AIPLA and Others Submit Comments in Response to FDA’s Notice And Public Hearing on Biologics Competition

Lynn Tyler

By Lynn C. Tyler [1]

In a Federal Register Notice published in late July, the FDA scheduled a public hearing for September 4 and requested comments “on FDA’s approach to enhancing competition and innovation in the biological products marketplace, including by facilitating greater availability of biosimilar and interchangeable products.” Members of our Committee attended the hearing on behalf of AIPLA and submitted draft comments for the Board’s consideration.

Previously, in a letter dated May 24, 2012, AIPLA recommended that FDA publish the date on which a biological product is or was “first licensed under subsection 351(a)” of the Public Health Service Act (PHSA), and/or the dates that are 4 years or 4 years and 6 months after such date, and the dates that are 12 years or 12 years and 6 months after such date.[2]  AIPLA further recommended that FDA publish the dates of supplementary approvals of products licensed under PHSA § 351(a) that may implicate the anti-evergreening provisions[3] or that may affect whether a biological product licensed prior to the enactment of the BPCIA may serve as a reference product.[4]

While the BPCIA does not mandate such publication, there is precedent in FDA’s publication of expiry dates of exclusivities in the Orange Book.[5]  FDA provides this listing of exclusivity expiry dates, even though the Hatch-Waxman Amendments to the FDCA did not mandate such publication.[6]  Likewise, FDA maintains a public, searchable database for approved and licensed products that have Orphan designations, which database includes the “Exclusivity Start Date” for each such product,[7] even though the Orphan Drug Act did not mandate FDA to make such information about exclusivity available.[8]

AIPLA reasoned that publishing such information would improve certainty for both reference product sponsors and subsection (k) applicants alike, and thereby foster investment and innovation.  In addition, where there is disagreement or uncertainty over the exclusivity expiry dates, publication of the date of first licensure or the date exclusivities expire would provide all concerned parties the ability to resolve such disagreement or uncertainty before significant changes in position are made.

Because it had already submitted these substantive comments, in response to the current Notice the Board simply requested an opportunity to comment on any specific proposal that may arise out of the current notice and hearing:

AIPLA requests that before making changes related to the Federal Register Notice and Public Hearing, FDA consider possible implications on intellectual property rights, the patent litigation scheme provided by the Biologics Price Competition and Innovation Act of 2009 (BPCIA), and how that scheme compares with the patent litigation scheme provided by the Drug Price Competition and Patent Term Restoration Act of 1984 (referred to as the Hatch-Waxman Act).  AIPLA also requests that FDA provide detailed notice of any proposed changes related to the Federal Register Notice and Public Hearing and its reasons for proposing those changes, as well as opportunity for meaningful comment from AIPLA and other stakeholders.  Furthermore, taking into account the existing legislations, AIPLA further requests that the FDA undertake an analysis of the implications on intellectual property of any proposed changes that the FDA might implement, and publish the results for further public comments.

AIPLA’s 2012 comments were adopted as the Purple Book includes the date a biosimilar or biologic was licensed and whether FDA evaluated the biological product for reference product exclusivity. It also includes whether a biological product has been determined by FDA to be biosimilar to or interchangeable with a reference product.

Other parties also submitted comments in response to the most recent notice. With respect to  exclusivity determinations, one party noted that FDA has yet to make an exclusivity determination for over 97 percent of products listed in the Purple Book that are eligible for exclusivity. Moreover as of August, FDA has listed first-licensure and exclusivity end dates for just five products.

Another comments suggested that FDA should update the Purple Book to clarify which products have been determined not to have exclusivity and those for which a decision is pending.

Another comment recommended the inclusion of approved indications for each biosimilar listed. The thrust of the comment was that, in cases where a biosimilar is not approved for all the same indications as the reference product, the specific indications for which it is approved should be listed to avoid any confusion.

Competing comments were submitted regarding whether or not the Purple Book should state when biosimilars have not been designated an interchangeable.

Interested parties should continue to monitor potential FDA actions related to this Notice and consider submitting their own comments and/or working through our Committee to have comments submitted on behalf of AIPLA.

[1]  Lynn C. Tyler is a partner and registered patent attorney in the Indianapolis office of Barnes & Thornburg LLP. He concentrates his practice in intellectual property litigation and FDA counseling. He is the chair of AIPLA’s Food and Drug Law Committee.

[2] See 42 U.S.C. §§ 262 (k)(7) and (m)(3).

[3] 42 U.S.C. § 262(k)(7)(C).

[4] Citizen Petition filed by Covington & Burling LLP on behalf of Abbott Laboratories, FDA Docket No. FDA2012-P-0317, April 2, 2012.

[5] Orange Book: Approved Drug Products with Therapeutic Equivalence Evaluations, which is available at

[6] See, e.g., 21 U.S.C. § 355(b)(1)(A).

[7] Available at

[8] See, e.g., 21 U.S.C. § 360aa.


District Court Holds on Summary Judgment that § 271(e)(1)’s Exemption from Patent Infringement Covers Use After End of Clinical Trial

By Lynn C. Tyler[1]

Lynn Tyler

Since 1984, § 271(e)(1) of the Patent Act has provided an exemption from patent infringement as follows:

It shall not be an act of infringement to make, use, offer to sell, or sell within the United States or import into the United States a patented invention … solely for uses reasonably related to the development and submission of information under a Federal law which regulates the manufacture, use, or sale of drugs or veterinary biological products.


35 U.S.C. § 271(e)(1) (2010).

In Merck KGAA v. Integra Lifesciences I, Ltd., 545 U.S. 193 (2005), the court gave § 271(e)(1) a broad reading when it unanimously held that the exemption covered “uses of patented inventions in preclinical research, the results of which are not ultimately included in a submission to the” FDA. 545 U.S. at 195. The Court concluded that “the use of patented compounds in preclinical studies is protected under § 271(e)(1) as long as there is a reasonable basis for believing that the experiments will produce ‘the types of information that are relevant to an IND or NDA.’” Id. at 208 (quoting Brief for United States as Amicus Curiae).

