If a man is alive, there is always danger that he may die, though the danger must be allowed to be less in proportion as he is dead-and-alive to begin with. A man sits as many risks as he runs.
– Henry David Thoreau
Stop me if you’ve heard this before: There is no such thing as a “safe drug”. It’s trite, but it’s true. Even an ultra-common drug like ibuprofen carries the weight of potentially serious side effects (e.g., severe allergic reaction, stomach bleeding).
I know, I’m probably preaching to the choir, but it can be easy to forget in today’s commercial environment. Drug development is always a balance of risk and benefit. Always. Just ask the FDA.
In conjunction with the New York Academy of Sciences, the FDA hosted a meeting titled “Risk-Benefit Considerations in Drug Regulatory Decision-Making” on 23 April 2010. At this meeting, John Jenkins, M.D. (Director, Office of New Drugs, Center for Drug Evaluation and Research, FDA) gave a talk about the FDA’s perspective on risk/benefit considerations that the agency takes into account when evaluating new drugs. You should read his slides for yourself, but here are some highlights from his presentation (emphasis original):
- Assessment of risk/benefit is a qualitative approach that is grounded in quantification of various data elements
- Benefits – Efficacy endpoints from controlled clinical trials
- Risks – Harms reported in clinical trials and other sources (e.g., spontaneous adverse event reports)
- Evaluation of risk/benefit is dynamic
- Knowledge of benefits and risks evolves over product life-cycle
- Decisions on risk/benefit require judgment on the part of the regulator and are influenced by:
- Statutory/regulatory standards
- Societal expectations
- Personal values and perspectives
I really don’t think I could agree more with these points. He then went on to describe some of the (many) factors that are considered by regulators during drug evaluations. Ultimately, context is critical. Sponsors should construct a framework around their drug that helps regulators understand the risk/benefit profile. It should be a “big picture” snapshot that facilitates examination of the data and should have the following properties:
- Simple and user-friendly [but not simplistic]
- Address critical issues [good and bad]
- Capture expert views faithfully
- Represent transparently
- Compatible with quantitative analysis of clinical benefit and safety information
- Facilitate communications (internal and external)
- Broadly applicable
Dr. Jenkins also gave an example of a high-level framework (in table format) that captures some of their routine considerations. It may seem simplistic, but never underestimate the power of laying out information in a clear, simple way (especially if you are the one laying it out).
Click to Enlarge
He concluded by saying:
- Regulatory risk/benefit decision-making is a qualitative science grounded in quantitative data
- Judgment is required in making regulatory risk/benefit decisions and those judgments are influenced by many factors, both extrinsic and intrinsic
- Clearly outlining the available data and how decisions (judgments) were made can improve transparency of the decision-making process
Again, it’s all about context. Risk/benefit cannot be evaluated in a vacuum. Give the FDA the data it needs to evaluate your drug. It seems appallingly obvious when stated that way, doesn’t it? However, in the frenzy surrounding an NDA submission, there can be pressure to just throw every bit of information at the FDA without guiding them to the salient data.
Here’s some free advice for whenever you’re asking the FDA to evaluate anything (from pre-IND to NDA and beyond): Make the FDA’s job easier.
