Cost inefficiencies in drug development are a major focus of discussion, especially with the many financial impacts affecting the pharmaceutical sponsors. One area in the crosshairs is centered right in the finance realm—budgeting and contracting for clinical studies. Recently, the Tufts Center for the Study of Drug Development conducted research on this process, which was funded by an unrestricted grant from ClearTrial. The results were discussed with leading executives at a roundtable last month.  

Ken Getz, Senior Research Fellow at the Tufts CSDD, offered that based on the research, budgeting and forecasting is a very unsophisticated activity and in a very nascent stage. 

Clement Popovici (left) Amy Guzman (center), and Scott Treiber (right) participated in a roundtable conversation on the financial aspects of clinical trials last month.  

In developing study budgets, 35% of the 31 respondents in the Tufts CSDD survey said that function rests with the clinical operations department, and is also a very decentralized activity. The remainder falls to procurement, project management, clinical teams, clinical finance, and a full 20% falls to "other."  

Other topics that were surveyed included the use of budget planning tools and software; formal processes to track time to plan the budget; importance of said activity; factors that affect study budget accuracy; and modifications to the study budget.  

Amy Guzman, Associate Director, Clinical Business Planning and Resource Management at Biogen Idec, noted that her company has had upper level management changes, including a new CEO within the past two years.  New leadership and other organizational changes have led to modifications to the budgeting process.  One is that Clinical Operations was moved into the Development Sciences organization aligning responsibility for the design and execution of clinical protocols in one organization.  "When those two things were separated," said Guzman, "it was more challenging, as those developing the protocol were doing so without the full understanding or consideration of the costs."  

In addition, Guzman notes balancing the need for managing resource demand strategically over a multi-year horizon with very specific near-term commitments in terms of meeting annual plan targets. "During last year's annual planning process, we made significant strides by presenting to senior management a combination of total program and individual study costs along with an analysis of current year variances to our annual plan.  This allowed our executive teams to see how shifting spend in or out of current year impacted our multi-year planning trajectory as well," she said. 

Scott Treiber, Vice President, Global Clinical Operations and Medical Affairs for Hospira, says the company is largely in the generic injectables and consumables for hospitals. Hospira is moving some of its generic injectables globally, but the overarching goal is toward biosimilar development. To that end, Hospira is running a large Phase III in the United States. So, the company has seen trial costs jump from a historical point of $5 million to $10 million per program, to over $100 million. Treiber's focus has been to find the right vendors for the Phase III trial, and to keep the budget at a 10% variance. Treiber noted that they, too, are tracking from a program standpoint, as is Biogen Idec.  

Treiber emphasizes planning and feasibility, two areas where there hasn't been sufficient time invested in the past. "When you get into complex global trials, everybody forgets about communication, logistics, and culture. And those are to me the driving forces behind a successful trial. If you get those things right, you're going to save money," said Treiber. 

Clement Popovici, Associate Director, Clinical Operations at Takeda Global R&D, notes that his company's historical path has led to clinical operations being responsible for the external study budgets. "That's not every individual's professional or educational background. The expectations, besides running the study, now also include extensive financial responsibilities regarding how to manage the spend over the next 12 months." 

The issue of cross-functioning teams working on a budget again led Popovici to point out the missing financial education piece. For example, additional functions like pharmacovigilance or regulatory departments will need to understand the costs of what they are outsourcing. Even study design teams don't necessarily understand the cost of different tests or procedures being considered. "We need to look at this as an opportunity to provide a training session like "finance and budgeting for the non-financial employee" to make them accountable and aware that the work they're doing and the work they are outsourcing and asking vendors to do has a direct impact from the fiscal area," said Popovici. 

Guzman, Treiber, and Popovici were clearly on track to improve and manage the financial expectations of the studies within a 10% budget variance or less. But when the topic evolved over to tools or software to help the budgeting process, it became clear that a dispersed situation existed. 

While there may be a move to standardize and/or aggregate data such as Oracle, which recently purchased ClearTrial, the difficulty for others is the ability to have flexibility, and to integrate and share the data with providers. And these participants noted that passing spreadsheets back and forth is not an ideal way to plan or budget. 

The Tufts CSDD survey uncovered these top four factors that harm study budget accuracy:   

CRO change orders and unplanned CRO costs

Clearly, the ability to share data and forecast budgets among internal and external collaborators would make the job of these executives a bit easier. 

ClearTrial offers an on-demand webcast at 

News

Cost inefficiencies in drug development are a major focus of discussion, especially with the many financial impacts affecting the pharmaceutical sponsors.

Managing Budgets in Complex Times with Tight Variances

Act cover

(King of Prussia, PA), a full-service contract research organization that provides core clinical research and development services, has named 

 Senior Vice President of Global Clinical Development. 

has been introduced as Executive Director of Corporate Development. 

 has joined the organization as Executive Director of Quality and Regulatory Affairs. O'Brien will be responsible for all quality assurance and regulatory affairs operations, including ensuring regulatory compliance and computer system validation processes. 

(ACR) (Reston, VA) has named medical imaging contract-research veteran 

 MD, Chief Medical Officer of ACR Image Metrix™.  Image Metrix is an imaging contract CRO and for-profit subsidiary of the ACR. Perlman has more than two decades of experience in radiology. 

 PhD, has joined the Infectious Diseases leadership team of INC Research, LLC (Raleigh, NC) as Vice President, Infectious Diseases. Young will lead the company's infectious diseases therapeutic unit globally. 

 (Princeton, NJ) announced the addition of two industry veterans to the company's leadership team. 

 joined Idis as Global Director of Regulatory and Medical Strategy, while 

 was appointed Senior Vice President of Global Business Development. 

 (Chippenham, UK), which specializes in developing therapies, principally for the treatment of respiratory diseases, announced that 

 BSc, PhD, MBA, has joined the company's board. 

 has joined the executive management team as Head of Business Development in Europe. Struik brings vast experience in the clinical research arena having worked in the clinical trials industry for more than 13 years and in all major therapeutic areas. 