More recently, the Northern District of California followed the Supreme Court’s lead in giving § 271(e)(1) a broad reading. In Nevro Corp. v. Boston Scientific Corp., Case No. 16-cv-06830-VC, slip op. (N.D. Cal. July 24, 2018), the Court entered summary judgment of non-infringement of three patents asserted by Nevro against two Boston Scientific spinal cord stimulators, the Spectra WaveWriter and the Precision with MultiWave systems. The issue was whether use of the stimulators by trial participants after their participation had ended fell within the exemption. In a single paragraph, the Court found that it did:

The use of the Spectra WaveWriter and the Precision with MultiWave systems in patients that have participated in the ACCELLERATE trial fits within the safe harbor provision of 35 U.S.C. § 271(e), even after the patients have completed their participation in the trial. This use is “reasonably related to the development and submission of information” to the FDA for device approval. The FDA specifically approved a trial plan that allowed participants to continue to receive treatment after results were collected. Dkt. No. 358-48, Wang Decl. Ex. 42 at BSCNVRO_00019250-51. And international standards for medical research require trial sponsors allow participants to access studied treatments even after the trial’s conclusion. Dkt. No. 358-49, Wang Decl. Ex. 43, World Medical Association, Helsinki Decl.: Ethical Principles for Medical Research Involving Human Subjects ¶ 34 (2013) [].

Id. at 8 (emphasis added).

Those who like this decision might wish that the court had discussed the parties’ arguments more and it reasons (beyond those stated, if any) for accepting and rejecting them. A more extended discussion might have made it more likely that other courts will reach the same conclusion if the issue comes up again. Further, it would be nice to know how much weight the court gave to the fact that “the FDA specifically approved a trial plan that allowed participants to continue to receive treatment after results were collected.” Id. It seems unlikely that the Helsinki Declaration will change any time soon on this point, so that factor will always be present. For the moment at least, it is an open question whether that alone, or perhaps coupled with the “reasonably related” language of § 271(e)(1), will lead courts to the same conclusion.

Further guidance on the issue may come within a year because Nevro recently appealed the district court’s decision to the Federal Circuit. It is not yet known what issues Nevro will raise on appeal, although this ruling on the scope of § 271(e)(1) seems likely to be one of them. It also remains to be seen how much discussion, if any, the Federal Circuit will devote to the issue. The Federal Circuit case number is 18-2220.

[1] Lynn C. Tyler is a partner and registered patent attorney in the Indianapolis office of Barnes & Thornburg LLP. He concentrates his practice in intellectual property litigation and FDA counseling. He is currently the chair of AIPLA’s Food and Drug Committee.


Weingarten_David                Cyr_Shana

By M. David Weingarten, Ph.D. [1] and Shana K. Cyr, Ph.D. [2]

On July 6, 2018, the U.S. Food and Drug Administration (FDA) issued draft guidance to assist applicants in writing the Indications and Usage section of labeling for human prescription drug and biological products, “Indications and Usage Section of Labeling for Human Prescription Drug and Biological Products—Content and Format,” Draft Guidance for Industry (July 2018). (“Draft Guidance”) at 1.  FDA’s recommendations in the Draft Guidance are intended to help ensure that the Indications and Usage section of labeling is “clear, concise, useful, and informative and, to the extent possible, consistent within and across drug and therapeutic classes.” Draft Guidance at 2.  The Draft Guidance supplements FDA’s labeling rules and guidances. See, e.g., “Requirements on Content and Format of Labeling for Human Prescription Drug and Biological Products,” 71 Fed. Reg. 3922 (Jan. 24, 2006).
First, the Draft Guidance provides general principles to consider when drafting the Indications and Usage section of labeling. Draft Guidance at 2-6.  According to FDA, “[t]he primary role of the Indications and Usage section … is to enable health care practitioners to readily identify appropriate therapies for patients by clearly communicating the drug’s approved indication(s).” Id. at 2. “Other sections of labeling (e.g., Dosage and Administration, Contraindications, Warnings and Precautions, Use in Specific Populations) … also provide essential details that enable safe and effective use of a drug, and labeling should be considered in its entirety for individual prescribing decisions.” Id. FDA cautions, however, that “[i]ndications or uses must not be implied or suggested in other sections of the labeling if not included” in the Indications and Usage section. Id. at 3 (quoting 21 C.F.R. § 201.57(c)(2)(iv), (v)). Additionally, FDA may require a specific warning in the Warnings and Precautions section of the labeling to address unapproved uses “if the drug is commonly prescribed for a disease or condition and if such usage is associated with a clinically significant risk or hazard.” Id. (citing 21 C.F.R. § 201.57(c)(6)(i)).
Second, the Draft Guidance discusses what information to include in the Indications and Usage section. Id. at 6-14. According to FDA, the section “must state that the drug is indicated for the treatment, prevention, mitigation, cure, or diagnosis of a recognized disease or condition, or of a manifestation of a recognized disease or condition, or for relief of symptoms associated with a recognized disease or condition.” Id. at 8 (quoting 21 C.F.R. § 201.57(c)(2)). The disease, condition, or manifestation should be referred to using high-level, clinically relevant terms that are well understood and easily recognized by health care practitioners. Id. Additionally, other information necessary to describe the approved indication, when applicable, should be identified. Id. at 7, 8-9. For example, descriptors or qualifiers of the population to be treated, such as approved age groups, patients previously treated with other therapies, or patients with a certain classification of the disease, may be important to include. Id. at 7, 8. The Indications and Usage section may also provide information about adjunctive or concomitant therapy, or specific tests needed for patient selection. Id. at 7, 9.
The Draft Guidance also states that limitations of use, which are presented separately from the indication within the Indications and Usage section, should be included “when there is reasonable concern or uncertainty among FDA’s expert reviewers … about a drug’s risk-benefit profile” and “the awareness of such information is important for practitioners to ensure the safe and effective use of the drug.” Id. at 10. FDA distinguishes limitations of use from contraindications, which are “situations in which the drug should not be used because the risk of use … clearly outweighs any possible therapeutic benefit,” and recommends avoiding redundancy in the labeling by not restating contraindications as limitations of use in the Indications and Usage section. Id. (quoting 21 C.F.R. § 201.57(c)(5)). FDA also recommends incorporating “information that essentially narrows or further defines a drug’s approved indication and is used to direct appropriate therapy … directly into the indication whenever possible,” rather than including it as a limitation of use. Id. Limitations of use may be appropriate if there is reasonable concern or uncertainty about a drug’s effectiveness or safety in a certain clinical situation; if a drug is approved without evidence of benefits known to occur with other drugs in the same class; or if a drug has certain dose, duration, or long-term use considerations. Id. at 11-13. Limitations of use would generally not be appropriate, however, to restate information already included in the indication or to address the absence of data in populations in which the drug was not studied. Id. at 13-14.
Third, the Draft Guidance makes recommendations about how to write, organize, and format the information within the Indications and Usage section. Id. at 14-17. FDA states that while a full description of how benefits of treatment were measured in clinical trials is generally unnecessary, a broad disease indication may be inappropriate where the drug affects only certain signs, symptoms, or manifestations of a disease. Id. at 14. The Indication and Usage section may include an indication identifying outcomes or endpoints when, for example, “the drug’s effect on the overall disease is not well understood; when different drugs have different effects on various manifestations of the diseases; when clinical trials evaluated only one or some of the manifestations of the disease; or when endpoints are different from the typical effectiveness measure.” Id. Additionally, governing statutory and regulatory provisions require or recommend language for certain products, such as systemic antibacterial drug products and products containing a single enantiomer of a previously approved racemic drug. Id. at 15. FDA notes that the phrase “reduce the risk of” is generally preferable to the word “prevent,” and that the words “only” and “also indicated” should generally not be used. Id. at 16.
Readers are encouraged to read the Draft Guidance in its entirety, as well as FDA’s related rules and other guidances, and to consult with legal counsel when making decisions about their product labeling.

