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The FDA Could Approve Almost Any Drug (But It Won't Approve That)

Welcome to Molecular Ideas, and thanks for sharing your time with us today! Today, we discuss the unique role of the FDA in the drug approval process and their recent approval of the controversial Alzheimer's drug, Aduhelm.

It's All Coming Back to Me Now

Once you've discovered a new drug candidate, there are three major barriers to be hurdled before patients at large can access it.

Of these, the one that stands out is the Food and Drug Administration, or the FDA for short.

On the one hand, you have the enigma of scientific discovery, made especially complex by the clinical trial process. Uncovering the secrets of the cellular machinery is analogous to reconstructing a puzzle made of infinite pieces with multiple configurations and no clear image of what the full picture looks like.

On the other hand, ensuring that your your drug is reimbursed by payors is a bureaucratic, disparate process. Reimbursement process ensures that someone (or multiple someones) will pay for your drug. Setting the patient and their contribution to drug costs aside, key players include insurance companies, integrated delivery networks (i.e., 'Payviders'), and the federal government.

The FDA stands out as a regulatory authority. Since the early 1900's, they've serve the public's interest by bridging the enigma of scientific discovery with protocol by ensuring the safety and efficacy of drugs, biological products, medical devices, food, cosmetics, and other products. When the FDA approves a drug, it means that the agency has determined the product "provides benefits that outweigh its known and potential risks for the intended population." You can read more about their mission and general capabilities here.

While the FDA does not get involved with reimbursement, there are very few elements of drug development, manufacturing, and marketing that it does not oversee.

You've head of the three main stages of clinical trials, often spanning a decade or more? Check.

Image Credit: PhRMA & Tufts Center for the Study of Drug Development (CSDD)

How about surprise FDA audits on your manufacturing, supply chain, and/or product? Check.

Image Credit: Shutterstock

Ever listen to the middle of a drug commercial on TV where a narrator rapidly lists off the possible side effects of the treatment you're learning about? Check.

Image Credit: Molecular Ideas (note - these side effects are for fictional drugs)

These are only three of the hundreds of other functions that the FDA handles in service to patients. They also issue hundreds of guidance documents per year that set the current gold standard for best practices in every aspect of drug development, production, and marketing that effectively serve as real-time regulatory updates.

Employing an estimated 18,000 individuals with a budget of $5.9bn, the scientists, practitioners, epidemiologists, economists, project managers, and many others who work there take on the Herculean task of balancing the urgency of drug developers to move forward due to limited capital and patients in need, with the broader interests of safeguarding public health and market competition.

Read 'Em and Weep

With this almost paradoxical balance between innovation and public health in mind, it's not surprising the that FDA is often portrayed in different lights in common discourse:

1) As a bureaucratic barrier to getting much-needed medications into the hands of patients and practitioners;

2) As the valiant defender of safety and efficacy standards for new medications, and;

3) As a partner in the drug development process.

Let's explore this last one for a moment. The drug development process is a long, arduous process in which all stakeholders hope for the same outcome - a new drug is safe and effective, it gets approved, and enters the market, thereby saving lives and (hopefully) driving down healthcare costs. With that in mind, the FDA can serve as an effective partner in helping you understand how your studies should be structured to ensure fair and equitable representation alongside generation of informative data. These are accomplished by both informal and formal meetings throughout the development and clinical trial processes. Keep in mind, nearly 45% of the FDA's budget comes from submission fees by pharmaceutical companies. That encourages a more open exchange of dialogue.

While some may see this as a possible conflict of interest, both parties are serving a common interest - and the FDA has thousands of staff dedicated to making sure that data from drug developers is accurate. The combination of these meetings and verification has contributed to an increase of new drug and biologic product approval rates over time.

Increasing approval for new drugs (i.e., new molecular entities or NMEs) has been attributed in part to more communication between companies and the FDA. Source:

When the trials are completed and your application is submitted, there are (broadly speaking) four possible outcomes:

1) Approval - Congratulations! You have shown your drug to be safe and effective compared to the standard of care and can market your drug. You may need to submit post-marketing surveillance data, but you're on your way to revenue. Good luck!

2) Conditional Approval - You have shown your drug is safe, but whether or not it is truly more efficacious than the standard of care is unclear. You must show a "reasonable expectation of effectiveness" but the application has not yet met the "substantial evidence" requirement needed for full approval. You can market your product, but you're not out of the woods yet - you will need to undergo a post-approval trial to verify whether it has the anticipated clinical benefit.

3) Complete Response Letter (CRL) - The other side of the grey area, a CRL is issued when the FDA has outstanding questions about the product application. This doesn't mean that the drug isn't safe and/or effective. Rather, a CRL allows the FDA to provide a drug developer with a systematic list of deficiencies within the submission package. While this stops short of requiring a full resubmission, it can be a devastating blow to a company's morale and share price.

