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.

Increasing Transparency in Drug/Medical Device Manufacturers

The National Academies of Science, Engineering and Medicine (NASEM) has published a report on resiliency in the medical supply chain that calls for the US Food and Drug Administration (FDA) to publicly disclose the location of all manufacturing facilities that supply ingredients and parts for pharmaceuticals and medical devices approved in the US.

The report recommends FDA publicly disclose information on drug sourcing, manufacturing quality and volume, and capacity for medical products approved for sale in the US.

“The manufacturer for a pharmaceutical drug should be required to publicly disclose the manufacturing location, in particular the FDA Establishment Identifier (FEI), the city, and the country for the finished dosage form (FDF), active pharmaceutical ingredient (API, major excipients, and major packaging and delivery devices for all pharmaceutical drugs sold in the United States,” said a report summary.

The same recommendation also applies to devices; device manufacturers should publicly disclose the manufacturing location in the FEI, the city, and the country involved in the device’s manufacturing and final assembly.

The report also recommends FDA make its risk-based site selection model scores publicly available. Wow, not only would that be good for consumers, I’d love to know where my sites fall in on that scoring.

Hurry up and put this recommendation in place!

Transparency is a good thing and it is shown to increase consumer safety. It is a problem that even a fairly knowledgeable industry professional like myself cannot figure out where generics are manufactured without making a few phone calls and shaking down my friend network. And even then, I’m never positive that I understand where my family’s medicine is coming from and the status of the sites involved in manufacturing and distributing the product.

Guidances in Administrative Law

Edward Rubin over on the Administrative Law JOTWELL, in the post “Uncovering the Hidden World of Administrative Guidance” exposed me to the 2019 article by Nicholas R. Parrillo “Federal Agency Guidance and the Power to Bind: An Empirical Study of Agencies and Industries” which I just find fascinating.

Guidances are an interesting part of our job. As a best practice, they show one way to get to the desired end result, but there can be other ways but the presence of guidance can obscure those possibilities. Often times if an agency goes to the level of detail to show you what good looks like you’d be foolish not to try to meet them there. Other times guidance can be a real head scratcher.

Good article, and of interest to the non-lawyers like myself who have to live within the boundaries.

Similac Recall is a Systematic Failure in our Food/Drug Safety

There has been a lot of press lately for the Abbott Nutrition recall of infant formula. Fundamentally this is a colossal failure of our regulatory program, another failure in a long string of failures, and confirmation that the time is now for radical changes in the agency.

Consumer Reports, in the article “How the FDA Bungled the Powdered Infant Formula Recall” does a good job covering the important points, so please read that article.

The optimist in me hopes that this calamity will drive needed change, as has been the unfortunate history of regulatory change in this country. I’m just not sure I hold enough confidence in Congress to get the job done.