Understanding risks.

When I treated people who were newly diagnosed with heart disease, their questions would gravitate to the risks: how does this disease affect my function, well-being and independence; does this diagnosis put my life at risk? And as treatments options were discussed, people wanted to know about the benefits and risks of each option.

Eventually, many of these people would become progressively more limited, enough that the conversation expanded to experimental treatments. These were more complicated discussions because less was known about these treatments. They had not been studied as much as the therapies that were already accepted as standard of care, which meant that the FDA (or a parallel government agency in countries outside the USA) was convinced that their benefits outweighed their risks.

To those suffering from a disease, the progress was not fast enough (and neither was it to those testing or those developing new treatments). The oversight of regulators appeared to slow progress, which I learned a lot about from working inside the FDA.

How the FDA Regulate New Drugs (pardon the simplistic view)

(Medical devices and drugs are regulated similarly but under separate laws. I’m focusing here on drug therapies.)

The laws passed by Congress determine the rules, though through their implementation, the FDA has some flexibility. For example, the law defines the requirement of “substantial evidence” of safety and effectiveness, which the FDA interpreted to mean that this evidence needed to be demonstrated in two adequate and well-controlled clinical trials. A drug must work and be safe, with those findings replicated.

During the initial years of the HIV/AIDS crisis, a new law was passed that meant certain drugs could be approved with lesser data (Subpart H – Accelerated Approval). Still requiring “substantial evidence” – this law made it easier for drug developers to secure FDA approval. In place of proving the clinical effectiveness exemplified by prolonging life, the trial(s) could show favorable outcomes on a surrogate measure that is reasonably likely to predict clinical effectiveness. For these initial HIV/AIDS drugs, the surrogate used was the number of a particular type of white blood cell necessary to fight an infection (CD4+ cells).

Over the past two decades, the FDA expanded its use of Subpart H to cancer drugs, which are a big reason for the incredible progress in the treatment of many cancers.

Unfortunately, the regulation of most drugs has not moved to the Subpart H (accelerated approval) pathway. I was lucky enough to be at the FDA as this started to take another turn towards processes that could move as fast as the drug developers.

Expanding Upon the Benefit-Risk Ratio

In the early 2000s, the focus of regulators was safety first. And in laws such as the FDA Amendments Act of 2007, risk and risk communications were explicitly called out.

By early 2010s, the FDA was starting to shift. I pushed for the shift to benefit-risk within the device center as colleagues in the drug center did the same for drug oversight. It seems small, but getting regulators to start with benefits meant they could be seen more easily than if one started by looking at potential risks. By 2012, both groups had published Guidance documents emphasizing the importance of “benefit-risk” frameworks.

But that was not enough. I pushed hard for another concept to be clearly stated as part of how the FDA would regulate devices. We would also consider (1) patient tolerance of risk and (2) availability (or not) of other therapeutic options. The Center for Drugs published a Guidance document in 2023 that called out the importance of the “therapeutic context” – the severity of the problem affecting patients and how well patients’ needs are met by available treatments.

Current State of the FDA

With another change in leadership at the Agency, it is difficult to know with certainty how drugs will be regulated in the coming months-years. But an important change was initiated earlier this year. The FDA stipulated that in many cases, substantial evidence requirement could be met by data from one (not two) adequate and well-controlled clinical trials. The risk is that drugs could be approved and later shown not to be effective and/or safe. The benefit is that drugs shown in one study to be safe and effective get approved and to the people in need faster.

The FDA conducts ongoing reviews of the drugs approved under the Accelerated Approval program. Of the first 347 drugs and biologics approved under Accelerated Approval, 4 approvals were subsequently withdrawn due to risks identified in later trials and/or clinical use, which the FDA labels a “safety concern.” One of these drugs remained on the market for a different purpose where the benefits outweighed the risks.

The data show that Accelerated Approval is a great path for the FDA, which is why I believe the recent Agency leadership was right to advocate for a shift from two “adequate and well-controlled clinical trials” to one “adequate and well-controlled clinical trial” as the basis for substantial evidence, and therefore, drug approval. While there were cases where an approval decision was reversed, the overwhelming majority of drugs approved through the Accelerated Approval pathway brought meaningful benefits to desperate and/or suffering people. The benefits of this regulatory pathway are greater to the general population than its risks, particularly in a context of inadequate available treatments, as is the case for Parkinson’s.

Is this relevant to RB-190?  

Yes!

If the FDA’s posture is changing to one where it is willing to accept the possibility of being wrong in some cases to get more drugs to people in need faster, then that is good for people who could be treated with RB-190, those suffering from Parkinson’s.