The Honorable Margaret A. Hamburg, M.D.
Commissioner, U.S. Food and Drug Administration
10903 New Hampshire Avenue
Silver Spring, MD 20993
Dear Commissioner Hamburg:
On August 14, 2014, eleven organizations representing physicians who prescribe biologics with regularity, the three physician co-conveners of the Biologics Prescribers Collaborative, and 19 individual physician members of the National Physicians Biologics Working Group of the Alliance for Patient Access (AfPA) sent a letter to the U.S. Food and Drug Administration outlining our shared perspectives on the implementation of the Biologics Price Competition and Innovation Act (BPCIA). On behalf of the three physician co-conveners, and the nine undersigned organizations, this letter is intended to expand on the previous letter to provide you with a more in depth perspective detailing our views on the issue of nomenclature, and specifically the need for distinguishable naming.
Unlike many physicians who may never prescribe a biologic, our physician members work in specialty areas where biologics are frequently prescribed because the health and lives of our patients depend on them. These innovative medicines can be lifesaving, but they are also complex; biosimilars made by different manufacturers may cause different reactions among patients with the same medical diagnoses and similar physical characteristics. As such, we feel it is imperative to provide FDA with our perspective.
Whether a biosimilar should share an International Nonproprietary Name (INN) with its reference product has become a hotly debated topic in the United States. As physicians, we believe that a biosimilar should have its own distinguishable name for the reasons outlined in our August 14 letter. Since then, we have encountered arguments advanced by stakeholders who favor common names for biosimilars that we feel warrant a response from our perspective as practicing physicians.
A shared INN implies interchangeability.
In the past, FDA has stated: “INNs should not be used to imply pharmacologic interchangeability of products with the same active ingredient(s) when no credible scientific data exist that demonstrate such.”1
We agree, and submit that this position supports the need for distinguishable names. The BPCIA contemplates two levels of “sameness”: biosimilarity and interchangeability. We are concerned that an identical INN for a product that is only biosimilar but not interchangeable would imply interchangeability, despite the fact that they are not interchangeable and the agency not having made that finding. As we noted in our first letter to the agency on this issue, physicians are not regulatory-law experts – nor should we want to be. We are concerned that patients, physicians and pharmacists will assume that an identical INN implies that the product is interchangeable.
In that same document, FDA noted that “If the outcome of assigning the same INN to two products with highly similar ingredient(s) created the implication that the two products were pharmacologically interchangeable AND there were NO scientific data to support that finding, then the U.S. FDA would have serious concerns about such an outcome, especially with more complicated proteins.”2 This perfectly sums up our concerns with allowing biosimilars to share a name with their reference products: it will create the implication of interchangeability even absent such a finding by FDA.
Applying for manufacturing changes is not the same as applying for marketing authorization.
Some argue that FDA evaluates manufacturing changes to marketed pioneer biologics under a “highly similar” standard and, thus, if FDA requires distinct INNs for biosimilars,
the agency ought to require the same whenever a pioneer product undergoes manufacturing changes.
While creative, this argument makes a meaningless comparison. The process a pioneer product must go through to prove that a post-approval manufacturing change results in a comparable product is not the same as the premarket approval process a biosimilar will go through to obtain authorization to market. According to FDA regulations, a manufacturer seeking to make a change to an already marketed product must “assess the effects of the change and demonstrate through appropriate validation and/or other clinical and/or nonclinical laboratory studies the lack of adverse effect of the change on the identity, strength, quality, purity, or potency of the product as they may relate to the
safety or effectiveness of the product.”3 While there has not been a regulation to describe further the “highly similar” standard that will be used for biosimilar approval, it is clear that these are two different standards for entirely different circumstances. It is also important to remember that, when applying for clearance to implement a manufacturing change, the pioneer product manufacturer has full access to its own clinical data and postmarket experiences.
From our perspective, we cannot judge whether the standard for a post-market manufacturing change is “better” or “worse” than the standard for biosimilar approval – we only note that it is different and thus has very little relationship or applicability to the naming question.
FDA’s decision on naming will, to a large extent, determine the answers to other outstanding regulatory questions.
As we noted in our first letter to FDA on naming, a recent survey of prescribers in Europe indicated that 61% of respondents believed that a shared INN implied that the follow-on product was approved for all of the same indications as the reference product.4 In other words, a shared INN may “preempt” the two other major remaining regulatory questions: what will be required for a showing of interchangeability and whether the biosimilar will be allowed to extrapolate between indications. Assign the biosimilar a shared INN and, de facto, many patients, physicians and pharmacists may assume interchangeability and shared indications. This is why we believe the naming issue is the most critical of the outstanding implementation issues.
INNs are used to identify products in the case of adverse events.
