Regulatory: FDA Warning Letter CSV Analysis

Note: All data correct as of 23-Jul-2008.

When the FDA issues a warning letter to a company, it lists out the critical non-compliances and concerns the inspectors found. The warning letter also cites the specific parts of the regulation that there is a non-compliance with. Sometimes a computer system is involved in the non-compliance in one of two ways:

• (a) the software is part of the product and not appropriately validated/controlled (such as software embedded in a medical device);
• (b) the software is used to manufacture product or control data relevant to the product (such as document control or ERP systems)

Within my warning letter database, I flag each letter that contains a citation related to a computer system. Across all life sciences companies cited the percentage of letters that have a CSV citation is around 10-12%. However we can see that there has been a small but steady increase in citations related to computer systems over the past few years; this is inevitable as industry increase its dependence on computer systems in all areas of the enterprise and FDA inspectors become more aware of computer use and more knowledgeable about the risks they can present to product safety and consumer health.

I also track whether a warning letter was issued as a result of foreign or US domestic inspection. This highlights an interesting bias:

The domestic warning letters show the same trend as the overall number, as expected since the domestic letters hugely outweigh foreign letters and thus skew the overall numbers.

However, when you extract the data for foreign warning letters only, the percentage that cite computer systems jumps to around 20-25%. This could be an artifact of the data due to the relatively small sample size, but when it happens in 3 out of 4 years it looks like a real phenomenon.

FDA does cite computer systems more during foreign inspections than domestic inspections. The key question is: Why is this? Here are some thoughts:

• The level of compliance in foreign companies is actually lower than that found in US companies. This may be true since a number of inspections take place in emerging economies such as China or India. Local regulations in these regions generally have lower expectations than the Code of Federal Regulations, and are often less rigorously enforced.

• Foreign companies do not prepare adequately for FDA inspections, leading to a poor presentation of their computer systems and supporting processes. This is probably true for companies operating in jurisdictions with mature regulatory governance such as the UK/EU and Japan, since these regions also have regulatory requirements for computer systems of a similar level to the FDA, so it is unlikely that the actual level of compliance that low.

• US Companies respond appropriately the FDA Form 483 that lists inspection findings.
  After an inspection, a form 483 is provided to the company, listing deficiencies. It is not mandatory that the company responds to this, detailing how it will address the FDA’s findings. Often, a company does a poor job of this and the FDA follows up with a warning letter. Non-us companies have less experience in this than US companies and will be issued with more warning letters as a result.
  Note that the FDA provided a presentation on “Writing An Effective 483 Response” at the 5th Annual FDA and the Changing Paradigm for HCT/P Regulation in January 2009 to address this topic.
  

• Fewer US companies rely on computer systems and therefore these are not a factor during an inspection. Historically, US industry has not been an “early adopter” of new technologies and processes, and is slow to change. For example, it is only over the past few years that US industry and the FDA have really begun to acknowledge international standards such as ISO and ICH. So although US companies may be using current software systems, they may take a more “conservative” approach and still rely heavily on paper based records and data to perform regulated activities, rather than implementing a fully computerised system.

I think all of these points play a part in causing a higher CSV citation percentage for foreign inspection.

Of course, a more cynical view is that the FDA applies higher standards to foreign companies than it does to domestic companies.