[1] Dr. Weingarten is an associate at the Atlanta office of Finnegan, Henderson, Farabow, Garrett & Dunner, LLP.

[2] Dr. Cyr is a partner at the Reston office of Finnegan, Henderson, Farabow, Garrett & Dunner, LLP.

Continued Uncertainty Over BPCIA Leads to Duplicative Lawsuits

Lynn Tyler  By Lynn C. Tyler [1]

Earlier this year, Genentech, Inc., Biogen, Inc., Hoffmann-La Roche Inc., and City of Hope (collectively, “Genentech”) filed a suit under the Biosimilars Price Competition and Innovation Act (“BPCIA”) against Celltrion, Inc., Celltrion Healthcare Co., Ltd., Teva Pharmaceuticals USA, Inc., and Teva Pharmaceuticals International GmbH (collectively, the “Defendants”) in the District of New Jersey. [2] The New Jersey Complaint alleged the Defendants would infringe forty patents with their proposed marketing of a biosimilar to Genentech’s Rituxan®.
Also earlier this year, the same plaintiffs (excluding Biogen) also sued the same Defendants under the BPCIA in Delaware. [3] The Delaware Complaint alleged the Defendants would infringe forty patents with their proposed marketing of a biosimilar to Genentech’s Herceptin®.
As regular readers of the Flash! are aware, the BPCIA sets forth a series of steps, known as the “patent dance,” through which patent owners and biosimilar developers may engage before beginning patent litigation. The dance begins when the biosimilar applicant, called a subsection (k) applicant by the statute, submits to the FDA an application for approval of a biosimilar drug. The statute states that “[w]hen a subsection (k) applicant submits an application” to the FDA, the applicant will give a copy of the application to one in-house lawyer for the patent owner, called the reference product sponsor, and to outside counsel for the sponsor, subject to certain confidentiality restrictions. 42 U.S.C. § 262(l)(1). Later, the statute states that the copy of the application must be provided to the sponsor “[n]ot later than 20 days after the Secretary [through the FDA] notifies the subsection (k) applicant that the application has been accepted for review.” § 262(l)(2). In addition, at that point the applicant must also provide “such other information that describes the process or processes used to manufacture the biological product that is the subject of the application.” Id.
The next step is that, within 60 days after the receipt of the application and process information, the sponsor must provide the applicant with a list of patents which the sponsor believes “could reasonably be asserted” and identify any that are available for license. § 262(l)(3)(A). Sixty days after receiving the sponsor’s list of patents, the applicant must provide the sponsor with (1) its own list of patents that it believes could be asserted, and either (2) a detailed statement, on a claim by claim basis, of the factual and legal basis why each patent on the sponsor’s and applicant’s (if any) list(s) is invalid, unenforceable, or would not be infringed, or (3) a statement that the applicant does not intend to market the product before the patent expires. The applicant must also provide a response to the sponsor’s indication of patents that are available for license. § 262(l)(3)(B).
The final step in this phase is that, within 60 days of receiving the applicant’s detailed statement, the sponsor must provide its own detailed statement, again on a claim by claim basis, of the factual and legal basis why each patent will be infringed and a response to the applicant’s statement on validity and enforceability. § 262(l)(3)(B).
After providing a relatively brief period for the parties to agree on patents to be litigated (§ 262(l)(4)), if the parties cannot agree the statute goes on to prescribe another set of steps in the pre-litigation dance. § 262(l)(5). The first of these is that the applicant notifies the sponsor of the number of patents the applicant will include on a list of patents to be litigated. § 262(l)(5)(A). Five days later, the parties simultaneously exchange lists of patents that each believes “should be the subject of an action for patent infringement.” § 262(l)(5)(B). The number of patents on the sponsor’s list cannot exceed the number on the applicant’s list, unless the applicant’s list does not include any patents, in which case the sponsor can list one patent. Id.
Whether the parties agreed on a list of patents to be litigated or exchanged lists, within 30 days of completing the applicable process the sponsor must file an infringement suit. If the parties agreed on patents to be included, the sponsor’s suit must include those patents. If the parties did not agree, the sponsor’s suit must include all the patents on the respective lists. § 262(l)(6).
Genentech’s Delaware and New Jersey Complaints both alleged that the Defendants had initially engaged in the patent dance, but withdrew before reaching the agreed or exchanged lists of patents to be litigated. Genentech’s Delaware Complaint alleges that the Defendants filed suit in the Northern District of California seeking a declaratory judgment. Both cases allege the Defendants gave Genentech a notice of commercial marketing.
Recently, Genentech filed new Complaints in Delaware [4] and New Jersey [5], asserting the same patents against the same proposed biosimilars. Both Complaints were accompanied by a letter to the Court [6] explaining the reasons for the duplicative filing. According to the letters, after previously abandoning the patent dance as described above, the Defendants allegedly sought to re-engage in the dance and complete the lists of patents to be litigated. As a result, Genentech alleged it was unclear under the BPCIA if it had to file a lawsuit within thirty days of the completion of that step and, if it did not, whether its damages could be limited to a reasonable royalty. To avoid those issues, Genentech filed the duplicative suits and advised the Courts it would seek to have them consolidated with the earlier ones by stipulation or motion.
In all likelihood, the Defendants will have a different view of what happened, why, and its legal effect. What seems beyond dispute, however, is that the BPCIA is full of ambiguities that will be litigated for years to come. Within a few months of its passage, it was deemed “the statute most likely to be amended or repealed” by panelists at a CLE, but sadly so far Congress has not taken any action to clarify the patent dance provisions. The current ambiguities likely do not benefit either patent owners or biosimilar applicants.
[1] Lynn C. Tyler is a registered patent attorney and a partner in the Indianapolis office of Barnes & Thornburg LLP. He is currently the chair of AIPLA’s Food and Drug Committee. He concentrates his practice in intellectual property litigation and FDA counseling.
[2] Case No. 1:18-cv-00574 (RMB) (KMW).
[3] C.A. No. 18-095.
[4] C.A. No. 18-1025.
[5] Case No. 1:18-cv-11553.
[6] ECF No. 39 in Delaware and ECF No. 49 in New Jersey.

