January 1, 1970 (Vol. , No. )

Robert Morrison, Ph.D.

Did you ever wish you had a crystal ball to predict the future? Relevant to drug development, the concept of having a fortune teller with a crystal ball to visualize a desired finished product can be productive. Such a mental exercise can help determine the critical steps necessary to achieve your vision. Too often, drug developers follow a standard path focused on safety and efficacy measurements with minimal consideration of other key factors that may mean the difference between commercial success or failure. Following the standard path to demonstrate adequate safety and efficacy may cause you to lose sight of the fact that the FDA consistently raises standards on safety. This fact necessitates that a drug developer clearly demonstrate product differentiation via prioritizing efficacy or safety compared to approved products as well as those under development. Measuring the value of a development stage drug in comparison with equivalent treatments is the most important driver in achieving success. Of course there is no such thing as a crystal ball but there are tools and concepts that enable you to envision the drug you would like to develop and then design your program to achieve your vision.

Utilization of these tools will enable you to perceive the ideal product and then put the pieces in place that will be necessary to make the desired product a reality. In addition to crystal ball-like tools, there are fortune tellers who can help predict the future. Don’t believe in fortune tellers? Experts in drug commercialization and marketing (e.g. market research and medical affairs professionals) can predict the future via their expertise from dialogue with doctors and patients. These folks have a thorough understanding of the needs that are not currently met and can help you design a program to document that your product addresses those needs. By tailoring your program to focus on those needs, you will better ensure the development of a product that will provide benefits to patients and thus contribute to the fortunes of you and your company. The following information describes the crystal ball tools and fortune tellers that may be of value to your vision of the ideal drug and help you and your company increase the probability of success in your development efforts.

Crystal Ball Tools

Translational Research

The translation of basic research into an actual therapy is the ultimate goal of a drug R&D program. The continuous translation of research over the course of drug development, however, is often over-looked resulting in missed opportunities for many drugs. Often referred to as bench to bedside research, translational studies involve a reciprocal relationship between basic researchers and clinicians. Preclinical researchers discover and provide tools for use in patients by clinicians who then utilize the tools and observe their effects the on progression of disease. Their observations often result in additional basic investigations and possibly new indications.

The key issue relates to sustaining a dialogue or at the very least, an effective transfer of knowledge from basic researchers to clinical development experts. According to Dr. Dominic Spinella who heads the clinical biomarker work for Pfizer’s oncology portfolio, translational research is about 70 percent from preclinical to clinical. The other 30 percent involves what is learned from clinical trials and from hypothesis-generating work with pharmacogenomics, proteomics and similar types of tools. Key information is fed back to the investigators to benefit the next generation of drugs.

If a large organization such as Pfizer can apply translational research to benefit future drug development programs, imagine what smaller, more nimble companies can do to benefit current development programs via utilization of enhanced assays for rapid deployment within clinical trials. Companies can also follow surrogate markers for efficacy or safety or extension of the therapeutic to new indication.

From a small company perspective, consider Cytokinetics, which is focused on drugs that affect cytoskeleton factors related to muscle contraction. The Company has exploited translational research and now has three oncology drug candidates in clinical trials. One candidate, GSK-923295, inhibits the mitotic protein CENP-E thus arresting cancer cell division and causing apoptosis. The company is developing the drug with partner GSK which includes a translational research component directed to CENP-E. From a start-up perspective, ApeX Therapeutics has successfully utilized a translational research approach via the commercialization of work that originated at Indiana University. The research program was enhanced via funding from a program that aids researchers in advancing discoveries into development for patient care. ApeX initiated a preclinical program to study inhibitors of the protein APE 1 as a treatment for macular degeneration based upon basic research of APE1 which demonstrated anti-angiogenesis effects.

Companies such as ApeX and Cytokinetics have demonstrated the capability to utilize translational research as a crystal ball to justify development of drugs in alternative indications and, in the case of Cytokinetics, attract the interest of a large pharma partner. Additional incentive to consider emphasizing translational approach may come from the US government which has stepped up to the plate in support of translational research. The NIH and FDA recently announced funding for efforts focused on translational and regulatory science to explore ways to move scientific breakthroughs from the microscope to the marketplace. The agencies will fund research involving new technologies for development and regulatory review of medical products.


The ability to identify patients with a high likelihood of treatment response or patients that may suffer from an adverse event (and thus excluded from trials) enables the drug developer to better predict therapeutic effects and refine development strategy at an early stage. Large and medium-sized pharmaceutical companies have pharmacogenomic programs that discover and utilize biomarkers in preclinical studies and ultimately in human clinical trials. For smaller companies that lack resources or infrastructure for integrated pharmacogenomic programs, contract research organizations (CROs) are a viable option. Large and specialty CROs have developed biomarker discovery programs along with the capability of utilizing relevant markers in human clinical trials.

