Outsourcing the Biotech Trial

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A biotech company with a promising pipeline of research products but lacking first-hand knowledge of planning and conducting its own clinical trials faces a certain set of challenges. Many of these biotechs have their roots in research projects, so it can be a huge step entering the clinical development phase. Because conducting a trial is very cost-intensive, high expectations in reaching targets are set. On the other hand, successful progress of projects in clinical development can considerably contribute to the value of a biotech company and may offset clinical development costs.

PHOTOGRAPHY: GETTY IMAGES ILLUSTRATION: PAUL A. BELCI

Conducting clinical research is a complex undertaking, so it may be useful to review the process flow of a clinical trial. This process flow is valid for all sponsors of clinical studies, regardless of whether the sponsor has previous experience conducting its own trials or not—as the case may be with many biotech companies (see Figure 1).

Figure 1. A depiction of a clinical trial from birth through completion broken down into three separate, well-defined phases.

The demarcation from one phase to the next can be fluid. A particular process may "flow" into the succeeding phase, so a distinct segregation may not be possible and also may not really be necessary.

As many sponsors choose to outsource some or all of the trial tasks to a CRO, it is worthwhile to take a closer look at these partnerships and the implications for the biotech with little or no experience in conducting such collaborative ventures.

Study phases

Planning phase. The selection of the CRO is done in this phase, and the first task is to create a detailed outsourcing plan that describes all activities to be performed by an external partner(s). Such activities can include: project management, monitoring, medical writing, data management, statistics, central lab, central evaluation of ECGs or MRIs, packaging and labeling of study medication, IVRS, distribution of study medication, and pharmacovigilance. The service provider(s) ultimately chosen should match the needs and specifications of the trial being planned.

When choosing a CRO service provider, two outsourcing models are popular. The first is commonly known as the one-stop shop model or full-service outsourcing. The second approach can be called functional outsourcing. The latter takes into account the sponsor's own resources or strategic considerations and establishes which functions a CRO partner will be contracted to perform. If the service provider performs a particular function well during a study, the sponsor may decide to continue to outsource that particular function to the same CRO for future projects.

It is also during this phase that the protocol is written. When creating a feasible study protocol, various clinical experts are required. Medical writers, statisticians, and medical doctors trained in the indication of the trial are essential and will need to work as a team when writing the study protocol. If the sponsor lacks these personnel, they may be drawn from the clinical CRO, which will take over the project management and monitoring and work directly with the study sites. If not, at least the clinical CRO will be requested to give input to the protocol prior to its finalization. Long-term experience and specialization in the trial's indication are key factors in choosing a CRO. Another consideration is a CRO's proven track record in successful completion of similar studies along with a good working relationship with investigators and study sites.

Conduct phase. This phase includes collaboration with study sites and is therefore crucial. Within a given time frame, the trial sites have to attract eligible consenting study subjects. If the selection and management of study sites is to be done by the clinical CRO (which in this case will be stipulated in the CRO and investigator contracts), then it will be of utmost importance to make sure that the CRO is held to the successful and timely recruitment throughout the study, which should be guaranteed in the contract. The day-to-day management of the study is most complex during this phase, and on-time patient recruitment is one of the major factors predicting its favorable conclusion.

Communication within the entire study team (between sponsor, CRO, study sites) is another indispensable factor for the successful outcome of the trial. Also, the process of collecting and validating clinical data is complex and often very challenging, regardless of whether monitoring and data management is provided by the same CRO or by different partners.

Evaluation phase. In a well-managed trial, the positive momentum that characterizes the planning and conduct phases must be maintained and transferred to the statistics evaluation phase. This process has to be anticipated and planned for during the conduct phase in order to facilitate a rapid evaluation of study results. Therefore, it is important to prepare the availability of the CRO's statistic team according to the evolution of the study to avoid any capacity bottlenecks. This may be a real challenge for the study management team since the actual completion of the conduct phase will be determined by the recruitment of the last patient, which can be difficult to foresee despite the fact that LPI (last patient in) and LPO (last patient out) timelines had been clearly defined in the agreement with the CRO.

During this phase, the close cooperation of the sponsor medic(s) and the CRO's medical writer is imperative for the timely finalization of the study report.

Selection of CROs

The biotech with little or no experience conducting its own clinical trials must carefully select its vendors based on a CRO's expertise and its assurances that the service vendor has the sponsor's best interests at heart. Sometimes that may mean not always going with the big, established players.

