Security has become increasingly important in all aspects of modern life, and clinical trials are no exception. In addition to close monitoring by investigators and pharmaceutical company sponsors, clinical trials are autonomously reviewed by Independent Review Boards (IRBs), Ethics Committees (ECs), and drug safety firms. This is where pharmacovigilance fits into the drug development process: to provide an extra level of security to ensure safe and effective products reach patients.

Pharmacovigilance, simply put, is drug safety. It is the science of understanding the adverse effects caused by a drug and assessing whether the drug benefits outweigh the risk. This includes detecting adverse events (AEs) during the clinical trial and post-marketing, monitoring and updating the risk-benefit ratio based on relevant findings, preventing and/or minimizing AEs, and, most importantly, harmonizing, and communicating findings to the relevant regulatory authorities in a timely way.

If at any time during the clinical development process the drug developer decides the risks associated with a compound outweigh its benefits, development may be discontinued altogether. By detecting safety signals early in the process, a strong pharmacovigilance system can help minimize the costs of discontinuing clinical development at a later phase.

The principle of vigilant pharmacovigilance in a clinical trial is well served by the establishment of strict eligibility criteria, which can help target the effect of a drug on a disease process with minimal interaction from comorbidities or concomitant medications. Such criteria can produce highly focused data that can be extrapolated to cover larger patient populations with a vast array of medical conditions. If the product receives marketing approval, it will be used in a far less controlled environment. One serious AE may not be statistically important in an arena with 8000 patients, but in a clinical trial of 150, it can change the course of the drug’s future.

Another benefit of pharmacovigilance is enhanced communication with IRBs, ECs, and regulatory authorities around the world. In addition to decreasing the potential for bias, global communication allows the results of a limited trial to be collated and compared to similar trials or similar drugs. Massive computer databases can be used to monitor safety signals that may not be apparent within the pharmaceutical company’s own database. As a result, the company gets a broader picture of a drug’s potential than that provided by a single trial. Such information also allows the company to lay the groundwork for a new trial without duplicating efforts from previous trials, thereby saving costs as well as time.

In today’s pharmaceutical marketplace, patients expect a medication’s benefits to outweigh its risks. Pharmacovigilance can help ensure that those expectations are met. Indeed, a robust, well-defined pharmacovigilance system, actively employed throughout the clinical development process, is the single most important process available to provide safe and effective drugs to patients around the world.

Love your smartphone? You’re not alone. According to Nielsen(1), more than 50% of all US cell phones will be smartphones by the end of 2011. The rapid growth in smartphone use has major implications for clinical trials, as the availability of inexpensive yet powerful smartphones and tablets with high-resolution displays, full touch screens, and full-time network connections will enable mobile interactive response technology (IRT) solutions to accommodate the needs of everyone involved in a study. By connecting the study team and participants in a controlled manner, new technologies will allow studies to be conducted with greater efficiency, greater accuracy, and lower cost. As changes driven by mobile IRT and other mobile clinical technologies take hold, study protocols will begin to directly leverage mobile technologies by requiring their use.If you’re a study monitor or project manager, you’ll be able to use your mobile device to view real time study reports that provide detailed enrollment metrics including screening, screen failure, randomization, and discontinue rates. Messaging capabilities within the IRT will automatically alert you to potential study issues such as low stock levels at depots, pending lot expirations, or compliance situations.

As mobile IRT becomes more common, the overlap between IRT and electronic patient reported outcomes (ePRO) solutions will expand. While ePRO systems are used at study sites to collect questionnaire input from patients, they generally do not support IRT functionality for tasks such as patient randomization, drug assignment, and drug supply management. With the ability to deploy mobile IRT support for patient ePROs, sponsors will likely choose mobile IRT to support ePRO instead of two separate systems.

As for electronic data capture (EDC) systems, suppliers may find it difficult to offer full EDC functionality using mobile technology. The requirements for complete information-gathering on case report forms necessitate inclusion of far more data points than is usually required in IRT and ePRO solutions. Such requirements will likely keep the primary EDC user interface on the desktop. However it is likely that certain aspects of EDC systems such as reporting will go mobile. Some EDC providers may also consider directly supporting ePRO data gathering by implementing mobile interfaces that are directly tied to the EDC server.

For certain types of trials, mobile IRT solutions may allow studies to be designed to combine actual study site visits with “eVisits”, whereby the patient uses the mobile device to record pertinent information. In some cases, the eVisit may utilize peripherals that complement the mobile device to allow patients to self-report key information. This capability may help lower the cost of conducting clinical trials.

