Regulatory and non-governmental initiatives prioritized pediatric drug research to address unmet clinical needs and to improve the accessibility to the pediatric population of innovative and safe medicines. In return, prolongation of patent protection has been offered by the regulators as an incentive and a reward. However, the execution of pediatric clinical studies presents unique challenges in terms of the requirement for specific designs, technical issues. and ethical considerations.

 

Increasing competition for patients has resulted in the globalization of trials, sometimes into emerging territories with associated need to address ethical and experience issues. The increase in complexity of clinical studies in children and the need to invest in solutions to solve these challenges have driven up the cost of pediatric clinical research. Managing these costs to ensure a return on investment is critical if the goal of improving the health of children through ethical and scientifically sound drug development is to be achieved.

 

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).

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.

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.

Under the present global operating environment, pharmaceutical and biotech companies face far more challenges with running clinical trials as fewer blockbuster drugs are making it to market. Limited financial resources, escalating costs, and intense pressure to bring new drugs to market are driving our clients to seek more methods to improve the efficiency and effectiveness of their clinical trials.

Over the past several years there has been a gradual paradigm shift in designing clinical trials that has come to be known as ‘Adaptive Trials’. More and more companies are adopting this method of conducting trials since it can provide a more cost efficient and effective way of running clinical trials. IRT systems are often an integral part of supporting adaptive trials and thus an essential tool that enables the smooth conduct of the trials with an adaptive design methodology.

The FDA defines adaptive trials as: “A study that includes a prospectively planned opportunity for modification of one or more specified aspects of the study design and hypothesis is based on analysis of data from subjects in the study.”

Adaptive trials require comprehensive planning and collaboration during the initiation phase from all stakeholders involved on the study design. Adaptive trials typically require certain team members to receive and review real time subject data on a periodic basis. Analysis of the data enables study teams to execute a defined change strategy as the study progresses. Decisions can be made to make changes as listed below but the change criteria and decision making has to be specified and defined up front during the protocol definition phase. Some common adaptive trial strategies include:

• Stopping the study early for utility or futility
• Modifying the sample size of the patient population by altering randomization schemes
• Adding or dropping a treatment arm

The biggest challenge in conducting a successful adaptive trial is the planning and logistics that surround the change strategy. This strategy must be carefully planned and incorporated in the trial with a comprehensive risk analysis of how changes will affect study logistics and how they will be integrated seamlessly, swiftly, and correctly. The use of technology can play an important role in this process, and is often an integral part of the study design. Since the change criteria are defined during the initiation phase, support for the adaptive trial design aspects need to be planned and built into the trial management systems including the IRT.

A well designed IRT is a key enabling technology in the successful conduct of the adaptive trials. The use of IRT system is important due to the following reasons:

• Access to real time data 24x7 Since frequent and timely analysis of the data is a key aspect of adaptive trials, real time data on patient recruitment, treatment, dosing and visit information can be made available to the study teams through the interactive reporting capabilities of the system.
• Controlled, dynamic adjustments that support the change criteria The IRT must be programmed and validated for to support the defined change scenarios. This allows study managers to switch to a new randomization scheme or turn off a treatment arm in an automated way via the system that ensures integrity of the study data. Changes can be implemented almost immediately with little or no downtime.
• Appropriate and optimal drug supply management Planned changes executed during the course of the study can have considerable impact on the drug supply at sites. Dropping or adding a treatment arm or deciding to change the treatment allocation ratios requires that the correct drug type and quantities continue to be supplied to the sites in the correct amounts. The IRT supply management must account for such changes so that the sites can continue randomizing and dosing patients without interruptions. This is accomplished by having the IRT automatically trigger the corresponding changes to the inventory management scheme; adjusting to supply the appropriate kits and quantities to the sites. This way sites are almost guaranteed to have the right treatment kits available in their inventory regardless of changes made during mid trial. Furthermore data collected in the IRT can help drug supply managers to run more realistic simulations to forecast optimal drug quantities and packaging runs needed for the remaining trial.

