Society of Cellular Therapy, and TxCell.
Kenneth Getz
Chief Executive Officer, Healthcare, Merck Group
Director, Sponsored Research Programs and Associate Professor, CSDD, Tufts University School of Medicine; Founder and Board Chair, CISCRP
Belén initially started out as a medical doctor, specializing in clinical pharmacology. She worked as a practicing physician for six years before moving to the pharmaceutical industry where she has spent the last 25 years. She has held diverse senior functions and worked in a number of countries – and was elected CEO of the year in Spain in 2009.
“CISCRP has recently been developing educational content for a new traveling science museum exhibit designed to teach elementary through high school children about what it means to be a clinical research study volunteer and the gift that clinical trial participation gives to advancing society’s health and wellbeing,” says Ken.
Belén Garijo
The Power List
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Dalvir Gill Chief Executive Officer and Member of the Board of Directors, TransCelerate BioPharma Recently, Gill has been involved in launching BioCelerate, a new subsidiary of TransCelerate, and its first initiative, Toxicology Data Sharing. “TransCelerate delivered some significant solutions that are positively impacting clinical development, including the Shared Investigator Platform and the Investigator Registry that work together to streamline investigative site communication, information sharing and monitoring tasks,” says Dalvir.
Laurent Grandidier
Fiona Greer
Chief Executive Officer, Xeltis
Global Director, BioPharma Services Development – Life Sciences, SGS
“Witnessing the first implant of our bioabsorbable technology in a child with congenital heart disease was truly remarkable,” says Laurent. “In that exact moment, our vision of a revolutionary approach to regenerative medicine, potentially transforming standards of care in cardiovascular treatment and allowing patients to live better lives, started becoming real.”
Fiona was a founding Director of M-Scan, where she pioneered new developments, particularly mass spectrometry, for analysis and sequencing of glycoproteins. For over 35 years, she has characterized a range of biotechnology products, both novel and biosimilar. Following acquisition (2010), she became Global Director, Biopharma Services Development, SGS Life Sciences.
Helen Hobbs Professor, Internal Medicine and Molecular Genetics; Director, Eugene McDermott Center for Human Growth and Development, University of Texas Southwestern Medical Center Helen was awarded the Breakthrough Life Sciences Prize in 2015 for her work on identifying key genes involved in lipid metabolism and fatty liver disease. Her work has also led to the development of a novel class of drugs for lowering LDL cholesterol by blocking PCSK9.
Jane Griffiths Company Group Chairman, Janssen, Europe, Middle East & Africa (EMEA) Jane is privileged to lead an “amazing team at Janssen, providing medicines every day to millions of people, helping to extend and improve lives”. Recently, she’s been getting ready to launch new medicines, continuing to develop Janssen’s people in the organization, and working on establishing more companies in Africa.
SeungSuh (Stanley) Hong
Robert J. Hugin
Mir Imran
President and Chief Executive Officer, Celltrion Healthcare Co. Ltd
Executive Chairman, Celgene
Chairman & Chief Executive Officer, InCube Labs
Stanley is both a scientist and a business man. He joined Celltrion in 2002 and is said to have made many contributions to the successful development of the company; he was also involved in the development of Remsima, the first biosimilar monoclonal antibody to be approved by the European Medicines Agency.
Robert joined Celgene back in 1999 – initially as Senior Vice President and Chief Financial Officer. In March 2016, he was appointed Executive Chairman. He is also a member of the Board of Trustees for a number of institutes, including Princeton University, The Medicines Company, and The Darden Foundation, University of Virginia.
After attending medical school, Mir began his career as a healthcare entrepreneur and has since founded more than 20 life sciences companies, more than half of which have been acquired. Mir has been running his R&D lab, InCube Labs, since 1995 and is recognized as one of the leading inventors and entrepreneurs in the field. www.themedicinemaker.com
Bahija Jallal Jayasree K. Iyer Executive Director, Access to Medicine Foundation Jayasree leads the strategic direction, research programs and stakeholder outreach of the Access to Medicine Foundation and is responsible for the Access to Medicine Index. She spearheads the Foundation’s discussions with, among others, companies, governments and key investors in the pharmaceutical industry.
Carl June Richard W. Vague Professor in Immunotherapy, University of Pennsylvania Carl is also Director of the Center for Cellular Immunotherapies and an investigator at the Abramson Family Cancer Research Institute, both located at the University of Pennsylvania. He maintains a research laboratory that studies various mechanisms of lymphocyte activation that relate to immune tolerance and adoptive immunotherapy for cancer and chronic infection.
Executive Vice President, AstraZeneca, and Head of MedImmune Bahija has guided the MedImmune R&D organization through the growth and expansion of its biologics pipeline from 40 drugs to more than 120 today. She also serves as a member of the Board of Directors for the Association of Women in Science, and as an advisory board member of the Healthcare Business Women’s Association.
Siu Ping Lam Michael Kopcha Director, Office of Pharmaceutical Quality (OPQ), FDA From 2013, until he took up his position as Director of the OPQ in 2015, Michael led R&D for Novartis’ cough, cold and respiratory division as Vice President. He has also served as Vice President for pharmaceutical development at KV Pharmaceutical, and as an adjunct assistant professor in the Department of Pharmaceutics at Rutgers University.
Robert Langer David H. Koch Institute Professor, Massachusetts Institute of Technology Considered one of the most prolific inventors in medicine, Robert Langer has over 1100 issued and pending patents. He previously served on the FDA’s Science Board and has been elected to the Institute of Medicine of the National Academy of Sciences, the National Academy of Engineering, and the National Academy of Inventors.
John C. Lechleiter Chairman, President and Chief Executive Officer, Eli Lilly and Company John joined Lilly in 1979 as a senior organic chemist in process research and development, and became head of that department in 1982. He has served as president and CEO since April 2008 and became chairman of the board of directors in January 2009.
Director, Licensing Division, UK Medicines and Healthcare products Regulatory Agency Siu Ping became the Director of MHRA’s Licensing Division in April 2014. He has over 24 years’ experience in medicines regulation. During this time he has shaped many changes in European directives for pharmaceuticals, set up the traditional herbal medicines registration scheme, the homeopathic medicines registration scheme and the medicine/device combination consultation operation.
Andrew Lees Scientific Director, Fina BioSolutions LLC “My most significant contribution is the development of CDAP chemistry for conjugate vaccines,” says Andrew. “CDAP is perhaps the simplest and most efficient chemistry for making conjugate vaccines. It is used by GSK in their pneumonia and meningococcal vaccines and emerging market manufacturers are using CDAP chemistry to develop more affordable conjugate vaccines.”
The Power List
Claus -Michael Lehr
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Olivier Loeillot
Professor, Helmholtz-Institute for Pharmaceutical Research Saarland (HIPS); Helmholtz Center for Infection Research (HZI); Saarland University
Arthur D. Levinson Chief Executive Officer, Calico
General Manager of Genomics & Cellular Research, GE Healthcare’s Life Sciences business
Claus-Michael was included in last year’s Power List. “Over the past year, in continuation of our approach to improve the delivery of drugs across biological barriers, we have expanded our focus to those barriers which are particularly relevant in the context of infectious diseases, such as immune cells, bacterial biofilms and the gram negative cellular envelope.”
As well as heading up biotech company Calico, Arthur (‘Art’) Levinson serves as Chairman of the Board of Apple and Genetech – where he spent 14 years as CEO. He’s authored or coauthored more than 80 scientific articles, holds 11 US patents and has received numerous awards, including the US National Medal of Technology and Innovation.
Olivier has around twenty years’ experience in the global life sciences and pharmaceutical industry. Previously, he was General Manager of BioProcess Asia and Enterprise Solutions, a global business unit of GE Healthcare’s Life Sciences division. In 2014, he was awarded the Bioprocess Industry Award for Excellence in Leadership.