As patient information-gathering applications become available in mobile form, computers in treatment rooms will be replaced by tablets, with the expectation that IRT and other clinical trial technologies will be available on these devices.

Are you intrigued by the speech recognition and text-to-speech capabilities offered by some of the new smartphones? These technologies will eventually be incorporated into mobile IRT solutions, enabling hands-free utilization of clinical applications by doctors, nurses, and site personnel. In addition to facilitating accurate information-gathering and dissemination, these applications will enable medical professionals and site personnel to focus more on their patients, while also simplifying the user experience.

Adoption of mobile clinical technologies by the user community will likely raise expectations of access via multiple devices and computers. Clinical technology providers and IT teams will need to define and execute a clear strategy to ensure consistency across the spectrum of computing devices. The expanding array of choices for users to stay connected to their studies will require study teams to increasingly rely upon robust technology and networks, thus raising the bar for reliability.

The advent of mobile IRT solutions promises to expand the communications possibilities for those involved in clinical trials. What does this mean for CROs? At the very least, CROs will need to develop and maintain expertise in matching a greater variety of technologies to the needs of particular studies. As mobile clinical technologies emerge, trial sponsors will expect CROs to propose innovative solutions that may require the seamless integration of technologies and support services from multiple suppliers. The choice of mobile devices to support clinical trials will be an important consideration, as will the management of device access for study personnel and patients. Suffice it to say that the mobile device may someday be as essential to the conduct of a clinical trial as the stethoscope.

Reference

1. Entner R. Smartphones to overtake feature phones in U.S. by 2011. Nielsen Wire, March 26, 2010. http://blog.nielsen.com/nielsenwire/consumer/smartphones-to-overtake-feature-phones-in-u-s-by-2011/. Accessed October 27, 2011.

Today’s quality challenge is how to implement a comprehensive quality program that ensures sustainable regulatory compliance and continual improvement, while contributing to improvements in business process, profitability, and customer satisfaction. Quality Assurance (QA) has a key role to play in achieving the transformation from an approach based on point-solutions to arising compliance issues, to having a harmonized, aligned quality system and culture. To become a valued partner in this transition, QA must adopt a strategic model that provides demonstrated value and constantly improving positive impact. A model that is engaging in its simplicity while retaining the key elements of more complex quality systems is the “Grip/Build/Engage” (GBE) model [1,2]. The system is designed based on the attributes of true effectiveness as demonstrated in various arenas, not just in the professional realm. An example of true effectiveness and impact is visually represented by looking at Tiger Woods’ golf swing, [http://www.youtube.com/watch?v=q3tazW9h7do]. To achieve his undeniably remarkable results Tiger Woods: • Maintains a solid grip on the ground and on the club at all times • Pulls the club away from its target, building a tension in his body while aiming and aligning • Engages effortlessly by releasing the tension and following through completely This is a powerful analogy for an effective quality system and business approach – the delivery of consistent high-impact results through aligned processes with an elegant simplicity that delights the customer. To translate this GBE approach to QA, an analogy can be made both to Tiger Woods’ golf swing and established quality models such as the Plan-Do-Study-Act (PDSA) cycle used by W. Edwards Deming [3], to describe the three overlapping phases.

Stage 1: Grip Foundations come first! A solid base is established by defining overall vision, strategy, principles, and values. This is most powerfully expressed by defining story, a narrative description of desired achievements and way of working. Balance is attained, monitoring and control activities are put in place to check results and systems, and mechanisms for taking effective corrective action are instituted. This “Grip” stage equates to the “Study” and “Act” sections of the PDSA cycle, studying first before acting to improve.

Stage 2: Build Developing people, process and structure, by taking actions that do not necessarily lead directly toward the desired goal. This stage is comprised of “important but not urgent” activities such as training and education, planning, determining strategy, and process improvement. This phase is especially critical to the eventual outcome as it will produce the acceleration and momentum needed to hit the target, minimizing the risk of unanticipated impediments or resistance. In PDSA terms, this is the “Plan” portion of the cycle; ensuring that the details have been studied, instruction and training are available and problems are anticipated.

