Investigators as Suppliers

Let's propose that in clinical development, investigators are suppliers. If this is the case, then sponsors can use supply chain management principles to help guide their relationships with investigators. Based on this proposal, the following article explores five supply chain management principles that have relevance for clinical development and specific ideas for how sponsors can apply them.

Clinical development & manufacturing

Supply chain management principles have usually been associated with manufacturing processes and therefore have not typically been applied to the process of clinical drug development. Clinical development professionals, after all, do research; they do not produce anything that requires raw materials from external suppliers. Instead, they collaborate with private physicians to conduct studies. If a new product is proven to be safe and effective, they pass the product over to their manufacturing colleagues who then need to worry about how they will work with suppliers to acquire the materials they need to make the product.

However, a closer look at the clinical development process reveals more parallels with manufacturing than first meets the eye. Like any process, clinical development has inputs, internal processing, and outputs (see Figure 1). Inputs are the new product candidates from preclinical research. Throughputs are the studies that development professionals design and conduct. Outputs are the clinical study reports that eventually become components of a marketing application. Hence, the mandate of clinical development is to "manufacture" clinical study reports.

Figure 1

Looking at the process from a supply chain perspective, clinical development can be viewed as a company with suppliers and customers (see Figure 2). The supplier is preclinical research (and/or the licensing department), and the customer of clinical development is the regulatory agency that eventually grants permission to market the product.

Figure 2

Depending on how the larger pharmaceutical, biotech, or device company is organized, clinical development's customer might be an internal regulatory affairs or regulatory submissions department whose specific responsibility is to keep abreast of the customer's (the regulatory agency's) requirements and to ensure that clinical development's product meets those requirements (see Figure 3).

Figure 3

In any case, for clinical development to "manufacture" their products (i.e., clinical study reports), they are dependent on a system of suppliers.

Understanding the role of investigator

Without question, the most challenging suppliers in need of management in this process are clinical investigators. This is not to suggest that physicians operate only in the role of investigators. They are of course still physicians, concerned primarily with providing quality care to their patients. However, when physicians take on the role of investigator they agree to provide the data that will become the essential raw material of a clinical study report.

Given the complete dependence of clinical development on a reliable supply of accurate and timely patient data, one would expect a dedication of resources commensurate with ensuring that every potential contributor to a win-win relationship with the investigators/suppliers is in place. Amazingly, however, investigators are typically the most undermanaged component in the clinical development supply chain.

Undermanagement is not necessarily intentional. Rather, it seems to be a case of unawareness of supply chain management principles or a reluctance to apply the model to a scientific research endeavor—as though application of a business model might somehow jeopardize the integrity of the science.

Another reason for the absence of supply chain management principles in clinical development is confusion over the role of investigators. For example, the clinical development organization of one top five pharmaceutical company did not view investigators as suppliers but as customers. The confusion is somewhat understandable: Investigators are potentially prescribing physicians—one of the company's ultimate customers. However, treating investigators as customers during clinical development is like Toyota treating its tire supplier as a customer because they want the tire supplier to buy Toyotas. Listening to the voice of the customer is a fine idea, but it does not really apply when the "customer" is a supplier.

If clinical development sponsors were to look to supply chain management for guidance on how to manage their relationships with investigators, they might find some very applicable pieces of advice. What follows is a sampling of supply chain management principles and examples of how these principles might be applied to clinical development.

A win-win situation

One piece of supply chain management advice is to create a win-win situation between the company and its suppliers. This is largely achieved through a contractual framework. Contracts or agreements should be structured so that when the terms of the agreement are met, both the company and the supplier get what they each need.

All clinical development sponsors negotiate contracts with their investigators, usually on a study-by-study basis. Typically the sponsor has established standard fees for clinical procedures, which are rolled up into per visit or per patient totals. Contract negotiations are then largely a matter of sponsors trying to pay less while investigators vie for more. A best case scenario outcome for these negotiations is for the sponsor to pay slightly less for some procedures and for the investigator to get slightly more for others. Then, both parties feel as if they won part of the negotiation.

Granted, money is an important component in establishing a win-win situation between sponsors and investigators. Ultimately, both sponsors and investigators need to make a profit. But is there a way for sponsors to structure payments so that the better an investigator performs the more money they receive, while at the same time keeping the overall cost of the study for the sponsor within budget? We believe there is, and we will return to this issue later in the section entitled "Create a relationship between compensation and performance."

