Most of you are familiar with Zeno's paradox regarding the impossibility of motion, Achilles and the tortoise dilemma. Zeno asserts that no matter how quickly Achilles races to cross the finish line ahead of the tortoise, he will never catch up to the turtle and hence fail to cross the line. I use this analogy to discuss a separate but comparable race: the tortoise of drug development and the business/commercial expectations driving it (Achilles). I'll outline the issue, its effects, and suggest a general plan for resolving it or some thoughts for the course we should take.
Tortoise comes first. Drug discovery and development is a lengthy, uncertain, and risky process that begins with the identification of a concept and ends with regulatory agency approval. With regard to their clinical testing, it closely resembles fundamental research. Consider the following scenarios: you have an idea, you test it, and it either 1) works, 2) doesn't work, or 3) kind of works. Unfortunately, scenario 3 is the most frequent; as a result, hard choices must be made regarding whether it was effective. If so, ought it should be improved? If not, should we attempt something entirely new, or should we try to determine why it didn't work? One of the most difficult (as well as irritating and draining) experiences you can imagine is trying to answer the last question.
This method is described by a single word: iterative. It comes from programming, where a fresh program is run repeatedly while being improved upon each time to produce the intended outcome. The process of developing new drugs is comparable. The fundamental distinction is that iterations are costly in terms of time, resources, and effort. The concept of "changing only one factor" does not really apply to the discovery and development of new drugs because, when working with living systems, you are regarded as operating in a "black box" where you are only aware of some of the components while ignoring others, let alone how they interact. Because of this, the process of developing new drugs is rather uncertain. Even with a great idea and the best strategy, you will almost certainly run against a brick wall sooner or later, forcing you to start over from scratch.
Given the large sums of money required and the substantial risks of preclinical/clinical/market failure they imply, funding for drug development often originates from two types of non-governmental investors: stock exchange markets and private investors (venture capitals, business angels, etc.). Beyond how everyone operates differently, there is a shared incentive: maximizing profit as quickly as feasible. With this in mind, investors make investments in businesses. If things don't go as planned, sooner or later, in the case of stock markets, they pull the plug and sell their stocks, which sharply lowers the firm's valuation, or in the case of private investors, they sell their company's shares and stop investing in the company. In both situations, taking such a step puts the company's plans and potentially its survival in grave danger.
This produces a certain dynamic between the investors and the corporate management. In order to ensure that their projects are scientifically and technically sound, the people working for these companies—often their founders—have to make sure that they employ the proper methodology to address the appropriate question and that they correctly interpret the data while adding value to the product they are developing. All of this must occur within an acceptable time period for investors, which means that events must proceed in a way and at a pace that gives them the assurance that they will obtain a "return" within their time frames.
This dynamic of "dancing quicker than the music" has two effects. First, businesses must modify their drug research initiatives to satisfy investor expectations, aiming for the best risk/profit ratio rather than only the best risk/societal benefit ratio. The second effect is that most companies and drug development programs simply fall short of expectations. This is not to say that they did a poor job or that the drug design is subpar; it simply means that it took too long or that certain decisions were made that did not result in an adequate risk/benefit ratio. These businesses will probably go out of business, and the things they create will be put on a shelf. Exactly like that.
This is concerning because it indicates that many medications with real clinical promise have been put on hold. According to Yale researchers, "strategic business decisions" were the second-most frequent cause for corporations to halt the development of experimental medications, ranking ahead of "safety issues" but behind only "a lack of efficacy." Although there may be solutions, safety issues like toxicity are often a trait of a drug that are quite difficult to eliminate. On the other hand, ineffectiveness can be overcome by altering variables including the target disease, dose, patient population, combination, scheme, and mode of administration, among others. It goes without saying that business strategy has little to do with how effective or harmful a drug is.
However, this occurrence has two intriguing side effects. First, troubled companies lose value, albeit that may not always be a terrible thing. That may in fact make them more desirable for big pharma to purchase them at a discount, giving their drug discovery programs a second chance. Second, other businesses can use these incomplete pharmaceuticals that have been put on hold to rework them so that they might benefit patients. From the perspective of a drug researcher, such a change has many benefits: the medication is already (almost) manufactured, its chemical and biological preclinical (and maybe clinical) behavior is understood, and the history of previous failures is an invaluable source of information.
Because they frequently take risks that major players won't, biotech startups may pursue the development of treatments that have been shelved. Many people want a chance to use treatments to turn underutilized assets into huge winners. Profits from the sale of these drugs will be split with the manufacturers, but more crucially, lives will be improved or even saved. The original proprietors must (ideally) make the intellectual property and their prior expertise available for this to occur.
This cooperative strategy offers so many opportunities that it is referred to as the "second wave of innovation" for these medications. But there are some snags in the road. A significant barrier is the culture of big pharma in particular and the pharmaceutical industry as a whole. When it comes to sharing its initiatives, big pharma, which owns the majority of these shelved medications, is more concerned with competition than partnership. They can become extremely anxious about giving something away and not receiving enough benefit from it, partly due to the financial loss sustained but also—and perhaps more importantly—because they run the risk of harm to their reputation. In such a cutthroat and complicated industry, nobody wants to come off as foolish.
However, there are some positive developments. Some businesses already give their unused medications to others who want to develop them further, sometimes even for free. Some large pharmaceutical corporations are setting up spin-offs with the goal of researching medications that have been put on hold for novel therapies.
There hasn't been a lot of activity in this area up to this point, but hopefully recent trends only herald the beginning of a success story that can usher in a true game-changer, such as a forgotten drug that was previously thought to be ineffective or catering to a small or crowded market that is now taken up by another group with a fresh perspective and made to work for patients, possibly in a disease completely unrelated to the original one. Such a discovery will undoubtedly attract the interest of investors and big pharma and open up new possibilities for the discipline. When it comes to purchasing innovation, huge pharma corporations behave like a herd: some ideas with promise are overlooked for years until something works, at which point everyone is lining up to create their own version. Immune checkpoint inhibitors and mRNA-based vaccines are two of many examples of useful technology that were overlooked before reaching this level of exponential popularity. Because the change won't be in the use of a specific technology but rather in the basics of how pharmaceuticals are generated, I suspect and hope that sooner or later the repurposing of shelved therapies will join that infamous list with a much wider impact.
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