Archie Lovatt
Ruth McKernan
Scientific Operations Director, SGS Life Sciences
Chief Executive, Innovate UK
Between 1996 and 2007, Archie was Scientific Director of Q-One Biotech-BioRelianceInvitrogen. In early 2007, he co-founded Vitrology, which was acquired by SGS in 2012. “Since last year’s Power List, I have been working on developing new methods for virus detection, and have joined USP expert panels for viral vaccine safety, and cell banking and characterization,” says Archie.
Ruth was previously the Chief Scientific Officer of Pfizer’s Neusentis Unit, which has funded groundbreaking work in regenerative medicine. Scientifically, Ruth is best known for her research in neuroscience on ligand-gated ion channels with over 130 publications and 15 patents. She has also won awards for science writing.
Christian Luber Line Manager, Protein Characterization, Protein Engineering Novo Nordisk A/S Christian has industry experience from positions at Pfizer, Novo Nordisk USA and Thermo Fisher. He joined Novo Nordisk, Denmark, as line manager in 2015 and together with his team is developing and applying cutting-edge mass spectrometrybased technologies to progress nextgeneration diabetes and obesity medicines.
Richard A. Miller Co-Founder President and Chief Executive Officer, Corvus Pharmaceuticals In previous roles, Richard led the initial discovery and development efforts for ibrutinib (developed at Pharmacyclics) and research efforts on lymphoma, culminating in the development of rituximab (developed at IDEC; now Biogen). Today, he is also Adjunct Clinical Professor of Medicine (Oncology) at Stanford University Medical Center.
Randy Mrsny Professor, Department of Pharmacy and Pharmacology, University of Bath Before taking up professorships, first at Cardiff University and now the University of Bath, Randy led research groups in two companies: ALZA and Genentech. He has also been involved in starting two new biotech companies through venture capital funding. www.themedicinemaker.com
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The Power List
Niclas Nilsson Head of R&D Open Innovation, LEO Pharma
Ian Muir
Kary Mullis
Managing Director, Aesica
Chief Scientific Advisor, Altermune Technologies
Ian holds a PhD in pharmaceutical science and has over 20 years’ experience in the pharma industry. He has worked in senior commercial positions for Catalent, Cardinal Health and RP Scherer. Today, in his current role, Ian has ultimate responsibility for driving growth across API and finished dose.
Kary serves on the board of scientific advisors of several companies, provides expert advice in legal matters involving DNA, and lectures at college campuses, corporations and academic meetings around the world. He received a Nobel Prize in chemistry in 1993, for his invention of the polymerase chain reaction (PCR).
Daniel O’Connor Expert Medical Assessor, UK Medicines and Healthcare products Regulatory Agency A medical assessor at MHRA, Daniel is instrumental in the UK’s Early Access to Medicines Scheme (EAMS). “My work has helped UK patients with life threatening or seriously debilitating conditions benefit from innovative medicines before they are licensed. Being part of the team that helped to set up EAMS has been an incredibly rewarding journey,” says Daniel.
Niclas says his proudest moment was “finally pressing the web portal’s GO-button and officially launching a truly open innovation platform”. Niclas is a strong supporter of exploring new external pharmaceutical collaborations that focus on science – and was recently instrumental in launching Leo Pharma’s open innovation platform. “Our platform could only have been completed by the inter-disciplinary and combined efforts of all involved,” he says.
Brian Overstreet Co-Founder and President, Advera Health Analytics Brian has more than fifteen years of experience building and managing companies in the healthcare data and analytics industry. “Since the last Power List, we’ve grown our data capabilities and coverage, and expanded our customer markets from payers and providers to also include pharmaceutical companies who want to leverage real world evidence for everything from outcomes research to trial design,” says Brian.
Elizabeth Parrish Chief Executive Officer, BioViva Sciences Liz is a strong proponent of gene therapy R&D, and frequently seeks to inform and engage the public in this field. She is actively involved in international educational media outreach and sits on the board of the International Longevity Alliance (ILA).
Nicholas A. Peppas Professor of Chemical Engineering, University of Texas at Austin Nicholas is a leading researcher, inventor and pacesetter in the field of drug delivery and controlled release. He has been the recipient of over 150 national and international awards. In 2008, he was selected as one of the 100 Engineers of the Modern Era by the American Institute of Chemical Engineers.
Daniel Podolsky President, University of Texas Southwestern Medical Center Daniel is a world-renowned researcher who has advanced knowledge of underlying mechanisms of disease and new therapies for gastrointestinal disorders. He is considered an international authority on trefoil proteins and innate immunity, and is past editor-in-chief of Gastroenterology and immediate past president of the American Gastroenterological Association.
The Power List
Chris Porter Professor, Monash Institute of Pharmaceutical Sciences In 2009 Chris was awarded the American Association of Pharmaceutical Scientists Lipid Based Drug Delivery Outstanding Research Award. More recently, his interests have expanded into the mechanisms of cellular transport of lipophilic drugs and the potential utility of dendrimers as drug delivery systems.
G. V. Prasad Chief Executive Officer, Dr. Reddy’s Laboratories Prasad has spearheaded Dr. Reddy’s foray into biosimilars and differentiated formulation as the architect of the company’s global generics and API strategies. He received the 2009 Distinguished Alumnus Award from Purdue University and he was identified as a ‘Young Global Leader for 2007’ by the World Economic Forum.
Clive Roberts Guido Rasi Executive Director, European Medicines Agency Guido is serving his second term as Executive Director of the EMA, having served as the EMA’s Principal Adviser in Charge of Strategy between terms. He has previously worked as a physician and has published more than 100 scientific papers.
Robin Robinson Retired During his time in the pharma industry, Robin has developed patented platform vaccine technologies including virus-like particles and subunit protein vaccines for human pathogens. He recently retired from the position of Director of Biomedical Advanced Research and Development Authority; and Deputy Assistant Secretary for Preparedness & Response, at the US Department of Health and Human Services.
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Professor, School of Pharmacy, University of Nottingham “I have been fortunate to have been involved in a number of medicine development and spin-out projects, and to work with talented academic and industrial colleagues, most memorably to date in working with Marcus Brewster at Janssen on the formulation of Intelence (Etravirine) used in the treatment of HIV,” says Clive.
Ian C. Read Chairman of the Board and Chief Executive Officer, Pfizer Ian began his career with Pfizer in 1978 as an operational auditor. In 2000, he became Executive Vice President, Europe, and was then named a Corporate Vice President in 2001. He came to assume responsibility for Canada and Europe, and later for operations in both the Africa/Middle East region and Latin America. He is a past Chairman of the Board of PhRMA.
Tomasz Sablinski Co-Founder and Chief Executive Officer, Transparency Life Sciences Tomasz’s most satisfying achievement to date is the ongoing experience of building a clinical-stage drug development company based on a vision of patient-centric clinical trials that use crowdsourcing and 21st century technologies; with goals that include increasing the availability, affordability and utility of new medicines.
Charles L. Sawyers Chair of the Human Oncology and Pathogenesis Program at Memorial Sloan Kettering Cancer Center Charles Sawyers is past President of the American Association for Cancer Research. He serves on the National Cancer Institute's Board of Scientific Counselors and his research focuses on the signaling pathways that drive the growth of cancer cells. www.themedicinemaker.com
Andreas Seidel-Morgenstern Director, Department of Physical and Chemical Foundation of Process Engineering, Max Planck Institute for Dynamics of Complex Technical Systems Andreas’ research focuses on developing concepts to better link the various steps involved in drug production. “Recently, we’ve worked on developing continuous processes combined with chemical synthesis and purification steps,” he says. “We would like to extend this concept by including, as a first step, the extraction of natural products.”
