Wednesday, March 24, 2010

The Wrong Medicine – Getting Personal

“I ain’t got a fever, got a permanent disease; It’ll take more than a doctor to prescribe a remedy; I got lots of money but it isn’t what I need; Gonna take more than a shot to get this poison out of me.” These are the opening lyrics to “Bad Medicine” from the rock group Bon Jovi. While the song concerns an addictive love affair, the words and the title bring to mind important issues concerning major challenges for the pharmaceutical industry. Google the term “bad or wrong medicine” and you will get results ranging from political views on healthcare reform to stories about patients exhibiting adverse drug reactions or being prescribed the wrong medication. If you dig hard enough, you will find news articles and commentaries based upon patients being treated with a drug that simply does not work. Within the context of patient efficacy and safety as well as the cost of some drugs, the wrong medicine has profound implications for the future of the pharmaceutical industry. These clinical and commercial aspects call into question issues concerning how patients and physicians will be able to avoid the wrong medications and realize the full benefits of an optimal therapy. Personalized medicine, the use of diagnostic testing to identify those patients most likely to benefit from a particular treatment, may be an answer. However, pharmaceutical companies will have to resolve whether personalized medicine is something of value or a necessary evil to be avoided when possible. If you ask Steve Burrill, CEO of the life sciences merchant bank Burrill & Company, personalized medicine and associated diagnostics will become more valuable than prescription drugs in the future. Mr. Burrill may be right. Pharmaceutical companies have traditionally shied away from targeted patient population markets due to concerns of perceived lower revenue and higher marketing costs. Now, as the prospects from pipelines have dwindled and major drugs face patent expiration, some companies are beginning to realize the potential benefits of targeting certain treatments to smaller patient populations. If the benefits of increased safety and/or efficacy are realized, as well as the higher probability that drugs will make it through development, marketing and R&D experts believe that personalized medicine may the right therapy for an ailing industry. An additional factor involves the recent passing of healthcare reform legislation in the US. The new law is projected to provide significant dividends to drug companies who will gain access to millions of more customers with the ability to pay for high cost treatments. However the situation is not so good for insurers who will have to pay for the expensive treatments. Why pay for a treatment that does not work, or worse, may result in harm to the patient and thus additional payments by the insurer? Such a scenario should bode well for broader development and commercialization of personalized medicines. However, who will lead the way? Will it be the insurers / payers, the drug companies or the test providers? Will all three entities work together or will two defer to the one with the most to gain to lead the way in terms of adoption? The answer may lie in a better understanding of who has the most to gain and what they do to capitalize on the opportunities and challenges associated with this intriguing area of healthcare. So, who has the most to gain?

The basis for personalized medicine lies in the fact that genetic variation within human populations results in patient-to-patient differences in drug response. The response may involve efficacy at the target site or metabolism of the drug to an inactive or active metabolite. There may also be variability for safety where some individuals metabolize the drug into a toxic metabolite. In addition to extensive research studies for drugs and genetic-based response, validity can be found in the recent actions of the US Food and Drug Administration (FDA) in modifying labels for drugs such as warfarin and clopidogrel to advise patients and practitioners that genetic variants warrant consideration of whether to use the drug and, if prescribed, carefully decide on the optimal dosage. There are several additional examples of drugs with available companion diagnostic tests to aid physicians in deciding whether to prescribe the corresponding drug.

Source: Personalized Medicine Coalition; The Case For Personalized Medicine 2009.