It is also worth noting that reimbursement for companion diagnostic tests is on the near term horizon with payers now starting to step to the plate as they realize that testing can actually lower overall therapeutic costs by treating only patients that are likely to respond. Relevant to your commercial prospects, targeting patient population subsets for which your drug has better efficacy will be recognized by physicians since they will be confident that their patients will benefit from your drug with a low risk of adverse events. These practitioners are more likely to exhibit product loyalty and their patients will likely realize long-term compliance. In addition to benefiting from the services of CROs, development-stage drug companies may consider partnerships with diagnostic test providers that have a track record for assay development and approval in sync with the therapeutic. The list of such companies continues to grow as more therapeutic–diagnostic combinations advance toward commercial launch. The drug and diagnostic company can work together to generate and utilize data to support marketing efforts by properly positioning the products enabling focus on patient sub-populations which will no doubt raise the value of the treatment.

Evidence for this may be the alliance between Vanda Pharmaceuticals and Labcorp related to Fanapta™, a schizophrenia treatment that involves administration of iloperidone to a sub-set of patients with specific genetic markers that respond to the treatment. Late last year, Vanda licensed the US rights to Novartis for an upfront payment of $200M.

Models & Simulations

A considerable amount of resources are lost during the course of what many experts describe as an inefficient trial-and-error drug development process. Inefficiencies related to unknowns concerning safety or efficacy of the candidate drug can be minimized if critical information is available at the beginning or during the early course of development. The use of models and simulation analysis has been successfully used in various technical disciplines and seems to have applicability in drug development.

While even the most comprehensive preclinical program to predict efficacy and safety is not immune to an unexpected result once the drug is administered to human subjects, comprehensive preclinical results can be strengthened with results from various physical and theoretical models as well as simulations. For instance, pharmacokinetic/pharmacodynamic (PK/PD) trial simulation models help investigators improve later-phase trial designs for several parameters. For some drugs, researchers have demonstrated the value of PK/PD forecasting models with Phase II data being used to develop a dose–response model that closely approximated what was eventually observed in an actual Phase III dose–response study. Use of such modeling and trial simulations may increase if adaptive trial methodologies catch on.

In addition, software tools that simulate disease and physiological processes using data from relevant published research are now being evaluated and show promise. For instance, the Optimata Virtual Patient tool has been used to estimate changes in tumor size as an important indicator of the disease status and predicts changes by particular treatments while accommodating for toxicity and other key limitations. The Optimata software provides for effective planning and decision-making during the course of clinical trial phases via computer-simulated treatment scenarios for multiple disease indications and patient-populations. Clinical trials based on such software have increased success rates thus shortening the drug development process and reducing costs.

The Fortune Tellers

Marketing / Medical Affairs Expertise

Today, drug approval requires addressing the issues posed by multiple stakeholders such as payers, healthcare providers as well as regulators. These entities have significant influence on a drug’s commercial potential. Marketing and medical affairs professionals are engaged to assist a pharmaceutical developers and manufacturers in developing a value profile of a drug to enable clinical trial design and drive a long-term marketing and pricing strategy. These professionals gain input from researchers payers, clinical advisors, and opinion leaders. Safety and efficacy factors most critical to the drug’s viability are identified from a clinical, reimbursement, and access perspective. The drug’s potential strengths and weaknesses relative to other available treatments are determined to prioritize importance of its features. This information is incorporated into the design of clinical trials to identify the most important points of competitive differentiation in the long-term marketing and pricing of the drug.

Intellectual Property & Regulatory Exclusivity

The Holy Grail of drug intellectual property comprises a comprehensive portfolio of patents that cover composition of matter of the molecule, relevant formulations as well as methods for the treatment of all conceivable diseases. For some drug developers, such a package is only a dream and drugs often do not see the light of day because of a perceived weak patent position. It is very important to have a frank discussion with your patent attorney so that he/she has a full understanding of your commercial vision for your product.

Consider your future fortunes by envisioning the type of drug you desire and provide the attorney with the key attributes the drug should have and ask them to work backwards, relative to existing data and that which may come from additional research (including a translational program), to enhance the patent protection of your product. A weak patent case can be strengthened, depending on the amount of prior art, by claiming relevant formulations, manufacturing methods as well as other elements that may hinder or prevent a competitor from developing a comparable product.

In addition, data required for regulatory approval should be considered when making decisions on the potential length of exclusivity. When developers are faced with no composition of matter protection (or limited term), the potential of patents covering formulations or delivery methods should be considered with a focus on formulations that cannot be easily substituted. Such a formulation may prohibit ANDA filings by generic companies and should obligate competitors to conduct studies to support an NDA filing. Such a scenario will result in a longer period of exclusivity for your drug. Under normal circumstances, this period of exclusivity may be at least five years. In the case of development programs that initiate well after patent claims have issued, remember that a short term patent may be extended depending on the time required for clinical trials and regulatory review.

Another aspect of regulatory exclusivity involves the 505(b)2 application which provides for three years data exclusivity for the first registrant or for a new indication of an already approved drug. Each of these elements concerning patent and data exclusivity should be fully considered at an early stage of drug development to ensure that you maximize your proprietary position once the drug is launched.

Robert Morrison, Ph.D. is Director, The Invotex Group, a specialty consulting firm that provides a range of financial and technical services to companies and academic institutions. Dr. Morrison’s practice focuses on issues associated with clinical development and intellectual property of pharmaceuticals and medical diagnostic applications.


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