FDA Issues Guidance on Formal Meetings between the FDA and Sponsors or Applicants of BsUFA Products


By Huihong Qiao [1]

Meetings between the FDA review staff and sponsors or applicants of biosimilar products often represent critical points in the regulatory and development process. To have consistent procedures for the timely and effective conduct of such meetings, the Food and Drug Administration (FDA) recently issued a draft guidance for industry. The draft guidance provides recommendations to a sponsor or applicant (Requester(s)) on formal meetings between the Center for Drug Evaluation and Research (CDER) or the Center for Biologics Evaluation and Research (CBER) and Requester relating to the development and review of biosimilar or interchangeable biological products. For the guidance, formal meeting includes any meeting that is requested in any format.


Types of the meetings. There are five types of formal meetings:  Biosimilar Initial Advisory (BIA), Biosimilar Biological Product Development (BPD) Type 1, BPD Type 2, BPD Type 3, and BPD Type 4. Please see table 1 for details. In general, for a particular biosimilar or interchangeable product, Requesters can request one BIA meeting and one BPD Type 4 meeting, but as many BPD Type 2 and Type 3 meetings as needed, and Requesters are not required to request meetings in sequential order.


Fee and format. No fee is associated with a BIA meeting. Concerning the assessment of BPD fees and the consequences for failure to pay any required BPD fees, refer to the draft guidance for industry, “Assessing User Fees Under the Biosimilar User Fee Amendments of 2017.” The formats of meetings include face to face, teleconference/videoconference, or written response only (WRO).


The procedure could be simplified as: submitting a meeting request and meeting package –> the FDA granting the request –> the FDA providing preliminary responses –> parties conducting a meeting –> the FDA providing meeting minutes to the requesters.


Each step is explained in the following paragraphs.


Requesting a meeting. The procedure begins with a request. Requesters should combine related product development issues into the fewest possible meetings. A request must be submitted in writing via paper submission or electronic gateway. Meeting requests sent by fax or email are considered copies of formal requests. The request should be submitted to the division that has regulatory oversight of the reference product if the proposed biosimilar or interchangeable product has multiple indications that span multiple review divisions. Requesters should consider the complexity of the questions it intends to submit and keep the questions limited to those can be reasonably answered within the allotted time in a single meeting. The planned attendees can change during the time between the request and the meeting. If there are changes, an updated list of attendees with their titles and affiliations should be provided to the appropriate FDA contact at least one week before the meeting. The draft guidance lists information that the FDA requires the request to include (Appendix I below) and a list of information recommended by the FDA (Appendix II below).


Meeting package. The meeting request should be accompanied by a meeting package. CDER strongly recommends submitting the package electronically and provide paper copies (desk copies) as well. CDER project manager will advise on the number of desk copies needed for the meeting attendees.  CDER neither requests nor accepts desk copies of meeting packages that have been electronically submitted. To facilitate FDA review, the meeting package content should be organized according to the proposed agenda.  “The meeting package should be a sequentially paginated document with a table of contents, appropriate indices, appendices, and cross references.  It should be tabbed or bookmarked to enhance reviewers’ navigation across different sections within the package, both in preparation for and during the meeting,” the guidance states. Meeting packages generally should include the information in the order listed in Appendix III below.


Denial of a meeting. The FDA generally honors requests for BPD Type 2, 3, and 4 meetings; however, it has the discretion to grant or deny BIA and BPD Type 2 meeting requests. If a meeting request is denied, the FDA will notify the requester in writing within 21 calendar days from receipt of the meeting request and meeting package (14 days for BPD Type 1 meeting). The reasons to deny a request include that it is premature for the stage of product development, clearly unnecessary, or inappropriate for the format requested. A subsequent request to schedule the meeting will be considered as a new request.


Grant of a meeting. The FDA will notify the applicant of the grant of a request in writing within the same time frame as the denial of a request.  For face-to-face and teleconference/videoconference meetings, the notification includes logistic information and expected FDA participants.  For BIA and BPD Type 2 WRO meetings, the notification will include the date the FDA intends to send the written response. The FDA will schedule the meeting consistent with the time frame outlined in Table 2 below.


Preliminary responses. Communications before the meeting between requesters and the FDA, including preliminary responses, can serve as a foundation for discussion or as the final meeting responses. The FDA holds internal meetings to discuss the content of meeting packages and generate preliminary responses. Except for WRO requests, the FDA will send the requesters its preliminary responses to the questions in the meeting package no later than 2-5 calendar days before the meeting date. Preliminary responses should not be construed as final unless agreed by the FDA and Requesters otherwise, nor intended to generate the submission of new information or new questions.


Rescheduling meetings. A meeting should be rescheduled as soon as possible after the original date, if the FDA or a Requester decides that it is necessary to do so. The exemplary situations in which the FDA may reschedule a meeting are: the review team determines that additional information is needed to address the requester’s questions or other important issues or essential attendees are not available for the scheduled date and time.


