Risks Associated with eCTD Refusal to File (RTF)

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Recently, eCTD has been in the news in a big way. Acorda Therapeutics announced that it received a refuse to file (RTF) letter from the U.S. Food and Drug Administration (FDA) regarding its New Drug Application (NDA) for Fampridine-SR, a novel therapy being developed to improve walking ability in people with multiple sclerosis (MS). The FDA has raised what it termed “format issues” regarding Acorda’s eCTD (electronic) submission.

If you are unfamiliar with a Refusal to File, this is the action that FDA takes when confronted with an application that they consider “plainly inadequate, nonreviewable without major repair, or that [that will] make review unreasonably difficult.” You can see the details on the FDA’s website in the 1993 guidance NEW DRUG EVALUATION GUIDANCE DOCUMENT: REFUSAL TO FILE.

An RTF has an immediate, material impact on the company, in that the FDA retains one-half of the 50% of the User Fee submitted by the sponsor at the time the application is filed (see FDA interim guidance Applicability of User Fees to … Applications the FDA has Refused to File). However, this impact is minor in comparison with the lost revenue due to the erosion of patent life (the time that the company will need to correct problems and re-submit the application comes directly out of the patent life of the drug).

To give you some idea of how significant this loss is, consider that the top 200 drugs earn between one and 23 million dollars every day. Finally, there is the impact on the stock price Acorda’s share price, which had been trading around $24/share, has since dropped to between $19 and $21- you can see the dramatic effect at http://www.zacks.com/stock/quote/acor.

Acorda later held a conference call where Ron Cohen, M.D., President and CEO of Acorda Therapeutics, stated that the company was “surprised” by this development. Dr. Cohen declined to discuss the details of the “format issues.”

The effect of this announcement on the sponsor community has been dramatic. Many sponsors are wondering whether this represents a change in direction from the FDA and what they need to do to protect themselves from such a devastating event.

In this area, it’s all about risk management. We don’t know what steps Acorda took in this area, although rumors (which will not be repeated here!) are rife. However, there are some basic considerations:

If you have not submitted an eCTD before, make sure that you are guided and advised by someone with experience. This may mean hiring an experienced person to be part of your own staff, or bringing in an outside consultant. Make sure that your advisor has verified references and a track record of successful eCTD submissions with the FDA.

  • Define your QC process. QC should consist of defined tasks supported by written checklists used in combination with technology. For eCTD validation, find out if your chosen solution (whether deployed in-house or outsourced) detects all errors considered critical by the FDA. If you are outsourcing, don’t make the mistake of believing that your partner is entirely responsible for this – Acorda apparently used an experienced partner but remained ultimately responsible for issues.
  • If you do not have 100% coverage, consider augmenting your solution with additional validation products, or determine if you can manually check the remaining critical items. FDA’s validation criteria are posted on their web site.
    Consider demonstrating your eCTD to the reviewer group shortly before the “real” submission. Virginia Ventura of the Electronic Submission Support Team (ESST) at the FDA has described a demonstration approach that works as follows:

    • Sponsors generally bring the application to FDA on a laptop and use their own viewing tools (which many differ from the FDA’s reviewing tool)
    • Sponsors get feedback on organization, reviewability, etc.
    • Sponsors can also request participation from a staff member from ESSTBottom line – if you have not done a risk assessment with regards to eCTD, it’s time to do so, especially if you are new to electronic submissions.


Author: GS

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