The FDA has required that test information be on the labels of several drugs such as tratzumab and the EGFR inhibitors cetuximab and panitumab (highlighted in blue) while for others (e.g. warfarin and clopidogrel) it is only recommended. But testing information on the label is just the beginning and may result in more questions than answers for patients and the medical community. Furthermore, the companion diagnostic test will present unique marketing challenges as well as opportunities for the commercial arms of drug and diagnostic companies. The opportunities and challenges may well revolve around the genetics education of physicians, many of whom may be ill-suited for practicing personalized medicine due to poor training. Of critical importance will be the assurance that physicians understand genetic variation principles in the human population and within the context of complex diseases. While a long term remedy would be for medical schools to improve their curricula relevant to basic concepts in genetics and genomics as well as practical applications in clinical medicine, over the next few years, medical affairs resources from the drug and testing companies will be required to effectively translate the science and the benefits of the tests to determine the optimal therapy. This will require either a divide and conquer strategy between the drug company and test provider or by consolidating the activity within a single organization. Unique skill sets will be needed by these organizations to effectively advise on the requirement for or promote the benefits of testing, depending on the specific circumstances of the drug-test combination. The challenges associated with this activity can be turned into opportunities for communicating the need to test patient populations to ensure that patients receive the optimal therapy. Such marketing activity can be coupled with a specific drug to drive script writing by a target physician audience.
The second component of the question, “who has the most to gain?” in the world of personalized medicine concerns the ratio of value between the drug and the test. This factor is of considerable interest from a licensing perspective relative to deal negotiation including milestone and royalty payments not to mention responsibilities during development of the drug and test. Traditionally, drugs have had much higher financial values compared to diagnostic tests. In fact, during the early days of personalized medicine, many industry experts questioned the viability of the concept given the substantial disparity between drug and test valuation. Unless the commercial rights for the test resided with the drug developer, why would a separate entity invest in development of a test if the bulk of the rewards go to the drug developer? This maxim may change, especially in situations where the test determines whether a patient will or will not receive the drug treatment. If the commercial rights to the diagnostic test belong to a separate test developer / provider, this entity will have considerable leverage with the drug developer in negotiating the terms of a license or collaborative agreement. Also, there now appears to be sufficient incentive for diagnostic companies to invest in the discovery and validation of relevant biomarkers and / or proprietary assay platforms that will enable efficient testing and provision of results during drug development and by physicians in clinical practice.
And what about the payers, what will they do or say regarding the adoption of personalized medicine? If you consider the health insurers that utilize Medco for prescription benefits, they may have already spoken in the positive. Medco Pharmacy claims to be on the cutting edge of personalized medicine via the Medco Research Institute. This institution is dedicated to translating science into clinical practice through research initiatives with an emphasis on comparative effectiveness research that includes personalized medicine. Much of the research is based upon the company’s extensive medical and pharmacy claims database and led by researchers from a personalized medicine division. Other insurers may partner with Medco or duplicate the company’s efforts to adopt a personalized medicine program.
While it appears that everyone has the potential for gain in the application of personalized medicine, the one who gains the most may be the patient. Many physicians, most notably oncologists, have been frustrated by relying on therapeutic regimens that they know will not cure their patients and in many cases have little or no benefit while causing severe side effects. Many of these treatments are very expensive and thus under the watchful eye of the payers. “Whooah, we’re half way there; Whooah, Livin on a prayer; Take my hand and we’ll make it, I swear; Whooah, Livin on a prayer.” These words form the chorus of another Bon Jovi song entitled “Living On A Prayer.” Perhaps personalized medicine will answer the prayers of patients as well as the healthcare industry that collectively must lead the way in avoiding the wrong medicines because of their profound financial as well as physical and emotional costs.

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.