For a young biotech moving into clinical research, sponsoring a clinical trial is a major step. While a large CRO is always happy to sign a contract with a sponsor, regardless of size, the relationship of small biotech and large CRO may not always be advantageous to the minor partner, especially if that partner does not have an experienced study manager. It may be worth considering outsourcing the services to an experienced but smaller CRO that would be willing to devote more attention to the sponsor's trial because the success of that trial will ultimately have a greater impact on that CRO's own success.

On the other hand, a large, multinational pivotal study involving thousands of patients will most likely need the proven skills of a large international CRO.

Relationship and cooperation

It has been shown that small biotech companies have real innovative compounds in development, which would create much more excitement with the investigator and may lead to better investigator performance. On the other hand, the biotech sponsor may not be well known yet to the investigator; therefore it is important that the study team (composed of the sponsor and CRO) shows coherence and creates confidence that it stands for a professional conduct of the study.

What Defines Good Communication?

From the sponsor's side, this includes building and maintaining relationships with investigators and seeking out their input and opinions. From the investigator's side, it is essential to ensure that investigators get their honorarium reliably. A clear, traceable method of payment smoothes this relationship. These are matters that may be of no concern to those established sponsors with whom the investigator might already have developed good long-standing relations. It is, therefore, the sponsor's advantage to choose a clinical CRO that already has developed proven relationships with the investigators as a reliable partner.

Much has been said about partnership, and the relationship between a biotech sponsor and CRO depends on good partnership. For the biotech sponsor, it is crucial to benefit from the CRO's expertise in the trial's indication and in its successful running of clinical trials in general.

Consequently, it is advantageous to let the CRO work according to its own standard operating procedures (SOPs). If this is the case, then it follows that the sponsor's study manager has a profound knowledge of those standard processes. Any tasks the CRO performs that arise from sponsor SOPs must be fixed in the contract. It will then be the responsibility of the sponsor's study manager to follow through and make sure that its SOPs are adhered to. It is not sufficient to just send the sponsor SOPs to the CRO and request that these are fulfilled word for word.

The experienced CRO must always be held accountable for the success of the study. On the other hand, CROs are likely to fulfill exactly only what the sponsor explicitly requests. For a biotech sponsor, this attitude is not sufficient. When it comes to essential documents, such as data validation plan, monitoring manual or investigator file logs, common CRO practice is to go the easy route and first provide only a rough draft and then wait for the sponsor's changes or corrections. The feedback and final approval process can be time consuming for the biotech sponsor with its limited staff resources. This process, though, cannot be avoided, as the sponsor has the ultimate responsibility for the study and its essential documents. However, the extent of time the sponsor will devote to this task is dependent on the CRO's willingness to actually leverage its full experience and knowledge and use this to the biotech sponsor's benefit.

It is important for the relationship that the biotech sponsor be seen as a reliable and fully accepted partner. The pivotal role of the biotech's study manager is key to this partnership.

Day-to-day tasks

Since the clinical study is very complex and several partners are usually involved, the rules for overall team communication are defined in a structured communication plan binding for the whole team (see Figure 2).

Figure 2. Such a plan clearly outlines how interpersonal communication will be handled throughout the trial.

It should be pointed out that the simple exchange and forwarding of dozens of emails daily as well as the unreasonable use of the telephone is not the best communication practice. Structured communication is needed, allowing time left over to do work. For the sponsor study manager and the CRO project manager this means giving the study team the necessary support. Management is about support. Good study management is characterized by a proactive approach and not by merely reacting to problems and issues.

Regular and ad hoc teleconferences and face-to-face meetings may be important and may also supplement daily communication. They assist in getting a better understanding of the team's needs. Keep in mind that too many meetings and teleconferences cost a lot of money and may not add value to the management of the trial.

In the communication plan, it should be clearly outlined how team communication can be supported by regular teleconferences. To make these efficient, the participants should be clearly defined.

Contract aspects

When partnering with a CRO in a clinical study, it is important for the biotech sponsor to opt for a fixed-price contract with the CROs involved. This also means that the scope of work must be clearly defined by either a sponsor bid grid or CRO bid grid being part of the contract. The latter is important for the efficient change-of-scope negotiations that can hardly be avoided. In other words, very rarely can a successful study be done without any contract amendments since a clinical study is too complex and unforeseen things will always happen.

Further, it is crucial for the cooperation of a biotech sponsor with CROs to define clear deliverables in the CRO contract—that is, milestones for the timely fulfillment of tasks. Payments for services will be made dependent on reaching these milestones. Also, a final payment must be agreed upon, and serves a lever for the CRO to fulfill all tasks in the end on time (e.g., finalization of the trial master file and provision to the biotech sponsor).

