Evolutionary Thinking: Pfizer Continues to Set a New Pace for Drug Development

Pfizer’s Worldwide Development Operations (Dev Ops) group stands at the forefront of a continuing evolution in drug development that is yielding dividends in the currency that matters most to the pharmaceutical industry – improvements in quality, speed and cost.

Seven years ago, Dev Ops took a leadership position in holding the line against increasing development timelines and costs by re-engineering development of drugs emerging from Pfizer’s laboratories. It was a time when Pfizer was returning to business not-as-usual following the second of two major acquisitions in three years, and the entire pharmaceutical industry was wrestling with a host of 21st Century challenges.

In addition to cycle time and cost concerns, lower industry productivity, slowing growth in traditional markets and a rising chorus of calls for healthcare reform increased the imperative of leveraging emerging markets and aging populations.

Meanwhile, the Dev Ops group was literally and figuratively worlds apart, hampered by far-flung geography and an absence of consistent standards, systems and processes. Its full-service outsourcing model, an industry standard in which a wide variety of Clinical Research Organizations (CROs) provided services to support global clinical trials, was no longer meeting Pfizer’s needs.

In addition to swelling costs and the number of vendors requiring management, the previous sourcing model was handicapped by several factors -- an inability to leverage advantages of scale, the sheer volume of compounds in development, increased off-shoring of trials and use of emerging markets, and a lack of standardization across key service areas.

This mounting resource crisis and business risk was putting at stake Pfizer’s ability to remain competitive.

Evolution in Drug Development

Dev Ops responded with a refined drug development model that it continues to aggressively adjust today. The results: world-class quality, speed and teamwork, as well as sustained cost savings in the face of an overall trend of rising drug development costs.

At the heart of the refined drug development model has been a worldwide Functional Service Provider (FSP) advanced outsourcing model made possible by Strategic Sourcing’s use of a Reverse Auction Process (RAP) for selecting the most cost-effective service providers meeting key selection criteria. In addition, Dev Ops’ adoption of a culture of “intrepreneurship” has driven continuous improvement (CI) to meet customer needs in novel ways.

Here we will discuss the continuing evolution of Dev Ops’ refined drug development model, the benefits that have accrued to date and the adjustments and new opportunities that have emerged along the way.

FSP and RAP: Targeting Quality Outsourcing

The benefits of leveraging Pfizer’s advantage of scale through the implementation of the Functional Service Provider (FSP) model and the Reverse Auction Process (RAP) have included sustained improvements in quality, speed and teamwork -- in addition to the development cost savings of about 30% that were anticipated.

In the FSP model, external providers such as CROs perform specific functions at which they are expert -- such as monitoring, study start-up (Regulatory Documents & Contracts), data management and clinical programming -- using Pfizer global drug development systems, processes and standard operating procedures (SOPs) to assure consistency.

The engagement of FSPs reduces the burden of resourcing, permitting Pfizer project teams to focus on study design, project deliverables and vendor oversight, while having trained resources ready for new projects. FSPs are managed as an extension of the functional lines and oversight is provided within the functional line at the study team level with monthly operational review meetings and governance.

Although Pfizer uses the FSP model to resource the majority of its clinical trials, there are circumstances that may lead project teams to consider other options. In these cases, Dev Ops works with the project teams to broker the resourcing model that best matches their needs, which may include traditional full-service outsourcing or a hybrid of non-FSP and FSP models.

One critical success factor ensuring the cost effectiveness of the FSP model has been a procurement technique called RAP, an online auction in which a small, select group of preferred CROs participate. Called a reverse auction because prices start at a specific point and go down instead of up, RAP has enabled Pfizer to meet the challenges of globalization while accelerating the negotiation of competitive rates for key services. A process that used to take six months is compressed to about six weeks.