George Scangos
Dolores Schendel Chief Executive Officer, Medigene AG
Chief Executive Officer, Biogen Idec George’s claim to fame is that he created the first transgenic mouse as a young postdoc. Before joining Bayer in 1987, George was a professor of biology at Johns Hopkins University for six years, where he is still an adjunct professor. In March 2016, he was elected Chairman of the Board of Pharmaceutical Research and Manufacturers of America (PhRMA).
Dolores has been a member of the German Research Foundation, German Cancer Aid and the European Research Council. She joined Medigene in 2014, when the company acquired Trianta Immunotherapy. She claims to be passionate about bringing individualized immunotherapies from bench to bed-side by moving herself and her team from in-depth research to the forefront of the biotech industry.
Joseph Schlessinger William H. Prusoff Professor and Chairman of the Pharmacology Department, Yale School of Medicine; Director, Yale Cancer Biology Institute “The focus of my research during the past 12 months has been the identification of the ligand for the orphan receptor tyrosine kinase (RTK) ALK, and elucidation of the mechanism of action of a therapeutic antibody using structural and biochemical studies, as well as exploration of signaling pathways that are aberrantly activated by oncogenic RTKs in cancer,” says Joseph.
Severin Schwan
Andy Skibo
Chief Executive Officer, Roche Group
Head of Global Biologics Operations and Global Engineering at AstraZeneca/ MedImmune
After completing his studies at the University of Innsbruck in Austria, Severin Schwan joined the Roche Group in 1993 as a trainee in corporate finance. Thirteen years later, he was appointed CEO of Roche’s Diagnostics Division and in 2008 he became CEO of the Roche Group.
Andy is a past Chair of the International Society for Pharmaceutical Engineering. He considers his proudest achievement to be helping launch at least four new medicines. “Nothing gives you a greater sense of why we’re in this industry,” he says. “At Genentech, they used to hand out flags on launch day and I still have every single one.”
Manish Soman President and Chief Executive Officer, Sciformix
Moncef Slaoui Chairman of Vaccines, GlaxoSmithKline Moncef was professor of immunology at the University of Mons, Belgium before his move into industry. He has published more than 100 scientific papers and is a member of the PhRMA Foundation Board of Directors. Moncef has been at the helm of GSK’s global vaccines business through its integration of the Novartis vaccine acquisition in 2015.
“It is an honor and very humbling to again be selected among such elite company,” says Manish. “It gives all the people on the list further motivation to take steps to boost the pharmaceutical industry, formulate long term solutions to industry problems, and find smarter and sustainable ways to innovate, grow and contribute to the enhancement of healthcare products and services worldwide.”
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Abbe Steele Lars Rebien Sørensen
Founder and Chief Executive Officer, HealthiVibe
President and Chief Executive Officer, Novo Nordisk A/S
Pascal Soriot
Lars Rebien Sørensen joined Novo Nordisk’s Enzymes Marketing in 1982 and in May 1994 he was appointed a member of Corporate Management. Seven months later, he was given special responsibility within Corporate Management for Health Care. He was appointed president and CEO in November 2000.
While at Roche, Soriot was in charge of integrating Genentech, the Californian biotech company, after a $47 billion takeover. He also led AstraZenica in a successful defense against acquisition by Pfizer in 2014 – a feat few envisaged before he took the reins. Soriot worked as a vet before embarking on his career in business.
Nigel Theobald Founder and Chief Executive Officer, N4 Pharma “For a small company to be recognized, and for me to receive a nomination for 2 years running, is a great achievement and only the start of things to come,” says Nigel. “As we bring our skills to play for a host of drugs and vaccines, I hope we will continue to feature prominently with such industry wide recognition.”
Bernhardt Trout Raymond F. Baddour, ScD, (1949) Professor of Chemical Engineering, Massachusetts Institute of Technology Bernhardt’s laboratory focuses on the development and application of molecular based computational and theoretical methods for the design of chemical systems and processes. He is also Director of the Novartis-MIT Center for Continuous Manufacturing, which develops new technologies to replace traditional batchbased processes.
Executive Director and Chief Executive Officer, AstraZeneca
Abbe was featured on last year’s Power List because of her work in patient-centric clinical trials. Over the past year, she’s been working on clinical trial simulations, where patients participate in a mock study setting to help sponsors gain patient insights into the impact of trial design and study requirements, and determine if these would hinder patient participation and compliance with the protocol.
Martin Tolar Founder, President and Chief Executive Officer, Alzheon During his academic career, Martin served as an Assistant Professor in the Department of Neurology at Yale University School of Medicine from 1992 to 1997, where he focused on movement disorders. Since then he has served as head of business development at Pfizer and more recently founded Alzheon, a clinicalstage biopharmaceutical company focused on brain health, memory and aging.
Timothy Wright Executive Vice President, Translational Sciences, Calibr Timothy began his career in academia and worked his way up to Chief of the Division of Rheumatology and Clinical Immunology at the University of Pittsburgh – and was awarded an endowed Professorship in 1998. He has previously worked in clinical development at Pfizer and Novartis, and also serves as a scientific advisor to several organizations, including the Bill and Melinda Gates Foundation.
Vikramaditya G. Yadav Assistant Professor, Department of Chemical and Biological Engineering, The University of British Columbia ‘Biosynthonics’ – a novel paradigm for discovering and synthesizing potent bioactive molecules – is a focus of Vikramaditya G. Yadav’s research group. The group also focuses on formulation and assembly of drugs and their translation to certain pathological conditions. www.themedicinemaker.com
18 Bill Lundberg
20 Ibraheem “Ibs” Mahmood
19 Rino Rappuoli
President and Chief Executive Officer, DrugDev
Chief Scientist and Head of External R&D, GSK Vaccines
Ibs hopes to make clinical trials faster, smarter and more efficient. DrugDev was recently chosen to develop and host the Investigator Databank, a global collaboration involving several large pharma companies. Ibs also co-founded the DrugDev Innovation Lab, a technology incubator to identify and develop innovative clinical solutions.
Rino is the author of over 600 research papers and has introduced a number of novel scientific concepts, with widespread impact on the vaccines industry, including genetic detoxification (1987), cellular microbiology (1996), reverse vaccinology (2000), and the pangenome (2005). Rino is the former Global Head of R&D at Novartis Vaccines.
Bill has extensive experience across all aspects and phases of drug development in both academic and industry settings. He was previously vice president and head of translational medicine at Alexion Pharmaceuticals, where he oversaw the progression of numerous compounds from early research to clinical proof-of-concept. Before that, Bill held senior positions at Taligen, Antisoma, Xanthus Wyeth and Genzyme.
16 Keith Thompson
15 J. Craig Venter
Chief Scientific Officer, Euclises Pharmaceuticals
Chief Executive, Cell and Gene Therapy Catapult
Founder, Chairman and Chief Executive Officer of the J. Craig Venter Institute
John is a co-inventor of eight marketed drugs, with several still in development, and has been honored with the PhRMA Discoverers Award. This past year, John has been working on the role of prostaglandins on immune surveillance in tumor micro-environment. “I am genuinely delighted to be chosen for the Power List for a second time,” he says.
Keith established a team of over 100 cell and gene therapy experts in laboratories in London and is now building a large-scale manufacturing center. Keith joined the Cell and Gene Therapy Catapult from the Scottish Blood Transfusion Service where he was National Director, focused on modernizing the blood supply from vein-tovein and expanding into cell and gene therapy.
John Craig Venter has made significant contributions to genomic research and his team has sequenced hundreds of genomes. He’s authored more than 280 research papers on subjects such as environmental genomics, the first complete diploid human genome, and the creation of the first self-replicating bacterial cell constructed entirely with synthetic DNA.