It may take as long as 5 to 10 years for a drug development program to progress through its requisite phases: drug discovery, preclinical development, clinical trials, marketing approval, and post-approval controls (including Phase IV studies). With so much riding on the outcome of such programs, pharmaceutical and biotechnology companies are increasingly likely to invest considerable time and resources to enhance the probability of success. Yet despite the dramatic increase in drug development expenditures over the last decade, the number of new chemical entities (NCEs) has actually decreased. Indeed, the industry has been plagued by high late-stage attrition rates and safety issues, creating a major problem not only for drug developers, but also for regulatory agencies, patients, and society in general. Clearly, the current trend toward larger and more costly drug development programs is not sustainable. New approaches and new science are needed to transform drug development.

A new paradigm focuses on “frontloading” safety and efficacy information in drug development, including early evaluation of compounds in humans as a means to make development programs more flexible in their design. The approach is based on the premise that projects should fail (whether due to a lack of efficacy or to safety/toxicity problems) as early as possible: driving the attrition rate early (i.e., to the proof-of-concept stage instead of Phase II or later) should improve the probability of success for late-stage projects. Flexible design has been facilitated by advances in genomics and proteomics, which have yielded a host of novel disease targets, several of which are human-specific. Such advances have also engendered the discovery and development of predictive tools, translational biomarkers, and new experimental models that can provide pharmacologic information at low doses. By enabling earlier evaluation in humans, flexible design offers many advantages, among them allowing for key decisions at single/few doses; minimization of subject exposure to ineffective medicines; minimization of animal usage; and earlier assessment of a compound’s benefit/risk ratio. These advantages confer the ability to terminate development of molecules that probably will not succeed clinically as early as possible.

A number of regulatory initiatives have helped to facilitate the new paradigm. The recently revised multidisciplinary International Conference on Harmonisation (ICH) M3 guideline , which focuses on non-clinical safety studies, allows for flexible design and the use of new methodologies in early human studies that seek to demonstrate “proof of activity” instead of tolerability. The ICH M3 guideline, which has been adopted by regulatory authorities in the US, European Union, and Japan, outlines several types of flexible designs for first-in-human trials including microdose trials (≤100 μg single dose or ≤500 μg cumulative dose per individual); single-dose trials starting at subtherapeutic doses; and multiple-dose trials for up to 14 days to determine pharmacokinetics and pharmacodynamics. In addition to allowing for fewer doses than those typically administered in conventionally designed trials, these flexible designs also may obviate the need to reach the maximum tolerated dose (MTD), thereby potentially sparing large numbers of trial participants from a variety of drug-related adverse effects. Flexibly designed exploratory studies may also enable less extensive – and less expensive – toxicology programs; for example, if a single low dose of a radiolabeled compound reaches its target receptor, a full 14-day toxicology study probably will not be necessary.

The amount of non-clinical data to support different types of exploratory trials will depend on the extent of proposed human exposure, both with respect to the maximum clinical dose and the duration of dosing. However, in all cases, the non-clinical requirements for flexibly designed exploratory trials are reduced compared to those for non-exploratory trials. The flexible-design approach can thus be a viable alternative not only for large pharmaceutical companies in terms of selecting promising candidates, but also for small companies that need to show proof of activity or principle in humans as a means to secure financial support to continue to sustain a drug development program. Already, the new paradigm appears to be catching on: in the UK, roughly 25% of Phase I studies are exploratory trials that incorporate a flexible design. Importantly, the flexible-design approach may not be appropriate for every program; the choice of an explorative vs. conventional design is one that should be made on a case-by-case basis. Nevertheless, as more companies around the world recognize the value of flexible design in devising tailor-made drug development programs, the industry stands to benefit from shortened development timelines and greater late-stage success rates.

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International Conference on Harmonisation. ICH topic M 3 (R2): non-clinical safety studies for the conduct of human clinical trials and marketing authorization for pharmaceuticals (CPMP/ICH/286/95). European Medicines Agency Web site. http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500002720.pdf. Published June 2009. Accessed September 23, 2010.