While Pfizer was the first pharmaceutical company to use RAP broadly as a means of obtaining competitive pricing from CROs, over time cost has remained a significant -- but definitely not the sole -- driver in FSP selection. RAP aids in identifying the market value for a service or activity. However, the provider posting the lowest bid may well lose the business to a competitor offering advantages of quality, speed, and a diligent management committed to collaboration and continuous improvement.

Such top FSPs, many of which surface incremental process and savings improvements over time, are recognized with Pfizer Development Operations’ Strategic Supplier Excellence Awards. Several years after their introduction, the use of FSPs and RAP continues to enable a focus on drug development cost whilst helping ensure the highest quality.

Dev Ops’ refined drug development model has also transformed the organization from a largely internally staffed group to one that is flexible, customer-focused and externally staffed. In the past five to seven years, the number of Pfizer colleagues performing clinical operations functions such as monitoring, data management and clinical programming has dropped from approximately 3,000 to 400, while the number of external colleagues has climbed from 100 to 2,400 working through 20 CROs in 10 geographic regions.

With measurable successes in quality, speed and cost under its belt, Dev Ops recently extended the use of FSPs to other services, including study management. Meanwhile, an estimated one in five other pharmaceutical companies, among them Lilly and Wyeth, have followed Pfizer’s lead by adopting similar outsourcing models.

Working Smarter with Optimized Monitoring

The recognition that all clinical trials and sites do not share identical monitoring needs led in 2008 to another refinement of the drug development model, Optimized Monitoring (OM). Thanks to OM, monitoring visits have been cut significantly, sending costs downward and the efficiency and value of monitoring interactions sharply upward.

The new monitoring model resulted from Dev Ops’ recognition that monitoring had gone off course. Monitoring visits, whose stated objective is ensuring data integrity and the safety of study volunteers, were taking place for the wrong reasons, including study recruitment. Furthermore, even with a whopping 22,000 monitoring visits in the first quarter of 2008 alone, compliance with the company’s own standards was not being met.

Working smarter is the rationale behind OM, which is based on a combination of volume and risk. Monitoring visits are redeployed where they are most needed -- to clinical sites that recruit high volumes of subjects or involve less experienced investigators; and to studies involving high-risk areas such as oncology, infectious diseases, and psychiatry, or vulnerable populations such as children.

A critical component in OM’s success has been the use of electronic data capture (EDC), which enables data to be reviewed remotely. Remote communication has also increased in importance as a means of sustaining relationships with study sites and personnel, an ongoing priority.

Separately, Dev Ops is investing additional resources into assuring the quality of protocols and site, coordinator, investigator and Institutional Review Board (IRB) training.

Pfizer has led the industry in EDC since 2000 and is now recognized as a leader in OM, an approach other pharmaceutical companies are implementing. We are further planning to implement an investigator site scorecard that will manage site performance against a number of key metrics, such as data entry timeliness, numbers of protocol deviations and study start up time.

Trial Footprint Emphasizes Speed and Quality

With the continued growth in high-quality clinical trials taking place in emerging markets, Pfizer again evaluated its resource strategies to meet changing drivers. A recent streamlining of the company’s clinical trial footprint is expected to lead to faster delivery of clinical trials, greater cost-effectiveness, and the agility that comes from concentrating clinical operations’ resources and infrastructure.

Pfizer will concentrate its clinical trials in 34 high-volume countries that were identified in 2009. The countries were selected based upon a careful analysis of country track records for enrolling clinical trial subjects, high standards of quality and compliance, and cost-effective environments.

High-volume countries, for example, recruit on average more than twice the number of suitable subjects per site than low-volume countries and are considerably faster at getting trials off the ground. As a result, between 74 and 88 percent of subjects in primary, specialty care and cancer trials underway today are in core countries.

The streamlined approach to conducting clinical trials globally is consistent with Pfizer’s recent decision, as part of the company’s ongoing business transformation, to reduce to six the number of therapeutic areas in which it will conduct highly focused research -- oncology, Alzheimer’s disease, psychoses, pain, inflammation and diabetes.