Canceling meetings. Some situations may result in canceling meetings, such as failure to pay required BPD fees for a product within the required time frame or the FDA determines that the meeting package is inadequate. If the requester determines that preliminary responses to its questions are sufficient for its needs and additional discussion is not necessary, the requester should contact the FDA regulatory project manager to request cancellation of the meeting.  The FDA will consider whether it agrees that the meeting should be canceled.  Some meetings can be valuable because of the discussion they generate and the opportunity for the division to ask about relevant matters.


Meeting conduct. An FDA staff member will chair the meeting and begin with introductions and an overview of the agenda.  Attendees should not make audio or visual recordings of discussions at meetings. Presentations by requesters generally are not needed. According to the guidance, “[i]f a Requester plans to make a presentation, the presentation should be discussed ahead of time with the FDA project manager,” the Guidance states. If the presentation includes content other than clarifying or explaining of previous data, the FDA staff may not be able to provide commentary.


Either a representative of the FDA or the requester should summarize the important discussion points, agreements, clarifications, and action items. A summary can be done at the end of the meeting or after the discussion of each question.  Generally, the requester will be asked to present the summary to ensure that there is a mutual understanding of meeting outcomes and action items. “At BPD Type 4 meetings, the requester and the FDA should also summarize agreements regarding the content of a complete application and any agreements reached on delayed submission of certain minor application components,” the guidance states.


Meeting minutes. The FDA will issue the official, finalized minutes to the requester within 30 calendar days after the meeting. The following steps should be taken when a requester disagrees that the minutes are an accurate account of the meeting: the requester should contact the FDA project manager and describe the concern. If after contacting the FDA project manager, the requester still disagrees with the content of the minutes, the requester should submit a description of the specific disagreements either:

‒ To the application; or

‒ If there is no application, in a letter to the division director, with a copy to the FDA project manager.

To request information on additional issues that were not addressed at the meeting, the requester should submit a new meeting request or a submission containing specific questions for FDA feedback.


Tables and Appendices: the tables and appendices are reproduced from the draft guidance.

Table 1 – Types of meetings between the FDA and Sponsors or Applicants of BsUFA Products

Type Purpose Contents
BIA An initial assessment limited to a general discussion about feasibility for a biosimilar product, and general advice on the expected content of the development program. Preliminary comparative analytical similarity data from at least one lot of the proposed biosimilar or interchangeable product compared to the U.S.-licensed reference product.
BPD Type 1 A meeting that is necessary for an otherwise stalled development program to proceed or a meeting to address an important safety issue. Exemplary topics:

• discuss clinical holds: (1) in which the requester seeks input on how to address the hold issues; or (2) in which a response to hold issues has been submitted, and reviewed by the FDA, but the FDA and the requester agree that the development is stalled and a new path forward should be discussed

• in response to an FDA nonagreement Special Protocol Assessment letter

• discussion of an important safety issue

• In response to an FDA regulatory action other than an approval

•  discussion of whether FDA should file the application within 30 days of the FDA issuance of a refuse-to-file letter

BPD Type 2 A meeting to discuss a specific issue or questions for which the FDA will provide targeted advice regarding an ongoing development program. This type of may include substantive review of summary data but does not include review of full study reports. Exemplary issues: ranking of quality attributes; chemistry, manufacturing, and controls such as control strategy; study design or endpoints; post- approval changes
BPD Type 3 This meeting type includes substantive review of full study reports or an extensive data package, and FDA advice regarding the need for additional studies, including design and analysis, based on a comprehensive data package. Exemplary submission:

datasets that support the full study reports;

full study report(s) for a clinical study or clinical studies;

proposal for any planned additional studies;

proposal for extrapolation

BPD Type 4 The meeting is to discuss the format and content of the planned submission and other items


Exemplary topics:

• identification of studies that the sponsor is relying on to support a demonstration of  biosimilarity or interchangeability

• discussion of any potential review issues identified based on the information provided

• identification of the status of ongoing or needed studies to adequately address the Pediatric Research Equity Act

• acquainting FDA reviewers with the general information to be submitted in the marketing application (including technical information)

• Discussion of the best approach to the presentation and formatting of data in the marketing application


Table 2:  FDA Meeting Scheduling Time Frames

Meeting Type Meeting Scheduling (calendar days from receipt of meeting request and meeting package)
BIA 75 days
BPD 1 30 days
BPD 2 90 days
BPD 3 120 days
BPD 4 60 days


Appendix I: The meeting request must include the following information:

  1. Type of the meeting being requested and rationale of the requesting.
  2. The proposed format of the meeting.
  3. A brief statement of the purpose of the meeting. This statement should include a brief background of the issues underlying the agenda.  It also can include a brief summary of completed or planned studies or data that the requester intends to discuss at the meeting, the general nature of the critical questions to be asked, and where the meeting fits in overall development plans.  Although the statement should not provide the details of study designs or completed studies, it should provide enough information to facilitate understanding of the issues, such as a small table that summarizes major results.
  4. A list of the specific objectives or outcomes the requester expects from the meeting.
  5. A proposed agenda, including estimated times needed for discussion of each agenda item.
  6. A list of questions, grouped by FDA discipline. For each question there should be a brief explanation of the context and purpose of the question.
  7. A list of planned attendees from the requester’s organization, which should include their names and titles. The list should also include the names, titles, and affiliations of consultants and interpreters, if applicable.
  8. A list of requested FDA attendees and/or discipline representative(s). Note that requests for attendance by FDA staff who are not otherwise essential to the application’s review may affect the ability to hold the meeting within the specified time frame of the meeting type being requested.  Therefore, when attendance by nonessential FDA staff is requested, the meeting request should provide a justification for such attendees and state whether or not a later meeting date is acceptable to the requester to accommodate the nonessential FDA attendees.
  9. Suggested dates and times (e.g., morning or afternoon) for the meeting that are within or beyond the appropriate scheduling time frame of the meeting type being requested (see Table 2 in section VII.B., Meeting Granted). Dates and times when the requester is not available should also be included.