CTI Clinical Trial and Consulting Services

 has joined as a biostatistician. Yeh brings with her over 20 years of experience working for Procter & Gamble (P&G). During her time at P&G, she served as both project statistician and statistical function leader for many different areas, such as gastroenterology, cardiology, pet care nutrition, and health technology. 

(King of Prussia, PA), a leading global provider of Microsoft SharePoint-based compliance solutions to life sciences organizations, to deliver solutions that provide easier access to clinical trial information and decrease the timeline for FDA submissions. 

 (New York, NY) worked with R&D and technical services institute

to upgrade the technology it uses to provide statistical and data coordinating services for National Institutes of Health-funded research. 

 (San Francisco, CA) have collaborated to co-promote clinical and commercial solutions for biopharmaceutical companies to reduce the time and expense associated with developing and marketing novel therapies. Quintiles will incorporate Archimedes' ARCHeS Innovator, and modeling consulting solutions, into its existing offerings. ARCHeS Innovator enables users to run clinically realistic virtual trials on any population and create compelling evidence.   

(Chicago, IL), a leading provider of cloud-based clinical trial operations and analytics products that help make the planning, sourcing, and tracking of clinical projects and financial performance faster and more accurate. The combination of the two companies is expected to deliver a comprehensive closed-loop clinical trial management offering from planning to payment. 

(Raleigh, NC), a therapeutically focused CRO has entered into a functional service provider alliance with 

 (Northbrook, IL), to drive global consistency, save time, and reduce costs for multiple clinical development programs across several therapeutic areas. In an initial three-year agreement, INC Research will deliver key functional services, including clinical monitoring, clinical data management, trial master file management, site start-up, and study feasibility activities.  

 (Exton, PA), a global CRO, will develop clinical trial supplies with 

 a biotech company focused on the research and development of compounds to regress atherosclerotic plaque. Under the agreement, Frontage will commence work on the formulation, compounding, and tabletization of the company's AHRO-001 product in advance of the upcoming Phase I human clinical studies. AHRO-001 is AtheroNova's first novel application for the treatment and prevention of atherosclerosis. 

 (Princeton, NJ), a provider of drug development services, and 

 a leading Japanese laboratory testing company, announced the expansion of the Covance-BML clinical trial laboratory in Kawagoe City, Saitama Prefecture, Japan to enhance the capacity and capabilities in the region. The companies, which opened the lab together in 2010 as part of a five-year agreement, will launch several new expansion-related services.  

 (Raleigh, NC), a CRO, announced a new agreement with 

 for a series of Phase III studies to develop several biosimilar drugs on a worldwide basis. PRA will serve as the sole provider of CRO services for these studies. The agreement is intended to govern the entire anticipated scope of Amgen's global biosimilar portfolio. 

 (Manchester, UK) has strengthened its leadership position in Poland with the acquisition of 

. Based in Warsaw, Medical Centre Osteomed is an FDA audited clinical research company, whose client list includes many of the world's leading pharmaceutical companies and CROs. 

(Bangalore, India) an NSF International Health Sciences Company with more than 25 years of experience in the pharmaceutical industry, has signed a collaborative agreement with 

of Bangalore to expand pharmaceutical training, auditing, consulting, and testing services throughout India. 

(Madison, WI) has launched the newest member of the Allegro®  product line: Allegro CTMS@Network™ . The new product aims to improve site selection, study start-up project management, and visibility into study conduct across multiple sites. 

The Clinical Data Interchange Standards Consortium 

(CDISC) (Round Rock, TX) has released the first iteration of a protocol representation "toolkit" for clinical research. The kit is designed to make it easy for authors of a research plan or protocol to reap the benefits of the protocol representation model, which has been developed over the past decade by global clinical research experts from academia, industry, and government. 

Clinical Data Interchange Standards Consortium 

(Round Rock, TX) won two recent Global R&D is Innovation Awards at Genzyme/Sanofi. GetSMART, which involved implementation of a number of CDISC standards, won in the Internal Business Value category. RegistryNXT!, which is based on the collaborative BRIDG model, won in the Value to Patients category.  

(Tempe, AZ), a community-based network of clinical trial sites, has been named Best Clinical Trial Site Network by the World Vaccine Congress. The award was announced at the 2012 Vaccine Industry Excellence Awards in Washington, DC. The VIE Awards celebrate the leaders, innovators, and pioneers in the vaccine industry. Clinical Research Advantage also received second place for Best Clinical Trial Site. 

(Middlesex, UK) has completed all the commissioning work for its new operational hub in Feltham, UK. The new location is within four miles of Heathrow Airport and part of the North Feltham Trading Estate Industrial Centre. 

 (Seattle, WA), a provider of global central laboratory services for the biopharmaceutical industry, has released its proprietary clinical trial sample tracking and management service: SampleGISTICS™ . The system provides web-based, real-time sample tracking including collection, shipment, and receipt at any laboratory or location worldwide. 

 (Redwood Shores, CA) has released the newest version of its Health Sciences Clinical Development Analytics. The application includes new functionality that expands visibility into clinical programs and studies, improves the quality and timeliness of clinical trial data, and helps to simplify and prioritize the rapidly expanding responsibilities of study managers, clinical data managers, and site monitors. 

• In response to regulators' increasing emphasis on patient centered data, including patient-, clinician-, and observer-reported outcomes (PRO, ClinRO, and ObsRO), 

 (Pittsburgh, PA) is integrating its consulting division—formerly PRO Consulting™ —into its portfolio of clinical outcome assessment consulting services. The new service will be called invivodata Consulting and will complement and integrate with the company's eSolutions and regulatory services. 

 (San Francisco, CA), an innovative clinical technology and services company for medical and pharmaceutical research, debuted its iPad application explaining informed consent prior to clinical trial patient enrollment. Using animation and other visual imagery, the application condenses the complex and critical disclosure information required at the start of a clinical trial into an easy-to-understand, digitized format.   

 (London, UK), a global CRO, announced the establishment of a new legal entity in Taiwan. Umakanta Sahoo, Chiltern Executive Director, Asia Pacific and Managing Director, India, will be leading the effort in Taiwan. 