Thursday, March 18, 2010

Patients & Physicians Know Best

A doctor whispered into the ear of a dying man’s wife, “I’m sorry, he’s gone.” The dying man responded, “I’m not gone yet” to which the wife replied, “Quiet dear, the doctor knows best.” Later, when the doctor complained to another patient that his check bounced, the patient replied, “so did my arthritis.” While some may agree with the expression, “the doctor knows best” and others relate better to the patient with recurring arthritis, both jokes, given the current state of the pharmaceutical industry, may provide very sound advice.
Pharmaceutical industry experts fear that the era of blockbuster drugs is over and that a plethora of efficacious generic drugs will transform the sector while having a negative impact on innovation desperately needed in key diseases. In fact, the market for US generic drugs is expected to increase by approximately 10% over the next several years. This growth will occur at the expense of branded drugs covered by patents which have or will soon expire. Another factor involves the global economic downturn and uncertainties regarding healthcare reform in the US. Most experts agree that there will be extreme pressure on reducing costs which no doubt will further expand the market for generic drugs and other low-cost therapies. Subsequent to a considerable amount of industry consolidation activity, large pharmaceutical companies have responded to these challenges by rationalizing their R&D efforts and abandoning therapeutic areas where treatment options are considered plentiful. While R&D investment by pharmaceutical and biotechnology companies increased by more than 2 percent in 2009 compared to the previous year, some companies have abandoned their research programs altogether while focusing development efforts within priority therapeutic areas. As reduced profitability looms due to patent expiration and with little hope from anemic development pipelines, companies have scoured the globe for deals with smaller enterprises that have innovative therapeutic programs.
To maintain current revenue and in what appears to be in the spirit of “if you can’t beat them, join them”, several pharmaceutical companies have acquired generic drug producers or established partnerships with low cost producers in developing countries. Their plans involve both established and emerging markets. The recent announcement by AstraZeneca that it will enter emerging markets with a branded generics strategy is a good example. The company estimates that approximately 70% of pharmaceutical growth will come from emerging markets over the next five years. Other companies including Pfizer, GlaxoSmithKline and Eli Lilly are eying emerging markets with a similar emphasis on branded generics.
Considering the industry preoccupation with generic drugs, a key question is do the pharmaceutical companies have the right strategy to sustain the industry during the current dry spell caused by patent expirations and not so robust pipelines? Will the flood of generic drugs into the market over the next few years mean reduced R&D investments and a corresponding stifling of innovation? Far be it from me to address such a profound question but I felt compelled to offer a partial answer based upon recent experiences and observations. The challenges facing the pharmaceutical industry are daunting and not easily resolved by spending more or less money. Sir James Black, a physician who never practiced medicine yet made enormous contributions to the pharmaceutical industry may have been a prophet. The Nobel Laureate once stated, “The most fruitful basis for the discovery of a new drug is to start with an old drug.” The problem, generic drugs, may be a key solution to the innovation challenges facing the industry. Off-patent drugs and their generic counter-parts have established efficacy and safety profiles but are these features optimized? If not, what is the best way to optimize key medications that will differentiate them from the generic forms? Optimization can be attained by developing medicines based upon the advice of prescribing physicians and the patients they treat. So how do you find out what the doctor knows or what the patient needs? Starting with old drugs (e.g. generics) and working with physicians to optimize available medications may seem like a daunting task, especially considering the many opinions among practitioners and those for whom they provide care. However, many companies have the resources and infrastructure within their medical affairs effort to obtain key information to design the therapies desired by physicians and needed by their patients. Medical Liaisons are routinely engaged in dialogue with physicians or studying reports for the purpose of identifying key information to support prescribing of their company’s drugs. Traditionally, these professionals provided scientific support to sales. As the market changed due to fewer drug approvals and more stringent regulatory hurdles, companies began to emphasize the fostering of productive relationships with key opinion leaders to help achieve company objectives through medical education. The expertise and relationships of medical liaison professionals can be utilized to obtain critical information on drugs that exhibit deficiencies from a clinical or patient perspective. A comprehensive study of relevant literature and conversations with physicians can identify the limitations of approved drug products and set the stage for optimization. These limitations can be the focus of R&D efforts which may lead to drug products sufficiently differentiated from generic versions in the form of increased efficacy and/or safety. The improvements may be the basis of 505(b)2 registrations for new indications or may support the submission of an NDA. Limited term data exclusivity for these filings may be enhanced by patent protection if the improvement involves the use of a proprietary formulation / delivery method or provides for a new invention via dosing or administration methods.
The field of dermatology offers several examples of therapeutics designed by physicians. EpiCeram® is an emulsion cream comprising an optimal 3:1:1 ratio of ceramides, cholesterol, and free fatty acids that normalizes skin barrier function. EpiCeram was invented by former professor of dermatology at UCSF, Dr. Peter Elias, a practicing dermatologist and now the CMO of Ceragenix (the company that developed the medication). Application of the medication on skin lesions associated with eczema results in resolution of impaired skin barrier that leads to inflammation and itching. Although eczema and related dermatoses are normally treated with topical steroids, Dr. Elias postulated that restoration of the skin barrier by the ceramide and fatty acid emulsion would result in resolution of the inflammation and itching symptoms. Dr. Elias and colleagues at Ceragenix have demonstrated Epiceram exhibits comparable efficacy to the steroid fluticasone propionate 0.05% cream in improving the signs and symptoms of eczema. Since steroids should be used sparingly, especially in pediatric patients, Epiceram cream represents a notable achievement for a disease that has very few treatment options.
Charles Crutchfield, M.D. offers an example from the perspective of a physician who recognized the limitations of standard steroid treatments for psoriasis patients. Dr. Crutchfield developed an aerosol spray formulation of clobetasol that proved more efficacious than other 0.05% clobetasol-containing products including lotions, creams, ointments and foams. Several of Dr. Crutchfield’s patients were able to finally experience full resolution of their psoriasis symptoms not seen for many years with conventional therapies. The formulation was granted a patent and is distributed by Cuticeuticals, Inc. under the brand name Cuticort Spray.
Outside the field of dermatology we have an example that was almost “thrown to the dogs”, literally. Dr. Renee Kaswan, a veterinarian from the University of Georgia, was looking for a treatment for dogs with dry eye. Dr. Kaswan realized from her practice and literature surveys that the vast majority of dry eye patients (dogs and humans) were suffering from an autoimmune disorder that caused destruction of the tear gland tissues. Her selection of the immune suppressant drug cyclosporine resulted in disruption of the immune disorder that proved efficacious for the treatment of dry eye in dogs. As a treatment for dry eye in humans, despite early rejection by several pharmaceutical companies, Dr. Kaswan persevered and ultimately convinced Allergan to develop the drug as a topical preparation which was branded as Restatsis.
Although evidence exists that physicians have succeed in optimizing the use of medications for existing or alternative indications, does it make sense for companies to utilize their medical affairs and liaison professionals to contribute to innovations as a means of adding to development pipelines? While there is information that some companies utilize medical liaison experts in the assessment of licensing opportunities, there are very few examples of coordinated efforts between R&D and the medical liaison efforts in the identification of drug optimization opportunities. The expertise of medical liaison professionals that engage practicing physicians in dialogue concerning the limitations and potential improvements of drugs with established efficacy and safety profiles holds great promise for a source of innovation so desperately needed by an industry facing great challenges in uncertain times.