Appendix II: The FDA recommends a meeting request should include the following information:

  1. The application number (if previously assigned).
  2. The development-phase code name of product (if pre-licensure).
  3. The proper name (if post-licensure).
  4. The structure (if applicable).
  5. The reference product proper and proprietary names.
  6. The proposed indication(s) or context of product development.
  7. Pediatric study plans, if applicable.
  8. Human factors engineering plan, if applicable.
  9. Combination product information (e.g., constituent parts, including details of the device constituent part, intended packaging, planned human factors studies), if applicable.

Appendix III: The FDA recommends the meeting package include the information listed in the order  below:

  1. The application number (if previously assigned).
  2. The development-phase code name of product (if pre-licensure).
  3. The proper name (if post-licensure).
  4. The structure (if applicable).
  5. The reference product proprietary and proper names.
  6. The proposed indication(s) or context of product development.
  7. The dosage form, route of administration, dosing regimen (frequency and duration), and presentation(s).
  8. Pediatric study plans, if applicable.
  9. Human factors engineering plan, if applicable.
  10. Combination product information (e.g., constituent parts, including details of the device constituent part, intended packaging, planned human factors studies), if applicable.
  11. A list of all individuals, with their titles and affiliations, who will attend the requested meeting from the requester’s organization, including consultants and interpreters, if applicable.
  12. A background section that includes the following:
  13. A brief history of the development program and relevant communications with the FDA before the meeting
  14. Substantive changes in product development plans (e.g., manufacturing changes, new study population or endpoint), when applicable
  15. The current status of product development (e.g., chemistry, manufacturing, and controls; nonclinical; and clinical, including any development outside the United States, as applicable)

[1] Huihong Qiao is a registered patent attorney before the U.S. Patent and Trademark Office (USPTO). She is a former postdoctoral researcher at the National Institutes of Health, and examined patent applications as an extern at the Biotechnology Center of the USPTO. She was admitted to the DC Bar in February, 2018.


john hamilton

By John Hamilton [1]


On June 8, 2018, the U.S. District Court for the District of Columbia (“the Court”) issued its opinion in Eagle Pharmaceuticals, Inc. (Eagle) v. Azar [2] announcing its intention to order the Food and Drug Administration (FDA) to recognize orphan drug exclusivity pursuant to 21 U.S.C. § 360cc(a) (2012) for Bendeka®.  Eagle had challenged in 2016 under the Administrative Procedure Act (5 U.S.C. § 551 et seq) the FDA’s denial under the pre-2017 version of the Orphan Drug Act (the pre-2017 ODA) [3] of Eagle’s request for the seven-year exclusivity for Bendeka®.  The exclusivity period serves as an incentive to develop drugs for rare diseases (i.e., affecting fewer than 200,000 patients in the U.S.), during which the FDA may not approve any other manufacturer’s application to market the same drug to treat the same rare disease.  Eagle claimed that it has a statutory right to such exclusivity for Bendeka®, which the FDA designated as an orphan drug and approved to treat two rare forms of cancer.  The FDA had argued that its denial was proper under its implementation of the ODA because the drug is the same as another drug, Treanda®, to which FDA had previously granted orphan-drug exclusivity.


In 1983, Congress enacted the ODA to encourage pharmaceutical companies to develop drugs for rare diseases. [4]  Under the ODA, if FDA designates a drug under development as an orphan drug, benefits such as a streamlined approval process and tax advantages accrue to the drug’s sponsor.  If the FDA then later approves the application to market the designated drug, the FDA “may not approve” any other application for “such drug” to treat the same rare disease until seven years have passed. [5]  The ODA does not explain when two “such drugs” are the same or different.  With the stated intent of preventing “evergreening” (or “serial exclusivity”), the FDA promulgated regulations providing that a new drug is generally the same as a previously approved drug if both share the same active ingredient – except if the new drug is “clinically superior” (i.e., is more effective, safer or “otherwise makes a major contribution to patient care”) to the previously approved drug, in which case the new drug is considered different. [6] The FDA applies the same drug concept first at designation stage [7], and then at marketing approval, with distinct evidentiary standards for determining “clinical superiority”. [8]


In Depomed, Inc. v. U.S. Dep’t of Health & Human Servs., [9], the Court had previously held FDA’s conditioning of exclusivity on “clinical superiority” at the marketing approval stage to be improper under the pre-2017 ODA, and that a grant of exclusivity was required following approval of a designated orphan drug.  FDA, after dropping its appeal, announced it would continue to apply its regulations as written, effectively taking the position that Depomed was wrongly decided. [10]  In 2017, Congress amended the ODA to supercede the Depomed holding [11], but the amendments did not apply retroactively to the FDA’s 2014 orphan drug designation and 2015 marketing approval determinations regarding Bendeka®.  FDA had concluded in its orphan drug designation that Eagle had shown a plausible hypothesis of clinical superiority for Bendeka® over Treanda® for the same two types of cancer, despite both drugs having bendamustine as their active ingredient.  But the FDA denied Eagle’s request for exclusivity for Bendeka® upon marketing approval, over Eagle’s argument that the drug was entitled to automatic exclusivity under Depomed, and also found inadequately supported Eagle’s additional arguments that Bendeka® was safer than Treanda® and provided a material contribution to patient care. [12] The FDA reasoned that the Depomed decision failed to consider that a dispositive showing of clinical superiority was not possible at the designation phase, which would lead to “absurd” results, including serial exclusivity and high drug costs for patients in dire need of care. [13]


The Court analyzed FDA’s interpretation of the pre-2017 ODA in its Bendeka® exclusivity decision under the two-step framework of Chevron U.S.A. Inc. v. Nat. Res. Def. Council, Inc. [14], as well as cases relating to court interpretations of ambiguous statutes [15] and found that the ODA unambiguously requires the FDA to afford Bendeka® the benefit of orphan-drug exclusivity.  The Court agreed with the conclusion of Depomed that nothing in the statute’s text would leave room for the FDA to apply its “clinical superiority” requirement after an orphan drug has been designated and approved. [16]  The Court rejected FDA’s argument that the pre-2017 ODA was ambiguous on the issue of “serial exclusivity” and the statute’s silence on the subject justifies FDA’s regulations prohibiting that practice.  In contrast, the Court found dispositive in its first Chevron analysis step that the plain language makes no distinction between a first sponsor to meet the statutory requirements of designation and approval and a second such sponsor, allowing for a duopoly between the sponsors. [17]