 (Rochester, NY) has advanced its hybrid central lab model in Mumbai, India with a state-of-the art operational facility dedicated to managing clinical trials testing in India and provides study support throughout Asia Pacific. ACM Global oversees the full complement of study support to keep clinical trials on schedule and on budget, including kit building, shipping logistics, project management, data management, and site support. 

 (Tampa, FL) has gone live with its next-generation health and research informatics platform, built on Oracle Health Sciences solutions. In early deployment, the new platform enables Moffitt to accelerate clinical trial patient recruitment and advance personalized medicine. The new informatics environment supports Moffitt's Total Cancer Care™  program by generating new intelligence from existing systems. 

(Cary, NC) announced the availability of a new report titled The State of Patient Recruitment in Clinical Trials, which provides sponsors and service providers with valuable insight into the activities and strategies that drive and restrict patient recruitment in clinical trials. 

 (Fremont, CA) announces its Research Accelerator platform for the life sciences, an end-to-end management solution for R&D that integrates clinical information management technology and business outcomes-based methodology for informed decision-making in R&D.  

 (Redwood Shores, CA) announced the latest version of its Translational Research Center, a platform that enables secondary use of electronic health records, administrative data, and omics data to help accelerate biomarker identification for drug discovery, clinical development, and translational research. This new release integrates genomic visualization tools that provide holistic views of multiple omics data modalities to enable systems biology-based approaches essential for understanding disease. 

, designed to give clinical trial sponsors and sites clinical training capabilities for site operations.The web-based application tracks, validates, and reports investigator training activity through one interface. 

(Charlottesville, VA) introduced OpenQ SafeGuard™ , a social enterprise compliance suite for managing social compliance risk. This patent-pending technology collects activity feeds, posts, and documents from social platforms and other enterprise interactions, to proactively identify and classify business and compliance risk. An intuitive interface helps manage compliance cases with classification of risk level according to industry driven and company-defined priorities. 

 (Malvern, PA) has expanded its suite of eClinical software solutions with Prime Publisher™ , a concatenation tool designed to streamline the content review process and combines multiple data forms into a single, navigable format. Prime Publisher simplifies processes such as reviewing large sections of the eCTD by combining them in a single document. 

 (Chicago, IL) released Merge eClinical OS, a new clinical trial operating solution that provides end-to-end study support for trials of all sizes. As a single, web-based solution, it has the flexibility to support trials in any phase, and capture any type of data, from any source, over any modality. Merge eClinical OS also has the scalability to grow if a trial increases in size, number or complexity. Merge eClinical OS provides a complete menu of clinical trial capabilities that can be mixed and matched to build a solid foundation for each trial environment. 

Business News

Industry news focusing on the people and organizations who work in the clinical trials profession.

Business and News Update July 2012

Risk-Based Monitoring – Part Two In Depth Review

What Do Risk-Based Monitoring and Patient Engagement Have in Common?

Has FDA Guidance on Risk-based Monitoring Impacted SDV Coverage Yet?

In a recent blog, we presented data highlighting the trend in the percentage of source document verification coverage (i.e., percent of eCRF data targeted for SDV) and in particular observed that it has been decreasing slightly over the past four years, presumably related to early adoption of targeted, risk-based monitoring strategies. While the overall decrease has been relatively modest to-date, one might expect that the amount of on-site time required by site monitors should correspondingly start decreasing.  

But this month';s Insights graph tells a different - and somewhat troubling - story. Using the Medidata Insights metrics warehouse- now comprising nearly 2,500 studies from 65 sponsor organizations - annual trends were computed and graphed of two critical monitoring efficiency metrics for Phase II/III studies:   

Monitoring on-site rate—the average number of on-site monitoring days per site per year

SDV velocity—the average number of eCRF data points SDV'd per on-site day

The data shows that site monitors are spending increasingly more days on-site per year, and performing increasing amounts of SDV during each on-site day. This increasing burden—and cost—of site monitoring and SDV can be attributed to the increasing complexity of protocols observed in recent years. It is another reminder of the serious challenges facing clinical R&D organizations and the need to move more aggressively towards a targeted, risk-based monitoring paradigm.  

Medidata is very interested to hear your take on these observed trends. Please also stay tuned as we continue to dig deeper into the Insights data through 2012. 


 Monitoring rates in Phase II-III trials, 2008-2011.

The percentage of source document verification coverage has been decreasing slightly over the past four years. Therefore, the amount of on-site time required by site monitors should also start decreasing.

Increasing Intensity of On-Site Monitoring a Troubling Trend

If any managers were worried that they might have to divert resources away from clinical trials to meet the requirements of new European rules on information to the public, they can relax. That's one set of rules that is not going to happen anytime soon. 

Not that this particular legislative initiative of the European Union presented any major threat to the operation of clinical trials—the connection between information to the public on prescription medicines and the development of new medicines is only indirect. But the saga of this ill-fated piece of legislation does say something about the navigational capacity of the European Union in the healthcare field—and that is a message that no one working in pharmaceuticals should ignore. 

To start from the end, the conclusion of this long-running bid to update EU rules on medicines information came late in June, at a meeting of EU health ministers. Like the chronicle of a death foretold, a statement to the ministers frankly admitted "widespread skepticism among member states towards these proposals originally presented in December 2008." 

The statement came from the Danish health ministry. Denmark has presided over meetings of EU ministers since the beginning of this year, taking its turn in the EU's bizarre rotating chair, which gives a different member state the privilege—or purgatory—every six months. It went on to note that, in its role as the presidency, instead of immediately accepting defeat, it had "decided to explore possible ways of taking the proposals forward through bilateral consultations with member states." Eventually, bilateral consultations were carried out across nearly all the 27 member states. But, as the statement concludes, "the presidency was not able to identify common ground." 

The health ministers meeting could do no more, in these circumstances, than to pronounce the proposal clinically dead. Its passing will not be widely lamented.  

From the moment the European Commission published its proposal, there was sharp criticism from nearly all sides.  