Although the vast majority of Pfizer’s clinical trials will now be conducted in high-volume countries, Dev Ops remains capable of conducting clinical studies in any country worldwide as needed, using its existing relationships with preferred CROs. Low-volume countries will continue to manage clinical trial activities until all ongoing studies conclude or close.

Clinical Research Units Aid Early Decisions

In addition to driving quality, fast and cost-saving decisions around early compound development, the Pfizer Clinical Research Units (PCRUs) make the company the undisputed industry leader for ethical and safety standards in early stage clinical research.

In 2009, Pfizer became the first pharmaceutical company to be accredited by the Association for the Accreditation of Human Research Protection Programs (AAHRPP) [1]. AAHRPP -- an independent, nonprofit agency that promotes high-quality, ethical research -- is the premier accreditation organization in the United States. Accreditation by AAHRPP, which applies to research conducted at the PCRUs, represents the “gold standard” for ensuring the protection of human subjects participating in early stage clinical trials.

The three PCRUs are located in New Haven, CT; Brussels, Belgium; and Singapore and are responsible for conducting the majority of Pfizer’s Phase 1 clinical studies, excluding oncology trials. Each unit is located within or adjacent to a large teaching hospital and is staffed by an experienced and diverse team that includes physicians, nurses, pharmacists and laboratory technicians.

Through global standardization of SOPs, processes and use of state-of-the-art technology, the PCRUs function as a single unit located at three sites. In close collaboration with project teams in the Pfizer Research and Business units, the PCRUs test a wide range of compounds including biologics, vaccines and novel new chemical entities (NCEs), and also undertake complex methodology studies.

The units are equipped with on-site technology that includes an electronic data capture system called PIMS (Phase 1 Management System) that acquires data directly from clinical instruments and pharmacies that support extemporaneous preparation of complex formulations. In addition, Biomarker Laboratories conduct in-house analyses of both laboratory and clinical biomarkers to document mechanism of action, potential clinical efficacy and, importantly, clinical safety. Database lock and table generation are routinely accomplished within 24 hours of Last Subject Last Visit (LSLV).

In addition to quality, speed, cost savings and flexibility benefits, the PCRUs are also successful in recruiting diverse populations, such as African-Americans, Hispanics and Japanese. Metrics now indicate, for example, that it is actually more cost-efficient to conduct studies of Japanese subjects in the PCRUs than it is to conduct the same studies in Japan.

Backend Services Lead in Data Management, Reporting and Disclosing Study Results

Pfizer’s commitment to increased transparency with respect to clinical trial results is the latest challenge for Dev Ops’ Clinical Programming and Writing (CPW) group, whose increasing speed at producing Clinical Study Reports (CSR) has made the company an industry leader in this area.

From database lock to final CSR, Pfizer has gone from 200 days to 80 days on average, now approaching 70 days.

The ability to achieve signed-off CSRs so rapidly enables Pfizer to accelerate its commitment to integrity and transparency in research by posting the results of its clinical trials at www.clinicalstudyresults.org  as early as possible. The results of all clinical trials have been posted since 2005, and starting in 2008, the results of all clinical studies, whether in patients or normal volunteers, were posted along with those of prospective observational studies.

Pfizer’s China Research & Development Center (CRDC) in Shanghai, which functions like an internal CRO to report all Phase 1 trials and transfer bodies of data for licensing, also plays a key role in the effort.

In the future, CPW will focus on increasing the user-friendliness of study results, developing a warehousing strategy that enhances the ability to obtain and use data effectively, and increasing the ease with which data can be disclosed and published.

In Data Management, Pfizer is an industry leader in cycle times, both in startup and release.

CI techniques such as Lean and Six Sigma have been used to streamline the study start-up process in data standards and database-building activities.