Stage 3: Engage Engaging with people, tasks, challenges and opportunities to produce results, the “Do” part of PDSA. The overriding principle of successful engagement is to get better results with less effort through using the following principles: • Reduce waste and cut all elements that do not contribute to story and goals, or do not relate to the GBE steps. This generates time that can be re-invested more profitably. • Focus on results by identifying and concentrating on the “elusive 10%” [1, 4] of activities that will provide 90% of results. This includes maintaining efforts to achieve stated objectives in-line with the QA story, and taking care to balance activities around the different steps of the GBE cycle. • Economy of effort: by not using more resource than is necessary to achieve a given outcome, goals can be achieved more rapidly and with less resource expended. • Pro-reactivity: using reactive, routine tasks to contribute to longer-term goals, not just completing the task, but also building something bigger at the same time. Identifying and capitalizing on high-leverage activities that create the largest effect per given input. • Simplification: compliance tends to be inversely related to complexity [5]; a more complex procedure will potentially have a higher occurrence of non-compliance and will require more resource. This is a commitment to using the minimum level of complexity necessary for comprehensive solutions.

By adopting this model and striving to balance activities around the three stages of GBE, a more powerful approach to attaining results is realized. Extending the golf analogy, this prevents repeated ineffective hacking at the ball using a lot of effort (expending resource inefficiently on tasks that do not provide value) and facilitates constant improvements in quality, compliance and profitability. The GBE model is a framework to make QA more rational, principle-based, efficient, and effective. As the workplace becomes increasingly complex, adopting a structured approach allows QA to remain a focused, balanced, and valued partner in making a positive impact on our business and the customers we serve.

References

1. Principles in Quality Assurance, Part 3: Making an Impact. Jones AB. Qual Assur J, 2009; 12, 132–138 (http://onlinelibrary.wiley.com/doi/10.1002/qaj.459/abstract).

2. Principles in Quality Assurance, Part 4: Putting it all Together. Jones AB, Quality Assurance Journal, Qual Assur J 2011; 14, 18–26 (http://onlinelibrary.wiley.com/doi/10.1002/qaj.486/abstract).

3. See: http://en.wikipedia.org/wiki/PDCA.

4. Drucker PF. Managing for Results. New York: Harper and Row; 1964.

5. Get to Market Now! Turn FDA Compliance into a Competitive Edge in the Era of Personalized Medicine. John Avellanet, Logos Press, May 2010 (http://www.get2marketnow.com).

Anyone active in pharmaceutical development and marketing has surely heard the phrase “comparative effectiveness” bandied about in recent years. The phrase has become popular in political and health policy circles since Congress passed the American Recovery and Reinvestment Act of 2009, which allocated $1.1 billion to the AHRQ to fund research in this area. Although the Patient Protection and Affordable Care Act of 2010 terminated the comparative effectiveness research programs created by the 2009 bill, it preserved their funding, and a Patient-Centered Outcomes Research Institute (PCORI) was created to identify research priorities and conduct the federally funded research.

The buzz created by those legislative actions might lead one to conclude that comparative effectiveness research is a novel concept, but such studies have been conducted routinely for decades to support product approvals and marketing authorizations. Current interest in this area appears to be driven by a perception that the body of robust “head-to-head” clinical data in many therapeutic areas is relatively limited (1). Whereas placebo comparison is usually sufficient to ensure a well-designed study to support product approval, interventional Phase IIIB and IV clinical trials often involve one or more active (i.e., non-placebo) comparators, and are frequently undertaken to generate evidence of a new product’s relative efficacy, safety, or tolerability versus current standards of care. Indeed, active comparator designs are commonly used in pivotal clinical trials, particularly in support of European regulatory filings for therapies where multiple therapeutic options exist (2).

If you thought money was a major driver of interest in comparative effectiveness research, you’d be correct. As various stakeholders seek to demonstrate cost-effectiveness, “value for money” is often assessed as the incremental cost per quality-adjusted life-year (QALY) gained. In some countries specific thresholds of cost-effectiveness have been promulgated as a means to determine whether a new therapy offers acceptable value for money. Over the last two decades thousands of “cost-utility” studies have been conducted to demonstrate the comparative value of new drugs. Notably, in the US, the Affordable Care Act specifically prohibited PCORI from developing or employing a dollars-per-QALY-based measure as a threshold to establish what type of health care is cost-effective or recommended (3).

Interest in comparative effectiveness has generated a spate of head-to-head studies, which can yield valuable insights on effectiveness and cost-effectiveness, but which require great care to ensure comparability across the populations studied. This is easily accomplished in interventional research through randomization and various methods of control. Comparability is more challenging in non-interventional studies, which, while generally less expensive than interventional studies, are considered less rigorous and more prone to bias and confounding. However, a well-designed non-interventional study that minimizes threats to validity and generalizability will probably be more robust than an interventional study with design flaws, and may be nearly as rigorous as a well-designed interventional study. When study cost and time to completion are considered, the thoughtful researcher or policy maker may decide that the potential loss of rigor associated with a non-interventional study design is a risk worth taking.