The European pharmaceutical industry saw risks of additional bureaucracy and cost in provisions to control product information more closely. Associations representing consumers and patients—and the majority of the European Parliament—claimed it represented a charter for direct-to-patient advertising of prescription medicines, which remains a taboo subject in Europe. And national governments feared it would generate huge amounts of work for very little constructive result. Even a late-2011 rejig of the proposals to placate critics (and an emergency re-presentation of them in early 2012) failed to win sufficient support. 

The question that this shambles provokes is why the European Commission came up with a proposal that, in the end, nobody wanted.  

It was Günter Verheugen, the then-European Commissioner responsible for industry, who proposed it in the first place. His strong sympathies for industry in general were long evident, not least in his open support for the car industry, particularly the big-car manufacturers in his native Germany. When Verheugen's term of office came to an end in 2010, responsibility for the pharmaceutical industry did not pass to his successor, the new industry commissioner Antonio Tajani. Instead, in a re-allocation of responsibilities that delighted health activists across Europe, pharmaceuticals were shifted across from the industry portfolio to the health department within the Commission—which had just become the responsibility of Health and Consumer Affairs Commissioner John Dalli.  

Dalli hesitated slightly at the taste of the poisoned chalice that had been put in front of him, but instead of dashing it to the ground as undrinkable, he promised to listen to a wide range of views before deciding what to do. It took the best part of a year before the European Parliament came up in late 2010 with its damning assessment of the proposal—claiming that it was biased far too much in favor of industry and far too little in favor of patients. Dalli promised to take account of the Parliament's views, which he did very largely, in his recast of the proposals—but it took him another year to get around to that. In addition, when he published his modified proposal in late 2011, he chose to link it with another proposal, on pharmacovigilance, which had been rapidly drafted during the year to plug gaps in the EU drug monitoring system exposed by the Mediator scandal in France.  

The modified proposal enjoyed no more success than its predecessor. It was still widely criticized, and—critically—it was shunned by national governments.  

In fact, so unenthusiastic were governments that they more or less demanded that it should be stripped away from the pharmacovigilance proposal—which they considered important and urgent—and relegated to a lower priority.  

Dalli duly complied with this, and in March this year he re-presented both the pharmacovigilance proposal and the information proposal as separate measures.  

Since then, agreement has been reached on the pharmacovigilance proposal among national governments, the European Parliament, and the European Commission (in record time in EU terms). But the information proposal lingered on, unloved and unattended, and has only now, mercifully, been given the last rites and duly buried. 

It has wasted a lot of time for a lot of people with many other more important things to do. It has illustrated a serious lack of political sensitivity among the officials that proposed it, and among the officials who subsequently declined to recognize that it was dead in the water.  

And it has offered further unwelcome evidence of the inefficiency of the EU's legislative machinery. On top of that, if there were any problems with the provision of information about medicines (and few would maintain that there are not), those problems are no nearer to a solution now than they were back in 2008 when the proposal first emerged. 

Anyone wishing to know how firm is the commission's strategic grasp on healthcare need only glance at the pronouncements of Health Commissioner John Dalli.  

He admitted in a recent speech that "The European Union is going through a challenging period: we are fighting a long and deep fiscal and economic crisis. At the same time, the aging of our society puts additional strain on our healthcare systems, and health inequalities are widening." He said that these challenges can be met only by "an inspired vision for healthcare."  

The growth in healthcare expenditure in the European Union, driven by increasing life expectancy, higher citizens' expectations, and technological innovation, "is unsustainable in the long run," Dalli recognized. "We therefore face a double challenge. We need to contain costs, starting now, while building modern, responsive, and sustainable health systems fit for the future," he observed, before setting out his "personal vision" of how to respond.  

Dalli's credo has, he says, three key elements. The first is sustainability and affordability. "Our health systems must—and can—become more cost-effective. We can provide better care at lower cost. The key is to use the vast potential of innovation in products and services. Innovation is not just a cost driver. If used intelligently, it can bring down costs significantly." 

High on his list of mechanisms for achieving this goal is the search for a common methodology for health technology assessments. Another is improving adherence to treatment regimes—particularly among older patients; Dalli says that at present only 79% of patients take their "once daily" dose, and only 51% of patients required to take four per day actually do so. And he places great reliance on the prospects for e-health. 

The second element is availability and universal access. He says he is determined to fight "the growing health inequalities in Europe," emphasizing that universal access to necessary healthcare is indispensable. One of the initiatives he has taken in relation to pharmaceuticals is to start an inquiry into why smaller markets sometimes suffer from lack of availability of some medicines. 

The third element consists of a combination of quality and safety. "The healthcare that patients receive in the European Union must be of the highest quality, and it must be safe," Dalli says—citing the new pharmacovigilance legislation and efforts to combat falsified medicines as examples of what he is doing. 

Unfortunately, on the one subject of most interest to readers of

, he has revealed little of what is planned for the impending review of the EU clinical trials rules. But there is talk in Brussels that the long-awaited proposal may emerge in July. Watch this space! 

is a freelance journalist who specializes in European health affairs and is based in Brussels, Belgium. 

View from Brussels

Proposed rule changes on public information in Europe never make it to fruition.

Drug Information? Forget it!

The role of clinical supply chain management is changing dramatically. Historically a function that is engaged after a study's clinical operations strategy has been established, clinical supply professionals are now playing a more active role in development, study strategy, planning, managing mission critical activities, and in forecasting and mitigating operating risk. To assess this evolving role, the Tufts Center for the Study of Drug Development surveyed 20 senior level executives in large- and mid-sized biopharmaceutical companies. The executives surveyed note that forecasting and risk management has moved to the forefront of their functional responsibilities and as key requirements for study success. Ensuring timely delivery and availability of supplies and investigational drugs for study volunteers has become far more demanding as clinical trials have become globally disbursed and cost pressures have reduced study drug overproduction and clinical supplies inventory.  

Despite the importance of accurate supply forecasting and planning, most respondents report using relatively unsophisticated approaches: Excel spreadsheets; in-house forecasting programs; and commercially-available web-based approaches.  

The most demanding clinical supply management requirements.			

