Bioequivalence and Bioavailability Forum

Hi Rosy,

oh dear, the FDA did it again (creating a mess while “improving” something). Quoting its site:

Product-Specific Guidances for Generic Drug Development

To further facilitate generic drug product availability and to assist the generic pharmaceutical industry with identifying the most appropriate methodology for developing drugs and generating evidence needed to support ANDA approval, FDA publishes product-specific guidances describing the Agency’s current thinking and expectations on how to develop generic drug products therapeutically equivalent to specific reference listed drugs.

Increased transparency on product-specific guidances gives applicants seeking to develop generic drugs a better opportunity to efficiently allocate resources. The agency aims to ensure that policies and regulations – and scientific standards – keep pace with the science of equivalence. Improving patient access to high quality and affordable medicines supports FDA’s mission to advance the public health.

The agency routinely posts and revises product-specific guidances. FDA always seeks feedback and considers all comments to the docket before it begins work on the final versions of product-specific guidances. The FDA posts plans for issuing new or revised product-specific guidances on the Upcoming Product-Specific Guidances for Complex Generic Drug Product Development web page.

In April 2019, the Product-Specific Guidances database was enhanced as follows:

• Text search of PSGs by active ingredient, or by the Reference Listed Drug (RLD) or Reference Standard (RS) application number
  
• Users can filter search results using a text search box
  
• Users can easily export search results in Excel, CSV, or PDF format
  
• Search results are now paginated, allowing for faster searching

All documents were renamed and moved to another location (changed URLs). As usual with the FDA no automatic redirection (HTTP 301). 
Hence, if you try to access an old link you end up in electronic limbo.
In German such an activity is called “Verschlimmbesserung” – a portmanteau word created from “Verschlimmerung” (aggravation, worsening) and “Ver­bes­se­rung” (improvement). Translations: ‘disimprovement’, ‘improvement for the worse’.
If it ain’t broke, don’t fix it!

As an example the ‘Draft Guidance on Miconazole’ (of 20 Feb 2019):

• The link which was active until at least 23 April
  https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM347006.pdf leads to
  
• https://www.fda.gov/regulatory-information/search-fda-guidance-documents/miconazole_22404
  which is an HTTP 404 “Not Found” page. Well done! 
  
• Don’t use some of the search-links at this page! You might get tons of hits. Details:
  •  Search → Miconazole Guidance → 122 results. Several results lead to other “Not Found” pages (a consequence of lacking redirections). However, the one we are looking for is not included.
    
  • Search FDA.gov → Miconazole Guidance → 40 results. The one we want is not included as well.
    
  • Check the FDA Archive → Search Terms: Miconazole Guidance, File Format: PDF → 61 matches. As of today the 6^th is the one we want → Show all captures → 12 Captures between Jan 13, 2017 – Apr 23, 2019. Surprise, the FDA mirrors the Internet Archive! Not bad, since we can access the first version of the guidance as well.
    
  • Don’t use the first link FDA.gov Web Archive page. 26 Captures and all of them useless.
    
  • Alternative: Access the Internet Archive and paste the old URL into the field → 19 Captures between October 23, 2016 and April 23, 2019. Interesting: Reaching to an earlier date than the FDA’s mirror. The first PDF was created March 21, 2013.
• Best solution for product-specific guidances: Navigate to the new search page and enter your keyword. Then you end up at
  https://www.accessdata.fda.gov/drugsatfda_docs/psg/Miconazole_Buccal_Tablet_50mg_NDA_22404_RV_Feb_2019.pdf

THX a lot for breaking linked references in publications, study protocols & reports!

Not only the product-specific guidances changed their URLs. Looking for the still applicable ‘Statistical Approaches to Establishing Bioequivalence’ of February 2001? The URL was https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm070244.pdf (which, of course, directly opened the PDF). Now you are redirected (wow!) to https://www.fda.gov/regulatory-information/search-fda-guidance-documents/statistical-approaches-establishing-bioequivalence¹ where you have to follow yet another link Download the Final Guidance Document.^2,3
The link to the Docket 01D-0027 (for submitting comments⁴) is nice but then you learn that JavaScript is required.⁵ Occasionally the server is not available, times out, etc. (HTTP 5xx). If you are lucky and the link to www.regulations.gov works, you might see this message:

Due to an internal error, we were unable to retrieve docket information for docket id 01D-0027 at this time. We are sorry about the inconvenience.

Before the change – when final versions were published – in many cases the last drafts were still available at the FDA’s site (different URLs). Now both URLs redirect to the final version. I’ll update the Guideline Collection. Will take a while; a lot of detective work involved.⁶

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1. @ Nerds: A true redirection (HTTP/1.1 301 Moved Permanently in the response-header). However, the page is not valid (11 errors and 13 warnings). 704 lines of code for such a simple page! In line 353 there is a telling HTML-comment:
   • <!-- Todo, this page triggers an error in the apache error log. Is this still an issue on 2-1-2018 -->
     Wow! How large are the FDA’s error logs?
   Visually impaired people relying on a screen reader will love that (invalid HTML breaks the translation). Professionals at work…
   
2. Let’s see what happens in my browsers on Windows.
   • 74.0.3.3729.131, 66.0.4, 60.0.3255.70:
     Opens the file with the built-in rendering engine. In saving the file-name 3616fnl.PDF is suggested. 
     
   • 11.0.9600.19326, 2.49.4:
     Opens the file with the Acrobat-Reader plugin. When you try to safe the file its suggested name is download. 
     Right-click → document properties…  → description  → title: 3616fnl.PDF
     Copy the title and click Cancel. Now safe the document with its title as the file-name.
   That’s funny. Before the last redesign (in June 2009) this file was found as 3616fnl.pdf (note the lower-case extension). For the next ten years the file was accessible as ucm070244.pdf and UCM070244.pdf. Back to the roots!
   
3. Say goodbye to linking to a particular page of a guidance. Previously is was possible to link e.g., to URI/foo.pdf#page=5. Gone with the wind. 
   
4. For some others dockets you are informed that the comment period is exhausted. However, you are told that you can submit comments at any time. I see!
   
5. Very bad practice. Any website should be accessible without JavaScript (full functionality provided as a fallback within the HTML <noscript></nocript> element). JS should only improve accessibility, not being mandatory.
   
6. Done. Some recent documents (e.g., this one of Dec 2018) only in the FDA’s  Web Archive. I didn’t have the patience to explore all hits in many cases; linked to the  Internet Archive instead.