Year after year, the Last Patient Last Visit (LPLV) to Database Release metric has continued downward; this is an impressive accomplishment considering that 1.2 databases are locked each day. These accomplishments were achieved through the implementation of an Every Patient, Every Visit (EPEV) strategy, working with all team members to clean and review data on an ongoing basis. The use of EDC and the real-time data availability it provides has been a key supporting tool.

Data Management is now focused on data visualization. Using off-the-shelf tools, Data Management can utilize the real-time data emerging from the EPEV strategy to create a customized set of patient profiles and graphs that allow project teams to see the data in useful formats.

In the future, Data Management will focus on the emergence of Electronic Health Records and how such information can be used in clinical trials to reduce the burden on investigator sites. How data are captured, managed and stored is expected to change dramatically in the future due to the emergence of new technologies.

Driving Continuous Improvement into Organizational ‘DNA’

There is no question that Cl has become an intrinsic part of Dev Ops’ culture, so much so that many refer to it as having been embedded into the organization’s DNA. An integral principle of CI deployment within Dev Ops is to drive continuous improvement efforts based on process performance. By establishing a clear line of sight between its strategic objectives and process performance metrics, Dev Ops is positioning itself to focus CI efforts on areas that are aligned with the organization’s strategy.

A cornerstone of CI in Dev Ops is its process performance driven culture. Dev Ops has established a process performance management framework by assigning Business Process Owners (BPO) that have single point of accountability for quality and performance of their processes. Each BPO has decision making authority to drive continuous improvement efforts focused on improving quality while balancing speed and cost. The BPOs along with Dev Ops leadership routinely review process performance metrics. The outputs from the reviews combined with customer specifications form the basis of decisions on where to target continuous improvement efforts.

The efforts have paid off. Over the last 3 years, several flagship Lean Six Sigma projects led to significant cycle time savings and cost reductions. Among the big wins to date in Lean Six Sigma process improvements: reductions in cycle times ranging from of 39% to >60% in several clinical trial processes (e.g. Clinical Study Report and Protocol Development processes).

As individual process improvements roll out, opportunities for additional improvements emerge. Improving Cycle Time (ICT) is an example. This flagship Lean Six Sigma project is focused on improving the cycle time between Final Approved Protocol (FAP) to Last Subject First Visit (LSFV) and thus enable fast and efficient completion of patient recruitment. A series of solutions have been implemented to date, one of which is the Pre-Trial Assessment (PTA) process that demonstrated a 57% reduction in cycle time.

PTA is a process by which Dev Ops assesses the capabilities of trial sites for executing on a protocol by examining the investigator/staff qualifications and their ability to recruit subjects. The information is used to determine whether a planned trial includes the right amount of qualified sites capable of recruiting patients, a key to being able to deliver on-time results.

CI has become an integral part of the way Dev Ops manages it’s business. Lean Six Sigma and Quality by Design methodologies are now routinely applied in understanding how we build quality into our processes and thus can consistently deliver against customer expectations.

Back to the Future

Evolution and refinement of Dev Ops’ drug development model will undoubtedly continue, driven by many of the same environmental factors that triggered the start of the process several years ago.

In the current environment , Pfizer’s Dev Ops professionals operating in 40 countries on six continents remain committed to keeping Pfizer competitive and nimble by continuously increasing the speed, reducing the cost and improving the quality of clinical trial execution .

In the end, they recognize that their efforts ultimately benefit patients and doctors across the globe, among whom are family and friends, who are anxiously awaiting new treatments in development for diseases such as cancer, diabetes and Alzheimer’s disease.

References

1. AAHRPP press release, “Pfizer is First Pharmaceutical Company to Earn Accreditation,” April 2, 2009; AAHRPP website http://www.aahrpp.org/www.aspx?PageID=287

This article was printed in the September/October 2010 issue of Pharmaceutical Outsourcing, Volume 11, Issue 5. Copyright rests with the publisher. For more information about Pharmaceutical Outsourcing and to read similar articles, visit www.pharmoutsourcing.com  and subscribe for free.