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.

Friday, March 12, 2010

Mid-Stream Changes In Drug Development

“Don't change horses in midstream” is a quote attributed to Abraham Lincoln from a speech in reply to an attempt to persuade “Honest Abe” to change political parties. The advice he attempted to convey was to not change your leader or your basic position when part-way through a campaign or project. While refraining from a change in leadership may have been good advice for politics during Lincoln’s time, changing your horse, even in midstream, may be the most prudent advice relevant to some drug development programs. Or better yet, having options relative to disease indications can substantially increase the probability of a drug making it through the development process. The best laid plans don’t always come to fruition. A change or addition, based upon the most relevant data from preclinical or early human studies, may be warranted to ensure that you and your company achieve success.

From a preclinical perspective, the standard route in research to development comprises the identification of compounds via assays from a validated disease target. Once a compound class is qualified, the best compounds are tested in various assays involving the target resulting in the determination of the lead drug with appropriate backup compounds. This compound then enters a battery of animal studies to qualify the efficacy and safety. If the data justify the initial hypothesis for efficacy and the compound exhibits an acceptable safety profile, a positive decision for human clinical studies is the likely next step. While the safety data is fundamental, for some drug developers, the efficacy results should be considered within a broader context than the initial hypothesis. Does the drug have activity at other targets or is the main target relevant to other disease indications? Answers to these questions are of considerable value to a company with limited resources. It is worth their while to use those resources wisely. Spending a little extra money during the preclinical stage may not only aid in better stewardship of resources during the clinical stage, a broader preclinical profile may offer an additional or alternative development plan for the drug. Having alternatives or additions to your development plan is like having several horses when you are ready to cross the stream or find yourself mid-stream and face key decisions regarding if or how to continue expensive and uncertain human clinical programs.

