Academic Institutions and Drug Discovery

The ability to manipulate the chemical composition of matter has led to new products and technologies emanating from almost every sector of industry. Of these sectors, among the most challenging and time-intensive activities is the discovery and development of new therapeutic agents. These challenges stem from:

• our increased need for safer and more effective products
• inherently long timelines from discovery to market
• the desire of the venture community to realize rapid returns on investments.

Examining these points from the perspective of cause and effect, the well justified need for safer and more effective products results in longer timelines from discovery to market. Unfortunately, long timelines are not compatible with rapid returns on investments. As such, investment capital has been shifting from high risk discovery programs to less risky development programs. In fact, it is not uncommon for investors to reserve capital for products already in clinical trials. The unfortunate consequence of this paradigm shift is that reduced capital for discovery programs has led to a reduced number of products transitioning from discovery to development. This transition begs the question FROM WHERE WILL THE NEXT GENERATION OF DRUG CANDIDATES EMERGE?

In previous posts, I highlighted issues relevant to this question including:

• Where big pharmaceutical companies will rebuild their pipeline of new drug candidates
• Large pharmaceutical firms turning to biopharmaceutical companies to fill their discovery pipelines
• Paradigm shifts incorporating outsourced services as replacements for high cost internal capabilities
• Academic institutions must continue to provide solid educational programs and degrees in chemistry - incorporating broad based and generally useful knowledge/skills

With the shrinking volume of venture capital funds available for early stage discovery startups and the continuing trend of large pharmaceutical companies filling their discovery pipeline through small company acquisitions, there is a sector looking to academic institutions to fill this gap. Having both attended graduate school and contributed to industrial drug discovery efforts, I can state with complete certainty that THIS IS A VERY BAD IDEA!!!

Yes, I said it. I mean it and I make no apologies for the frankness of my statement. Academic institutions are not suitable engines for both drug discovery and the training of our next generation of scientists. To qualify this statement, consider that the drug discovery process requires activities including:

• Compound synthesis/purification/analysis
• Enzyme assays
• Cell-based assays
• Animal models of disease
• Pharmacology
• Formulations
• Metabolite ID/bioanalytical

Each one of these activities requires the involvement of highly trained and knowledgeable scientists. Furthermore, each of these areas must be coordinated with one another in order to enable generation of the data required to accurately evaluate all potential drug candidates. In an academic setting - the setting responsible for much of the cutting edge advancements ultimately benefiting the pharmaceutical industry - such activities are not likely to be implementable without a detrimental effect on the training grounds of the next generation of scientists.

Put another way, where are we to generate the next generation of innovative, highly trained and knowledgeable scientists if our educational resources are diverted to commercial interests?

Organic Chemistry vs Medicinal Chemistry

During my undergraduate research activities with Professor Henry Rapoport at UC Berkeley, I found that my greatest interest was in the discovery of new medicines. Recognizing that the career opportunities I sought required an advanced degree, I began asking about which type of graduate program to pursue - organic chemistry or medicinal chemistry. The input I received overwhelmingly favored a PhD in organic chemistry. The rationale behind this bias was quite simple - the most important skill for a chemist in drug discovery is the mastery of organic chemistry.

Education in organic chemistry programs is not limited solely to reactions. The diverse set of skills, generally applicable to drug discovery (and other industries) are:

• Synthetic organic chemistry technique
• Practice in hundreds of different reactions
• Exposure to many more reaction types
• Scales from mg to multigram
• Training in the logic behind synthetic pathway selection
• Training in all spectroscopic/analytic/purification techniques

While organic chemistry and medicinal chemistry programs both teach organic chemistry, medicinal chemistry programs tend to dilute the breadth of chemistry exposure with the biological aspects of drug discovery activities. These biological aspects, as my colleagues explained to me, are skills that can be learned on the job. However, the on-the-job expansion of organic chemistry knowledge is considerably more difficult to accomplish. From this philosophy, it is not surprising that at every company I worked, the most successful job candidates had degrees in organic chemistry with a strong focus on synthesis.

In my August 21 post, I pointed out that in order to motivate our next generation of scientists,

• Industry must work to prevent chemistry, a discipline requiring intensive education/training, from evolving into a service
• Academic institutions must continue to provide solid educational programs and degrees in chemistry - incorporating broad based and generally useful knowledge/skills

I am, and always have been, enthusiastically in favor of graduate and undergraduate level curricula focusing on the practical and philosophical aspects of the pharmaceutical industry. Such coursework can only serve to prepare students for what will be expected of them as they progress through their professional development. However, replacing or diluting the development of core skills can only compromise our next generation's ability to maintain a competitive edge in a global marketplace. Industry must look elsewhere for its discovery pipeline lest the current trickle of new drug candidates dries up completely.