Today’s fast-paced drug development environment is characterized by the generation of voluminous amounts of data at a breathtaking rate. Drug developers are under increasing pressure to collect and analyze data in order to facilitate timely decision-making. Indeed, the ability to efficiently extract pertinent knowledge from new data is the cornerstone of successful and cost-effective drug development.

Drug developers are therefore making increasing use of extractive tools such as pharmacometrics, “an emerging science that quantifies drug, disease and trial information to aid efficient drug development and/or regulatory decisions,” as defined by the FDA. Pharmacometrics makes extensive use of drug models “to describe the relationship between exposure (or pharmacokinetics [PK]), response (or pharmacodynamics [PD]) for both desired and undesired effects, and individual patient characteristics…These Pharmacometric analyses are designed, conducted and presented in the context of drug development, therapeutic and regulatory decisions. The single-most important strength of such analyses is [their] ability to integrate knowledge across the development program and compounds, and biology.”1

Pharmacometrics takes large amounts of data from various phases of clinical development and tests hypotheses through computer-based simulations. This process frequently involves estimation of PK and PD and development of clinical outcome models, as well as evaluation of different study designs, in order to understand the impact of variables such as dosing strategies, patient selection criteria, and selection of clinical endpoints.

Both the FDA and EMA have issued extensive regulatory guidance documents focusing on pharmacometrics or in which pharmacometrics methodologies are advocated. Increasingly, the FDA requests the inclusion of pharmacometric analyses in submission packages and often performs such analyses when evaluating a sponsor’s submission.

The pressure to reduce development costs borne by pharmaceutical companies, the FDA’s increasing interest in predictive as opposed to descriptive analytical methods, and the availability of analytic tools are making pharmacometrics more feasible and attractive to CROs as service offerings. Nevertheless, pharmacometrics remains a specialized offering and PharmaNet is one of five CROs who are able to provide these services.

Pharmacometrics has become a key specialty area at PharmaNet Canada, where we provide modeling services to inform clients’ critical decision-making processes. Our pharmacometrics service offerings cover all stages of drug development, starting in the non-clinical setting, in which toxicology, PK, and PD data from various species can be used to model human exposure, adverse events, and clinical responses, factoring in various doses and regimens to help design informative first-in-human studies.

In Phase I, pharmacometrics is used to extract essential knowledge regarding PK (e.g., dose- and time-dependence, effect of demographic variables, effect of food, drug-drug interactions) and PD (e.g., adverse event profiles, biomarkers, QT prolongation, early clinical efficacy findings). This knowledge is leveraged to optimize Phase II study designs through simulations.

Results of Phase IIa studies are used to refine models for adverse events profiles, biomarkers, and clinical outcomes to inform the design of Phase IIb studies. At this stage, sparse PK sampling data can be merged with PK data from previous studies to enable extrapolation of sound PK parameters and to provide robust exposure-response models. These models can then drive Phase IIb study design through biomarker and clinical outcome simulations.

A pharmacometrics-driven approach throughout the development process should yield sufficient information to perform clinical trial modeling that takes into account PK/PD, efficacy, disease, and patient characteristics. Ultimately, the approach should allow performing full-fledged Phase III trials in silico through clinical-trial simulations, allowing the testing of various efficacy study scenarios, which can mitigate the chances of primary outcome failure.

The above processes are often the apanage of big pharmaceutical companies and regulatory agencies. Pharmacometrics services at Anapharm and other CROs can help sponsors answer more specific questions. Our work normally relates to population analysis methods, where the interest is in identifying correlates of exposure and response to elaborate dosing recommendations, as well as obtaining exposure-response information in special populations. Population methods are now commonly included in submission packages and will continue to gain importance, thanks to regulators’ growing interest in these methods. Other modeling service offerings at Anapharm include allometric scaling, in vitro–in vivo correlations, and time-to-event analysis. As sponsors and regulators continue to pay increasing attention to such analyses, the importance of pharmacometrics will loom ever larger in drug development.

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[1] Pharmacometrics at FDA. Rockville, MD: U.S. Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER). http://www.fda.gov/AboutFDA/CentersOffices/CDER/ucm167032.htm.  Updated September 22, 2010. Accessed October 5, 2010.