Applied Clinical Trials
The organization of healthcare is changing rapidly. The healthcare delivery system is increasingly powered by payers and regulators, and this directs both clinical medicine and drug development. Partly because of this change, the drug development process has been heavily scrutinized, and a great emphasis has been placed on more efficient translation of basic science into useful medicines.
The organization of healthcare is changing rapidly. The healthcare delivery system is increasingly powered by payers and regulators, and this directs both clinical medicine and drug development. Partly because of this change, the drug development process has been heavily scrutinized, and a great emphasis has been placed on more efficient translation of basic science into useful medicines. In response, the pharmaceutical and healthcare delivery industries (hospitals and outpatient physician services), the two largest players in the post-clinical translational medicine process, are spending billions of dollars to make major changes in the way they operate. These changes, made at the expense of these two industries, present a unique opportunity to reinvent the clinical trial site industry.
The changing healthcare marketplace has caused healthcare providers to consolidate.1 Hospitals have either closed or organized themselves into ever larger systems, trying to capture greater market share and utilize economies of scale in order to best respond to falling reimbursements. Physicians have not been immune. The number of employed physicians has risen 34% from 2000 to 2012 as hospitals and physicians merge into integrated healthcare systems around the country.2 Approximately 60% of hospitals now utilize hospitalists, and they are rapidly replacing independent hospital staff.2 The advent of metric-based payment schedules and accountable care organizations have demanded that hospitals have more control and a better understanding of how care is conducted within their walls and in clinics. In response, billions of dollars have been spent on electronic medical record (EMR) systems that create searchable databases of unprecedented size and detail. These databases cover both the inpatient and outpatient activities of these growing integrated systems. The emphasis on up-to-date problem lists and the adoption of ICD-10 billing codes has made diagnostic documentation more precise.
The pharmaceutical industry has followed suit, driven by falling reimbursements and the growth of the generic drug industry.3 They have undergone massive consolidation, long ago shedding much of their drug development operations to contract research organizations (CROs). Early R&D is increasingly becoming the responsibility of biotechnology companies, as evidenced by Merck & Co.'s recent layoff of thousands of employees, mostly from R&D. In addition, conversion of clinical trial data capture from paper to electronic systems is just about complete.
All this activity is an attempt to adapt to the changing marketplace. In response to falling prices and rising generic competition, companies need to reduce costs to continue to sell in "commoditized" markets, such as hypertension. In addition, they need to find new markets with less competition and, hopefully, better margins (i.e., diseases without adequate treatment). Both of these strategies put pressure, albeit different types of pressure, on the drug development process.
In the pharmaceutical industry, reduction in development costs should mean shorter development times. However, clinical development timelines continues to rise. From 2000-2012, mean clinical development time has risen from 6.3 years to 6.8 years, even as the mean time to regulatory approval has been halved.4,5
Why? Because successful drug development plans now require a greater number of studies before approval than they did 14 years ago. Moreover, these studies are more complex, demanding larger pre-screen patient pools and more efficient recruitment techniques. Most new drugs, particularly those with the greatest humanitarian and economic potential, are difficult in this regard. Many orphan drugs, by definition, look at more obscure patient populations. Genomic drugs also look at greatly narrowed patient populations and require more precise data on each individual. Even more common, devastating diseases for which there is no treatment, such as Alzheimer's disease, demand more complex approaches, as simpler approaches prove to be inadequate. In all these cases, the major rate-limiting step is slow recruitment.6,7,8 The message is clear. Sites must find a way to draw from larger patient populations in a more systematized and precise way.
It won't be easy. In spite of these pressures, the clinical trials site system, designed in another era, continues to operate as a cottage industry. By definition, cottage industries lack the cohesiveness and resources necessary for sustained coordinated change. The most basic unit of clinical trial execution, where the protocol meets the subject, continues to be the individually owned clinical research site. The best of these sites are led by competent professional clinician investigators, but their patient bases and financial resources are limited.
