In passing the 1984 Hatch-Waxman Amendments to the Federal Food, Drug & Cosmetic Act, Congress created a system that balances encouraging and rewarding medical innovation with facilitating robust and timely market competition. One of the primary ways that FDA facilitates a competitive marketplace is through the efficient approval of generic drugs, which are often lower-cost than brand drugs.
Unfortunately, the process established by Congress may not always function as intended. At times, certain “gaming” tactics have been used to delay generic competition. One example of such gaming is when potential generic applicants are prevented from obtaining samples of certain brand products necessary to support approval of a generic drug. The inability of generic companies to purchase the samples they need slows down, or entirely impedes, the generic drug development process – leading to delays in bringing affordable generic alternatives to patients in need.
As described in further detail below, these kinds of problems with generic access to necessary samples may occur when brand products are subject to limited distribution – whether the company has voluntarily adopted limitations on distribution, or the limitations have been imposed in connection with a Risk Evaluation and Mitigation Strategy (or REMS), a program that FDA implements for certain drugs to help ensure that their benefits outweigh their risks. In some cases, brand drug sponsors may use these limited distribution arrangements, whether or not they are REMS-related, as a basis for blocking potential generic applicants from accessing the samples they need.
As part of the FDA’s Drug Competition Action Plan (DCAP), FDA is committed – among other things – to addressing and improving transparency about this and other gaming tactics that delay the generic competition Congress intended.
RLD 1 Access Inquiries
FDA has received numerous inquiries from prospective generic applicants indicating that they would like to develop a generic version of a marketed drug, but are unable to obtain the necessary samples of the reference listed drug (RLD) – typically referred to as the brand drug – because the RLD is subject to limited distribution. The products we have received inquiries about include both drugs that are under REMS and those that are not.
To help address this issue and to provide transparency regarding these inquiries, FDA is posting a list identifying all drug products for which FDA has received an RLD access inquiry related to limited distribution of the marketed RLD, with details regarding, among other things, the RLD sponsor, the drug product, and the number of inquiries we have received. 2 We also are disclosing when we have communicated directly to the RLD sponsor at the generic company’s request. We note that such a communication is voluntary and is only an option for certain products (as further outlined below). As also described below, FDA regularly refers the RLD access inquiries we receive to the Federal Trade Commission (FTC).
Why are samples of the RLD important to a prospective ANDA applicant?
To obtain approval for a generic drug, the generic company needs to show, among other things, that its version of the product is bioequivalent to the RLD. This usually requires the generic company to conduct bioequivalence studies comparing its product to the RLD, and to retain samples of the RLD used in testing after a study is complete. To conduct these kinds of bioequivalence studies, the generic company needs to obtain samples (generally between 1,500 and 5,000 units) of the RLD.
Why are prospective generic applicants having difficulty obtaining samples of the RLD in some cases?
Often, generic companies are able to obtain RLD samples through normal drug distribution channels, i.e., via wholesalers. Sometimes, however, samples of the RLD are not available through normal distribution channels. A drug may not be available through standard distribution channels because the RLD sponsor limits the distribution of the drug (for example, by selling it through a central or small group of pharmacies) on its own initiative for a variety of business reasons. In other cases, a REMS with elements to assure safe use (ETASU) might impact the way the product is distributed. For example, only a limited number of pharmacies might be willing and/or able to meet the specific pharmacy certification requirements in a REMS. Once such limitations are in place, we understand that some RLD sponsors (1) refuse to sell the product directly to the generic company (or impose terms on the sale that generic companies find burdensome or impossible to comply with), or (2) place limitations on the ability of pharmacies or wholesalers to sell samples to the generic companies for development purposes.
How does FDA facilitate access to the RLD if that drug product is subject to a REMS with ETASU Impacting Distribution?
In some cases, we understand that RLD sponsors have asserted that their products’ REMS prohibit them from selling RLD samples to generic companies for testing. To address these cases, FDA developed a process for informing the RLD sponsor in writing that FDA will not consider providing the RLD for these purposes to be a violation of the REMS. This process is described in FDA’s draft guidance on How to Obtain a Letter from FDA Stating that Bioequivalence Study Protocols Contain Safety Protections Comparable to Applicable REMS for RLD (How to Obtain a Letter Draft Guidance).