17 John Talley
Chief Scientific Officer, CRISPR Therapeutics
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14 Gert Riethmueller Professor Emeritus of Immunology, Ludwig-Maximillian University of Munich Gert is a prolific researcher with a strong interest in autoimmune diseases and cancer. He is considered a pioneer in tumor immunology and was one of the first to introduce monoclonal antibodies and immune cells into medical practice. In 1994, he published a landmark clinical study in The Lancet on the treatment of metastatic colon carcinoma, which led to the approval of the world’s first monoclonal cancer antibody (17-1A).
13 Martin Van Trieste Senior Vice President of Quality, Amgen A judge praised Martin for his quality leadership in biologics, and more widely he is known throughout industry for his work on advancing quality assurance and helping to ensure a more reliable supply of high-quality medicines. At Amgen, Martin is responsible for aspects such as quality assurance, quality control, compliance and operational excellence, but he is also actively involved with trade organizations including, but not limited to, the United States Pharmacopeia, Pharmaceutical Manufacturers and Researchers of America, and the Pharmaceutical Quality Research institute. He is a founder of Rx-360 – and remains a board member today.
11 Peter Seeberger
12 Shinya Yamanaka Director and Professor, Center for iPS Cell Research and Application (CiRA), Kyoto University Another returnee from last year’s Power List; Shinya has stormed into the top 20 for his work in stem cells. After reprogramming adult mouse (2006) and human (2007) somatic cells into what are now called induced pluripotent stem (iPS) cells, he was awarded a 2012 Nobel Prize. In the past year, Shinya has been working on an iPSC stock project in which iPSC clones are established from donors with a homologous HLA haplotype. “Homologous HLA lessens the risk of transplant rejection and promises quality-assured iPSCs for future cell therapies,” says Shinya. “We started distributing iPSC stock clones to corporate and medical institutions last year.”
Director at the Max-Planck Institute for Colloids and Interfaces, and Professor, Free University of Berlin Peter’s research covers a broad range of topics from engineering to immunology, and has been documented in over 420 peer-reviewed journal articles, more than 40 patents, and more than 750 invited lectures. His work on continuous chemistry, which he hopes will make drugs against malaria and HIV more affordable, won him and his collaborator, Andreas Seidel-Morgenstern, the 2015 Humanity in Science Award. “It’s motivating to be able to appear on this list twice!” says Peter. “Since the last list, we’ve had two big breakthroughs: the proof-of-principle for an expanded synthetic vaccine against S. pneumoniae and the development of a continuous process to produce the most important HIV medication. We are also about to submit several manuscripts describing vaccine candidates against dangerous hospital acquired infections.” www.themedicinemaker.com
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The Power List
10 Kiran Mazumdar-Shaw Chairperson and Managing Director of Biocon From a tiny start-up company launched in 1978 with seed funds of Rs 10,000 and run from her garage, Kiran Mazumdar-Shaw has grown Biocon into a leading producer of generics, floated on the stock market in 2004 with a valuation of $1.1 billion. And Kiran has no plans to slow down– aiming to bring revenue up to the $1 billion mark by 2018. She is also known for her philanthropic work, through the Biocon Foundation, which provides healthcare for marginalized communities.
9 Robert A. Bradway Chairman and Chief Executive Officer, Amgen In 2006, Robert joined Amgen as Vice President, Operations Strategy. He was appointed to the Amgen Board of Directors in October 2011, and became Chairman in January 2013 and CEO in May 2012. Before Amgen, he was a managing director at Morgan Stanley in London where he had responsibility for the firm’s banking department and corporate finance activities in Europe.
8 Carol Lynch
7 Thomas Cech
Global Head of Biopharmaceuticals & Oncology Injectables, Sandoz
Distinguished Professor, University of Colorado Boulder
Judges praised Carol for her role in the biosimilars industry and in the launch of the first US biosimilar. She joined Sandoz in 2014 and is focused on leading efforts in the development, manufacture and commercialization of biosimilars and oncology injectables. In February 2016, she was elected as Chair of the European Generic Medicines Association’s European Biosimilars Group, where she will be working to improve stakeholder awareness and understanding of, and confidence in biosimilars and advocating for policies that support the growth of the biosimilars industry.
Thomas holds multiple roles. He is a scientist with the Howard Hughes Medical Institute, and also a Distinguished Professor at the University of Colorado and Director of the university’s BioFrontiers Institute. His research speciality is RNA – specifically the structure and mechanism of long noncoding RNAs and RNA-protein complexes – and he shared a Nobel Prize in Chemistry for the discovery of the catalytic properties of RNA in 1989. A more recent achievement is his induction to the 2016 class of Fellows of the American Association for Cancer Research.
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4 Raman Singh President, Mundipharma Asia Pacific, Latin America, Middle East and Africa
6 Anthony Fauci Director, US National Institute of Allergy and Infectious Diseases (NIAID) Anthony Fauci has been vocal on the challenges of important global health issues, including Ebola and Zika, and he has been instrumental in US efforts to tackle these outbreaks and to quell public panic. Despite his heavy workload, Fauci is also known for donning hazmat suits to directly work with US Ebola patients. He is also one of the most prolific researchers of this century; in a 2016 analysis of Google Scholar citations, he ranked as the 18th most highly cited researcher of all time.
During his career, Raman has worked in many markets including Thailand, Singapore, South Korea, Australia, the US and the UK. He has been in his current role since October 2011, where he oversees all aspects of the Mundipharma business across his territories, which operate as a network of independent companies. “It’s been a fascinating opportunity to change the way a company is looked at as a business. When I started in 2011, the emerging markets contributed to less than one percent in terms of global turnover. Now, we’re close to 14 percent – and we’re aiming for around 30 by 2017,” he says. Prior to Mundipharma, Raman was the Vice President of Commercial Operations for Emerging Markets at GlaxoSmithKline.
5 David Baltimore President Emeritus and Robert Andrews Millikan Professor of Biology, California Institute of Technology David Baltimore’s love for experimental science was born after spending a summer at the Jackson Laboratory in 1955. And since then his achievements have been numerous, including a Nobel Prize in 1970 for the discovery of reverse transcriptase, which implied that cancer could be caused by genetic means, which was a wide-open question at the time. Today, his laboratory at Caltech focuses on the basic investigation of the development and functioning of the mammalian immune system, as well as translational studies using viral vectors. www.themedicinemaker.com
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The Power List
2 Catherine Tuleu Reader, University College London School of Pharmacy
3 Harold Varmus Lewis Thomas University Professor, Weill Cornell Medical College Harold Varmus originally obtained a degree in English literature – with a desire to be a writer – before deciding to pursue a career in medicine. He worked at a missionary hospital in India and then turned his attention to research – and has since been involved in numerous groundbreaking discoveries connected to cancer. In 1989, he was the co-winner of a Nobel Prize (alongside Michael Bishop) for the discovery of the cellular origin of retroviral oncogenes – how malignant tumors are formed from normal cells. As well as his research accomplishments, Harold has held a number of high-level positions. From 1993 to 1999, he was director of the US National Institutes of Health (NIH) where, among other achievements, he was involved in establishing PubMed Central in order to enhance access to scientific papers through the Internet. Since leaving NIH, he has been president of Memorial Sloan-Kettering Cancer Center in New York, a co-chair of President Obama’s Council of Advisors on Science and Technology, and director of the US National Cancer Institute, a post he held until March 2015. In April 2015, Harold took up his role at the Weill Cornell Medical College faculty. He is also a Senior Associate Core Member at the New York Genome Center where he promotes the use of cancer genomics throughout the New York region.