Apart from money, are there other factors that can contribute to establishing a win-win relationship between sponsors and investigators/suppliers? Are there things besides money that investigators need or want from participating in a clinical trial? The only real way to answer that question is to talk with individual investigator candidates. Potentially, an investigator might consider the following outcomes as "wins":

• Having the opportunity to be an expert presenter at a medical conference

• Becoming an expert consultant on future protocols

• Being invited to join an elite group of the sponsor's "preferred investigators"

• Being listed as an author on published study reports.

Assuming that the development product makes it to market, all of these things are obviously wins for the sponsor as well, and any of them could be included in negotiations.

None of this focus on establishing a win-win situation is intended to overlook the fact that for many sponsors and investigators, the most significant and satisfying win occurs when a product proves to be of real benefit to patients.

Clear & detailed specifications

Another piece of advice from supply chain management: Provide clear and detailed specifications to suppliers. Most clinical development professionals probably think they do this by writing study protocols and providing tools to record patient data (i.e., case report forms or electronic data capture systems). In fact, sponsors are required by law to not only develop protocols but to also train investigators and study nurses on how to conduct the study. The typical method for training investigators and their staff is to hold a one- or two-day meeting during which time the sponsor delivers a series of lectures on protocol-specific and GCP requirements.

Although sponsors write protocols and hold investigator meetings, they are invariably plagued with data discrepancies, protocol violations, and delayed patient enrollment. All of these problems are expensive to fix and in some cases can even render the study data unusable. So what makes these defects occur with such relentless frequency? The problem is multifaceted. Part of it lies not in the lack of clarity or detail, but rather in the way the specifications are communicated.

Investigator meetings are clearly inadequate. A large percentage of investigators do not even attend the meetings. In one recent 70 site study conducted by a large pharmaceutical company, only 18% of the investigators attended the investigator meeting. For those investigators who do attend meetings, sponsors typically make no attempt to assess whether they actually understand the study specs presented. Furthermore, even if they understand the specs, it can be anywhere from one day to three months (or more) before the investigators screen their first patient. At this point, it is unlikely that they will remember the details of what they are supposed to do.

Recently, supply chain management experts have been advising companies to establish more open, real time communication channels with their suppliers. These communication channels can be used to meet a variety of information exchange needs, including information on specifications.

It is now relatively easy and inexpensive to create a secure Web portal through which clinical development professionals can initially deliver training on protocol specifications to investigators and study nurses. The information can remain available on the portal 24/7 for study staff to access whenever needed throughout the duration of the study. And if the specs change, as frequently happens with protocol amendments, the changes can immediately be posted on the portal. In addition to being easy to post, training modules can easily be used to test the learner's comprehension of the material and track successful completion of protocol-specific or GCP training.

Sponsors and regulators alike are beginning to recognize the inadequacy of the traditional approach to delivering study specifications. After an investigator meeting, the sponsor ends up on an attendee list. The list tells the sponsor and regulator nothing about whether the attendees actually learned anything at the meeting. On the other hand, by delivering protocol-specific training via the Web, the sponsor can easily end up with a list of investigators and study coordinators who have demonstrated their understanding of study procedures.

Requiring medical professionals to become "certified" in specific procedures is certainly not a novel concept. After all, physicians do not earn medical degrees simply by attending classes at medical school. They must pass the exams.

The use of Internet/Web technology can indeed improve the way sponsors communicate study-specific requirements.

Defining material defects

Supply chain management experts also point out the importance of up front clarity regarding defects in materials. Suppliers need to know how the company defines a defect, how defects will be measured, and how defects will be handled.

In clinical development, sponsors contract with investigators to supply patient data in an agreed time frame. Rarely, however, are sponsors specific about their definition of defects or the steps that will be taken if defects are unacceptable. Obvious data defects include missing information, errors, and inconsistencies. But the definition of what actually constitutes an error needs to be spelled out. Data management departments are notorious for sending questions back to the investigator for resolution. Does every question sent to the investigator signify a defect? Are GCP or protocol violations considered defects? What about missed deadlines?

Defining what constitutes a defect and how defects will be counted is only important when there are consequences to the supplier related to the number of defects.

Connecting compensation & performance

This leads to a fourth insight from supply chain management experts: Create a relationship between investigator compensation and investigator performance.

