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REMS/ETASU and Safe Use in Bioequivalence trials

We’ve previously commented regarding the predilection of RLD holders whose product approvals include a Risk Evaluation and Mitigation Strategy (REMS) and Elements To Assure Safe Use (ETASU) to use the REMS/ETASU as a barrier to entry for generic completion. Specifically, the RLD holder will refuse to sell their product to the prospective generic manufacturers, who need it to conduct bioequivalence (BE) testing, claiming that the REMS/ETASU will not allow them to supply the product.  There have been several instances of litigation connected with these situations, where the generic firm involved has sued the RLD holder, generally using a theory of anti-competitive behavior.  These cases have generally ended in some sort of settlement, with the result that the court never gets to the merits of the case; so the beat goes on.

Late in 2014, FDA issued a draft guidance presumably in an attempt to at least reduce the instances where a REMS/ETASU is employed as described above. The guidance is somewhat breathtakingly titled How to Obtain a Letter from FDA Stating that Bioequivalence Study Protocols Contain Safety Protections Comparable to Applicable REMS for RLD.  The title describes the contents pretty well.  FDA’s apparent reasoning is that assuming the RLD holder 1) does not want to endanger patients/study subjects or 2) risk enforcement action by providing the product subject to the REMS/ETSAU to another company seeking generic product approval, FDA will provide a “safe passage” process.

Once a prospective generic applicant has determined that there is a REMS/ETASU is in place, they must prepare the necessary BE protocols, incorporating appropriate steps and assurances such that the planned study components are sufficiently comparable to the established REMS/ETASU.  This can also include, for example, informed consent forms, training materials for investigators and pharmacists and other “informational materials.”  The materials are sent to FDA,, electronic submissions strongly preferred.  Next, the Office of Generic Drugs’ (OGD) Office of Bioequivalence’s Division of Bioequivalence (DBE) and Division of Clinical Review (DCR) will review the draft BE 109 protocol(s), informed consent document(s), and informational materials submitted, with consultation from others if it is deemed necessary.  Following the review, OGD will either request changes from the generic applicant or inform the applicant it has found its proposed safety protections comparable to the REMS/ETSAU, and ask the prospective applicant for a completed disclosure authorization form.  An example is provided in the guidance.  This form is essentially a “hold harmless” agreement protecting FDA and authorizing them to provide specific information to the RLD holder.  It’s not quite as bad as it sounds:

Information to be shared: FDA has received a request from [insert name of prospective ANDA applicant] for assistance in obtaining supplies of [insert name of drug product] for the purpose of testing a proposed generic [active ingredient] product against [brand drug name] as the reference listed drug. [Insert name of prospective ANDA applicant] has submitted for FDA’s review study protocols that include safety precautions for testing comparable to those set forth in the FDA-mandated REMS for [brand drug name].

The generic applicant would also need to tell FDA how much product it needs to complete the proposed protocols, per strength if necessary.

Once all that’s done, at the applicant’s request, FDA will send a letter to the RLD holder stating

1)  The Agency has determined that the protocols, informed consent documents, and informational materials contain safety protections comparable to those in the applicable REMS ETASU.

2) FDA will not consider it a violation of REMS for the RLD sponsor to provide the designated potential ANDA applicant (or its agent) a sufficient quantity of drug product to allow it to perform the testing necessary to support its ANDA and otherwise meet the requirements for ANDA approval.

Problem solved, right?  Well, no, probably not.  Remember, this (draft) guidance contains the “black box” describing the legal status of the guidance.  Like virtually all guidances, it’s reflective of FDA’s thinking and is not enforceable as such.  Further, it doesn’t say anything about what, if any, expectations there are regarding what the RLD holder will do following receipt of the letter.

So will it help or not?  On one hand, it might apply a bit of pressure on RLD holders who could be subject to “public shaming” if they still refuse to supply product.  On the other hand, will this be just another hurdle prospective generic competitors will have to jump, e.g., if they decide to sue, assuming that the FDA letter will be ignored, would a court send them away for “failing to exhaust administrative remedies”? The guidance specifies that seeking the letter is not a legal requirement, but it’s likely that argument will be made in that situation.  While REMS/ETASUs are published, the guidance is silent as to whether the letter requests described will be made public, so it may be difficult to gauge their effectiveness.