—Tufts Center for the Study of Drug Development, 

Supply Chain Management

 Biosimilars Development Raises Research Questions

 FDA, Sponsors Gear Up for User-Fee Action

 Risk & Resources to Shape Trial Operations

Biological medicines (biologics) are drugs derived from living cells. They have been used in medicine for centuries. With the advent of recombinant DNA technology in the late 1970s and early 1980s, recombinant human therapeutic proteins emerged as a new source of biological medicines in the necessary amounts for routine therapy. Before that, therapeutic proteins such as insulin, somatropin, interferons, and blood factors could only be sourced from animal tissues, human body fluids, or cadavers. In some cases, such as epoetin and colony stimulating factors (G-CSFs), recombinant DNA technology made it possible to produce these medicines for the first time. Monoclonal antibodies derived from mice hybridoma cells were first developed in 1975, but failed as therapeutic proteins due to their excessive immunogenicity given that they were essentially mouse xenoproteins. In the 1990s, the first chimeric and humanized recombinant monoclonal antibodies, such as rituximab, infliximab, and trastuzumab, became available. Since then, the number of approved recombinant therapeutic proteins has expanded greatly, and many of these products soon reached blockbuster status. Today's global sales of recombinant therapeutic proteins are above $130 billion, and these sales are expected to grow at least twice as fast as those of small molecule drugs. It is anticipated that by 2016, eight of the top-10 selling drugs will be recombinant proteins—of these, five (Humira® , Avastin® , Rituxan® , Prolia® , and Remicade® ) are monoclonal antibodies, and one (Enbrel® ) is a fusion protein containing antibody components. The others are hormones (Lantus® , Epogen® /Procrit® ). The key patents protecting many of the recombinant human proteins already have (EU), or soon will (US) expire, and from 2013, the first monoclonal antibodies will start losing their patent protection. 

Biosimilars represent a slowly emerging, but steadily growing new field of pharmaceutical biotechnology, analytical development, and clinical research. Their development requires a fundamentally different approach to that used for originator biopharmaceuticals, and analytical design becomes particularly critical. Meanwhile, regulatory authorities are working in each of their jurisdictions, but also collectively worldwide, on the development of guidance documents for biosimilar medicines. However, despite the recognition of the need for global harmonization of pharmaceutical standards, at least three different approaches for the development of biosimilars are observable (Figure 1). In the following discussion, each of these approaches will be reviewed in the context of an evolving global biosimilar market.  

Europe was the first highly regulated region where patents for recombinant protein drugs started to expire from 2000 on. The European Union (EU) has been in the forefront of biosimilar regulation since 2001, when the revisions to the EU laws governing pharmaceuticals created a pathway for the approval of biosimilar versions of biologics. The European Medical Evaluation Agency (then known as EMEA, now EMA) began soon after with the issuance of three over-arching biosimilar guidelines,

  describing general requirements; quality; and non-clinical and clinical development, before they then issued product class specific guidelines for the non-clinical and clinical data requirement for insulin, somatropin, epoetin, G-CSF, interferon-alfa, and LMWH (Table 1). Many EU biosimilar guidelines including the Guideline on Similar Biological Medicinal Products, the Guideline on Non-clinical and Clinical Issues, and the Guideline on Quality Issues are currently under revision to integrate and update the documents based on the experience gained with the approval of the first biosimilars in the European Union (Table 2). Furthermore, draft guidelines for interferon beta, Follicle Stimulation Hormone, and biosimilar monoclonal antibodies have been published and the public comments received are now under review. Based on the successful experiences with the biosimilar regulations in the European Union, other highly regulated markets such as Japan, Canada, and Australia have adopted similar approaches, and approval of a biosimilar based on an EU biosimilar data set and, in some cases, dossier in these countries would require only limited additional efforts. 

Figure 1. Europe has been leading the way in biosimilar standards since 2001. 

First and foremost, a biosimilar is a biologic. As such, biosimilar medicines in the European Union must be manufactured following the same quality standards as for all other medicines (e.g., compliance with EU/ICH guidelines for process development and analytics, GMP, GLP, and GCP). EU regulatory authorities also perform regular inspections of the manufacturing sites. A biosimilar, according to the EU definition, is a medicine which is similar to a biologic that has already been authorized in the European Union. The active substance must be similar to the one in the reference biologic. Studies comparing the biosimilar and the reference product have to be carried out systematically in a step-by-step manner, starting with a comparison of the quality of the two products, both at the active substance and at the drug product level. The submission for marketing approval of a biosimilar requires a complete, standalone CMC package as described by Module 3 of the Common Technical Document (CTD). This includes an extensive analytical characterization of the active substance and the drug product. General test procedures and acceptance criteria for characterization and quality control of biopharmaceuticals are described in ICH Q6B.

  In addition, the so-called comparability exercise

 —a data package that is included in a separate chapter of the filing—has to be provided on top of the characterization studies. The importance of the quality comparability exercise cannot be overstated. It builds the backbone of each comparability-based regulatory submission. A successful CMC comparability exercise, demonstrating that the two products are comparable (or in US terminology highly similar), can provide the basis for a significantly reduced pre-clinical and clinical testing program (Figure 2) (this is yet to be confirmed in the United States but is fundamental to the concept of an abbreviated pathway and therefore will always be necessary even if not sufficient). Based on the CMC comparability exercise, a hypothesis is generated that the two products are similar, and it is therefore not necessary to repeat the full preclinical and clinical program of the reference biologic. The FDA has expressed this in terms of it not being necessary for the biosimilar sponsor to re-establish the safety, purity, and potency of the active moiety, but just to confirm biosimilarity, and indeed this is specified in the US Statute.

  The CMC comparability exercise also forms a cornerstone for extrapolation between indications; in this case the indications must share the same mechanism-of-action. 

Table 1. The EMA began its biosimilar regulations with general requirements, quality, and non-clinical and clinical development standards, before issuing product class specific guidelines. 

