Aug 11 2010

Accelerated Approval

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One must strike the right balance between speed and quality.

Clare Short

Accelerated approval has been in the news for a while, so it seems like a good time to go over some of the basics:  What is accelerated approval and how does it work?

The process is defined in 21 CFR 314 – Subpart H “Accelerated Approval of New Drugs for Serious or Life-Threatening Illnesses”, but it is essentially a way of getting drugs through to approval faster.  Not all drugs qualify; they must be designed to treat serious or life threatening illnesses and offer a benefit over current treatments.

Now, “faster” here does not imply shortcutting a thorough examination of safety and effectiveness.  However, Subpart H allows the FDA to grant approval based on studies that use a surrogate endpoint (or “on the basis of an effect on a clinical endpoint other than survival or irreversible morbidity”).

Importantly, really importantly, the surrogate endpoint must be “reasonably likely” to predict a clinical benefit.  For example, a drug’s effect on blood pressure could be used as a surrogate endpoint for certain cardiac indications.  There is a huge, and obvious, development benefit to not conducting longer term studies to assess an endpoint like “length of time until next ischemic attack” or survival.

Drugs approved under accelerated approval are subject to requirements for further studies “to verify and describe its clinical benefit”.  These would be postmarketing (Phase 4) studies, which Subpart H says “would usually be studies already underway”, but that is less common than it used to be.  The FDA may also apply extra restrictions to ensure safe usage of the product (e.g., tight controls on distribution).  Oh, and let’s not forget that you have to submit marketing materials to DDMAC for review and approval before using them.

How important are all of these restrictions?  Very.  You eventually have to pay the piper if the drug isn’t as safe as it appeared to be, if the surrogate endpoint does not correlate to a clinical benefit, or if you don’t comply.  The FDA also has authority to withdraw approval of an ‘accelerated’ product if:

  • The postmarketing clinical study fails to verify clinical benefit;
  • The applicant fails to perform the required postmarketing study with due diligence (e.g., dragging your feet, conducting a study that does not address the same target endpoints, just not doing the study at all)
  • The postmarketing restrictions end up being inadequate to assure safe use of the drug;
  • The applicant fails to adhere to the postmarketing restrictions agreed upon;
  • The promotional materials are false or misleading; or
  • Any other evidence demonstrates that the drug is not safe or effective under its conditions of use.

Accelerated approval can help get your product to market faster, but it will attract more scrutiny both before and after approval.  I am tempted to conclude with something cliché here like “be careful what you wish for”, but this is often a price well worth paying to speed up realization of revenue on your investment.