FDA Prescription Drug User Fee Renewals

Senators grill industry groups over FDA user fee agreements to fund the agency through 2027

I am not a huge fan of PDUFA. It puts the wrong cast on things. Fees are something I pay for a service, and it should put me in the driver’s seat (well except for airlines and everyone hates that). We tax for government services. Making the FDA dependent on pharma creates an imbalance in power that quite frankly shouldn’t exist.

The extent of statutorily required industry input in the drug regulation and reauthorization processes has increased as a result of the PDUFA reauthorization. The centrality of user fees to the modern FDA has led some observers to express concern that they have contributed to “corrosive capture” of the agency (i.e., a weakening of regulatory independence and of the ability of the agency to uphold traditional efficacy and safety standards) by shaping discourse about how drugs should be regulated or by enabling an unhealthy culture of closeness between the FDA and industry. Each successive PDUFA has required the FDA to be increasingly responsive to industry concerns.

The FDA plays a crucial role in protecting the health of the public while approving new treatments in a timely fashion. Thirty years of experience with user fees has shown that, in the face of inadequate public funding of the personnel budget of the FDA, increased funding by its egulated industries can indeed improve regulatory timelines. This increased speed has also raised questions related to the decisions being made and the growing reliance of the agency on financial support from the companies it regulates, as the user-fee model has fundamentally changed the way that the FDA interacts with industry. In a different political climate, adequate public funding in place of user fees would allow the FDA to continue its current performance levels while adding further confidence that the public remains the primary client of the FDA.

FDA Final Guidance on Recalls

The FDA published the final guidance for “Initiation of Voluntary Recalls Under 21 CFR Part 7, Subpart C” in March of 2022.

Nothing new here really, as the FDA has just finalized recommendations that companies make adequate preparations to operations in advance of when a recall may be needed (e.g., prepare and execute a recall communications plan). In addition to these preparations, the FDA recommends that companies consider preparing, maintaining, and documenting written procedures (in paper or electronic format) for initiating a recall and performing actions related to initiating a recall. Moreover, the document addresses how companies should develop a recall strategy and train personnel on executing a recall, as well as how companies should use adequate product coding.

Poorly Incentived for Quality

Luis Charles Chavarría recently posted about watches and quality. Reading that, and several of the responses remind how pharmaceutical quality is often just framed in terms of regulatory adherence instead of a broader approach. ISO9001 and other major quality models basically break down to having 8 dimensions of quality.

In a lot of industries, it is very visible to the customer whether quality exists. Shoes, cars, toaster ovens – I can gauge them based on multiple of the criteria above before I buy. I can go on credible review sites, use tools like Consumer Reports, get reliable feedback from others. When a friend recommends a couch, I can trust their opinions.

We have none of that in the regulated areas of pharma and much of medical devices. Patients are prescribed product, and even when there are multiple generics available the only real criteria is price. Chances are the patient barely knows the manufacturer, let alone the manufacturing site. It can be very difficult for a patient, or even doctor, to gauge the quality of the product.

It is for this reason we need more transparency throughout the supply chain, through the development of products. The National Academies of Science, Engineering and Medicine (NASEM) report is a start and needs to be implemented quickly. As a beginning it can really help start to shift the needle and make large parts of this industry more receptive to

Remote Inspections and Computer Systems

The US FDA recently changed the Investigations Operations Manual to allow Investigators direct access to a company’s databases during a BIMO inspection (See Section 5.10.2.1)

As the conduct of clinical and non-clinical trials increasingly moves toward 100% electronic data capture, to include electronic case report forms, medical records, patient-reported outcomes, informed consent systems and other electronic study records, it has become necessary for bioresearch monitoring investigators to have access to these electronic systems and databases in order to successfully perform inspections. Overseeing the firm’s personnel while they access their system is not always practical in BIMO inspections, as this can result in the firm having to dedicate an individual to this task.
FDA Investiations Operations Manual section 5.10.2.1

Obviously, if you haven’t, you should be updating your GCP Inspections SOP, especially since they have a few interesting requirements, such as “While you may complete a form needed by the firm in order to obtain read-only access, such as an account request form, you will not sign such form as per section 5.1.2.3. You may acknowledge via email that you have completed any required training necessary for access.”

I think for many in the GCP world this change is sort of a sleeper change. We have been used to giving access to EMA inspectors for years, who often know more about your TMF than you do by the time they walk in the door.

The real interesting thing is how this spells a shift in attitude at the agency that has been a long-time coming. And how it fits into recent trends in the increase in remote inspections.

Remote inspections are here to stay. Set aside the FDA’s current view that a remote event is not an inspection. And one of the big things that stand out about remote inspections is they do not work well to find data integrity issues, as we’ve seen from the decrease in observations that is not proportionate to the overall size of inspections. I think what we are seeing here is a recognition of that, and the first shift in mindset at the agency.

I’d expect to see the FDA change their approach on the GMP side as they continue to absorb the lessons learned from remote inspections. It is a trend that I would be paying attention to as you continue your digital journey. It is always important to think “how will an inspector view this data”. Usually, we think in terms of printouts. You should also be thinking about read-only access in the near future.

Descriptive versus Prescriptive Regulatory Guidance and Quality

There are two different ways that language is discussed and taught: descriptive grammar vs. prescriptive grammar.

Prescriptive grammar describes when people focus on talking about how a language should or ought to be used. Prescriptive grammar tells you how you should speak, and what type of language to avoid. This is commonly found in English classes where the aim is to teach people how to use language in a very particular (typically described as ‘proper’ or ‘correct’) way.

Descriptive grammar, on the other hand, focuses on describing the language as it is used, not saying how it should be used. For example, think about a prescriptive rule like Don’t split infinitives. A descriptive grammarian would see a sentence like “To boldly go where no man has gone before” and would try to describe how the mental grammar can cause that ordering of words, rather than saying that the surface form is faulty due to prescriptive rules (which would require the sentence “To go boldly where no man has gone before”). Linguistics takes this approach to language.

We have a similar thing in pharmaceutical regulations, often seen by how the FDA looks at certain issues and how the EMA and PIC/S looks at them.

For example, the FDA is proceeding with draft guidance on setting up inspection testing programs for detecting visible particles in injectable drugs is meant to address this issue from a good manufacturing practices (GMP) standpoint. This is mostly a descriptive approach, as it sets a lot of desirable outcomes but you few strong requirements for how to get there.

The EMA has a draft Annex 1 which lays out a pretty strong set of requirements for exactly how to perform contamination control, telling you exactly what to have and what it should look like.

The difference can be pretty evident when you hear the different regulators discuss their approaches. I’ve certainly heard more than one present or former FDA regulator say that adopting Annex 1 isn’t necessary because the GMPs already have the requirements built in.

You see a similar approach when it comes to QPs or the GCPs.

The prescriptive versus descriptive difference even comes up during inspections. Most people will talk about how the FDA focuses on artifacts and the EMA goes deep on the process.

A similar divide can happen in your quality system where you see different approaches (often a hodge-podge) between controlling the bad and promoting the good.

Being a pragmatist I often see benefits in both approaches (the same way I find value navigating between FDA and EMA approaches). The key thing is being deliberate about it.