There are those who maintain that National Drug Codes (NDCs) provide a better way to trace products in the case of adverse events. While the NDC provides one potential way of tracking where it is used, FDA does not require the NDC to appear on prescription drug labels.5 Thus, a consumer using FDA’s Adverse Event Reporting System may be forced to leave the NDC field blank. Even where the NDC does appear on the label, the risk of errors in transcribing a ten-digit code is far greater than that in transcribing a
Unfortunately, we already have an example of what can occur when adverse event reports must rely on the INN, and we urge FDA to revisit the Citizen Petition filed by Johnson & Johnson for a description of that example.6 Between 2004 and 2007, there were 11 pure red cell aplasia (PRCA) cases in Thailand in patients with chronic kidney disease who had been administered subcutaneous epoetin alfa. Several different erythropoietins were used and some of these products shared the same nonproprietary name, but records did not reliably identify which specific product a patient had received. This complicated the manufacturer’s ability to identify the product responsible for the PRCA. Indeed, the Petition states: “To our knowledge, the product(s) responsible for the increased rate of PRCA in Thailand has never been identified.” Perhaps more than any argument we can formulate, this sobering sentence ought to give the agency pause as it decides whether to require distinguishable naming for biosimilars.
Regulatory systems around the world have proposed to distinguish biosimilars by name.
The regulatory decisions made in other countries have little bearing on FDA’s responsibility to protect the safety of U.S. patients but, in any event, the idea that a distinguishable INN will “decouple” the U.S. from the rest of the world is not entirely accurate. For example, Australia has distinguished biosimilars through the use of a prefix and three-letter code. In explaining its reasoning, Australia’s Department of Health’s
Therapeutic Goods Administration noted:
As small differences between biosimilars can give rise to differences in clinical behaviour, in particular in immunogenic effects, certain additional nomenclature provisions are necessary to ensure that it is possible to distinguish between biosimilars and clearly identify the reference product. […] The object of this
naming policy is to allow prescribers to identify the reference product and to distinguish clearly between biosimilars. These distinctions are also important for pharmacovigilance purposes.7
In addition, the World Health Organization recently proposed “Biological Qualifiers” for all biologic products.8
The INN system was developed in 1950 for small molecule chemical compounds. At that time, the complex proteins available today could not even be imagined. In creating a distinct pathway for approval of biosimilars, Congress clearly believed that biologic products could not be forced to conform to the existing regulatory structure for small molecules – or it would have required them to do so. The issue of naming is no exception. We urge FDA not to force the existing INN system onto the complex products we prescribe every day.
In enacting the BPCIA, Congress intended to increase patient access to safe, affordable biologics. As we noted in our previous letter to FDA, we believe that distinct INNs are needed to maintain clarity and safety and create prescribing confidence among physicians. Without that confidence, it will be impossible to grow the vibrant biosimilar marketplace that will benefit our patients.
Should you have any questions, please contact Dr. Dennis Cryer ([email protected]), Dr. Gregory Schimizzi ([email protected]), Dr. David Charles ([email protected]), or any of the undersigned organizations.
Thank you for your consideration.
Alliance for Patient Access
American Academy of Allergy, Asthma & Immunology
American Association of Clinical Endocrinologists
American College of Rheumatology
American Gastroenterological Association
American Urological Association
Clinical Immunology Society
Coalition of State Rheumatology Organizations
Physician Co-Conveners, Biologics Prescribers Collaborative:
Dennis Cryer, MD – Genetics and Metabolism, Washington, DC
David Charles, MD – Neurology, Nashville, TN; Alliance for Patient Access, National
Gregory Schimizzi, MD – Rheumatology, Wilmington, NC
The Honorable Lamar Alexander
Sylvia M. Burwell, Secretary, HHS
Rima Cohen, Counselor to the Secretary for Health Policy, HHS
Francis S. Collins, MD, PhD, Director, NIH
Bill Corr, Deputy Secretary, HHS
Leslie Dach, Senior Counselor to the Secretary, HHS
Paul T. Dioguardi, Director, IEA
Shaun Donovan, Director, OMB
Jim Esquea, Assistant Secretary for Legislation, HHS
Thomas Frieden, MD, Director, CDC
Richard G. Frank, Assistant Secretary for Planning and Evaluation, HHS
The Honorable Tom Harkin
Marc Garufi, Chief, Public Health Branch, OMB
Wanda K. Jones, Dr.P.H., Acting Assistant Secretary for Health, HHS
The Honorable Jimmy Kolker, Assistant Secretary of Global Affairs, HHS
1 U.S. FDA Considerations: Discussion by National Regulatory Authorities with World Health Organization (WHO) On Possible International Non-proprietary Name (INN) Policies for Biosimilars (Sept. 1, 2006), available: http://www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/Approval Applications/TherapeuticBiologicApplications/Biosimilars/ucm375086.htm
3 21 CFR 601.12 (“Changes to an approved application.”)
4 Generics and Biosimilars Initiative Journal, vol. 3 issue 2 (2014), available: http://gabi-journal.net/asbm-
5 21 CFR 207.35
6 Citizen Petition to FDA by Johnson & Johnson (January 7, 2014), available:
7 See: http://www.tga.gov.au/industry/pm-argpm-biosimilars-10.htm#.VC2gDEu4mFI
INN Working Doc. 14.342, Revised draft July 2014, available:
http://www.who.int/medicines/services/inn/bq_innproposal201407.pdf.Association of Black Cardiologists, Inc.