What is the comparative effectiveness researcher to do with all the data that have been collected? A common approach is to use those data in conjunction with costs and other economic data within a modeling framework to estimate the cost-effectiveness and budgetary impact of various treatment options, whether with regard to an individual patient, the national health system, or an individual payer in multi-payer markets. The broad applicability of comparative effectiveness research appears to be a major reason for its popularity within our industry, although time will tell whether this will be an enduring popularity.

Comparative effectiveness research can support the establishment of funding priorities by enhancing decision-makers’ understanding of a product’s true clinical value. The debate, then, should focus on whether and how to use this information to inform coverage and reimbursement decisions. Markets experienced with rationing or queuing may be more willing to engage in such a debate than countries such as the US, where Congress’ ban on the use of comparative effectiveness data to argue cost-effectiveness may have been motivated by the desire to avoid rationing. Over the long term, comparative effectiveness research may therefore gain more policy traction in the EU than in the US. For now, it will be interesting to see how long comparative effectiveness remains a “buzzword du jour,” and whether it becomes an enduring discipline.

REFERENCES

1. Luce BR, Kramer JM, Goodman SN, Connor JT, Tunis S, Whicher D, Schwartz JS. Rethinking randomized clinical trials for comparative effectiveness research: the need for transformational change. Ann Intern Med 2009;151(3):206-9.

2. EU Standard of Medicinal Product Registration: Clinical Evaluation of Risk-Benefit – The role of Comparator Studies. London: European Medicines Agency, October 21, 2004. Available at: http://www.ema.europa.eu/docs/en_GB/document_library/Position_statement/2009/12/WC500017660.pdf. Accessed September 13, 2011.

3. The Patient Protection and Affordable Care Act. Public Law 111-148, 111th Congress, March 23, 2010.

The development of biosimilar products has become a reality, as evidenced by the significant number of “similar” biologic products marketed throughout the past decade. Although the regulatory pathway has not yet been completely defined by the US FDA, progress has been made in other markets, where a variety of guidelines have been successfully implemented which led to the approval of many biosimilars world-wide.

Due to the inherent complexity of biologics, the manufacturing and characterization processes should be thoroughly designed to ensure a product’s quality, safety, and efficacy. The establishment of “similarity,” as opposed to standard bioequivalence, follows the so-called “comparability exercise,” which includes characterization of the physicochemical and analytical properties of a biologic product, comparative bioassays and in vivo animal testing, as well as comparative immunogenicity and in vivo clinical studies. The clinical development program for a biosimilar product starts with assessing its pharmacokinetics (PK) and, whenever possible, its pharmacodynamic (PD) characteristics against the reference product. The comparability of the critical PK parameters is essential to demonstrate systemic exposure similarity. In the event differences are seen, the developers should justify how these differences would be reasonable from a safety and efficacy perspective. The comparability of the PD characteristics, when validated and relevant PD markers exist, should yield more insights into the expected therapeutic response during the clinical efficacy demonstration, and in rare cases, could perhaps be used as surrogate markers of efficacy. Usually, evidence of a biosimilar product’s efficacy and safety is not based only on PD data in healthy volunteers, but rather on Phase III data in patients in whom the clinical endpoints and acceptance margins are defined based on the targeted indication. This is required most of the time in well-controlled clinical trials in the target patient population. Should the developers plan to target another indication, other well-controlled efficacy studies would be needed particularly when the mechanism of action is different from the brand which was approved.

PK/PD studies are an important step in the comparability exercise as reliable data are necessary to support drug development and to provide direction for Phase III efficacy trials. How many Phase 1 trials would the sponsor need to plan? This is difficult to answer as each biologic should be treated specifically and the number of required PK/PD studies will vary from one biosimilar program to another, depending on the knowledge of the product’s PK characteristics, the extent of available PK/PD data in the literature, and the relevance of non-clinical data. One may think about more than one dose and in the event the product is to be administered via two different route (e.g., subcutaneous and intravenously), we may think about assessing head-to-head comparability using the different doses and the different route of administration.

