Part Two: Finding New Drugs Q&A
Q1. Who finds novel drug entities, and at what cost? Why are some new drugs discarded or never pursued for approval?
A1. It has been determined that only one in 30,000 chemicals (compounds/biologics) ever gets to be a drug. On average, the cost to bring one from the chemist’s bench to the desk of an FDA reviewer exceeds $10,000,000 and takes ten years at the minimum. I was in the Netherlands working with world famous drug discovery and evaluation experts with decades of experience in drug discovery programs. They announced to me that after tables were prepared listing every pharmaceutical agent, they showed of the hundreds, and even thousands of such agents, one could recognize those which had useful therapeutic properties, and those that failed to have any important therapeutic roles.
Q2. How many therapeutic entities have potential, how do they fare, and what is the chance that they will be drugs?
A2. While humans have long recognized that certain substances either isolated from natural products or assembled in the laboratory could make life more desirable and often less painful, only a handful were eventually considered part of the therapeutic armamentarium. With those odds stacked against us, it seems almost miraculous that we have new drugs frequently enough to make medical strides, and that these substances make significant advances to provide new health care opportunities. I have personally seen and taken active roles in every aspect of this process, from the initiation through the approval process itself. This has occurred over the forty-plus years I have been involved in the process, and working with Nobel recipients such as my major professor and persons lucky enough to have found interesting substances by chance and developed them further.
Q3. Where and how are drugs found in nature? What motivates researchers to synthesize new drugs, and how is it done?
A3. In the “old days,” drugs were “found” by testing myriad compounds, often prepared by the medicinal chemist according to an idea or relevant information that would suggest interesting and/or useful pharmacological activity. Little or no attention was paid to patentability or potential mechanism of action. In the new drug discovery process, we are talking about finding a new drug by accident, as well as painstakingly developing a chemical or biologic through synthesis or extraction from biologic (usually botanical) sources. Most people have little idea that many of our most potent and useful agents were derived from plant sources. This includes narcotics, anti-cancer agents, and everything in between. New methodology using biologic entities has increased the ability of medical practitioners to treat important illnesses in a way that enhances the pharmaceutical treatment modalities.
Q4. Who finds novel drug entities and at what cost?
A4. Novel drug entities are often not “found,” but are rather conceived. A chemist may have ideas about particular chemical entities that he feels merit additional or different chemical configurations. Many “new” drugs are variants of old ones. For instance, a Canadian chemist looking for variants of the opioid chemicals prepared many variants and gave them identifiers. One variant called W18 was found to be hundreds, if not thousands, of times more potent than morphine. While this was rather unexpected, W18 was quickly put through many tests that indicated a novel drug entity had been discovered.
Q5. Why doesn’t the FDA actively seek out new drugs for themselves?
A5. FDA plays an important role in drug development; The tasks and ideas about drug discovery are covered in earlier blogs that describe ways drugs are developed and/or approved. Given the poor chance of successfully finding a useful drug to treat disease, it is important to know what happens to these substances next. FDA cannot develop drugs on their own and also cannot act as a commercial sponsor might. For instance, while commercial sponsors can develop the drugs in ways that would make commercial sense, FDA is not in the position to do anything that would be considered necessary to get the drug approved. By law, they can only comment and act to make certain, whoever the drug’s sponsor will be, that FDA and commercial guidelines are followed.
The FDA cannot make a drug ready for commercialization and, as a matter of fact, any activity towards commercialization would cause a conflict of interest in the ultimate approval scenario. Even though FDA realizes that a drug represents an important therapeutic entity that should be developed to treat a clinical condition, they are not allowed to develop nor promote the drug. Because FDA is a government entity subject to the rules already made years ago, their role in the new drug process is carefully controlled and conflicts of interest are easily developed. Even working with a commercial entity outside of FDA makes it impossible for an FDA reviewer to be given permission to evaluate that entity without complications.
Even natural products that are often the most active substances are subject to conflicts if a developer works on the substance after joining FDA. Every effort is made to prevent anyone from saying that favoritism colored the FDA evaluation process. Commercial manufacturers and sponsors must therefore act carefully not only to evaluate patent positions, but potential regulatory ones as well. That makes any activity that FDA may carry out about a drug, and any FDA input before approval, somewhat suspect.
All of the foregoing makes it clear that any substance isolated from natural complexes must fulfill the same set of rules governing substances made from scratch by chemists. FDA and commercial manufacturers are well aware that drugs or substances to be used as clinical entities must pass difficult evaluations, including toxicity. Challenges involve preparing satisfactory substances that are acceptable in the chemical nature, manufacture and controls which limit whether a substance can ever be approved.
Given these requirements, many substances never get to full evaluation, since it may be determined at an early date that they would not be acceptable. So many of the 30,000 or similar number of substances get discarded at an early stage. Anyone recognizing the difficulties in drug discovery or approval already discussed here can now understand the time and costs associated with new drug development. Despite these difficulties and low chance for success, the researchers and scientists in new drug discovery and approval still move forward in their ultimate quests. This is because so many people suffering from diseases that affect both survival and enjoyment of life must be handled in ways that are beneficial.