Is FDA Leaving Orphans Out in the Cold?

In the last 12 months, the US Food and Drug Administration (FDA) has taken certain actions that, on their face, seem to be potentially limiting the benefits of orphan drug exclusivity (ODE). It is too soon to tell. However, FDA's actions are worth a review, because they demonstrate that the once-sacrosanct ODE is not invincible. At a minimum, it is interesting that, nearly 30 years since the passage of the Orphan Drug Act, the agency's views continue to emerge.

Rescission of Orphan Drug Exclusivity

In what appears to be a first, in August 2012, FDA rescinded the ODE it had granted to a drug company, claiming it had made a mistake. In its decision, made in response to a Citizen Petition, FDA made a strong distinction between orphan drug designation for the affected product, which it continued to recognize, and orphan drug exclusivity, which it took away in this case.1

Overview of Important Facts

In 2009, Octapharma USA Inc. obtained an ODE after demonstrating to FDA that its biological product, Wilate (von Willebrand Factor/Coagulation Factor VIII Complex (Human)), was clinically superior to CSL Behring LLC's Humate-P product.
In 2011, CSL Behring submitted a Citizen Petition, questioning the evidentiary support for superiority and asking FDA to rescind Wilate's orphan drug designation and exclusivity (CSL made other requests, which FDA rejected and are not discussed here).
On 8 August 2012, FDA granted CSL's Citizen Petition in part and denied it in part.

Key FDA Findings

FDA rescinded the ODE for Wilate, thereby revoking Octapharma's seven-year exclusivity that started in 2009. FDA concluded that Octapharma's Wilate was not clinically superior to CSL's Humate-P, despite a different decision two years earlier. The law allows a competitor drug to be granted orphan drug designation and exclusivity, despite another's orphan drug exclusivity, if it demonstrates clinical superiority to the first drug approved for the orphan indication.2,3 One product can show superiority in safety, efficacy or a major contribution to patient care.4 Demonstration of clinical superiority is not common. After FDA re-reviewed Wilate, it concluded that the data did not "support a conclusion that Wilate has been demonstrated to 'provide a significant therapeutic advantage over and above that provided' by Humate."5 As such, the agency found it had erred in granting exclusivity and was, therefore, revoking the exclusivity.
FDA allowed Octapharma to keep its orphan designation. The agency said a plausible hypothesis of superiority is sufficient to obtain orphan drug designation.6,7 However, this hypothesis must be proven to secure exclusivity. Thus, Octapharma demonstrated a plausible hypothesis in 2009 that Wilate was clinically superior to CSL's product, sufficient for designation, which it can keep.
FDA rejected CSL's request that the agency require head-to-head comparative clinical evidence of superiority in future orphan designation and exclusivity review, stating that the regulations "embody a case-by-case approach" rather than "prescribing the precise type and amount of evidence necessary."8 Rather, FDA will evaluate each case individually to determine what information is required to demonstrate clinical superiority.

Proposed Changes to Clarify Orphan Drug Regulations

FDA published a Federal Register notice announcing proposed amendments to its 1992 orphan drug regulations.9,10 The proposed changes, which address a variety of issues related to orphan drug designation and exclusive approval, are intended to clarify existing regulatory provisions. This article will focus only on proposals that potentially narrow the ODE.

Demonstrating a "Medically Plausible" Orphan Subset

By law, FDA will designate a product as an orphan drug if the sponsor demonstrates, among other things, that the drug is intended for a rare disease or condition that affects fewer than 200,000 people per year in the US.1^1,12 In some cases, however, FDA grants orphan designation for a "non-rare" disease or condition (i.e., one that affects more than 200,000 people annually). To obtain orphan designation for a non-rare disease or condition the sponsor must demonstrate that the drug will treat only a subset of people with the particular disease or condition. The patient subset group must fall under the orphan prevalence limit of 200,000 annually, and the sponsor must have a "medically plausible" reason for limiting treatment to the subset.1³

The current orphan drug regulations do not define the term medically plausible and, according to FDA, the term has been misinterpreted as referring to any clinically distinguishable subset of people. To address this confusion, FDA proposed removing "medically plausible" from the regulations, instead providing a description of how sponsors should identify an appropriate orphan subset. The proposed amendment would require that the subset not be arbitrarily chosen merely to reduce the disease prevalence for the purposes of obtaining orphan designation. Rather, the product sponsor must develop a reasonable scientific or medical rationale for limiting the drug investigation to a specific subset.

