How to Obtain a Letter from FDA Stating that Bioequivalence Study Protocols Contain Safety Protections Comparable to Applicable REMS for RLD Guidance for Industry

Late last year, the FDA released draft guidance for the pharmaceutical industry entitled “How to Obtain a Letter from FDA Stating that Bioequivalence Study Protocols Contain Safety Protections Comparable to Applicable REMS for RLD.” The guidance is meant to address the situation where a sponsor of a reference listed drug (RLD)—the FDA-approved product to which new generics are compared—has refused to sell their drug to prospective generic manufacturers who need to show their generics are bioequivalent.

Background

A generic applicant submits an abbreviated new drug application (ANDA) based on a previously approved drug product known as the reference listed drug (RLD). FDA lists approved drugs that may be referenced in an ANDA in the Approved Drug Products with Therapeutic Equivalence Evaluations (the Orange Book).

ANDA applicants may rely on the FDA’s previous findings of safety and effectiveness for a RLD when seeking approval to market a generic drug. However, ANDA applicants generally must demonstrate that the proposed generic drug is bioequivalent to the RLD. Bioequivalence can be demonstrated through studies in which the proposed generic drug is compared to the RLD, which requires the ANDA applicant to have access to the RLD to conduct the comparison. 

A generic company’s request for a sample from the reference product manufacturer will not necessarily be met with enthusiasm. In fact, RLD sponsors may want to refuse these requests if possible.

Enter REMS.

FDA has the authority to require a Risk Evaluation and Mitigation Strategy (REMS) if the agency determines that additional safety measures are needed beyond the labeling to ensure that a drug’s benefits outweigh its risks. For example, a REMS known as ETASU, or Elements to Assure Safe Use, may require that pharmacies, practitioners or healthcare settings that dispense a drug be specially certified, or that a drug be dispensed only in certain healthcare settings.

FDA illustrates the issue here:

“FDA is aware of instances in which an RLD sponsor has refused to sell drug product to a prospective ANDA applicant seeking to conduct the testing needed to obtain approval, and the RLD sponsor has cited the REMS ETASU as justification.”

Essentially, sponsors will point to their REMS to avoid handing out a sample to the generic applicant. However, FDA’s guidance seeks to help ANDA applicants work around this problem:

In the interest of facilitating prospective generic applicants’ access to RLD supplies to conduct the testing necessary to support ANDA approval, FDA has, on request, reviewed the [bioequivalence] study protocols proposed by prospective ANDA applicants to assess whether they provide safety protections comparable to those in the applicable REMS ETASU. When the Agency has determined that comparable protections existed, FDA has issued letters to the RLD sponsors stating so and indicating that FDA would not consider it to be a violation of the REMS for the RLD sponsor to provide drug product to the prospective ANDA applicant.

FDA’s guidance lays out the procedure for how ANDA applicants should go about obtaining such a letter. 

Procedures for Submission and Review of Bioequivalence Protocals for Drug Protocols for Drug Product with REMS ETASU

Submission

(1)  The prospective ANDA applicant should check the Agency’s online listing of approved REMS to determine whether the proposed RLD is subject to an approved REMS with ETASU.

(2)  If the proposed RLD is a drug product that is subject to an approved REMS with ETASU, the prospective ANDA applicant should prepare one or more (as necessary) complete bioequivalence protocol that incorporate the elements of the RLD’s labeling and ETASU that are necessary to conduct the bioequivalence study in a safe manner. For example, if the applicable REMS is designed to prevent fetal exposure to a drug, then the BE protocol should protect against pregnancy in a manner comparable to what is provided for in the REMS.

(3)  The prospective ANDA applicant may submit to GenericDrugs@fda.hhs.gov the draft bioequivalence protocol, all informed consent documents, and all informational materials that will be distributed to the study investigators, pharmacists, and subjects. Electronic submissions are strongly preferred.

FDA Review

(1)  The Office of Generic Drugs will then review the draft bioequivalence protocol(s), informed consent document(s), and informational materials submitted. Others within the Agency may be consulted as necessary. Any concerns identified during this review will be communicated in a letter to the prospective ANDA applicant along with recommended changes.

(2)  If there are recommended changes, the prospective ANDA applicant should revise the materials as appropriate and submit them for review, preferably electronically.

(3)  If FDA determines that the protocols, informed consent documents, and informational materials contain safety protections comparable to those in the REMS ETASU, OGD will notify the prospective ANDA applicant in a letter that this determination has been made. This letter will advise the prospective ANDA applicant to provide a completed disclosure authorization form if they wish to have FDA issue a letter to the RLD sponsor, and will request that the prospective ANDA applicant provide FDA with the quantity of drug product per strength necessary to support its ANDA.  Download the Disclosure Authorization Form

(4)  At the prospective ANDA applicant’s request, FDA will send a letter to the RLD sponsor stating that:

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

Legislative Side- FAST Generics Act

In addition to FDA guidance on the issue of REMS, The Fair Access for Safe and Timely (FAST) Generics Act aims to shut down loopholes that generic pharmaceutical companies say are being exploited by branded pharmaceutical companies. It specifies that REMS could not be used to restrict access to products which are sought for “development purposes” so long as access to the product is “reasonably necessary to demonstrate sameness, biosimilarity or interchangeability.”

The proposed language reads:

“As a condition of approval or licensure, or continuation or renewal of approval or licensure, of a covered product under section 505 of this Act or section 351 of the Public Health Service Act, respectively, the Secretary shall require that the covered product’s license holder not adopt, impose, or enforce any condition relating to the sale, resale, or distribution of the covered product, including any condition adopted, imposed, or enforced as an aspect of a risk evaluation and mitigation strategy approved by the Secretary, that restricts or has the effect of restricting the supply of such covered product to an eligible product developer for development or testing purposes.” (bold added for emphasis)