Catherine was featured in the 2015 Power List, but this year she has stormed her way into the top two. Catherine is a UK-qualified French pharmacist and her first experience of University College London (UCL; The School of Pharmacy, University of London until 2012) was as a postdoc student, and then a research assistant in the Department of Pharmaceutics with Professor Michael Newton. After a stint as a lecturer at Kingston University, she returned to UCL in January 2003 as Pfizer Paediatric Drug Delivery Lecturer for the then newly established Centre for Pediatric Pharmacy Research, of which she is now director. She was promoted to reader in 2011. Catherine has traditionally been interested in gastrointestinal drug delivery, particularly colonic targeting, but since 2003 her main focus of research has been on drug delivery systems for neonates, infants and children. “In the last year, my research has focused on the most challenging pediatric subset: neonates – with a focus on those in low resource settings, as well as formulating for rare and neglected diseases,” says Catherine. She has been involved in various projects ranging from repurposing drugs, designing fast disintegrating tablets for a nipple shield to dose babies while breastfeeding, to exploring the rectal route of drug delivery, and gaining knowledge on the acceptability of flexible solid oral dosage forms, such as multiparticulates. She has also been working on establishing methods to assess the taste of medicines in vitro. As well as her work at UCL, Catherine is involved in a number of paediatric initiatives; she leads the European Paediatric Formulation Initiative, and is an external technical expert on pediatric formulations for EMA, the UK’s MHRA and WHO. She is a partner in the FP 7 funded network of excellence Global Research in Paediatrics (GRiP).
1 Heather Bresch Chief Executive Officer and Executive Director, Mylan Heather has spent her entire pharma career at Mylan. She became CEO and Executive Director of Mylan in January 2012, but her first job at the company in the 1990s was anything but glamourous – she was first employed as a data-entry clerk, tasked with typing out labels. Over the years, she moved onto other departments within the company and eventually stepped up to executive roles, including Senior Vice President of Corporate Strategic Development, Head of North American Operations, Chief Operating Officer and Chief Integration Officer, where she led the integration of Matrix Laboratories and Merck KGaA following acquisitions. Her appointment to CEO was announced in 2011 and she is one of the first women to take the reins of a western pharma company. Her goals as CEO are to double the size of Mylan’s product portfolio, manufacturing capacity and earnings by 2018. Heather has been included in Fortune magazine’s annual 50 Most Powerful Women in Business list since 2012.
Contributions to industry & healthcare • Contributed to the development of the 2003 Medicare Prescription Drug, Improvement, and Modernization Act. • A strong advocate for the Generic Drug User Fee Amendments. • Actively involved in the Generic Pharmaceutical Association (GPhA) – in February 2016 she was elected to serve as chair of GPhA’s board of directors; she previously served two one-year terms as the chair of the association in 2004 and 2005, and two one-year terms as vice chair in 2003 and 2006. • Championed initiatives to raise awareness of anaphylaxis, particularly in schools. • Championed initiatives to give patients in developing countries greater access to HIV medicines.
Judge’s comment: “Mylan and Heather Bresch have been involved in a lot of drama in the past 12 months, including fighting a hostile takeover bid from Teva and then failing to acquire Perrigo in Mylan’s own hostile takeover attempt, but she is also undoubtedly a powerful leader and has greatly influenced the generic drug industry, among other things.” www.themedicinemaker.com
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T h e M e d i c in e M ake r × C a t al e n t A p p lie d D r u g D eli ve r y I ns t i tu te
More Trial, Less Error The pressure for increased efficiency pervades the pharma industry, including the clinical trials sector, where traditional supply models can lead to overstocking, waste and higher costs. Is there a more effective supply strategy? The traditional approach to clinical trials’ supplies involves a centralized supply model, whereby primary packed materials are stored in bulk at a central warehouse and labeled with multilingual booklets, allowing central stock to be shipped to any site, regardless of local language. It’s a well-used model that appears to make sense. But does it? Wetteny Joseph and Stephen Flaherty have both been instrumental in building Catalent’s clinical supply services. Joseph is President of Clinical Supply Services, but originally started out by working in the finance sector before transitioning to clinical supplies and using his experience to examine the cost drivers in the industry. Flaherty, on the other hand, has been leading the development of Catalent’s demand-led supply offering, which both he and Joseph believe is a far more flexible approach to clinical trials. Trials and tribulations There are many problems with a centralized supply model, most of which are caused by its inherent inflexibility. Supplies are sent to sites based on preliminary forecasts and planned recruitment at the start of the program. “This model is very static and linear – and tends to require long lead times in order to generate the batches and the unique labeling information, as
well as to stockpile the finished patient kits,” says Joseph. “It is also industry practice to overshoot expected targets – often by 200 percent or more – which generates waste of both the product being trialed, and also the comparator products.” But the opposite can also happen in that demand may turn out to be far higher than expected, which can lead to stock outs, putting patients or the whole study at risk depending on the severity of the delay. Another big challenge comes with changes. Indeed, the inflexibility of the traditional system hinders one’s ability to modify the trial design in response to early data. There are also added difficulties when attempting to modify the trial design, such as the addition of new countries or territories. It’s clearly not the most efficient method and, as Joseph adds, an inefficient supply chain “exponentially increases the cost of running trials”. Even the multilingual booklets themselves are a problem; not only can there be delays in getting the text approved (and a delay from one country will delay all of the booklets) but, from a usability point of view, it can also make it awkward for patients to find the relevant information. Tradition on trial: the DLS approach A few alternatives to centralized supply have emerged in recent years, including the ‘Just in Time’ model. “In reality, this is just an enhancement on the traditional model whereby stocks of partially finished patient kits are labeled and held at central depots, but there’s some customization that happens just before shipment, such as adding an investigator name. It still has some of the drawbacks of the traditional model in that you need to build up bulk supplies,” says Flaherty. Instead, Catalent is developing a demand-led supply (DLS) approach, which is a decentralized approach to clinical supply. “It’s fast and efficient.
Instead of pushing out large batches of packaged patient kits to clinics based on preliminary estimates, a continuous flow of kits is generated and they are only sent out in accordance with patient demand,” says Joseph. Reg iona l GM P fac i l it ies eac h hold small stocks of primary packed material, or “bright stock”, which are then secondary packaged, labeled and released only in response to specific requests from clinical sites, allowing companies to adapt to slower or faster recruitment in different countries. Since the bright stock is locally held prior to labeling, shipping times also tend to be faster and clinical sites can receive their supplies in a matter of a few days.
“A fixed model costs more than a demand-led system because it’s so wasteful.” One might think that a central supply model would save costs due to its fixed, predicted demand and budget, but this isn’t actually the case. “A fixed model costs more than a demand-led system because it’s so wasteful,” says Joseph. “In the traditional model, patient kits are distributed to clinical sites based on recruitment forecasts, but we all know that patient recruitment is unpredictable, so stock often goes unused. And, as already indicated, there are also extra costs and time delays if anything needs to change.” Furthermore, DLS eliminates the need for a multilingual booklet, which
T h e M e d i c in e M ake r × C a t al e n t A p p lie d D r u g D eli ve r y I ns t i tu te
39
Catalent Clinical Trial Supplies Under the Lens
... that’s a total of over
5 million countries receive
200,000 clinical trial supply shipments every year
is replaced with single panel labels. “Each label can be patient- and countryspecific, so it’s much easier for patients and clinic staff to use rather than finding the right page in a thick booklet,” says Flaherty. “As soon as you have a label approved for a given country, you could supply to that country, without the need to wait for the final, approved label text from the other countries within a booklet, which can be a bottleneck and delay start up of a trial.’’ Another aspect of improved efficiency associated with DLS is the ability to pool supplies. “With the bright stock
... which equals more than
15 kits
shipped every minute
... that’s a new trial every
5 HOURS staged at regional facilities, you can use it across multiple protocols because you’re only secondary packaging and labeling it when the demand arises,” says Flaherty. “Also, the flexibility of DLS permits items with the shortest expiry time to be used first; thus, with DLS, efficiency is increased, enabling material with varying expiry dates to be used much more effectively.” DLS is a relatively new model of supplying clinical trials, but both Joseph and Flaherty are positive that it is an innovation genuinely needed by the industry in order to meet the challenges of
Catalent have supplied over
5,000 clinical trial studies in the past
3
years alone
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today’s complex and far more sophisticated clinical trials. So far, it’s drawn a lot of interest because of its flexibility and speed, and the fact that it can be used for virtually any study, so Joseph and Flaherty are also positive about the future. “Importantly, I think DLS also reflects the growing importance of the ‘voice of the patient’ in the pharma industry,” says Joseph. “We need to meet the needs of individual patients, including ensuring that they are not inconvenienced or placed at risk when patient kits are not supplied on time. DLS allows this – it’s a win for the patient, not just for the industry.” www.themedicinemaker.com
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Best Practice Technology Quality Compliance
42-45 Beyond Keeping Up Appearances Manufacturers often ask if they need to coat their tablets or not. Coated tablets certainly look nicer than their uncoated counterparts, but is that all there is to it?