As the How to Obtain a Letter Draft Guidance explains, upon request from a prospective generic applicant, FDA reviews their bioequivalence study protocols to assess whether they contain safety protections comparable to those in the applicable REMS for the RLD. If FDA determines that they do, we notify the prospective generic applicant of this determination by letter. The prospective generic applicant then can request that FDA send a second, separate letter (the Safety Determination Letter 3) directly to the RLD sponsor stating that FDA will not consider providing product to the particular generic applicant to be a violation of the REMS for the RLD.
Once the generic applicant authorizes the Agency’s disclosure of this information to the RLD sponsor, FDA issues such a letter to the RLD sponsor. In connection with the Generic Drug User Fee Amendments Reauthorization of 2017 (GDUFA II), FDA committed to issuing 90% of Safety Determination Letters within 60 days of the date of submission of disclosure authorization.
What does the Safety Determination Letter say?
The letter states FDA’s determination that the generic company’s study protocols include safety precautions for testing comparable to those set forth in the RLD’s REMS and that FDA will not consider it a violation of the REMS for the RLD sponsor to provide to the generic company or its agent a quantity of the RLD sufficient to allow the generic company to perform the testing necessary to support its abbreviated new drug application and otherwise meet the requirements of approval. The Safety Determination Letter is available here.
Has FDA issued Safety Determination Letters for all the protocol review requests it has received under the How to Obtain a Letter Draft Guidance? Why has FDA Issued so few Safety Determination Letters (when compared to the total number of RLD access inquiries the Agency has received)?
Safety Determination Letters are only available for a subset of the products the Agency has received RLD access inquiries about: those that have REMS with ETASU impacting distribution. The Agency regularly receives RLD access inquiries about products for which any distribution restrictions are voluntarily imposed by the brand company, and no REMS impacting distribution is in place. Such products are not eligible for a Safety Determination Letter. For those products that are eligible for a Safety Determination Letter, not all requests for such a letter result in the issuance of such a letter. This is because some of the protocol reviews are still in process internally or externally (either the Agency is still reviewing the protocols, or FDA has reviewed the protocols and communicated requested protocol revisions to the prospective generic applicant and we are awaiting a protocol resubmission). In addition, some prospective ANDA applicants do not resubmit protocols after FDA requests revisions to the original protocols. Finally, FDA has found that not all prospective ANDA applicants that have submitted protocols for review pursuant to the How to Obtain a Letter Draft Guidance continue the process and request a letter with the accompanying disclosure authorization after receiving FDA’s determination that the protocols contain safety protections comparable to those in the REMS for the RLD. Prospective applicants generally do not notify the Agency why they choose not to continue with the process in either case.
How long does it take FDA to review protocols as described in the How to Obtain a Letter Draft Guidance?
In connection with GDUFA II, FDA committed to reviewing 90% of bioequivalence study protocols for RLDs subject to a REMS with ETASU within 120 days of submission date. We note that, in some cases, prospective applicants may need to submit revised protocols and complete more than one review cycle for FDA to determine that the study protocols contain safety protections comparable to those in the REMS for the RLD.
Does FDA review bioequivalence study protocols for drugs that are not subject to REMS with ETASU impacting distribution under the How to Obtain a Letter guidance? If not, what options are available for these drugs?
No. FDA does not undertake a protocol review process (or issue letters of the kind described in the How to Obtain a Letter Draft Guidance) for products that are under voluntarily imposed limited distribution programs because there is no REMS in place that might impact access to the drug product for which assurances of safety must be evaluated. Instead, we typically respond to such inquiries by noting that the product at issue is not subject to a REMS with ETASU impacting distribution and encouraging the inquirer to raise the matter with the Federal Trade Commission if it believes anticompetitive conduct has taken place. FDA also regularly refers the RLD access inquiries it receives (including those involving products under REMS with ETASU impacting distribution) to the Federal Trade Commission.
Has the issuance of Safety Determination Letters resulted in the RLD sponsor providing samples of the RLD to generic companies?
Brand companies generally do not inform the Agency whether they have made samples of the RLD available after receiving a Safety Determination Letter.
Does this list reflect all the RLD access inquiries FDA has received?
This list reflects the RLD access inquiries FDA has received from prospective generic applicants about marketed RLD products. FDA has also received RLD (or reference product) access inquiries from prospective applicants who intend to submit new drug applications under section 505(b)(2) of the FD&C Act or biologics license applications under section 351(k) of the Public Health Service Act. This webpage, however, is focused on providing transparency about the potential impact of this issue on generic drug market competition.