The Court also found unconvincing the FDA’s arguments that consideration of the pre-2017 ODA’s “legislative history, structure, and purpose” reveals the statutory ambiguity that FDA’s clinical superiority policy resolves.  First, the FDA argued that the statute’s purpose of incentivizing sponsors is furthered only if the benefit of exclusivity is reserved for the first manufacturer to earn it.  Secondly, the FDA argued that the “timing structure” of the ODA indicated Congressional intent that orphan drug designations (and attendant benefits) were to be handed out liberally to assist in drug development, while exclusivity grants were intended for a single manufacturer meeting stricter requirements. [18]  Thirdly, the FDA presented a number of contemporaneous legislator statements supporting FDA’s policy, and argued that an inference could be drawn that Congress’s 2017 amendment of the ODA to authorize the FDA to require a showing of clinical superiority before recognizing orphan-drug exclusivity was a ratification of FDA’s policy [19] (despite Congress’s express instruction that “[n]othing in the amendments . . shall affect any determination under” the prior orphan-drug exclusivity provision.) [20]  But again, the Court held the statute’s unambiguous text controlling over the broadly stated statutory purpose, and that the FDA’s arguments were essentially just policy arguments for revising the statute in order for it to work better.


As a result of the Court’s decision, the FDA will not be able to approve any drug applications referencing Bendeka® until the orphan drug exclusivity expires in December 2022.


[1]  John Hamilton is the founder of the Law Office of John A. Hamilton LLC, located west of Boston.  He worked 12 years for FDA’s CDRH and New England District Office, and now concentrates his law practice in IP prosecution, transactions, and FDA counseling.

[2]  Eagle Pharmaceuticals v. Alex M. Azar. 16-CV-790 (D.D.C. Jun. 8, 2018)

[3] Orphan Drug Act, Pub. L. No. 97-414, 96 Stat. 2049 (1983), a part of the Federal Food, Drug, and Cosmetic Act, 21 U.S.C. § 301 et seq.

[4] Eagle, page 2, citing Spectrum Pharm., Inc. v. Burwell, 824 F.3d 1062, 1064 (D.C. Cir. 2016); Genentech, Inc. v. Bowen, 676 F. Supp. 301, 302-03 (D.D.C. 1987).

[5] 21 U.S.C. § 360cc(a) (2012).

[6] Eagle, page 3. See also 21 C.F.R. § 316.3(b)(14).

[7] “a medically plausible hypothesis for the possible clinical superiority of the subsequent drug.” 21 C.F.R. § 316.25(a)(3).

[8] Actual clinical superiority, in order to obtain orphan-drug exclusivity. 21 C.F.R. § 316.34(c).

[9] Depomed, Inc. v. U.S. Dep’t of Health & Human Servs., 66 F. Supp. 3d 217, 226 (D.D.C. 2014),

[10] Eagle, page 5, citing FDA’s Policy on Orphan-Drug Exclusivity; Clarification, 79 Fed. Reg. 76,888 (Dec. 23, 2014).

[11] See FDA Reauthorization Act of 2017, Pub. L. No. 115-52, sec. 607(a), § 527(c)-(d), 131 Stat. 1005, 1049-50 (amending U.S.C. § 360cc).

[12] Eagle, page 6.  Administrative Record for Bendeka® as provided by FDA, FDA_AR 13, 470, 487.

[13] Id. AR 35-37

[14] Chevron U.S.A. Inc. v. Nat. Res. Def. Council, Inc., 467 U.S. 837 (1984)).

[15] Eagle, page 10. Citing Lindeen v. SEC, 825 F.3d 646, 653 (D.C. Cir. 2016), Cmty. for Creative Non-Violence v. Reid, 490 U.S. 730, 739 (1989)), Czyzewski v. Jevic Holding Corp., 137 S. Ct. 973, 985 (2017), Kelly v. Robinson, 479 U.S. 36, 43 (1986)), et al.

[16] Id., page 11, citing Depomed.

[17] Id., page 17.

[18] Id., pages 16-17.

[19] Id., pages 19-20.

[20] FDA Reauthorization Act] of 2017, sec. 607(b), 131 Stat. at 1050.

Recent Developments in Regulation of Software as a Medical Device


Andrea Berenbaum and Noel Courage [1]

The digital health technology sector has undergone rapid expansion in recent years, and its growth is forecasted to continue. One noteworthy class of technology in this sector is software as a medical device (SaMD). SaMD has been defined by the International Medical Device Regulators Forum (IMDRF) as “software intended to be used for one or more medical purposes that perform these purposes without being part of a hardware medical device.” [2] However, it is not always straightforward to distinguish between SaMD and other software such as medically-related non-SaMD. [3]

As new innovations emerge and the field continues to evolve, some medical device regulators are working to adapt their policies and processes to uphold safety and efficacy, while also better aligning with the rapid design, development and modification cycle associated with SaMD. There is also a need for clarity as to what software fits within the definition of SaMD. This article provides an overview of a few of the recent developments in this regard at the US Food and Drug Administration (FDA) and Health Canada. Companies making SaMD should keep on top of regulatory developments because the clear trend appears to be to try to accelerate the regulatory path to approval.

United States – Working Model for Software Precertification Program Released

As part of its Digital Health Innovation Action Plan, the FDA recently released an update to its Software Precertification Pilot Program. It includes a working model [4] that outlines its vision for the pilot. It also asks for specific input from stakeholders.

The Software Precertification Program (the “program”) is envisioned by the FDA as a voluntary pathway more tailored to suit software technologies than the existing regulatory regime. Its scope is currently limited to FDA-regulated SaMD, as defined by the above IMDRF definition. It therefore does not apply to other types of medically-related software such as software in a medical device (SiMD). It also does not apply to certain software excluded from being regulated as a medical device, for example because it relates to health administration or encouraging a healthy lifestyle. [5]

In contrast to the existing regulatory regime for medical devices, in which the obligations and procedures depend primarily on the classification of the medical device, the new program would use an organization-based approach comprising precertification of SaMD manufacturers. The program itself would be divided into four components: 1) excellence appraisal and precertification of the organization; 2) review pathway determination; 3) streamlined premarket review; and 4) real world performance.