In my view, the ultimate example of having a team of horses when crossing that stream in the development program is duloxetine (Cymbalta) from Lilly. Duloxetine is often referred to as the “Swiss Army Knife" of drugs considering the multiple indication approvals. The drug is approved by the FDA for the treatment of depression, general anxiety disorder, fibromyalgia and diabetic nerve pain. Lilly is pursuing additional indications including chronic knee and low back pain as well as chronic fatigue. Although Lilly states that the exact mechanism of action of duloxetine is not known, their scientists have generated data that demonstrates the drug causes an increase in activity of serotonin and norepinephrine in the central nervous system along with other data that links these effects with the approved and pending indications. This knowledge of the effects of duloxetine and its translation into clinical evidence and approved indications resulted in annual sales in excess of $2B over the last several years. The anti-TNF (tumor necrosis factor) biological drugs represent another example of a drug class where a good understanding of the target and its implication in other diseases was exploited early in development resulting in additional indications that have contributed substantial value to drugs such as etanercept (Enbrel) and adalimumab (Humira). Both drugs are approved for the treatment of rheumatoid and juvenile idiopathic arthritis as well as the related psoriatic arthritis. The drugs are also approved as treatments for psoriasis and ankylosing spondylitis.. Adalimumab has an added approved indication for Chron’s disease. The fundamental role of TNF in the initiation and progression of these inflammation-based diseases no doubt led to the obvious preclinical studies that ultimately supported the human clinical work and resulting indication approvals. These drugs had combined annual sales of over $8B.

I know what you are thinking – “What do these blockbusters from large pharmaceutical companies have to do with my program?” While these companies may have vast resources compared to your company, the analogy of a robust preclinical program is still relevant. After all, the preclinical program is the most affordable part of your entire development program. Why not pretend you are a large pharmaceutical company and at least consider additional or alternative indications? You may be surprised about what such an exercise presents to you and your colleagues. Need a relevant example? Consider the Janus kinase (JAK) inhibitor program from Incyte. Perhaps by considering the success of the related anti-TNF drug development programs, Incyte scientists explored similar preclinical studies of the JAK inhibitor INC 18424 which ultimately set the stage for justification of several clinical programs for inflammation-based diseases including myelofibrosis, polycythemia vera and essential thrombocythemia. A topical formulation of the drug is in clinical trials for the treatment of psoriasis. In late 2009, Incyte announced that it entered into an agreement with Novartis for INCB18424 for myelofibrosis and the other indications. The company stated that it received upfront and immediate milestone fees totaling $210M (which included rights to an earlier-stage drug), a handsome reward for extending the preclinical effort to justify programs in more than one hematology indication. The company announced that it will engage dermatology companies in discussions concerning the development of the topical psoriasis treatment which may be viewed as “icing on the cake”. Had Incyte not succeeded in advancing the hematology indications, the dermatology treatment may be viewed as an extra horse to carry the company across the stream to the side of a drug approval.

In my experience, more and more companies have extended their preclinical programs to ensure that they achieve an approval of their drug and thus increase prospects of the company. In addition, companies have been responsive to consider additional or alternative development programs when presented with potential value of their drug in an indication that was not contemplated prior to the clinical development decision. While there are concerns such as an adverse events or safety issues arising from trials for an alternative indication affecting the lead treatment under investigation, such issues can be managed by effective preclinical programs and advice from potential partners that have the experience from pursuing multiple indications for a single drug. Development-stage companies should also consider potential partners as a good source of advice on commercial issues (e.g. price differential between indications) that can be invaluable to a small company considering whether to increase investment in an alternative indication. Think about the analogy of crossing the stream. How many horses would you like to have at mid-stream?

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.


Tuesday, March 2, 2010

Predicting The Future During Drug Development

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 FanaptaTM, 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.