Opportunity for effective clinical development

Opportunity 1: Target Product Profile vs. Medical Needs

At the conceptual level, the target product profile must be rooted in a realistic view of the goals for the product. Now, how to determine which goals are realistic, and which are not? For products being developed for medical purposes, the only relevant reference point is actual medical needs. Thus, a correct target product profile should describe the exact medical need(s) that a given product intends to address, the minimum safety and efficacy requirements that must be met for the intended indication, the optimal and acceptable options for less critical items such as formulation (i.e., once-a-day versus multiple dosing), and the conditions under which it the product is worth developing, considering the intended market size.

Medical needs assessment requires medical input, both from industry physicians and from practicing advisors. Once both groups are well-informed about the product and its intended goals, are confident that the target medical-needs specific to the product are genuinely real, and that the product is well characterized in terms of expected performance, that then the probable market size (in number of patients) can then be assessed. At this point, fundamental manufacturing issues should have been identified, and the basic cost of goods should have been estimated. The business potential of the new product should now be clear, and the time for confirming a green light has arrived.

It is equally important that the product’s medical potential is evaluated independently of corporate and market goals. It is not uncommon to see a product decreed a “failure” when it sells at lower volumes than corporate projections. When this occurs, it is critical to verify whether the target product profile had originally been defined on a sound medical basis. In more blunt terms, it is critical to reassess candidly if the product’s medical needs and the corresponding goals were, in fact, realistic. This type of failure can easily be avoided if the product’s medical needs are thoughtfully identified from the inception of the program, because the failure ultimately hurts, in a very real manner, the company as a whole, as well as the individuals who are held accountable.

What is much less easy to see is when the product’s potential is not fully realized, despite the fact that there is a strong market need for some of its uses. This happens when pre-launch market projections actually underestimate medical needs. In this case, companies are quick to be happy as sales expectations are met or even exceeded, despite the fact that the product has more potential than its actual sales shows. Indeed, when a market need is so big that sales follow as long as the product is available, regardless of any sales and promotion, the lost opportunity goes unnoticed, as sales expectations are met or exceeded, because the reference against which performance is assessed is actually off. In such situations, products that meet expectations actually fall well behind their true potential as this oversight leads to allocating resources that are insufficient to explore fully the product’s potential and expand its indications. In summary, companies and their products may fall behind their potential because business goals were either inflated relative to actual medical needs, or because the product true potential (i.e., medical needs or their business correlate) were underestimated and not enough resources were assigned to support the product.

As complex and critical as these early conceptual efforts are, they remains relatively easy, when personnel with higher expertise are involved, and the required resources remain within easily manageable limits. The next steps on the development pipeline are increasingly complex, involving more personnel as progress is made. Their management is naturally of increasing complexity as well.

Opportunity 2: A Meaningful Clinical Development Plan

The most critical step is writing a meaningful Clinical Development Plan (CDP) and establishing the basis for its flawless execution. Keeping in mind that we are seeking the optimization of the product relative to its potential, we believe that the CDP is the corner stone on which the success of a product, medically and financially, depends totally.

There are again two aspects to a CDP, one conceptual in nature, and the other operational. Ultimately, the CDP should provide clear guidance as to the indications (concepts) that will be supported and what corresponding clinical studies will be executed, how and when (operations).

Conceptual aspects are critical, as it is at this level of conceiving the Clinical Development Plan that the future of a product is actually determined. Indeed, no product can be really successful without appropriate clinical data behind its use, whether within approved indications or off-label. Likewise, no launch will fully succeed if there is no convincing data and credible evidence available to back it up. Furthermore, major reimbursement hurdles cannot be passed without appropriate objective support. Finally – this is a fact that is often ignored – no product can reach its truly complete potential without being proactively managed throughout its market life. Consequently, the acceptable CDP addresses from the beginning all aspects of the planned life cycle, the timing of each indication that is envisioned, the corresponding criteria of acceptance, an outline of the studies that need to be performed at specific times, as well as the corresponding resources that need to be committed.

Each indication requires a specific set of supporting data, first for approval, then for market adoption and reimbursement. If a CDP focuses only on satisfying regulatory requirements, the Development Team must be forgetting that regulatory approval simply gives a license to sell, and does not generate in and of itself, any revenue. Furthermore, such limited view creates a gap in research activities between the end of phase 3 studies (pivotal studies if a medical device) and launch time, the obvious consequence being that at the time of launch, there is nothing new to say that could get key opinion leaders and their audience excited about the otherwise new product.

When conceived as a continuum, the Clinical Development Plan provides, for each indication, a clear path of research across the life of the product, thus allowing the company to claim a truly leading role in its key business areas.

