In a draft guidance published December 4, 2014,[1] the Food and Drug Administration (FDA) has attempted to remove, at least in part, a legal hurdle that had created challenges for generic drug companies: Acquiring the samples of brand name products required to perform the bioequivalence studies that are the linchpin to the generic drug approval process, as well as other analytical comparisons required for submission and approval of an Abbreviated New Drug Application (ANDA).

Background on REMS Programs and Their Impact on Generic Access to Innovator Product Samples

FDA long has recognized that some drugs that pose significant benefit/risk issues that might otherwise keep them from being approved could come to the market if additional measures beyond those provided in the product labeling were implemented relative to the drug posing the questionable benefit/risk ratio. Thus, with drugs such as Accutane® and Thalomid®, both of which can cause birth defects, the agency and the drugs' sponsors entered into arrangements where, as a condition of approval, the sponsors agreed to certain measures such as requiring women of childbearing years to agree to a pregnancy test before initiating treatment and to use birth control while taking the drugs.

Initially, these arrangements were not formally authorized by the Federal Food, Drug, and Cosmetic Act (FFDCA), but the sponsors agreed to the risk management provisions in order to secure approval. In 2007, Congress passed the Food and Drug Administration Amendments Act (the 2007 Amendments),[2] which formally gave FDA the power to require innovative drug sponsors to initiate such programs – called Risk Evaluation and Mitigation Strategies (REMS) when the agency believed the risk/benefit ratio required such measures.

While many common REMS measures, such as medication guides and communication plans, do not directly impede access to the drug, the 2007 Amendments also gave FDA the power to require, in appropriate circumstances, that the innovator implement certain Elements To Assure Safe Use (ETASU)—such as the pregnancy test and contraception requirements already in place for Accutane®—for drugs that posed, in the agency's view, great enough risks that other measures were inadequate to ensure that the products could be safely used. In conjunction with giving FDA the power to require an ETASU, the 2007 Amendments also amended the FFDCA to render as misbranded any drug that was in violation of a REMS program measure such as ETASU requirements.[3]

An unintended consequence of approving a new drug application (NDA) for a drug with an ETASU program has been that, in many cases, generic firms seeking to acquire the samples of the NDA product found themselves unable to acquire the products from the holder of the NDA due to the ETASU restrictions. When pushed by generic firms to make samples of drugs subject to an ETASU available, holders of the approval for the brand NDA – referred to in the generic drug approval process as the "reference listed drug" (RLD) – have cited a number of grounds for why they should not be required to provide the samples to the generics, especially falling back on the assertion that they cannot legally provide the product under the REMS misbranding provisions of the FFDCA. Innovators also claimed that state tort law/products liability considerations also would expose them to liability by providing the samples to generic companies.

What the Draft Guidance Provides

In the draft guidance issued December 4, FDA created a mechanism for generic firms to request that FDA send a letter to the RLD holder of a drug subject to an ETASU. Before the letter can be sent to the RLD NDA holder, a generic firm will have to submit its bioequivalence protocol—including informed consent documents and other "informational materials"—reflecting the required ETASU elements to the agency for review. If FDA agrees that the protocol does contain the required ETASU measures, the generic firm will also have to provide FDA with a completed "disclosure authorization form" before FDA can issue the letter to the RLD holder.

In the letter to the RLD holder, FDA would inform the firm that the agency would not regard the innovator's provision of the samples of the RLD to the generic as a "violation of REMS." Specifically, the letter would state:

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.[4]

The guidance does not say how quickly FDA will respond to ANDA applicant requests for letters to the RLD holder of ETASU-restricted drugs. However, as the agency has a commitment to trying to secure the approval of "first generics" of previously sole source brand name products, FDA is likely to move fairly quickly on any requests made under the draft guidance.

Will the Draft Guidance Really Generate Access to Innovator Samples Subject to ETASU?

While the draft guidance would appear to remove one crucial element of innovator resistance to providing samples of the RLD to generic firms where an ETASU is in place, we expect that RLD holders will continue to resist making these products available. Indeed, several issues are not addressed by the draft guidance.

First, from an administrative law perspective, the draft guidance, even if it was in final form, would not have the force and effect of a law, as it is neither a regulation nor a statute. FDA makes clear that guidance documents are neither binding on FDA nor on industry. In addition, the guidance expresses, as a matter of policy, FDA's decision to, in effect, exercise its "enforcement discretion" to not hold an innovator company in violation of the law if it distributes a product in a manner that is not fully consistent with an ETASU in order to make samples available to a generic firm. We expect that some innovators may assert that they still would be technically in violation of the FFDCA by deviating from a REMS program and decline to make samples available under that rationale.

In addition, the draft guidance does not compel an innovator to provide the generic with samples. To date, this issue, which includes a focus on the non-FDA legal issue of whether a person can decline to do business with another person, has been the subject of litigation in several federal district courts. However, none of those lawsuits has resulted in a decision with any precedential value.

Finally, innovator companies contend that, even with FDA's blessing as reflected in the draft guidance, the innovators would expose themselves to liability under various state products liability and tort principles if they were to provide samples of a drug subject to an ETASU to a generic firm. While a generic firm could agree to indemnify and hold harmless an innovator under such circumstances, absent a court finding that the innovator must deal with the generic and provide samples, we would expect that innovators continue to decline to make samples available for as long as they can continue to assert a colorable argument from both a legal and policy perspective that they are not required to share their product with the generic industry.

Congress may eventually have to weigh in on this issue. Indeed, in September 2014, H.R. 5657, the Fair Access for Safety and Timely (FAST) Generics Act,[5] was introduced by Reps. Steve Stivers (R-Ohio) and Peter Welch (D-Vt.). If enacted, the FAST Generics Act, among other things, actually would render misbranded any drug subject to a REMS if the NDA holder failed to supply samples of REMS-restricted RLD to an ANDA applicant or an applicant seeking to approval of a biosimilar under the Biosimilar Price Competition and Innovation Act of 2009. While it appears to enjoy bipartisan support, it remains to be seen how fast the FAST Generics Act moves through the halls of Congress.