42
Best Practice
Beyond Keeping Up Appearances You have the perfect drug and the right packaging to protect it. All is well until the medication reaches the patient, who habitually pops the tablets into another container for easy storage or leaves them exposed to the atmosphere. Film coatings are more than just a pretty face. By Charlotte Miller Film coating is a well-established technique in the pharma industry for solid oral dosage forms, like tablets and
multiparticulates, but its usage varies. Most tablet manufacturers choose to film coat every product, whereas others will only apply a coating if they feel that it is essential. The most popular reason for applying a film coating is to enhance and protect the dosage form, provide branding or modify the drug release profile. For example, enteric coatings can be used to protect a tablet from dissolution in the stomach, or extended release coatings can (as the name suggests) provide drug release over an extended period of time. The film coating process is a proven and well-used practice, whether using a company’s own equipment or through a contract manufacturer. A variety of different coatings are available and, generally speaking, most coatings work in the majority of standard coating machines; so once you’ve invested in the process for
one product it’s easy enough to use it to coat another. However, if you have a drug in a solid dosage form that does not require a specialized coating then an obvious question is, should you coat or not? Creating the perfect finish … It seems reasonable to assume that choosing not to film coat a tablet will save money, but I believe this is a misconception when the multiple benefits of coating are considered, alongside the fact that the cost per tablet is tiny. An uncoated tablet can still be therapeutically effective – but only if the patient takes it. Tablet design is becoming an increasingly important issue for manufacturers, especially given that polypharmacy, the practice of prescribing multiple medications to the same patient,
Best Practice
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“The FDA, in particular, has been paying a lot of attention to tablet design...” is becoming more common among the elderly population. Good design can be used to provide product differentiation, avoid medication mix-ups and deter counterfeiting (1). It can also affect patient compliance. When looking at a tablet, you need to ask if patients will want to take it. The FDA, in particular, has been paying a lot of attention to tablet design – and has just recently (April 2016) issued guidance on Safety Considerations for Product Design to Minimize Medication Errors (2), in addition to earlier draft guidance on Size, Shape, and Other Physical Attributes of Generic Tablets and Capsules (2014). One good reason to add a coating to a previously uncoated tablet would be to improve patient compliance through brand identification and to bring the tablet into line with the FDA’s current recommendations. Purely from an aesthetic point of view, uncoated tablets are uninspiring. In addition, an especially rough-looking tablet can appear as poor quality; it’s human nature to question the condition of something with a poor appearance, especially a medicine. Some uncoated tablets also have a surprisingly bad odor. Any negative aspect of a medicine can affect patient compliance – if the patient has a poor impression of their medicine the moment they take it out of the packaging, it could be destined for failure simply because the patient doesn’t take it as prescribed. Moreover, if patients do get beyond the
Myth Busting “A coating will impact my drug release profile.” Immediate release coatings do not impact drug release; there are specific coatings formulated to extend or delay drug release and coatings can also be applied to multiparticulate dosage forms. “A coating might not work with my equipment.” Optimization of the process is key, as the best coatings will work across a range of equipment and coating specialists work closely with machine manufacturers. After all, it’s pointless to develop a coating that only works on one machine. If there are mechanical problems, they can usually be resolved easily. “I don’t want to use organic solvents.” There are two types of coating – aqueous and organic, the latter involves use of volatile solvents, and historically, many tablets were coated using organic solvent, due to their sensitivity to water. But coatings have advanced so much that aqueous is now the preferred – and most common – coating method around the world. Many companies
that previously used solvent coating are transitioning the same products to aqueous coatings. “I’m concerned that pigmented coatings will lead to regulatory issues.” Ye s , t here a re reg u l at ions for ingredients that mean certain pigments may not be approved for use in all markets, and there may be aversions to some colors in certain markets. Nevertheless, there are palettes of colors that are acceptable for use in the major international markets – and expert coating suppliers should be able to advise on these. “My product cannot be coated.” Great! Because coating specialists love a challenge! And most have some special skills up their sleeves to demonstrate that the seemingly “impossible to coat” can indeed be coated. Even tablets that are highly sensitive to water can be coated (it’s even possible to coat orally dispersible tablets that disintegrate in seconds). Some tricky products may be more testing to coat and the biggest challenge would be an API that is sensitive to both temperature and water. www.themedicinemaker.com
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Best Practice
Coat of Regulations By Kevin Hughes, Regulatory Affairs Manager, Colorcon Back in the 1950s and 1960s, before the advent of film coatings, sugar coatings were widely used on pharmaceuticals. A small number of companies still use sugar coating, but for the most part film coating is the most widely used process today. Film coatings continue to advance, so even if a tablet could not previously be coated, it does not mean that it cannot be coated today. In addition, there is potential for improving tablets that currently use an older technology coating. Some companies have concerns about changing a coating due to the regulatory impact. But from a regulatory standpoint, changing a cosmetic coat is relatively simple since it’s not expected to impact drug release. For example, changing a white coated tablet to a red color coated tablet is seen as a Type 1A variation in Europe. This is a minor change; drug companies make these changes all the time and can even bundle up all of their Type 1A and 1B changes together in one submission.
aesthetics and the smell, they often find that uncoated tablets are more difficult to swallow. They can be chalky or gritty, and may stick in the throat because they start to disintegrate the moment they are exposed to moisture. A film coating gives the tablet a smoother, more finished appearance and helps maintain the tablet integrity. As human beings, we tend to perceive glossier things as being more slippery and therefore easier to swallow – and adding a coating is known to enhance swallowability and aid oesophageal transit; in contrast, uncoated
Some uncoated tablets have been on the market for a long time, and I’ve seen companies add a coating to a previously uncoated tablet to improve the product’s position in the market and present a stronger brand identity. This is a bigger regulatory change than changing a coated tablet, because you are adding a new component rather than changing one component to another. There needs to be some stability work, which any company would want to do anyway, and you will need to assess the impact on drug release both in vitro and, in rare cases, in vivo. However, you may encounter more hurdles for BCS Class 2 and 4 drugs due to their poor solubility and permeability (the BCS classification system categorizes dr ugs based upon their solubility and intestinal permeability, i.e., how easy it is for them to be absorbed by the body) and you may require a Type 2 variation, which will involve bioequivalence work. Companies usually try to avoid this due to the work involved, but for some drug substances there are options you can explore to keep the changes as 1B. For example, you may
tablets and even capsules are more likely to become stuck (3,4). And though there are a few approaches that can be used to make an uncoated tablet more palatable (for example, adding color, taste masking ingredients or changing the shape to make swallowing a little easier), generally speaking, your options are more limited compared to simply adding a film coating. Film coatings give you access to not only a wide range of colors, but also to other useful functionalities. Most coatings offer some sort of taste- and odor-masking
be able to achieve a bio-waiver for BCS class 1 and 3 drug substances, if you can justify that demonstrating bioequivalence is unnecessary. In general, regulators like to see changes that improve product quality and patient compliance. There will always be a workload and a cost to making a variation – but isn’t that what regulatory departments are for?