Fear Mongering: Good for Nutraceuticals, Bad for You

Until now, my posts focused on philosophies regarding the current state of education and industry. In fact, when I started this blog, my intent was to focus solely on issues which are constructive to the advancement of science and innovation. I had no desire whatsoever to address divisive political topics. However, with the continued onslaught of negative press and political agendas targeting the pharmaceutical industry, I feel compelled to add my voice. To this end, I want to thank Dr. Andrew Weil for providing me with material for this posting.

While I do not know Dr. Weil and I doubt that I will ever have any personal interaction with him, I know that he is extremely knowledgeable and well respected. It is not my intent to detract from his stature and I apologize if this posting does that. My intent here is to engage in an intelligent debate based upon Dr. Weil's blog of September 2, 2009 as published in the Huffington Post (http://www.huffingtonpost.com/andrew-weil-md/disease-mongering-good-fo_b_275616.html). In this posting, Dr. Weil, discusses the term "disease mongering" as a mechanism used by the pharmaceutical industry to take advantage of uninformed consumers. As Dr. Weil states,

"A central disease-mongering tactic is to attach polysyllabic, clinical-sounding names to what used to be seen as trivial or transient conditions. In most cases, the new, formidable names come complete with acronyms, which add even more gravitas."

Before I go any further, I would like to point out that when a significant population experiences a common symptom, illness, syndrome or disorder, it makes good sense to classify these indications under a common name. This helps doctors to identify patient populations they may be able to help. Furthermore, patients are supported through the knowledge that there are others sharing their discomfort. Finally, pharmaceutical companies are assisted through the identification of populations suffering (for whatever reason) from indications for which there is no treatment. Through the identification of disorders with established unmet medical needs, pharmaceutical firms are able to identify markets and drive research activities to the eventual benefit of these patient populations.

Dr. Weil, in his September 2 posting, highlights five indications that are established disorders requiring, in many cases, medical intervention. These indications, along with Dr. Weil's "disease mongering" examples are:

• Occasional heartburn becomes "gastro-esophageal reflux disease" or GERD.
• Impotence becomes "erectile dysfunction" or ED.
• Premenstrual tension becomes "premenstrual dysphoric disorder" or PMDD.
• Shyness becomes "social anxiety disorder" or SAD.
• Fidgeting legs becomes "restless leg syndrome" or RLS.

In listing these example, Dr. Weil does nothing more than trivialize these indications and the patients who suffer from them. I, myself, suffer from GERD. For many years, I experienced chronic heartburn independent of diet. At one point, the pain was so severe that it was debilitating. I began taking proton pump inhibitors and eventually had surgery to tighten my lower esophageal sphincter muscle. While I am doing much better, I still have to take occasional medication to control lingering symptoms. I must also submit to periodic esophageal endoscopy procedures to monitor my Barrett's esophagus - a precancerous condition caused by GERD. For me, GERD is not an indication that can be treated by giving my body's "healing mechanisms a chance to find equilibrium."

Pharmaceuticals and Nutraceuticals - Marketing on an Equal Playing Field

In reading Dr. Weil's posting, I understand that part of his message relates to the practice of drug companies marketing their products directly to consumers. Personally, I see no problem with this practice. If a consumer is to be able to make informed decisions regarding healthcare, that consumer should know about all possible medical treatments - including pharmaceuticals. After all, if vitamins, dietary supplements and herbs (all classified as nutraceuticals) can be directly marketed to consumers, why can't prescription medications?

In the interest of fairness, I fully support the right of consumers to seek whatever medical interventions are best for them. I fully respect the history behind folk remedies and I do not pass any judgement upon those who choose alternatives to prescription medications. After all, herbs have served as sources for many modern therapeutics from aspirin to morphine.

While nutraceuticals, derived from herbal remedies, may deliver some potential therapeutic benefits, they are not regulated or controlled under the same requirements as prescription drugs. For example:

• Prescription drugs must be proven safe and efficacious through human clinical trials - nutraceuticals are not held to this standard
• Prescription drugs, when marketed, must have a package insert detailing adverse effects, dosage information and potential drug-drug interactions - nutraceuticals are not held to this standard

Because herbal remedies and dietary supplements contain naturally occurring pharmaceutically active components, patient who use these alternatives through self medication are putting themselves at risk based upon uncontrolled or arbitrary dosing and potential interactions with medications they may be taking by prescription.

If consumers are to have the ability to make informed choices regarding their healthcare options, all products marketed as potential health remedies must be held to the same standards. Unfortunately, they are not. This is the result of two issues:

• It is not in the best interests of nutraceutical companies to fund clinical trials demonstrating efficacy when they are not required to do so
• It is not in the best interest of pharmaceutical companies to fund head-to-head clinical trials of any competing product against their own

WHERE DO THE BEST INTERESTS OF THE CONSUMERS COME IN???

In order for consumers to be able to make the most informed healthcare decisions, all alternative medications must be held to the same clinical and regulatory standards as prescription medications. Only in this scenario can patients, with the assistance of their doctors, objectively evaluate the best course of care while minimizing adverse events and drug-drug interactions.