How often will this list be updated?
FDA will update this list on a semi-annual basis.
RLD Access Inquiries
|Product||RLD Sponsor 4,5||Number of Inquiries Received by FDA||Does the product have a REMS with ETASU Impacting Distribution?||For Products with REMS with ETASU Impacting Distribution: Date(s) of Safety Determination Letter(s) Issued (if applicable)|
|Absorica (isotretinoin)||RANBAXY INC/SUN PHARMACEUTICAL INDUSTRIES INC||6||Yes||12/9/2015|
|Abstral (fentanyl citrate)||GALENA BIOPHARMA||1||Yes|
|Accutane (isotretinoin)||ROCHE PALO ALTO LLC||2||Yes||6/23/2009|
|Adempas (riociguat)||BAYER HEALTHCARE PHARMACEUTICALS INC||2||Yes||9/27/2016; 5/2/2017|
|Afinitor (everolimus)||NOVARTIS PHARMACEUTICALS CORP||1||No||N/A|
|Amnesteem (isotretinoin)||MYLAN PHARMACEUTICALS INC||3||Yes|
|Ampyra (dalfampridine)||ACORDA THERAPEUTICS INC||4||No||N/A|
|Brilinta (ticagrelor)||ASTRAZENECA LP||1||No||N/A|
|Claravis (isotretinoin)||TEVA PHARMACEUTICALS USA||4||Yes|
|Clozaril (clozapine)||HERITAGE LIFE SCIENCES BARBADOS INC||1||Yes|
|Cystadane (betaine hydrochloride)||ORPHAN EUROPE SARL||1||No||N/A|
|Daraprim (pyrimethamine)||VYERA PHARMACEUTICALS LLC||2||No||N/A|
|Embeda (morphine sulfate; naltrexone hydrochloride)||ALPHARMA PHARMACEUTICALS LLC KING PHARMACEUTICALS||1||No||N/A|
|Entereg (alvimopan)||CUBIST PHARMACEUTICALS INC||5||Yes|
|Exjade (deferasirox)||NOVARTIS PHARMACEUTICALS CORP||6||No||N/A|
|Fazaclo ODT (clozapine)||JAZZ PHARMACEUTICALS III INTERNATIONAL LTD||1||Yes||8/20/2018|
|Fentora (fentanyl citrate)||CEPHALON INC||1||Yes|
|Ferriprox (deferiprone)||APOPHARMA INC||1||No||N/A|
|Firazyr (icatibant acetate)||SHIRE ORPHAN THERAPIES INC||2||No||N/A|
|Gattex Kit (teduglutide recombinant)||NPS PHARMACEUTICALS INC||1||No||N/A|
|Gilotrif (afatinib dimaleate)||BOEHRINGER INGELHEIM||1||No||N/A|
|H.P. Acthar Gel (corticotropin)||QUESTCOR PHARMACEUTICALS INC||2||No||N/A|
|Hemabate (carboprost tromethamine)||PHARMACIA AND UPJOHN CO||1||No||N/A|
|Juxtapid (lomitapide mesylate)||AEGERION PHARMACEUTICALS INC||3||Yes|
|Jynarque (tolvaptan)||OTSUKA PHARMACEUTICAL CO LTD||2||Yes|
|Korlym (mifepristone)||CORCEPT THERAPEUTICS INC||2||No||N/A|
|Kuvan (sapropterin dihydrochloride)||BIOMARIN PHARMACEUTICAL INC||3||No||N/A|
|Letairis (ambrisentan)||GILEAD SCIENCES INC||10||Yes||9/1/2015; 7/5/2016|
|Methadone Hydrochloride (methadone hydrochloride)||ROXANE LABORATORIES INC||1||No||N/A|
|Mifeprex (mifepristone)||DANCO LABORATORIES LLC||2||Yes|
|Nexavar (sorafenib tosylate)||BAYER HEALTHCARE PHARMACEUTICALS INC||2||No||N/A|
|Onsolis (fentanyl citrate)||MEDA PHARMACEUTICALS INC||1||Yes|
|Opsumit (macitentan)||ACTELION PHARMACEUTICALS LTD||8||Yes||7/5/2016; 12/8/2016; 4/23/2018|
|Orfadin (nitisinone)||SWEDISH ORPHAN BIOVITRUM AB PUBL||3||No||N/A|
|Pomalyst (pomalidomide)||CELGENE CORP||8||Yes||6/1/2018|
|Promacta (eltrombopag olamine)||GLAXOSMITHKLINE||3||Yes/No 6|
|Qsymia (phentermine hydrochloride; topiramate)||VIVUS INC||8||Yes||8/13/2015|
|Ravicti (glycerol phenylbutyrate)||HYPERION THERAPEUTICS INC||1||No||N/A|