ability, but some are better than others. A particularly pungent odor may start to come through the coating with time, in which case a coating that has been specifically designed to conceal odor may be needed. Contingency coating Aside from maintaining appearances, film coatings offer protection, helping to prevent tablet breakage and acting as a barrier against moisture and other environmental conditions. The protective aspect is a well-known benefit – but is
Best Practice
it needed if you are planning on highquality packaging? A common reason cited by manufacturers not to film coat their tablets is a belief that packaging alone will suffice. After all, if you are using individual blister packs, then why go the extra mile (or spend the associated extra costs) by coating individual tablets? The truth is, once a package is in the hands of a patient, anything can happen! Many patients, especially those taking multiple medications, decant their tablets into tablet boxes or bottles, and others may just take a tablet out of the blister pack as a reminder and leave it on their bedside table all day. Most people assume that a given drug will do its job 100 percent of the time – and give less thought to the storage conditions of medicines than they do to food. It’s surprising how many people keep medicines in a nice moist bathroom cupboard; although it may not directly affect the safety of the medication, it could reduce its efficacy. Safety at work We’ve examined the impact that coated tablets have on patients – and that is typically the first consideration that springs to mind. But from the manufacturer’s perspective, a key consideration for film coating is safety. Once a tablet is coated, it’s safer for anyone else who might handle it. Nurses and healthcare workers often handle bulk or unpackaged tablets and although they are supposed to wear gloves, it’s not guaranteed. Absorption of active ingredients, through the skin can cause rashes or other problems. Extreme cases are rare, but if the tablet was coated, then the risk is diminished. Of course, you could also make uncoated tablets safer by educating people about proper storage and handling of medicines (no easy task), but the health hazards of uncoated tablets also apply to pharma workers, particularly those on the packing lines. If you’ve ever worked on (or visited) a packing line with uncoated tablets
then you’ll know it’s a challenging environment. Cleaning is a significant part of pharmaceutical manufacturing to prevent cross-contamination. In the case of uncoated tablets, dust is generated as the tablets move through the manufacturing lines, which necessitates extensive cleaning.
“There are a number of approved tablets on the market that are currently uncoated because of limitations during the time they were approved. ” Coating a tablet adds minimal cost, and the financials are offset by savings that can be attributed to the coating benefits throughout the production line. Coated tablets reduce dust, so your cleaning burden will be lower and workers better protected. Another side benefit is that glossy, coated tablets also tend to run faster through packaging lines because they are more slippery than uncoated tablets. And reject rates can also be down because the tablets are less likely to break (5). Is it possible to be uncoated I’ve focused on all of the reasons why I think it makes sense to coat. Are there any reasons not to coat your tablet? I hear a few common reasons (see sidebar: Myth Busting), but I’m always interested
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in new ones! It’s fair to say that genuine reasons not to coat are rare. All coatings, regardless of functionality, will improve the tablet appearance at the very least. And good tablet design is no longer simply ‘nice to have’. The FDA’s recently published guidance continues to drive manufacturers to pay more attention to tablet design and differentiation. We now see most new tablets being film coated; virtually all NDAs are coated. But you don’t need to stop at new tablets – there are a huge number of approved tablets on the market that are currently uncoated because of limitations during the time they were approved. Most companies don’t like to make changes to already-approved medicines because of regulations, but it’s not as difficult as you might think (see Coat of Regulations). Giving an old tablet a fresh coat can grant it a new lease of life and, more importantly, it can improve patient compliance as well as add brand value. And patient safety should always be at the top of the agenda. Charlotte Miller is a Tablet Design Technologist, BEST – Unique Tablet Design Service – at Colorcon, Dartford, UK. References
1. C. Miller, “Dare to be Different,”
The Medicine Maker (February, 2015).
2. FDA Guidance for Industry, “Safety
Considerations for Product Design to Minimize Medication Errors,” (April, 2016). http://1.usa.gov/1SMyvSN
3. C. Wilson et al., “Opadry II / Opadry / Opaglos 2”, poster presented at AAPS, Salt Lake City (23- 26 October 2003).
4. The Patients Association, “Survey of Medicines Related Care of Residents with Dysphagia in Care Homes,” (October, 2015). http://bit.ly/1N8nyOQ
5. Colorcon, Application Data, “Investigation into the Flow Properties of Coated and Uncoated Tablets and Its Relevance to Blister Packing Efficiency,” (2009). http://bit.ly/25ZGhCv
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Waseem Asghar
Meet the Winner Waseem Asghar
Could it be you in 2017?
Waseem Asghar, Assistant Professor at the Departments of Computer Engineering & Electrical Engineering, Computer Science, and Biological Sciences, Florida Atlantic University, USA, has been chosen as the winner of the 2016 Humanity in Science Award for “development of a new paper and flexible material-based diagnostic biosensing platform that could be used to remotely detect and determine treatment options for HIV, E. coli, Staphylococcus aureus and other pathogens.”
Analytical science has been at the heart of many scientific breakthroughs that have helped to improve people’s lives worldwide. And yet analytical scientists rarely receive fanfare for their humble but lifechanging work. The Humanity in Science Award was launched to recognize and reward analytical scientists who are changing lives for the better.
Waseem will be presented with a humble prize of $25,000 during an all-expenses-paid trip to Analytica 2016 in Munich, and his work will feature in an upcoming issue of The Analytical Scientist.
Has your own work had a positive impact on people’s health and wellbeing? Details of the 2017 Humanity in Science Award will be announced soon.
@Humanityaward
www.humanityinscienceaward.com
Humanity in Science Award
Business Economic drivers Emerging trends Business strategies
48-49 Making Small Biotech Work How can small companies convince investors to fund promising compounds? By having a solid regulatory strategy, according to Bruno Speder.