Working within this system, the pharmaceutical industry has responded by increasing the number of sites per study; if 30 doesn't do it, maybe 200 will. This Band-Aid approach involves bringing in many novice investigators and often stretches the ability of pharmaceutical companies and regulators to ensure quality. Further, it has not resulted in a shortened clinical development time. With the entire drug development process taking an average of 15 years on a 20-year patent, time is of the essence.9
What is needed is a more efficient clinical trial unit, with greater resources, true inpatient, outpatient, and multispecialty capability, more capital, and a much larger patient base connected by an EMR system operating in real time. But how does this transition take place in such a fragmented industry? The National Institutes of Health (NIH) thinks it has the answer for NIH-sponsored research.10 In December 2011, the NIH created its 27th Institute, the National Center for Advancing Translational Sciences (NCATS). NCATS has adopted the institutional Clinical and Translational Science Award (CTSA) program that was initiated by the NIH in 2006. Under NCATS, the goal of the CTSA program remains focused on integrated "academic homes" for the clinical and translational sciences that increase the quality, safety, efficiency, and speed of clinical and translational research, particularly for NIH-supported research.
Institutional CTSAs are made to degree-granting institutions or groups of institutions that receive significant funding from the NIH. CTSAs require:
In other words, the effort should be taken seriously by the institution and should be piloted by a strong leader who has the authority to gather and direct the resources needed to get the job done. This is a tall order for a research enterprise that, by definition, has to operate across many departments and existing programs in a highly decentralized academic environment.
In spite of the difficulties of implementing this concept in academic institutions, the NIH has a few things going for it. It has the resources and, therefore, the influence to support a change in the way academic clinical research is done. In contrast, the fragmented clinical trial site industry has no such rich uncle. If the answer for the NIH is the concept of "academic homes," how would that translate into the private sector? Who will provide the capital and the drive?
We need to take a look at the process of translational medicine. Figure 1 illustrates the journey of a molecule from "first time in man" to a fully utilized member of the pharmacopeia. Molecules enter at T1, and 5% of them emerge, about 15 years later, at T4, as safe and effective drugs that are integrated into healthcare delivery systems.
A major rate-limiting step involves the planning and execution of clinical trials in T1 and T2. This job is done cooperatively between the pharmaceutical and clinical trial site industry. On the face of the matter, it may seem reasonable for the pharmaceutical industry to eliminate this step by using its formidable resources to buy sites and make them into more efficient entities.
This cannot happen, since by design, these two players must remain under separate ownership to ensure objectivity. Clinical sites-an independent contractor participating mostly in multisite studies and blinded to the drug-would have difficultly willfully influencing the outcome of a trial if they wanted to. The compensation structure, where sites are paid for work done regardless of the outcome of the trial, removes the motive to do so.
If the clinical trial site industry cannot look to pharma for the capital necessary to create a more efficient system, where can they go? They must look to the healthcare delivery industry. More specifically, competent professional clinician investigators must merge with integrated medical systems to form integrated clinical research systems. For the site wishing to integrate into the larger system, costs vs. starting a standalone site are not the issue. The key is cooperation with the system, and time and perseverance to integrate with their existing procedures and assets. However, if additional capital is needed, it can come from the medical systems, which will see the business sense of reorganizing their existing assets to provide a new service.
Integrated clinical research systems could take many forms, but are essentially research arms of large integrated medical systems, run by an experienced investigator, that has access to the larger institution's EMR and clinical resources. Installing the integrated clinical research system as the new basic unit of clinical research creates a single business unit for the entire translational process. Some of its advantages are as follows:
Broader patient base with real-time access: Integrated medical systems tie together hundreds of thousands of inpatients and outpatients in real time with EMR. The scale of the database is orders of magnitude greater than what could be constructed by a standalone site. Although size and complexity have their own problems, the power of a large integrated entity, with the necessary resources to provide data, in real time, with large number of search fields and the availability of 24-hour IT support is very different from what the standalone site could provide.
Better feasibility assessments: To better understand the power of integrated clinical research systems to develop improved development plans and protocols, let's examine the "translational train" in Figure 1 again. There are a few things to notice:
We most often think of drugs as being pushed through the drug development process, but, in fact, in the new healthcare delivery system they are more often pulled through by the payers. If there is no market for the drug in T4, then there is no sense in proceeding. Pharmaceuticals must be integrated into the changing healthcare delivery system. It is obvious that sponsors understand this, as evidenced by the adoption of "payerspeak" in many new protocols, with numerous studies having endpoints like "reduction in hospital length of stay" or "readmission rates."
