The FDA is the major governing body in the US that helps researchers understand what data they need to proceed with designing clinical studies. Typically each project team will have a regulatory affairs member who has either worked at the FDA previously, or has expert knowledge on the requirements for each product type. The regulatory affairs member will outline exactly what deliverables will be needed to present to the FDA to move onto the next stage of the process, this include preclinical data before going into the design of a clinical study (for pre-market approval products). For 510K/ substantially equivalent products, the similar guidelines for required preclinical data (mechanical testing, shelf-life, biocompatibility) are given during the concept/development phase of the project without the need for designing clinical studies. There are nice to have's in terms of characterization of a product and its performance but necessary deliverables are clear.

This is an interesting question because I don't think there is ever a point where researchers can say they have eliminated every possible risk before going into human trials. To me, the decision is more about whether enough evidence has been collected to understand the major risks and whether the potential benefit justifies moving forward. More testing can always be done, but at some point doing additional studies may not provide enough new information to justify delaying the next step.

Working in CAR-T manufacturing has also made me think differently about the time side of this. We usually talk about delays in terms of money and project deadlines, but in healthcare there are also patients waiting for new treatment options. At the same time, moving too quickly without enough evidence could put those same patients at risk. So I think the difficult part is finding that point where the remaining uncertainty is acceptable rather than trying to completely eliminate uncertainty.

Do you think the level of evidence needed before moving to human trials should depend on how serious the condition is and whether patients already have other treatment options available?

@ahmed-elmonier I would definitely say the level of evidence needed before moving on should depend on the details of the condition. For example, if a new technology is being developed to potentially reduce the deterioration of a degenerative muscular disease, the risk of performing experimental testing on a human may be outweighed by the risk of not attempting any testing. If a participant is willing to participate in the testing, and a level of promise has been shown in the technology's ability to accomplish its intended effect, I think the research should be able to proceed. Like @afg28 said, however, the FDA determines the level of evidence required for human testing. This is done on a case by case basis, however, allowing for varying levels of evidence to be accepted based on the conditions of the condition.

An important factor in determining clinical readiness is by looking at whether lab and animal studies showcase enough evidence of safety and efficacy. At the same time, one should identify the major risks that could affect human trials. The goal shouldn't be to eliminate every uncertainty to but it should be to make sure if the risks are acceptable. Even if lab and animal testing reveal good results, moving into a clinical trial may be risky if there are still variations on how the device is manufactured or even how the drug is produced. Therefore, if a product changes in its performance between one and another patient, it can become difficult to determine if the product is safe. Researchers need to ensure that the technology has been produced and can operate reliably. If there is constant variation in manufacturing or in operation, then it can become difficult to determine if unusual results are caused by the treatment or by the inconsistent process. Marketing, finance, and industry pressures can also influence timing, especially if companies have invested in the project. A way to reduce these pressure factors is to establish transparent go or no-go criteria before there is a final result. In this case do you think a product should be delayed if researchers can't prove if it can be produced consistently?

Finances and industry pressure can certainly affect the timing of the clinical readiness of a project. When competitors are fighting within the same market, the pressure to fast-track a product is massive. A previous post mentioned how we can never completely eliminate every possible risk before moving into human trials. I think we will always face a constant balancing act between gathering enough preclinical data to satisfy regulatory bodies like the FDA and actually getting a life changing device to those who need it. We have heard this in the lecture, specifically about scope changes altering project timelines and how if a company is burning through its funding, managers might be tempted to push a device to clinical trials the moment it checks the minimum regulatory boxes rather than waiting for exhaustive research results. 

To answer Ahmed's question, I definitely think that the required level of evidence should depend on how serious the condition is and I'd add that beyond regulatory standards, it is our ethical responsibility to stop the production of a project if not enough research has been done or it has the potential of harming patients. For example, if we are developing a orthopedic implant where patients have plenty of other safe, effective alternatives, the threshold for risk should be very low. But if we are looking at a terminal illness or a severe degenerative condition without any previous existing treatments, then the ethical responsibility shifts.