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B usin e s s
Making Small Biotech Work Innovation is increasingly coming from small biotechs, but such companies rely on external funding to develop the compounds. A solid regulatory strategy is essential to convince investors to fund the further development. By Bruno Speder Histor ica l ly, it ’s been the la rge pharmaceutical companies who have been able to bring treatments to the market but in the 1990s, industry started to see a rise in the number of marketing authorization applications coming from sma l ler companies (particularly biotechs). During this era, it was traditional for a company to work alone in taking its compound all the way from research to approval, but this has changed in the past years. Pipelines have dwindled and drug development costs have risen sharply; in the 1950s, you could put around 50 drugs on the market with $1 billion in R&D spending. Today, $1 billion isn’t enough to get even one drug on the market (1) – see Figure 1. Since 2000, there has been a big increase in the number of industry acquisitions, licensing deals and other commercial partnerships. Big pharma companies still have their own internally generated R&D projects, but they are also increasingly relying on innovation from biotech companies – and, in fact, in several pharma companies, a large part of the pipeline consists of compounds that have been acquired from small companies or biotechs. Today’s huge drug development costs mean that it is difficult for small
“Thinking about all of this early on will help to optimize your development.” companies to take a drug through to marketing authorization approval without obtaining external funding. Unfortunately, big pharma companies aren’t look ing for compounds in preclinical testing; in general, it is expected that the biotech will already have taken the compound through clinical proof of concept – which still involves a lot of work and cost. Biotechs can often get funding for promising compounds through venture capitalists, but again investors prefer to have proof of concept data. Settling on a strategy Implementing a regulatory strategy to help ensure that a drug in development meets the f inal specif ications for approval is critical. But given that most small companies have their eyes on
obtaining proof of concept and reaching phase II, is a regulatory strategy still needed? The answer is def initely “yes”. With big pharma and investors becoming increasingly cautious – and the biotech world becoming more competitive – small companies need to be more strategic than ever before, and early regulatory due diligence is a must. Even if a small company is intending to sell a compound rather than taking it to marketing authorization approval personally, they must be able to demonstrate that the compound is as promising as possible to clinch the deal (and to get the best possible price). The same is true if you’re looking for investment – investors want to know that the compound is approvable. For the inexperienced company (and even the experienced company), developing a regulatory strategy can be riddled with pitfalls. The most important aspect is to remain aware of the long term goals and to have a clear picture of where you want to go with you compound. A target product profile (TPP) is an excellent tool to base yourself on while developing the regulatory strateg y of your product. Is your
49
B usin e s s
Number of drugs per billion US$ R&D spending*
company developing a biotech or chemical product? What is the intended indication? Which indication is best suited to have clear proof of concept? The indication in which you might have the clearest proof of concept data might not be the indication in which you might eventually want to market the product. It is critical to keep the overall goal of the compound in mind; will you be selling your compound after a certain stage in the development, or will you bring the compound to the market yourself? It is also important to consider the intended market for the drug. For example, if you’re developing a drug for use in the tropic regions, it is key to design your stability program around that. In that case, it is also critical to engage in early discussions with regulators in that region and to pay close attention to local regulations. You should never assume that the North American or European regulations will suit all markets. Thinking about all of this early on will help to optimize your development, as you can decide which regional regulations should be taken into account. In addition, it’s worth looking at whether your compound is eligible for any kind of special status or fast track for approval in your selected market. This can be very beneficial if your compound works in multiple indications – you can pursue the special status for one indication to potentially accelerate time to market (and return on investment). It may not be the ultimate intended indication for your compound, but it is one way to start getting return on investment a little faster – and again could be enticing for investors or buyers. Speed to market is important, but robust data is critical. Trying to reach phase II as quickly as possible is very tempting, but a well-designed phase
Overall trend in R&D efficiency (inflation adjusted)
100
10
1.0
0.1 1950
1960
1970
1980
1990
2000
2010
Figure 1: Overall trend in R&D efficiency (inflation adjusted). Adapted from (1).
Pre clinical testing (1-3 years) Formulation lab testing Short term animal studies
Clinical development (2-10 years)
Phase I
Phase II
MAA review (1-2 years)
Phase III
Post marketing surveillance
MMA/NDA/BLA review
Long term animal studies
Initial Synthesis
MAA submission
MAA approved
Figure 2: The drug development pathway. Adapted from M. Dickson and J.P. Gagnon, "Key Factors in the Rising Cost of New Drug Discovery and Development," Nature Reviews Drug Discovery 3, 417-429 (2004).
I single ascending dose/multiple ascending dose study is fundamental to your clinical development plan. It is critical to have robust safety data at the intended therapeutic dose to efficiently move to the next stages. Insufficient or incomplete phase I data will create concerns with potential investors. Even getting a drug to phase II can be extremely costly. As described above, it is important to be as thorough as possible in the early stages, but you may find yourself limited by the available budget. In this case, it is necessary to prioritize the essential aspects of your development. In addition, it is useful to engage with regulators early through
Scientific Advice in order to de-risk your development program. This gives you a chance to approach potential venture capitalists and partners earlier because you will be able to show that the (non) clinical program has been validated by a regulatory authority. Bruno Speder is Head of Clinical Regulatory Affairs, at SGS - Life Sciences, Belgium. Reference
1. J.W. Scannell et al., “Diagnosing the Decline in Pharmaceutical R&D Efficiency,” Nature
Reviews Drug Discovery 11, 191-200 (2012). doi:10.1038/nrd3681
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Back to Biologics Sitting Down With... Christian Schneider, Director of the National Institute for Biological Standards and Control (NIBSC), UK.
Si t t in g D ow n W i t h
You took up your new role at NIBSC on April 1 – how does it feel? I’m very proud to be the Director of NIBSC – it’s a bit like coming home to biologicals. The early part of my career was spent as a post-doctoral researcher in the Max Planck Institute in Germany, working in immunology, but later I got involved with regulatory affairs when I became a clinical expert in the area of biotechnology-derived medicines at the Paul Ehrlich Institute (one of the two German drug regulatory agencies). Directly before NIBSC, I was Medical Head of the licensing division at the Danish Medicines Agency in Copenhagen, and though it was very enjoyable, I missed working more indepth on biologicals. I’m delighted to be back in this area, especially as NIBSC has a great deal of sought-after knowledge in biotechnology. What is the most rewarding aspect of being involved in regulation? It’s rewarding to know that the application of your knowledge and expertise – and the resulting decisions – make a huge difference to people. Not just to individual patients, but also – in the case of vaccines, for example – to healthy people, including children. And though it is rewarding, it is also challenging. A medical doctor working with a patient can make a big difference to that particular patient; but a regulator makes a big difference to hundreds or thousands of patients at the same time, by approving – or not approving – a drug. What has been the most difficult moment of your career to date? Almost exactly ten years ago, in 2006, a trial of a new monoclonal antibody (mAb) in the UK’s Northwick Park Hospital caused serious adverse events in six healthy volunteers – the TeGenero event. At that time, I was the head of the mAb section at the Paul Ehrlich Institute, and my team had just approved the clinical
trial authorization for the same antibody in Germany. The German trials never went ahead, but we still had to examine why we had approved it and look again to discover if there was anything in the data that should have warned us about the dangers of this drug. We scrutinized everything, but in the end we found that all of the data were generated according to the then state of the art – and all our decisions were appropriate. Nevertheless, the event drew attention to the fact that standard models for testing medicine safety – particularly animal models – are not always completely suitable for cutting-edge biotech products. We had to adapt the system to help ensure that the risk for similar events ever happening again was as small as absolutely possible, without, at the same time, hindering the development of advanced therapies. If we’d over-reacted and prevented the development of all mAbs then we would also have prevented some of the major breakthroughs that we’ve seen in the last ten years. There are always new products coming through and new mechanisms of action being found, so there will always be challenges. You can never reduce the risk to absolute zero, but we now have processes in place to ensure the risks are more fully understood. Appropriate risk minimization measures are in place too so that no clinical trial should ever be considered high risk. How challenging is it for regulations to keep up with medical advances? I was the first-ever chair of the EMA’s Committee for Advanced Therapies (founded in 2009) and I was lucky enough to be directly involved in implementing the updated regulations for advanced therapies. I served in that capacit y for a lmost t wo f ul l terms. It was very rewarding to build up the committee and to see the first approvals, but I also became aware that the regulatory system needs to evolve
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to accommodate these very specialized products. Advanced therapies are mainly made by small companies, such as spin-offs from universities, or by academic groups, but the European regulatory system was mainly built on “big pharma products”. At present, the regulatory requirements for biologicals are very high – and rightly so – but some of them may or may not fit advanced therapies, and smaller companies may find it more difficult to meet them. I’m not suggesting we should have one standard for big companies and another for small ones; the regulations should apply to all products in the same way. However, I do think we need to find the right balance in regulating advanced therapies. What do you hope to achieve at NIBSC? I want to expand NIBSC’s network of expertise by collaborating with academia. Academic colleagues have a lot of knowledge, but often lack regulatory experience; conversely, in some areas, our knowledge would benefit from collaboration with academia – it’s a winwin situation. In May, NIBSC will be celebrating its 40th birthday at a symposium that will address questions such as: how do we make best use of “big data” – such as from genomics? What are the next steps for mAbs and advanced therapies? How do we keep the vaccine pipeline flowing? It will be a networking event for academics, regulators and industry; I think it’s very rare that you get all these people together in one room. If you have only regulators, they talk only about regulators’ problems, and if you have only industry, they talk only about industry problems; but if you have all the stakeholders around one table, you can go into much more depth. You can find more details about the event at: www.nibsc40.co.uk www.themedicinemaker.com
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