|Revlimid (lenalidomide)||CELGENE CORP||14||Yes||7/31/2012; 5/19/2014; 2/22/2017; 8/15/2017; 8/20/2018|
|Sabril (vigabatrin) for solution||LUNDBECK LLC / LUNDBECK PHARMACEUTICALS LLC||5||Yes|
|Sabril (vigabatrin) tablet||LUNDBECK LLC / LUNDBECK PHARMACEUTICALS LLC||4||Yes|
|Sublocade (buprenorphine)||INDIVIOR INC||1||Yes|
|Subsys (fentanyl)||INSYS THERAPEUTICS INC||2||Yes|
|Tasigna (nilotinib hydrochloride monohydrate)||NOVARTIS PHARMACEUTICALS CORP||4||No||N/A|
|Tecfidera (dimethyl fumarate)||BIOGEN IDEC INC||1||No||N/A|
|Thalomid (thalidomide)||CELGENE CORP||10||Yes||12/11/2007; 1/17/2008|
|Thiola (tiopronin)||MISSION PHARMACAL CO||4||No||N/A|
|Tikosyn (dofetilide)||PFIZER PHARMACEUTICALS PRODUCTION CORP LTD||4||Yes|
|Tracleer (bosentan)||ACTELION PHARMACEUTICALS LTD||14||Yes||7/31/2013; 9/1/2015; 9/1/2015; 10/16/2015; 1/29/2016|
|Truvada (emtricitabine; tenofovir disoproxil fumarate)||GILEAD SCIENCES INC||1||No||N/A|
|Tykerb (lapatinib ditosylate)||SMITHKLINE BEECHAM CORP DBA GLAXOSMITHKLINE||1||No||N/A|
|Veletri (epoprostenol sodium)||ACTELION PHARMACEUTICALS LTD||1||No||N/A|
|Xenazine (tetrabenazine)||VALEANT INTERNATIONAL BERMUDA/VALEANT PHARMACEUTICALS NORTH AMERICA LLC||4||No||N/A|
|Zavesca (miglustat)||ACTELION PHARMACEUTICALS LTD||3||No||N/A|
|Zortress (everolimus)||NOVARTIS PHARMACEUTICALS CORP||1||No||N/A|
- 1. On this webpage, the terms “RLD” and “brand” may also refer to the reference standard (RS) in cases where the RLD is no longer marketed. The RS is the drug product selected by FDA that an applicant seeking approval of an ANDA must use in conducting any bioequivalence study in humans for approval of the ANDA. Ordinarily, the RS selected by FDA will be the RLD. Where the RLD has been withdrawn from sale (for reasons other than safety and effectiveness), FDA generally will select a previously approved ANDA that referred to the RLD as the RS. Because of this, on this web page, “RLD” and “brand” may also refer to RS if the product for which a generic drug developer sought assistance in obtaining samples was the RS.
- 2. We note that FDA has not independently investigated or confirmed the access limitations described in the inquiries received.
- 3. This term is defined in the GDUFA II commitment letter as the letter sent by FDA stating that a bioequivalence study protocol contains safety protections comparable to those in the applicable REMS for the RLD.
- 4. This list may include inquiries from generic drug developers seeking assistance in obtaining samples of the reference standard (RS).
- 5. The RLD sponsor on this list is the RLD sponsor listed in the Orange Book at the time of inquiry. In some cases where FDA received more than one inquiry about a particular product, the listed RLD sponsor changed from one inquiry to the next – for example, if the product changed hands from one company to another. In such cases, the chart includes the names of the different listed RLD sponsors.
- 6. Two inquiries were received when this product was under a REMS with ETASU; one inquiry was received after the ETASU were eliminated from the product’s REMS.