The study population must be carefully selected, as it should enable detection of any potential differences between the innovator and biosimilar products. Usually, healthy volunteers are considered the most sensitive model to demonstrate biosimilarity, and they do not pose the risk of interference or bias caused by the disease itself. Ideally, PK/PD studies should use predefined and justified acceptance criteria based on clinical safety and efficacy. However, in case the product is known to be cytotoxic or inducing serious adverse events, the targeted patient population should be used. The sponsor would need to consider this aspect not only from an investment standpoint but also from a recruiting and timelines perspective. The targeted population may also be under other medication which may interfere with the study drug in-vivo but also during the bioanalysis.

Standard acceptance criteria for traditional generics (i.e., a 90% confidence interval [CI] falling within 80-125% for key parameters) may not be appropriate for biosimilars depending on the products’ characteristics and relevance from a clinical application. In some cases a wider acceptance range for some PK paramters such as AUCt (e.g., 90% CI falling between 75%-133%) may be justified. The criteria should be considered when determining the sample size to power the study. Stringent criteria will require more subject to achieve at least 80% power to meet them. Also, developers should also think about the parameters to measure, such as maximum concentration (Cmax), AUCinf, time to Cmax (Tmax), half-life, and clearance, in addition to AUCt, which is usually the primary PK parameter for biosimilars.

It is clear that biosimilar development is not an easy task as it is the case for chemically synthetic products. Sponsors would need to work together with an expert CRO to plan what would a scientifically sound plan and discuss this with the intended regulatory agency in a step- by-step approach. It is critical to determine with the agency what would be reasonable and how to move from one step to another. A pre-IND meeting and scientific advice are excellent opportunities to have that discussion with your CRO.

By simulating natural patterns of therapy, observational study designs create conditions for high patient compliance with study procedures. Participants see involvement with the study as a logical extension of their treatment. However, when observational studies lack clear objectives, inclusive patient eligibility criteria, easily quantifiable endpoints, or a single method for collecting data, patient participation can be compromised. Without such discipline, study designs grow increasingly complicated, deviate from standard of care, offer patients few reasons to participate, and ultimately limit one of the major goals of observational research: to gather information that reflects standard of care.

Some factors that can help enhance patient compliance to better ensure observational research data is as representative and meaningful as possible are:

Choosing the Right Method for Data Collection: Patients are generally willing to participate in observational studies and complete outcomes-related questionnaires, unless the amount of information to be collected is onerous or the mode of collection represents a significant imposition. Observational studies work best when procedures conform to standard clinical practice. Whereas various approaches (e.g., patient diaries, interactive voice response telephone systems, use of a dedicated website) are available to collect patient-reported outcomes, the most widely accepted approach is to obtain data when patients return to the physician’s office.

Choosing the Right Data to Collect: All successful observational studies begin by identifying a tangible goal and working backwards to determine what type of data should be collected to achieve the desired result, as well as how much data are needed. These decisions will influence the burden the study places on patients, investigators, and their staff, and therefore the willingness of these individuals to comply with the project requirements.

Maximizing Participation of Patients and Sites: Maintaining a high level of engagement with investigators and patients throughout the duration of an observational study is critical and requires a carefully considered and focused approach. Given the close relationship between such engagement and compliance, the following approaches can enhance the shared sense of community that is essential to successful observational studies:

• Establishment of a Scientific Advisory Board: In addition to providing input into study design and publication initiatives, a well-constructed advisory board can provide encouragement and/or inspiration to participating sites throughout the course of the study, creating a clear and compelling rationale for both sites and patients to join the project.
• Branding: Observational studies benefit from a clear, recognizable, and memorable visual identity applied consistently to all study-related materials.
• Benchmark reporting to physicians: Observational studies often include a large percentage of research-naïve physicians who value the opportunity to contrast their experience with that of other practitioners. Benchmark reporting can provide useful insights into characteristics and optimal uses of new products that can be associated with “best practices.” .

Traditionally, clinical trial application (CTA) approval in EU member states was subject to national legislation. Consequently, assessment of a CTA that was filed simultaneously in several member states often resulted in varying final decisions and unnecessary delays. Country-specific modifications to the application often occurred due to changes requested by the different competent authorities and ethics committees. In some cases, a clinical trial might be approved in one member state and rejected in another. The entire procedure could be extremely time-consuming and the country-specific modifications might dilute the scientific value of trial results.

In response, the EU Heads of Medicines Agencies (HMA) in 2004 established a Clinical Trials Facilitation Group (CTFG) to coordinate the implementation of the EU clinical trials directive 2001/20 EC across the member states. The directive was guided by calls for harmonization of the assessment of multinational CTAs, as well as by the need to protect clinical trial participants, ensure high-quality research, and bring innovative medicines to patients as quickly as possible. In 2009, the CTFG proposed a Voluntary Harmonization Procedure (VHP) to streamline the assessment of multinational CTAs in order to enlarge the scope of the pilot phase and shorten the timelines.