According to the working model, the FDA will evaluate organizational excellence based on principles of product quality, patient safety, clinical responsibility, cybersecurity responsibility and proactive culture. Then, leveraging the data gathered from this precertification process, the FDA would determine the review pathway of the SaMD.

It is envisioned there would be two levels of companies demonstrating capabilities in all five excellence principles; those without a track record in delivering SaMD (“Level 1 Pre-Cert”) and those having a demonstrated track record in delivering SaMD and/or medical devices (“Level 2 Pre-Cert”). This level would be used as one of three factors in determining premarket review pathway. The second factor in the initial model is the risk category of the SaMD. In contrast to the existing regulatory regime for medical devices, with its three classes and the classification regulations contained in 21 CFR 862-892, the working model proposes using IMDRF types I to IV and subtypes 1 to 9. [6] The third factor considers whether the SaMD is a new device, an iteration of an existing device with major changes or an iteration of an existing device with minor changes.

In the proposed new regulatory regime, there is a significant number of cases where a precertified organization would not need to make a premarket submission. This includes all instances of minor changes, many instances of major changes (subtypes 1-8 for Level 2 organizations and subtypes 1-5 for Level 1 organizations) and even a number of new products (subtypes 1-6 for Level 2 organizations and subtypes 1-3 for Level 1 organizations). For the remaining categories of SaMD, i.e. those deemed to have the highest risk, streamlined premarket review would be required. According to the working model, this would take advantage of the information available from precertification and would potentially be supported by automated analysis with the goal of providing a decision more rapidly than with a traditional premarket review process.

Finally, the working model indicates that the FDA intends to use real world performance data [7] for monitoring and feedback at product, organizational and program levels.

Nine companies (Apple, Fitbit, Johnson & Johnson, Pear Therapeutics, Phosphorus, Roche, Samsung, Tidepool and Verily) were selected to participate in the development of the pilot program. The FDA hosted an interactive session on May 10, 2018 to discuss progress the agency has made on the Software Precertification Pilot Program to date [8] and sought public feedback (until May 31, 2018) on the initial version of the working model. It will be of interest to watch for further developments regarding this initiative.

Canada – New Digital Health Review Division and SaMD Scientific Advisory Panel

Health Canada recently announced it is establishing a new Digital Health Review Division “to allow for a more targeted pre-market review of digital health technologies, to adapt to rapidly changing technologies in digital health, and to respond to fast innovation cycles”. [9] SaMD is considered a “key area of focus” [10] under this new initiative.

Like other medical device products, SaMD are currently regulated by Health Canada using a risk-based classification system governed by the provisions of the Canadian Food and Drugs Act [11] and Medical Devices Regulations [12]. Schedule I to the Regulations sets out the rules for sorting a medical device into one of four classes, where Class I devices are perceived to represent the lowest risk and Class IV devices are perceived to represent the highest risk. There are two sets of risk-based classification rules in Schedule I; one for in vitro diagnostic devices (IVDDs) and another for non-IVDDs.

Comparable to the system in the US, regulatory obligations vary by class. For example, under the Canadian regulatory regime, medical devices in Classes II, III and IV generally require a medical device license to be imported, sold or advertised for sale whereas those in Class I are exempt from this requirement. Additionally, the information required in the application for a medical device license varies depending on class, with more onerous information requirements correlating with increased perceived risk.

Given the varying obligations depending on class, it is important to stakeholders that there be clarity and certainty in how the rules of Schedule I of the Regulations are applied to new digital health technologies such as SaMD. Encouragingly, Health Canada appears to have recognized this and has developed a draft guidance document intended to provide a definition of SaMD and guidance as to how SaMD may be classified. [13] A Scientific Advisory Panel has been engaged to solicit feedback on the draft guidance prior to external consultation as well as provide comments on the future of medical device software including SaMD and Health Canada’s regulatory approach.

While the draft guidance is not yet publically available, the questions considered by the panel shed some light on potential future directions. For example, Health Canada was seeking feedback on whether SaMD should be regulated within the current regulatory framework or alternatively whether the regulatory framework should be modified or even a new framework created to address SaMD. [14] It is still very early in the consultation process and it will be of interest to watch for the public release of draft guidance as well as the record of proceedings of the panel which met earlier this year.


[1] Andrea Berenbaum is a lawyer in Toronto, Canada. Noel Courage is a lawyer with Bereskin & Parr LLP, in Toronto, Canada.
[2] IMDRF SaMD Working Group “Software as a Medical Device (SaMD): Key Definitions” (9 December 2013), online: IMDRF
[3] The FDA has provided some examples of software considered to be SaMD and that considered not to be SaMD. See: “What are examples of Software as a Medical Device?” (6 December 2017), online: FDA
[4] “Developing a Software Precertification Program: A Working Model” (26 April 2018), online: FDA 
[5] Such software functions were excluded from the definition of “device” in the Food, Drug and Cosmetic Act by the 21st Century Cures Act. See: 21 USC § 360j(o). Software excluded includes certain software intended for administrative support of a health care facility, for maintaining or encouraging a healthy lifestyle, to serve as electronic patient records and for transferring, storing, converting formats, or displaying clinical laboratory test or other device data and results, findings by a health care professional with respect to such data and results, general information about such findings, and general background information about such laboratory test or other device.
[6] Adopted by the FDA as a guidance document: “Software as a Medical Device (SAMD): Clinical Evaluation: Guidance for Industry and Food and Drug Administration Staff” (8 December 2017), online: FDA 
[7] Defined in the working model as “all data relevant to the safety, effectiveness, and performance of a marketed SaMD product from a precertified manufacturer”.
[8] “User Session – Digital Health Software Precertification (Pre-Cert) Pilot Program” (10 May 2018), online: FDA 
[9] “Notice: Health Canada’s Approach to Digital Health Technologies” (10 April 2018), online: Health Canada
[10] Ibid. The other six key areas of focus listed in the notice are wireless medical devices, mobile medical apps, telemedicine, artificial intelligence, cybersecurity and medical device interoperability.
[11] Food and Drugs Act, RSC 1985, c F-27.
[12] Medical Devices Regulations, SOR/98-282 [“Regulations”].
[13] “Scientific Advisory Panel on Software as a Medical Device (SAP-SaMD) – Questions” (26 January 2018), online: Health Canada
[14] Ibid. Question 2.1.