 Every biologic medicine has a certain degree of batch-to-batch variability. The active ingredients of recombinant protein drugs are produced in a complex multi-step process, including culture of living cells, protein purification, formulation, storage, and distribution. The degree of protein heterogeneity depends on the cell culture manufacturing process, stability, storage, and transport conditions of the biologic drug, as well as the nature of the active biologic moiety itself. Schiestl et al.

 have recently shown analytical data on the acceptable levels of batch-to-batch variability within originator batches of Aranesp® , Rituximab® , and Enbrel® . It is the aim of the quality CMC comparability exercise to demonstrate that the degree of heterogeneity is not significantly different between the biosimilar and the reference biologic. However, it is not expected that the two products are identical. Minor differences are acceptable, if justification can be provided, that these differences have no influence on the clinical activity (safety and efficacy in Europe; safety, purity, and potency in the United States). Justification of minor differences may rely on supplementary biophysical, or in-vitro studies; for some differences, it may require specifically designed in-vivo, toxicology, pharmacokinetic (PK)/ pharmacodynamic (PD) or clinical studies.  

Table 2. The biosimiliar guidelines are under revision in 2012. 

Generally, a physicochemical comparability program will include a determination of the primary structure, composition, and physical properties of the two products. The amino acid sequence should be confirmed by appropriate methods. The variability of N- and C- terminal amino-acid sequences should be analyzed. Free sulphydryl groups and disulfide bridge integrity should be described. The distribution and structure of the glycan structures should be determined. Higher-order structure, biophysical, and biological properties of the products should be characterized by appropriate methodologies. For monoclonal antibodies, antigen binding, epitope specificity, binding to Fc receptors, and complement factors should be evaluated. Finally, a battery of in-vitro potency assays (e.g., tests for ADCC, CDC, and apoptosis), should complement the physicochemical and biophysical comparability exercise. Table 3 shows frequently employed methods for higher-order structure and in-vitro pharmacology. 

Figure 2. It has become expected that for biosimilarity and extrapolation the mechanism of action must be known. 

The comparability exercise should be conducted as a head-to-head comparison of the two products, namely the biosimilar and the originator reference, if the performance of the assays allows it. Some of the highly sophisticated analytical methods may only be applicable to the purified active ingredient, since the non-active constituents of the formulation may interfere with the assay. The revised version of the over arching EU biosimilar quality guideline will also provide guidance on this topic.  

Table 3. Frequently employed methods for higher-order structure and in-vitro pharmacology. 

 Results from the physicochemical, biophysical, and in-vitro biological comparability studies should be reviewed for potential impact on efficacy and safety. If animal studies are determined to be necessary for further confirmation of biosimilarity, such studies should be performed in a relevant species. Where possible, PK and/or PD effects relevant to the clinical application should be investigated. At least one repeat dose toxicity study, including toxicokinetic measurements and determination of antibody titers, including cross reactivity and neutralizing capacity, should be performed. Toxicity of monoclonal antibodies is mainly target related. For a biosimilar monoclonal antibody, it may be acceptable to perform the toxicity study as a single arm, non-comparative, one gender study. This topic will be further addressed in the final biosimilar monoclonal antibody guideline. Local tolerance can be addressed in the same repeat dose toxicity study. Other routine toxicological studies, which are normally required for the development of a novel biologic, such as safety pharmacology, reproduction toxicology, mutagenicity, and carcinogenicity studies are not required for similar biological medicinal products in the European Union. 

 A clinical comparability exercise has been expected for European biosimilars to date, but the extent of the data required has varied considerably even for biosimilars made by different sponsors to the same reference product.

  These studies should begin with PK and PD studies followed by clinical efficacy and safety trial(s) or, when validated surrogate parameters for clinical endpoints are available, PK/PD studies for demonstrating clinical comparability. Dose finding studies are generally not required for biosimilars. In certain cases, where validated surrogate PD parameters exist, comparative PK/PD studies between the similar biological medicinal product and the reference medicinal product may be sufficient to demonstrate clinical comparability. According to the EU product specific biosimilar guidelines, the case for insulin and filgrastim, and indeed a biosimilar filgrastim, has been approved on this basis. The European Union has yet to approve a biosimilar insulin. Clinical comparability margins should be predefined and justified based on ICH topic E10.

 For a biosimilar and the reference biologic, the same dose needs to result in the same effect, and in many cases not only a lower margin but also an upper margin for the equivalence studies needs to be defined. One big advantage of pursuing the development of a biosimilar over a standalone biologic in the European Union is the opportunity to extrapolate to other indications. For a biosimilar, it is not necessary to demonstrate comparable safety and efficacy in every indication. The sponsor of a biosimilar development program should carefully select the indication, patient population, and dosing regimens for the pivotal Phase III study. These parameters need to be based on sensitivity for expected side effects and potential dose-efficacy differences, and regulators will likely require this justification by the sponsor. Based on the demonstration of comparable safety and efficacy in a carefully designed pivotal Phase III trial, other indications of the reference biologic can be approved if they share the same mechanism of action (Figure 2). Unlike the use of comparability for the support of manufacturing changes where the mechanism of action does not need to be known for extrapolation between indications, it has become expected that for biosimilarity and extrapolation, the MOA must be known. This is one area where the use of the same standard does not apply in Europe to all biologics, and likely will not in the United States either. Immunogenicity has been a major concern for all protein drugs, irrespective of whether they are originator or biosimilar, and at least 12-month immunogenicity data will be required pre-authorization for most chronically administered biosimilars. Traditionally, these studies have not had to be repeated after manufacturing changes, even though the most oft-cited case of an immunogenicity problem

One outstanding issue recognized as critical in all the highly regulated markets is the challenge facing biosimilar sponsors: the appropriate choice of the reference product. Each biosimilar law only applies to the jurisdiction for which it is written. The way most are configured states that the reference product has to have been approved in the same jurisdiction to be available as a reference for a biosimilar. And it is the label on the product that determines its approval status, rather than what is in the vial itself. Thus many of the head-to-head studies expected for a biosimilar may have to be repeated with locally-labeled reference product (even if the source of all the reference product in the world is a single factory). It is not clear how this will be managed and whether the bridging of reference products in dossiers for different jurisdictions will be allowed, which would enable a single global development program for a biosimilar. Absent some resolution, the need to repeat studies will hamper any economies of scale otherwise expected for the biosimilar. Given that originator products can now be developed for a global market, this would be particularly unfortunate. 