Despite the fact that all members of the EU (excluding Poland) have accepted the VHP as a valid approach to gaining clinical trial approval, many trial sponsors and CROs have yet to use it. This reluctance is due to a number of factors. One is the perceived risk associated with a new procedure. Lacking familiarity with the process, some sponsors may fear it might not be as effective as promised and may choose to follow established, more commonly used processes. Another factor is the fact that the VHP is free-of-charge: many sponsors believe that non-paid approval procedures are of low value compared to submissions which are subject to a fee.

Although more efficient promotion might have generated wider acceptance of the VHP within the industry, it has proven to be a low-risk and highly beneficial procedure, with more than 50 successful applications completed to date. As more concrete results demonstrate its utility and a greater understanding of its benefits is communicated, more widespread adoption of the VHP can be expected.

The VHP provides two main advantages: time efficiencies and uniformity. Sponsors no longer need to interface individually with different national agencies, repeatedly answering similar questions and losing valuable time. The procedure is fully harmonized and consolidated and all national agencies involved in approving a clinical trial are simultaneously aware of the sponsor’s information, resulting in faster commencement of the trial.

One important benefit of the VHP is that it can be initiated early on, before sponsors have finalized all information about a clinical trial. In such cases, the application form needs to contain detailed, top-line information about the trial, but other information, such as the names of trial sites and/or investigators, can be provided when submitting the country-specific application, following VHP approval.

An additional time-efficient characteristic of the VHP is that once approval has been granted, any modifications to the study protocol requested by the VHP and accepted by the sponsor are incorporated within the procedure, obviating the need to file a protocol amendment. Prior to establishment of the VHP, sponsors wishing to introduce such modifications requested by the agencies of the participating countries during their initial study protocol review could only do so by resubmitting the protocol amendment to each of the concerned agencies.

The VHP procedure allows for incorporation of additional EU countries even after a trial is VHP-approved. In such cases, each additional country may accept the existing VHP approval and allow the sponsor to proceed with the country-specific application, with final approval coming 10 working days after submission of the country-specific dossier. Following the clinical trial approval, additional protocol amendments can be submitted to the VHP Committee for their assessment and approval in a manner similar to the initial approval. The VHP procedure again provides time efficiencies and uniformity in the approval of protocol amendments.

By consolidating multinational CTA activities within a single submission, the VHP procedure offers a streamlined approval process for all technical documentation for every country/agency involved, potentially saving sponsors up to two months’ time in setting up and initiating clinical trials. With the VHP being the CTA approval pathway of the future, sponsors and CROs should consider its use now when planning future pan-European clinical trials.

In its recently released draft guidelines on similar biological medicinal products containing monoclonal antibodies (mAbs)¹, the European Medicines Agency (EMA) seeks to establish a practical pathway for the approval of such products. While the establishment of biosimilarity for mAbs would require biologically based studies (e.g., binding studies and functional assays) as well as clinical studies, the draft guidelines offer developers of such products some important flexibilities, among them the ability to use surrogate endpoints in clinical trials.

Employing available and appropriate surrogate endpoints, such as tumor-response rates over specified time intervals in trials of anticancer therapies, is expected to become a key strategy for companies seeking to develop biosimilar mAbs for European Union (EU) markets, as such endpoints provide a degree of maneuverability in designing clinical trials. Indeed, the draft guidelines suggest a willingness on the part of the EMA to consider novel trial designs, in keeping with the aim of demonstrating comparability as opposed to re-establishing efficacy.

A key potential benefit of surrogate endpoints is that their use may limit the size of trials to feasible levels. This benefit can be achieved without compromising one of the goals of biosimilar development, which is to front-load the development program with as much pre-clinical information as possible. Even moderately powered equivalence trials against an established disease end-point would likely involve large numbers of study subjects -- potentially requiring a larger number of subjects than were involved in trials supporting the original approval. This is especially true in cases in which the drug effect is modest (15-20%), as is often the case with mAbs used in anticancer treatment. By limiting trial size, the use of surrogate endpoints would not only be more economical in terms of program development costs, but might also be considered more ethical, as it could reduce the extent of human clinical trials. Investigators would still need to demonstrate similarity at every step and explain any differences to the reference drug as they arise. That is an important consideration for mAbs, which are among the more complex of the therapeutic proteins.