The question of whether other third-party providers such as a central safety laboratory should be selected and contracted by the biotech sponsor or CRO is difficult to answer in general. It depends on the study and the possible established working relationship between the CRO and such a provider. It might be of advantage if the contract is made directly by the biotech sponsor, which also means that the management of this provider is the sponsor's responsibility. The idea that the CRO also manages other providers and takes on full responsibility for their performance seems to be attractive, but this assumption has often proven to be wrong.

With regard to the investigator contracts, there are two options: directly by the sponsor or by the CRO. It might be advisable that the CRO take responsibility for setting up the contracts with the investigators and also for the administration of the investigator fee payments. This responsibility and the deliverables (e.g., regular payment of sites on a quarterly basis) must be clearly defined in the biotech/CRO contract. Of course, the sponsor needs to check the CRO investigator contract templates carefully and request any changes, if necessary (e.g., IP protection and publication of study results).

Impediments to success

Sponsors also need to be aware of the following potential pitfalls in the biotech/CRO relationship.

Micromanagement is the opposite of the approach characterized by making use of the expertise and experience of the CRO for the success of the study. Requesting the CRO's proactive input based on its experience, which is by all means necessary, is not micromanagement, nor is the sponsor's hands-on involvement into details of processes in order to solve issues and problems that arise in any study. Micromanagement is when a lack of trust leads to second guessing, redundancies, and a bogging down of study conduct. Timelines are postponed and enthusiasm in the project wanes. The biotech sponsor, in particular, must ensure that the study is progressing as planned and is always in good hands. Therefore, trusting the CRO is important; for if there is no trust, the successful completion of the study will turn into a challenging and risky endeavor.

Another pitfall to avoid has to do with the study manager. Sometimes the understanding of the senior management of the biotech is that the success of a clinical trial can be guaranteed solely by a state-of-the art contract with the CRO. Neglecting or underestimating the responsibility that a sponsor's study manager has in the day-to-day conduct of the trial will lead to an expensive lesson in how not to conduct a clinical trial. This function is absolutely crucial for the success of a clinical study. This person, after all, must represent and defend the sponsor's interests vis-a-vis all service partners and investigators. Requirements for a sponsor study manager must be:

• Profound knowledge of all processes within a clinical study

• Experience with good CRO management

• Very good communication skills

• A structured and organized working style

• A proactive nature

• Well-developed management skills.

In case the biotech sponsor's study manager lacks sufficient experience, this function may be supported by senior management. If the biotech has no in-house resources available for this role, this person can be found by qualified third-party study management consultancy services.

Study sites and staff changes

The CRO must be made accountable for a successful and timely recruitment of study subjects. This starts with selecting the right CRO, which should prove to have a clear and convincing understanding of the number of sites, the countries involved, and the kind of study sites (academia or medical practices) required to ensure the recruitment targets. This must be captured clearly in the CRO contract, with implications on the study budget if the CRO fails (bonus rather than penalty; carrot rather than stick). The biotech sponsor should think twice before compelling the CRO to involve particular sites that were not initially on the CRO list unless the biotech sponsor is aware that he would also take over some responsibility for these sites' performance. That means that the sponsor study manager would need to manage these sites to some extent.

Staff turnover is part of any clinical trial and can hardly be avoided. The biotech-sponsored study must be managed in a way that everybody may be replaced (including the sponsor study manager and the CRO project manager) without causing real harm to the study. In particular on the biotech sponsor side, with usually few staff available, staff changes may have a negative effect on study conduct. Therefore, it is advisable to establish beforehand an internal substitute who will need to be kept in the loop with regard to regular reporting and involvement of the basics of the study.

Staff turnover on the CRO side should be well covered in the CRO contract (e.g., a change of project manager for business reasons is excluded or the ratio between senior CRAs and junior CRAs must be maintained throughout the study).

Finding success

Outsourcing a clinical study by a biotech sponsor clearly demands a high level of professionalism and care when choosing the CRO partner. The success of the trial and the biotech–CRO relationship depend on a well thought out protocol and study conduct plan. These truths are more evident when the sponsor is a small biotech taking the large first step into clinical research. The importance of this decision must be reflected in management's commitment to allocate sufficient resources and provide ample support to the sponsor study management. Considerable efforts need to be taken to ensure that the trial is conducted using best practices to ensure its successful outcome.

Frank Henke, Dr med vet, is head of clinical operations at elbion GmbH, Meissner Strasse 191, 01445 Radebeul, Germany, email: frank.henke@elbion.com