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.

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