However, reducing the number of trial participants for efficacy studies through novel trial design could be a double-edged sword, as a relatively small sample size might not be enough to generate sufficient safety and immunogenicity data. To illustrate, consider the hypothetical case of an innovator mAb that produces an immune response at a 1% level. If, for example, it was necessary to rule out a potential doubling of the immune response with the biosimilar mAb at a significance level (alpha) equal to 0.05, with 80% power, approximately 1,400 subjects per arm would be required. If the rate of immune reactions for the innovator mAb was less than 1%, or if the biosimilar mAb manufacturer were required to rule out a smaller difference in relative immune rates, or both, still larger trials would be required. Such trials would, in most instances, be significantly larger than the clinical trials that were originally carried out to demonstrate the safety and efficacy of the innovator product. Immunogenicity trials for interchangeable biosimilar products might still be larger, given the additional requirement to demonstrate that alternating between the innovator and biosimilar would not result in an immune response that is greater than that for the innovator alone.

Over time, the EMA’s draft guideline will likely evolve into an overarching mAb document, complemented by guidelines on the use of mAbs in specific indication areas, such as oncology or inflammatory conditions. At the same time, while the draft guideline makes possible the extrapolation of mAb indications, this would be difficult without clinical trials.

As these issues take on increasing relevance in future iterations of the draft guideline, and as more is learned about the mechanisms of mAbs, the U.S. FDA, other regulatory bodies around the world, and the industry itself will surely continue to follow the EMA’s deliberations with great interest.

¹Committee for Medicinal Products for Human Use (CHMP). Guideline on Similar Biological Medicinal Products Containing Monoclonal Antibodies (draft). London, UK: European Medicines Agency, EMA/CHMP/BMWP/403543/2010, November 18, 2010. http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2010/11/WC500099361.pdf. Accessed May 9, 2011.

 

According to the Congressional Budget Office, a viable market for biosimilar products may save consumers and health systems as much as $25 billion over 10 years as newly approved biosimilars drive the prices of biological drugs downward¹. Such expectations of rapid growth amid significant cost savings are exerting considerable pressure on biopharma manufacturers as they strive to remain competitive within a volatile marketplace.

The expected growth of the biosimilars market has prompted the FDA and other legislative bodies around the world to introduce regulatory pathways to ensure these products’ safety and efficacy. In March 2010, the U.S. Congress passed the Patient Protection and Affordable Care Act², which provides an approval pathway for biosimilar products. The Act defines a biosimilar as a product that is highly similar to the reference biological product, notwithstanding minor differences in clinically inactive components, and which exhibits no clinically meaningful differences with the reference product in terms of safety, purity, and potency. The Act stipulates that assessment of similarity/comparability should encompass the totality of data, including analytical data, animal testing data, and clinical data on the immunogenicity, pharmacokinetics, and pharmacodynamics of the biosimilar product.

The signing of the Patient Protection and Affordable Care Act, which includes the Biologics Price Competition and Innovation Act, paves the way for establishment of a regulatory framework in the U.S. by which manufacturers of biosimilars can secure marketing approval from the FDA. Not surprisingly, many companies engaged in development of biosimilars are seeking to ensure an efficient approval pathway as they strive to reduce time to market – processes that can be facilitated through appropriate outsourcing.

The manufacture of biosimilar drugs requires specialized capabilities, meticulous planning, highly skilled staff, and significant financial investment in equipment, technology, materials, and personnel. For many companies, such a level of investment can strain resources and dilute overall success. As a result, companies with biosimilar drug candidates are increasingly turning to contract manufacturing organizations (CMOs) and clinical research organizations (CROs) that already offer the proficiency, staffing, and state-of-the-art technology for developing and validating analytical methods, preclinical and clinical development strategies, and biomanufacturing processes. Manufacturers are increasingly outsourcing to CROs that provide a full spectrum of services encompassing drug discovery, development, and preclinical and clinical trial processes. These capabilities can include preclinical evaluations, study design, trial management, data collection, statistical analysis, and fulfillment of regulatory requirements. In addition to facilitating access to a wealth of solutions, technology, and equipment, CROs can provide a wide range of expertise, having often been involved in the development of the original biological products. Such expertise can be extremely useful to biosimilar manufacturers throughout all stages of development, particularly when technical issues arise.

A fundamental benefit of outsourcing is reduced pressure on companies’ own resources and the ability to free up capacities for innovative or high-margin products. Outsourcing can also enhance capital efficiency, enabling companies to fund their research cost-effectively, while obviating the need to invest in expensive equipment, software, and the personnel to operate them. Such savings can be crucial to a company before its biosimilar candidate has demonstrated viability in terms of regulatory and marketing potential.