Opportunity 3: Designing for Speed

Much can be said in regards to streamlining the execution of the Clinical Development Plan, and virtually all company, big or small, claim to aim at efficiently developing their product. The question that we keep having, after so many years of industry experience, is whether companies truly mean it. Systems in place today are based on processes that were developed many years ago, before the implementation of electronic data capture. These processes have changed little if at al (in substance) for at least 20 years despite the advent of technologies that are capable of supporting much more efficient methods of managing studies and data. Whether the industry is ready for a real, in-depth rethinking of this aspect of product development remains to me an open question, regardless of the official positions that are voiced by most. Such significant change is possible, but only with the shear, unwavering will to see it happen.

The design and implementation of clinical studies also offers significant room for improvement. For instance, adaptive design protocols offer clear opportunities to accelerate the acquisition of data pertinent to providing “reasonable assurance of safety and effectiveness”. Yet, this type of design is seldom used, especially in the development of drugs. Its adoption by device manufacturers is somewhat higher, probably due to the fact that the concept of adaptive design is well-suited to the challenges specific to the development of medical devices. Yet, as adaptive design protocols allow for mitigating the time spent between 2 study phases (say, transition from Phase 2 to Phase 3), it is surprising that the adoption of adaptive design protocols remains so limited even though regulators are open to this concept.

Opportunity 4: Speeding, Anyone?

The information technology that is available today allows for real-time collaboration on every aspect of a clinical study, from the development of all study documents to day-to-day management of the project, to all aspects of data management and safety review. This may require a significant overhaul of most processes that are currently “industry standards” and may be even considered “best practices” today.

Let’s consider a few scenarios, starting with protocol design. The theoretical potential of adaptive design protocols to optimize the execution of the clinical development phase of drugs or medical devices is well know and recognized by all key players, including the regulatory agencies. However, it does require, to obtain all the potential benefits of such design, two key elements that are by no means standard, even though both are highly desired: real time access to clean data and pre-defined statistics on one end, and close collaboration between the sponsor, the various study committees (most critically, the data monitoring committee) and the regulatory agencies. For the latter to happen, the idea of “close collaboration” needs to be taken beyond the norm. Indeed, it is only if all players work truly as a team, with the shared objective of bringing a safe and efficacious product to market better and faster, that it is possible to save time by using advanced protocol design concepts. Otherwise, the time saving resulting from advanced protocol design are then wasted in inefficient communications and useless negotiations.

Next, let’s consider data management and monitoring. Electronic or fax back data acquisition are proven technologies that enable near-real time access to the data. As a company, we expect that all data be available to us for review within 24 hours of any study visit, and will pester the sites if we do not receive the data within 48 hours thereof. Most sites comply, proving that this is possible. If this required from study sites there is no reason to delay a response to the sites within the same time frame with at the least the most obvious data clarification requests. It is true that some queries cannot be issued without a review of consolidated data listings. However, a great deal of all data issues can be dealt with quite fast. Why wait? Likewise, why not monitor the data remotely, with enough time at hand and specialized personnel with direct access to medical monitors, instead of almost exclusively relying on site monitors pressed for time while monitoring on a tight schedule? We believe that site monitoring visits should focus on work that requires physical presence at the study site, nothing else, such as verifying source documents, adverse events, as well as IRB / EC and regulatory files. Data issues are better dealt with remotely, with time at hands and focused minds.

Conclusion

How fast can a drug go from compound discovery to market? If one compares to the rapid very short time line that are required to address bacteriological threats, going from an engineered germ to an efficacious and safe treatment in a matter of months, this is much faster than what we see now. Yet, even under such extraordinary circumstances, it is be possible only if there is a will to challenge the usual without compromising the quality, to really work in unison and to rethink the way we use advanced concepts and technologies.

About Paul-André de Lame

Paul-André de Lame, M.D. is president and CEO of Anabase International Corp. He has more than 20 years of industry experience and a broad knowledge of product development, clinical research, and related regulatory issues. He made critical contribution to a number new product launches while organizing multiple research projects at the domestic and international levels. His team-based approach to global project management has proven extremely efficient in organizing complex projects with short- and long-term business relevance. Building on this industry experience, Dr. de Lame and Dr. Lemaire co-founded Anabase International Corp. in 1996. Anabase is dedicated to providing strategic consulting, clinical research services, regulatory affair support, and information management systems to the Pharmaceutical, Medical Device and Health Care Industries. Prior to founding Anabase, Dr. de Lame obtained his M.D. degree from the Catholic University of Louvain (Belgium) with a specialization in anesthesiology and intensive care medicine. He spent several years as Head of Intensive Care in a private hospital in Brussels (Belgium) before joining Merck Sharp & Dohme, Belgium. He then joined Warner Lambert Parke-Davis, where he was a critical contributor to the successful launch of atorvastatin.

About the company

Anabase International Corp. provides consulting services for clinical development and regulatory strategies, medical and safety monitoring, integrated study and data management systems and processes. Information regarding Anabase International Corp. can be found on the web at www.anabase.com .