Risk management program and pharmacovigilance. 

As required in general for all recombinant protein drugs, the sponsor should provide a risk management program (RMP) and pharmacovigilance plan at the time of submission of a biosimilar marketing authorization dossier, in accordance with current EU legislation and pharmacovigilance guidelines. Any specific risk identified during development of the biosimilar must be taken into account. In the case where specific safety monitoring is required for the reference product or class, this must be considered also for the biosimilar. In many cases, at least one Phase IV study will be part of the RMP. 

Experience with EU biosimilar approvals. 

Omnitrope®  (somatotropin) was the first biosimilar recombinant protein approved in the European Union in 2006. The first biosimilar glycoprotein was epoetin alfa, approved in 2007, it is marketed under three names: Binocrit® , Epoetin alfa Hexal® , and Abseamed® . Just as is the case for small molecule generics, biosimilar companies submitted multiple applications with different names for one development program. In the future, only one marketing authorization per development program will be allowed per company. So far, 10 different development programs for somatropin, epoetin, filgrastim, and insulin have been submitted to the EMA, comprising 19 product names. Seven programs have been approved (Table 4). Two applications (interferon alfa and interferon beta 1a) have been rejected, and two other applications (insulin and epoetin alfa) have been withdrawn. This suggests that the same rigorous standards are applied to biosimilars and originator biologics, and there is no reason to expect any difference in the quality of a biosimilar and an originator biologic. Five biosimilar marketing authorization applications are currently under review (three human insulin, one follitropin alfa, and one infliximab). 

Table 4. Biosimilar development programs submitted for marketing approval at EMA. 

While the scientific principles are universal, and the United States led with the development of comparability, implemented by guidance in 1996 (neither statutes nor regulations being considered necessary at the time), the FDA waited for formal legislation before allowing biosimilars to be considered for the majority of biologic products approved in the United States. The terminology used in the US legislation, BPCIA enacted March 23, 2010, is "highly similar,"

 which is a perfect match for the definition of comparable in ICH Q5E.

  (Table 5). Nonetheless, many stakeholders expect a substantial public process to ensue before FDA approves biosimilars, or interchangeable biosimilars. This is even though neither regulations nor new guidances are required by the statute, and biosimilar applications could have been filed from the day of enactment. FDA has been given a unique authority by Congress, in having the ability to designate biosimilars as interchangeable with their reference product. This occurs nowhere else in the world. For instance, in Europe, while comparability is the standard used to establish biosimilarity, the final marketing authorization is silent on the interchangeability of a biosimilar with its reference product (albeit the EPAR says that the active ingredient in each product is similar that in its reference). 

Table 5. Comparable and biosimilar are the same as a matter of science. 

FDA held a public meeting in November 2010 to hear stakeholder opinions on how they should implement BPCIA, has subsequently received many written comments to the docket, and has initiated a formal public process concerning biosimilar user fees

  which has recently passed Congress. The agency published its scientific principles for biosimilars in August 2011

  and eventually released three draft guideline documents on February 9, 2012 (Table 6) which are currently under stakeholder discussion. Although it is not expected that the US guidelines will exactly match the EU biosimilars system, the scientific foundations will be the same. This has already been the case in the FDA's approval of subsequent versions of those biologic drugs that happen to have been approved under the Federal Food Drug & Cosmetic Act as opposed to the Public Health Service Act. 

Table 6. FDA draft guidance on biosimilar product development, February 9, 2012. 

Only about 15% of the world population lives in highly regulated countries, while 85% live in less- or un-regulated countries. To increase the access to affordable, safe, and effective biological medicines in all countries is therefore of utmost importance. Emerging countries, such as Brazil, Russia, Korea, India, and China have defined local requirements for development and manufacturing of follow-on versions of biologics. These jurisdictions address the unmet medical need in each of these countries, but they are not biosimilars according to the standards in highly regulated markets. For these products, the term "alternative biologics" have been used.

  Each is developed with a specific structure and function in mind to the standards of that country, but not based on a thorough comparison to a specific individual product already approved in that country. Also, the stringent ICH development guidelines and GLP and GMP requirements of the highly regulated markets are not a basis of marketing approval. Cost of development for such alternative biologics may be less than 10% of the development costs for a biosimilar in the highly regulated markets. Also, the development timelines are much shorter. This has raised some questions as to the level of comparability between an alternative biologic and an innovator reference biologic. Several alternative recombinant erythropoietins manufactured in Asia analyzed with isoelectric focusing gels were not comparable with recombinant erythropoietin preparations licensed in the EU.

  This is unlike approved EU biosimilars, which are highly similar to a specific identified originator reference marketed in that same jurisdiction.

It can be expected that many more emerging countries will soon issue country-specific biosimilar guidelines. India has specific guidance documents for generics, but these do not apply for alternate biologics. In the past, these products were approved in India on a case-by-case basis, and clinical studies for biologics required only a limited number of patients; Phase I and Phase II trials were typically not required. The Department of Biotechnology approves protocols up to animal toxicity studies, and the Drug Controller General of India approves clinical trials and final product for marketing. The Indian Food and Drug Control Administration issues the manufacturing license based on a local GMP audit.  

The World Health Organization (WHO), while not a formal regulatory authority, in October 2009 created a guideline on similar biotherapeutic products that will raise the standards for alternative biologics in the emerging markets.

  However, although the standards are largely derived from biosimilar guidelines in the European Union, Australia, Canada, and Japan, this WHO standard alone will not be sufficient to achieve a biosimilar approval in highly regulated markets. Nonetheless, companies from emerging countries may soon reach the standard of the highly regulated markets, as for instance some companies from Korea and India have recently formed alliances with US pharma companies for the development of global biosimilars. 