4) Disapproval / Application Rejection - As said famously by Dr. Seuss in Oh, the Places You'll Go: "You'll be famous as famous can be, with the whole wide world watching you win on TV - except when they don't, because, sometimes, you won't".

Out of the Frying Pan (and Into the Fire)

The FDA's thorough review process does not always mean that they get it right, or that approvals come without controversy. Tragically, there are several instances over the course of the FDA's history where drugs were approved and required recalls due to poor safety. In more recent times, we have begun to grapple with the tragic effects of opioid addiction, for which the FDA bears some responsibility and is taking measures to address.

Examples of pharmaceuticals approved and removed from the market by the FDA

In many of these cases, it is unclear as to whether the FDA could have known about these effects at the time of submission, which only underlines the importance of issuing guidance to reflect the latest research.

Of note, the FDA did not approve thalidomide in the 1950's and 1960's. If you'd like to read more about that moment in medical history, check out this article on Reuters.

All of this leads us to the recent and controversial conditional approval of Biogen's long-shot drug for Alzheimer's Disease, Aduhelm (aducanumab-avwa). The last of many, seemingly Sisyphean struggles of big pharma, Alzheimer's Disease has proven to be one of the most notable and most challenging diseases to address of this generation. It is currently estimated that 1 in 9 people in the U.S. over the age of 65 has Alzheimer's. The current patient population of approximately 5.8 million is expected to continue growing as the population ages.

Alzheimer's is a tragic disease of the brain with complex underlying biology and many influences around its development. It also represents a massive, unparalleled public health need with a relatively open market.

Image Credit: Shutterstock

While there are currently around 100 unique therapies being tested in clinical trials for Alzheimer's, industry leaders like Pfizer and J&J, as well as maverick biopharma companies like Biohaven have struggled to slow the disease's progression. Aduhelm represents the first drug to be approved to treat Alzheimer's since 2003.

For many patients and their families, Aduhelm represented a great hope that their loved ones would be able to keep their minds and health, if not just for a little longer. In clinical trials, patient's thinking skills declined by only 22%. While this rate was more slowly than the placebo treatment, it is unclear if the data translates into practical benefits such as the patient’s ability to have greater independence.

Given the lack of understanding about the underlying biology of Alzheimer's and the limited metrics we have to measure outcomes with this disease, Aduhelm's approval was fraught with controversy. While the safety data checked out, the argument against approval is that it sets a precarious precedent of allowing future approvals to be granted for treatments with limited, unclear, or questionable benefits. The counter-argument is that while Aduhelm is thought to only be truly beneficial for a small part of the Alzheimer's population, anything is better than nothing.

You can read about the Aduhelm approval timeline here; it was ultimately granted conditional approval, but not without cost. Three senior FDA advisors resigned over the agency's decision. Uncharacteristic 'off-the-books' meetings between Biogen and the FDA have launched a massive, public investigation. What's more, the drug has thoroughly underperformed in Q3 due to the mass of media attention on these events and limited coverage by insurance companies. Total sales thus far have been approximately $2mm, though Wall Street analysts had expected it to reach as high as $12mm.

While it's unclear as to whether Aduhelm has established a precedent for approvals based on limited evidence, it is almost certain that it will remain a polarizing case study for years to come.

Objects in the Rear View Mirror May Appear Closer Than They Are

The FDA is meant to meant to safeguard our interests by balancing the need for pharmaceutical innovation with the need for public health protections. By leveraging thousands of brilliant minds, detailed protocols and guidance based on the latest scientific thinking, and its authority as the governing regulatory body of the life sciences, it has stopped hundreds - if not thousands - of unsafe or non-efficacious products from reaching the market.

However, the FDA is not infallible. It is an agency run by humans who work to quantify the need for novel treatments and validate the science of cutting-edge therapies. On occasion - due to oversights, incomplete information, or conflicting priorities - they get it wrong.

As we grapple with diseases in our homes and pandemics in our world, it is critical to maintain an informed discourse with the FDA. It is our job to understand their way of thinking so we can better articulate our needs as their constituents. It is their job to be both vanguard and mediator on the edge of what is known so that we can be sure what we put in our bodies is relatively safe and will work as prescribed.

Experience as an entrepreneur has shown me that some of the best partnerships are formed on the ability to have difficult conversations. Sometimes that means running towards the truth like a bat out of hell.

However, that's not all! Later this week, we will share a song parody that reflects the FDA's role as a key partner in drug development. We won't disclose what the name of the song is, but I bet you can guess. And if I took the words right out of your must have been because you knew where this post was going.

That’s all for today! Thanks for spending your time with us. Please share this article, and sign up to leave your thoughts, ideas, and opinions in the comments. Your feedback is always welcome and helps Molecular Ideas grow!


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