Would you take a pill for your headache if it made you extremely nauseous? Most likely not. Nevertheless, extreme nausea is a risk people are willing to take when taking medicines in hope of getting cured from Cancer.
In a nutshell, this is the risk-assessment we all do when choosing to use medicines or undergo any medical intervention. On one hand, we want to cure disease and alleviate our suffering, on the other hand, we must accept some level of risk, due to complications and side-effects. A common saying is that if there are no side-effects, there probably are no Effects either.
To make an informed decision, the context is critical: what is it we are trying to solve here? Is it a minor annoyance, or a life-threatening condition? Are we going to have to take this for the rest of our lives, or is it a one-time treatment? Do we have enough information to make this decision?
These questions are probably familiar to you and are guiding principles for people who work in Pharmaceutical Development.
So in brief, Pharmaceutical Development is the effort to find new and effective drugs within the context of uncertainty and risk.
Similar to other medical practices, it shares the same basic ethical principles :
Do no harm
Help the suffering
And with these principles in mind, we start working.
Having discovered a potential drug, the development process goal is to establish that the drug is Safe and Effective.
The Journey of Pharmaceutical Development
We embark on the Preclinical (animal) studies, to demonstrate some initial safety, then we go on to Humans, in the clinical trials Phase 1, 2 and 3- where we test our product on an increasing amount of people, going baby steps in monitoring the safety of the drug, while collecting enough statistically-significant data on its efficacy.
Throughout these phases, we need to manufacture enough material for the trials, in the appropriate Pharmaceutical quality grade- which is the work of CMC.
CMC, short of Chemistry, Manufacturing and Controls, covers all the aspects of making the drug: what is the molecule at hand? How is it made? How is it provided to the patient? How do we ensure its quality?
The manufacturing process development takes place in parallel to the clinical research. Initially, very little amounts are needed as the material is tested in small animals and small groups of people. At these early stages, manufacturing is sometimes done in lab scale. As we progress, the required amounts increase, so we take immense efforts in scaling up the process, while maintaining our product "similar" throughout (otherwise, we would not be able to count on all the safety data we gathered so far...). What is “the same” is a big question called Comparability, which overarches the entire development process and is encountered in each step of the way, when the process scale increases and improvements are made to the manufacturing process.
The manufacturing process development culminates with a Commercial manufacturing process which provides a consistent quality, Pharmaceutical Grade product in marketing volumes. This very short paragraph hides the remarkable technological breakthroughs we are making, enabling us to manufacture ever-more complex biological materials, while maintaining consistency and quality.
The gatekeeper between the companies developing drugs and the patients are the Regulatory Authorities worldwide, the most famous of which are FDA in the US and EMA in the EU. Each nation assigns a government agency to assess the complex data provided by the companies developing Bio/Pharmaceuticals and decide whether to approve its commercial distribution in that country.
The regulatory authorities have the final say on any use in Humans- by approving the material for clinical trials, and by providing the ultimate marketing authorization.
The authorities and the companies are managing a complex array of liabilities: The risk of harming patients is terrifying, but there is a constant pressure to cure disease, especially for global pandemics like Diabetes, COVID-19 and countless other ailments. So it very quickly becomes a dense forest of competing factors: being too "safe" (risk-averse) might prevent a life-saving drug to hit the market, but releasing a harmful drug in massive amounts could result in a catastrophe for all parties involved.
On top of that, there is a mutual run of the companies and regulatory authorities as our scientific and technological understanding expands. Our regulatory paradigms must be adjusted very quickly to new technologies, and the expectations coming from the People are that we must react faster, thanks to that knowledge (the "long-awaited for" COVID vaccines are an unbelievable achievement, even in terms of just a few years ago).
The authorities are aware that the regulatory process is highly intricate and is increasingly more nuanced, so they encourage companies to reach out and discuss their data and concerns throughout development. There are many interactions with them throughout development, which culminates in the marketing application. This ongoing interaction is handled by the RA teams and consultants.
The funnel of Death
A short moment of silence, for the many projects which failed through what is known as “The funnel of death”.
As a kid, I used to hear the wish, which has become a cliché, that “one day, someone will find a cure for Cancer”. I’ve grown to understand that there are many cures for cancer, its just that there are many types of cancer, and not all cures are equally effective, and some projects fail because they lack funding or luck, and the list goes on and on.
The industry works within a tension between the ultimate goal (provide safe and effective drugs to people), and real-world constraints (Technology, knowledge, budget, luck, etc.). Any of the above could fail the project, especially at early development stages when the amount of knowledge is lowest and risk is proportionally high.
Drawn on a timeline, the number of viable projects decreases dramatically over time, creating the shape of a funnel- which only select few products come out as viable products to the market.
The light at the end of the Funnel
Finally, the tough ones made it through with a new drug, with established safety and efficacy and obtained regulatory approval for commercial distribution. Now its the time to manufacture the new product in amounts that meet market demands and to the Pharmaceutical Standards. Is the story of Pharmaceutical Development over? of course not- as more real-life data comes in, our knowledge expands and we continuously improve our procedures and our products.
With the help of their doctors, our patients can make an informed decision whether to take this drug or not, given all that we know about it, and the underlying situation.
Beyond CMC is set on a mission to curate Knowledge and Know-how on Pharmaceutical Development, CMC and Beyond!
Check out the free mini-course on the Pharmaceutical Development Journey- See more details in the Online Courses page.