Let's say Investigator A enrolls patients not only on time but also ahead of schedule and is actually ready to enroll more patients if given the okay. In addition, informed consent is correctly obtained and documented for each patient, and the data the investigator submits has a defect rate of less than one per thousand. Investigator B, on the other hand, is several months late in enrolling patients, the informed consents frequently have date or signature problems, and when the data are finally submitted there is an average of three defects per patient visit.

Subsequently, the sponsor will need to spend far less on Investigator A than Investigator B in terms of correcting errors and monitoring patient enrollment. Should Investigator A get paid the same amount per patient as Investigator B? While the answer seems obvious, most sponsors pay high performers and low performers the same amount.

So why aren't sponsors creating a relationship between compensation and performance? One sponsor did not want to be bothered with creating the tracking system required for measuring investigator performance. This concern seems rather insubstantial since most clinical data systems already have the information needed to assess investigator performance. All that is required are some computer programs to extract and report the required information.

Another sponsor did not want to relate compensation to performance for ethical reasons, wary that paying more for clean data and fast enrollment might induce investigators to submit "favorable" data or enroll unqualified patients. The sponsor was also worried about how regulators would view relating compensation to performance. Again, this concern seems rather insubstantial and superficial.

First, in placebo-controlled clinical studies, it would be very difficult if not impossible to provide "favorable" data. Even in trials that are not blinded or placebo controlled, there remains a clear distinction between error-free data and "favorable" data. Error-free data are data that have no missing values, no recording errors, no illegibility, no inconsistencies across data fields, etc. "Favorable" data, on the other hand, are data that are modified to give the impression that the product is more safe or effective than it really is. In short, it is fraud.

If investigators supply error-free data, they should be rewarded. If investigators provide intentionally biased data, they should be blacklisted. It is very difficult to see how a policy of reward for providing error-free data—when clearly stated and defined up front by the sponsor—could be construed as an inducement to commit fraud and not as the traditional practice of paying investigators for data.

Secondly, regarding enrollment speed, is it not more ethically responsible to reach decisions regarding a product's safety and efficacy in a short time frame rather than a long one? If the product is approved, patients will benefit sooner. If a safety or lack of efficacy issue is uncovered, medication to subjects involved in clinical trials can be stopped sooner.

Finally, one would think regulators would support compensation policies that promote better GCP and protocol compliance, fewer defects in study data, and timely decision-making.

Sponsors would do well to devise and implement a compensation system based on performance. A system that provided "bonuses" to high performers would probably be more palatable to sponsors and investigators than a system that penalized low performers. Sponsors shouldn't have a problem paying more for high performance because high performers help get the product to market faster and save them money—funds that would have been spent on correcting errors. Investigators would likely not object to getting bonuses for good performance, which could provide low performers with an incentive to improve. Finally, regulators shouldn't have a problem with variable compensation policies aimed at increasing the quality of the clinical study reports they eventually review.

Preferred supplier relationships

In addition to paying more to high-performing suppliers, supply chain management experts say it's a good idea to form preferred supplier relationships with top performers. A preferred supplier relationship is one in which a company makes certain commitments to a supplier for future interactions.

In terms of clinical development, a sponsor might commit to giving preferred investigators first rights to participate in future protocols, particularly when the sponsor plans to conduct several studies in the same development program. The sponsor might invite preferred investigators to serve as consultants on future protocols or even invite proposals for future study designs from preferred investigators. The sponsor might also invite preferred investigators to present study results at professional conferences.

Maintaining a database of preferred investigators can save the sponsor time in recruiting investigators for a new study. It can also help reduce the risk of contracting with new, unknown investigators who may not perform as expected. The preferred investigator in turn gets recognition and status from being included in an exclusive group.

Conclusion

Insights from supply chain management are finding useful applications in the world of clinical development. By viewing investigators as suppliers in the clinical development process, sponsors can potentially realize significant cost savings and efficiencies. It is in the sponsor's hands to start applying these principles to their operations. Once they take the first steps, further opportunities for improvement in managing relationships with investigators will undoubtedly be clarified.

Robert Zuercher is a partner with KLZ Consulting, 15 Shinnecock Court, Monroe Township, NJ 08831, bobzuercher@comcast.net

References

1. M. Hugos, Essentials of Supply Chain Management (John Wiley & Sons, Hoboken, NJ, 2003).

2. Harvard Business Review on Managing the Value Chain (Harvard Business School Press, Boston, MA, 2000).