Some outsourcing providers also have special expertise in applying techniques such as mass spectrometry to characterize and profile biologics. For biosimilars, these providers can also conduct comparative analyses with a reference product and offer high-quality immunoassay and bioanalytical services. In terms of clinical trials support, outsourcing providers can offer a wide range of technologies including electronic data capture (EDC) and management systems, and can also implement risk management plans through follow-up systems such as Web-based patient registries.

Although biopharmaceutical companies face a host of challenges in developing biosimilar products, these challenges present clear and promising market opportunities. Outsourcing may enable such companies to accelerate time to market in the most cost-effective manner. CMOs and CROs, with their wealth of knowledge, experience, understanding, technology, skills, and financial control, can make outsourcing a solution that companies can use to their advantage.

¹Congressional Budget Office Cost Estimate. S.1695: Biologic Price Competition and Innovation Act of 2007. Washington, DC: Congressional Budget Office, June 25, 2008. United States Congress.

²The Patient Protection and Affordable Care Act. Public Law 111-148, March 23, 2010. http://www.gpo.gov/fdsys/pkg/PLAW-111publ148/pdf/PLAW-111publ148.pdf. Accessed May 5, 2011.

 

Many biopharmaceutical companies have experienced financial pressures exacerbated by the global recession. However, these pressures provided the incentive for the industry to take a fresh look at the innovation process as a means to accelerate drug development and make it more cost-effective. For some larger companies, this has led to a relaxed “guardianship” of intellectual property, as evidenced by sharing of assays and compound libraries with government and academic research organizations, as well as with smaller biotech companies, in an effort to facilitate identification of early drug candidates.¹

At the same time, many drug makers are pursuing more aggressive outsourcing strategies as a means to increase the volume of quality data while reducing time to market.² Consequently, clinical trial sponsors increasingly view CROs as partners with whom they can build relationships and infrastructure to create integrated systems and harmonize standard operating procedures and business practices.

As sponsors have become more reliant on outsourcing, this has prompted CROs to develop new business models and to strengthen continuous improvement initiatives while collaborating with their biopharmaceutical partners on pipeline-rebuilding strategies. Such efforts, combined with an industry-wide normalization of project cancellations and a strong recovery in late-stage development (Phase II-IV studies), have fueled CRO growth in recent years.³

CROs make for attractive partners because their diverse client rosters and range of therapeutic experience allow them to cast wider nets than some biopharmaceutical companies, and they frequently have more recent experience in a particular research area. These credentials can be helpful in developing sound protocols and boosting patient recruitment.⁴ CROs can help trial sponsors adapt to the changing environment through technological savvy, flexible staffing, and novel approaches to registrational trials. They can also provide crucial support for Phase IV studies which are designed to answer questions about a product’s post-marketing use, safety, and effectiveness. CROs can thus help companies address post-marketing studies in a more focused manner, making these studies’ designs far less complicated and more cost-efficient to implement.

Nevertheless, CROs must rethink their relationships with sponsors to address their new approaches to product innovation and development. Some CROs are adopting risk-sharing models whereby they invest in development of novel drug candidates, which may generate revenue through milestones, payments, and royalties. Such models may incorporate time-based incentives and disincentives, upfront discounts with downstream benefit (pending product approval), or asset transfers with service contracts.

In short, CROs can add measurable value to the drug innovation and development process – an important consideration in a changing business environment that places a premium on performance metrics. As their role continues to expand, CROs will increasingly be viewed as an extension of their sponsors, a characterization that should help the industry continue to thrive well into the 21st century.

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¹Koch K. Can open innovation solve pharma’s productivity crisis? Hypios.com Web site. http://www.hypios.com/thinking/ 2010/06/10/Can-open-innovation-solve-pharmas-productivity-crisis. Posted June 10, 2010. Accessed January 17, 2011.

²Lipp E. CRO relationships get more serious. Genetic Engineering News 2010 Jul 1;30(13). http://genengnews.com/gen-articles/cro-relationships-get-more-serious/3346/. Accessed December 22, 2010.

³Data on file. PharmaNet Development Group, Inc., 2011.

⁴Clinical Trial Patient Recruitment (PH140). Durham, NC: Cutting Edge Information, 2010. http://www.cuttingedgeinfo.com/clinical-trial-patient-recruitment/. Accessed January 17, 2011.