It is anticipated that by 2016, eight of the top-10 selling drugs will be recombinant proteins. The size of the current global market for recombinant proteins is more than $130 billion. With the loss of patent protection for most of these products starting in 2013, the development of follow-on versions of recombinant proteins, so called biosimilars, becomes a steadily growing new field of biopharmaceutical development and clinical research. In contrast to small molecule generics, pre-clinical and clinical studies will be required for most biosimilars. The biosimilar regulations are currently evolving in Europe, the United States, and in many emerging countries. For the successful development and commercialization of biosimilars in a global market, it will be important to understand the specific requirements for clinical development of biosimilars in these regions—where they are the same and especially where they differ. Clinical development managers will also need to understand the concepts of quality CMC comparability, the value of in-vitro pharmacology, and non-clinical studies, since this will form the basis for each biosimilar clinical development program. 

PhD, is Owner and Managing Director of Brockmeyer Biopharma GmbH, Luetjen Feldsweg 28, 37081 Goettingen, Germany, e-mail: 

 MA, Vice President, FDA Regulatory Strategy and Policy at Avalere Health.

*To whom all correspondence should be addressed. 

1. European Medicines Agency, "Multidisciplinary: Biosimilar," 

2. International Conference On Harmonization, "Specifications: Test Procedures and Acceptance Criteria for Biotechnical/Biological," (1999), 

3. International Conference On Harmonization, Comparability of Biotechnological/Biological Products Subject to Changes in Their Manufacturing Process," (2004),  

4. One Hundred Eleventh Congress of the United States of America, "The Patient Protection and Affordable Care Act (PPACA),"  (2010) 

5. M. Schiestl et al., "Acceptable Changes in Quality Attributes of Glycosylated Biopharmaceuticals," 

6. European Medicines Agency, "European Public Assessment Reports,"  

Feature Article

Biosimilars are a steadily growing new field of biopharmaceutical development and clinical research.

Developing Quality Biosimilars

Recruitment of subjects for clinical trials remains an ongoing and increasing challenge, with nearly 90% of industry-sponsored clinical trials experiencing delayed enrollment.

  Since these delays often last six months or more, patient recruitment is one of the most important determinants of the clinical program timeline.

  In addition to being an important timeline driver, patient recruitment also represents a significant portion of program costs. A large amount of resources are spent starting-up and monitoring sites, approximately 50% of which will recruit one or no patients in their studies.

In order to expedite study timelines and decrease costs, researchers are actively seeking opportunities to speed enrollment, and supplemental patient recruitment is one such option. For the purposes of this article, supplemental recruitment is defined as the practice of pre-qualifying community-based patients and referring them to clinical trial sites for study screening. 

The portion of patients available for supplemental recruitment is large, with studies suggesting that fewer than 5% of all eligible adult patients are enrolled in therapeutic studies and this proportion is even lower among the elderly, women, and racial and ethnic minorities.

  To better understand the reasons why these patients do not participate in clinical trials, ECRI conducted a meta-analysis of 14 published studies and concluded that three factors were important: fear of placebo or randomization; too far to travel; and the desire to have the physician choose the treatment rather than accept a process that uses randomization to assign patients to a treatment group.

 and published in the 2009 Industry Standard Research report titled "Success in Patient and Investigator Recruitment," however, showed different results. The MediGuard survey of clinical trial naïve patients found that the primary reason that patients do not participate in clinical trials is simply that they are unaware of opportunities to do so (69% of respondents).

  As a result, physician investigator sites and other researchers are actively seeking opportunities to make community-based patients aware of clinical trials. With ever-increasing numbers of patients seeking health information on the Internet, digital outreach programs through search engines, social media, and online patient communities are becoming more commonplace. Although the number of clinical trials using supplemental patient recruitment has grown substantially, there is little information available in the literature on patient level of interest in studies and patient characteristics associated with study interest. This article seeks to contribute to researchers' understanding of patient interest in clinical trials by analyzing the results of patient feasibility and recruitment studies conducted across a broad range of medical conditions. 

 All feasibility and recruitment screening studies conducted with patients between January 2009 and July 2011 in the United States or United Kingdom by 

 were searched. Specifically, patient questionnaires that contained a question regarding patient consent to contact if a clinical trial were available at a nearby site were identified. The response to this question on consent to referral (yes, no) was extracted into a patient-level, de-identified study database, along with any other patient characteristics available from the screening survey including: treatment history (disease, number of medications, side effects, and treatment satisfaction), patient demographics (age, gender, race, country, and previous clinical trial experience), and other socioeconomic variables (employment and insurance status).  

 All surveys were conducted online with members of 

, a free online service that monitors the safety of prescription medicines, over-the-counter medicines, and healthcare supplements for over 2.5 million patients in the United States, United Kingdom, France, Germany, Spain, and Australia. These online surveys were sponsored by the owner of 

 Quintiles Inc., a pharmaceutical services company offering clinical trial support solutions.  

Patients enrolling in the service consent to be contacted about research opportunities as part of the registration process. When a specific research opportunity arises, an e-mail is sent to potentially eligible members who can click on a link in the e-mail to read about study details, screen for eligibility, and provide further consent to have their contact details sent to an investigator site.  

 Univariate logistic regression was used to assess the association of patient interest in referral with each study variable. All analyses were conducted using SAS version 9.2 for Windows (SAS Institute Inc, Cary, NC). Subsequent to the univariate analysis, a multivariate, step-wise logistic regression was conducted to identify the characteristics that were predictors of a patient's interest in referral to a nearby clinical trial site.   

 Information was extracted from 206 feasibility and recruitment screening studies involving 8,599 patient responses. Characteristics for the sample are displayed in Table 1. Of the 8,599 patients responding, 68% were aged under 65, and 68% were female. Only 14% of respondents did not have health insurance, although a majority (55%) was unemployed (i.e., unemployed, working in the home, retired, or disabled).  

Table 1. The demographics of the survey participants. 			

 Across all conditions, the average rate of patient interest in being referred for a clinical trial was 72% (see Table 2). Patient interest ranged from a low of 56% among cancer patients to a high of 83% for those with chronic infectious diseases (e.g., HIV and hepatitis).  

Table 2. Patient interest ranged from a low of 56% among cancer patients to a high of 83% for those with chronic infectious diseases.			

Factors correlated with patient interest.

Analysis suggests age, condition, and treatment satisfaction have most significant effect on participation.

Applied Clinical Trials-07-01-2012