Integrated clinical research systems will contain expertise across the entire spectrum of the post-clinical translational process, including knowledge of current payment systems. They can form teams that not only include clinical personnel, but everyone involved in T3 and T4, all of whom are represented in the integrated medical system. Teams consisting of physicians from all specialties, pharmacy managers, insurance company personnel, database managers, case coordination, billing, and administration can evaluate development plans on the front end, commenting on their eventual suitability for T3 and T4.
In addition, integrated clinical research systems are well positioned to advise on the feasibility of individual protocols. Instead of opinion, the percentage of potentially eligible individuals could be determined precisely, using sample sizes in the hundreds of thousands in real-world situations. This will reduce the number of costly and time-consuming protocol amendments11,12,13 and will result in better protocols, reducing the failure rate and accelerating the drug development process, particularly in T1 and T2.
Safer Phase I units: Pressure to reduce the utilization of inpatient beds have produced a surplus. Integrated clinical research systems have the capacity to place Phase I units within hospitals. This gives them access to immediate consults from all specialties, as well as the rapid response and code teams.
Increased access to capital and resources: Integrated clinical research systems have complete compliance and marketing departments, as well as fully staffed pharmacies. The system owns all diagnostic equipment necessary to run a hospital and clinic and generally employs or has relationships with doctors in every specialty.
The formation of full-scale integrated clinical research systems will be difficult and will take time. However, widespread adoption of this system will go a long way toward shortening development times by improving the design and implementation of individual protocols. More importantly, entire development plans can be made more coherent by utilizing accurate real-time information from a variety of sources at the end of the translational pathway, hopefully resulting in more and better drugs to treat the devastating diseases that afflict our patients.
Richard G. Pellegrino,MD, PhD, is President and CEO, Baptist Health Center for Clinical Research.
1. Leemore Dafny, "Hospital Industry Consolidation-Still More to Come?," N Engl J Med 370 198-199(2014).
2. Robert Lowes, "The Number of Hospitals Employing Physicians is Snowballing," Medscape, Jan. 24, 2012. http://www.medscape.com (accessed 9/15/2014)
3. Peter Loftus, "Merck CEO Sees More Drug Industry Consolidation," The Wall Street Journal, Jan. 3, 2013. http://blogs.wsj.com/deals/2013/01/03/ (accessed 4/17/2014)
4. Ken Getz, "Personal Communication," Tufts Center for the Study of Drug development, Tufts University (2013).
5. Staff writer, "How Long Does Drug Development Take?" Pharmatech, Jan. 15,2009. http://www.pharmatech.com (accessed 4/17/2014)
6. BH Chang, et al., "Patient Recruitment to a Randomized Clinical Trial of Behavioral Therapy for Chronic Heart Failure," Med Res Methodol 4(8) (2004).
7. D Ferland et al., "Recruitment Strategies in Superiority Trials in SLE: Lessons from the Study of Methotrexate in Lupus Erythematosus (SMILE)", Lupus 8 606-611 (1999).
8. PD Walson,"Patient Recruitment: US Perspective", Pediatrics 104 619-622 (1999).
9. Staff writer,"Drug Development Timeline" PKD Foundation, 2014. http://www.pkdcure.org/research/drug-development/timeline (accessed 4/17/2014)
10. Meredith Wadman, "NIH Director Wins Bid for Translational Medicine Center," Nature, Dec. 8, 2010. http://www.nature.com/ (accessed 4/17/14)
11. Ken Getz et al., "Variability in Protocol Design Complexity by Phase and Therapeutic Area," Drug Info J 45(4); 413-420 (2011).
12. Ken Getz, et al.,"Assessing the Impact of Protocol Design Change on Clinical Trial Performance," Amer J Therapeutics 15(5) 450-457 (2008).
13. Ken Getz, et al. "Measuring the Incidence, Causes and Repercussions of Protocol Amendments, Drug Info J 45(3); 265-275.