FDA explained that the drug's pharmacological properties or prior clinical experience with the drug might provide an appropriate basis for an orphan subset. For example, a cancer-fighting antibody product might have the pharmacological property of attacking a specific antigen type. In such a case, it would be appropriate to identify an orphan subset based on the subtypes of tumors that possess the specific antigen and to exclude from the prevalence calculation patients with tumors that lack the antigen. Similarly, if existing clinical data (from a completed trial or from published literature) show that a cancer-fighting drug is only effective against a certain subset of tumors, an orphan subset may be identified accordingly.

In the proposed rule, FDA suggests that sponsors ask two practical questions to evaluate whether a patient sub-group may appropriately be treated as an orphan subset:

Is the intended subset artificially restricted in any way?
Given that the drug may potentially benefit a particular patient subset, is there a reasonable scientific or medical basis for believing that the drug will also benefit the remaining population with the disease or condition? If not, why not?

If the subset is not artificially restricted, and there is a medical or scientific basis to explain why the drug will not benefit the patients excluded from the subset, then it is likely that a valid and "medically plausible" orphan subset has been identified.

Obtaining Orphan Designation When FDA Already Approved the Same Drug for Orphan Indication

Under the current orphan drug regulations, a sponsor of a subsequent drug that is the same as an "approved orphan drug" may not obtain orphan designation for the same indication as the existing drug, unless the sponsor can demonstrate that the subsequent drug is clinically superior.1^4-16 FDA has proposed deleting the word "orphan" from the phrase "approved orphan drug" in current regulatory sections to clarify that this non-designation rule applies whether or not the existing drug has orphan exclusivity for the indication in question. That is, if finalized, the agency will not grant orphan designation to a drug that is the same as (and not clinically superior to) an already approved drug for the orphan indication, regardless of whether the approved drug has orphan exclusivity.

Eligibility for Multiple Orphan Exclusive Approvals

FDA has proposed adding language to the orphan drug regulations to clarify that the scope of orphan exclusivity is limited to the approved indication or use, even if the underlying orphan designation is broader. For example, a drug might have orphan designation for treatment of T-cell non-Hodgkin's lymphoma; however, the data submitted for product approval might only support treatment of cutaneous manifestations of the disease. In this example, the sponsor would receive orphan exclusivity only for the narrow indication of treatment in patients with cutaneous manifestations of T-cell non-Hodgkin's lymphoma. The orphan exclusivity would not cover other subsets of T-cell non-Hodgkin's lymphoma. The proposed approach of limiting the orphan exclusivity to the approved indication means that, in some cases, multiple orphan drug approvals with exclusivity could exist for the same underlying disease or condition. This approach has important implications both for the initial orphan drug sponsor and subsequent sponsors of the same drug. Returning to the lymphoma example, if the initial sponsor, or a subsequent sponsor with orphan drug designation, later submits data and obtains approval for treatment of another subset of T-cell non-Hodgkin's lymphoma (e.g., treatment of anaplastic large cell lymphoma), the sponsor will be eligible for orphan exclusivity for the new indication, effective on the date of approval.

Demonstrating Clinical Superiority

As noted above, a drug sponsor must demonstrate clinical superiority to obtain orphan designation for a drug that is the same as a drug already approved for the orphan indication.1^7,18 The current regulations specify that, if a sponsor is unable to demonstrate greater safety or effectiveness, FDA still may consider the drug "clinically superior" if it makes a major contribution to patient care.1⁹ FDA is proposing additions to the definition of clinically superior to clarify that a major contribution to patient care is only meaningful in cases where the drug can demonstrate at least safety and effectiveness comparable to the approved drug.

For example, a sponsor might wish to demonstrate clinical superiority by showing that a drug has made a major contribution to patient care through a new formulation or route of administration. FDA also will require that sponsor to show that this change does not render the drug less safe or effective than the approved drug.

FDA Recognition of Orphan Drug Exclusivity

Sponsors that demonstrate clinical superiority for the purpose of obtaining orphan drug designation also must be able to demonstrate clinical superiority at the time of product approval to be eligible for an ODE. FDA will not grant orphan exclusivity to a drug that is the same as an already approved drug if the sponsor fails to substantiate in the marketing application the clinical superiority hypothesis that was the original basis for orphan drug designation. To clarify this existing policy, FDA proposes adding the following language to the regulations:

If a drug is otherwise the same as a previously approved drug, FDA will not recognize orphan-drug exclusive approval if the sponsor fails to substantiate, at the time of marketing approval, the hypothesis of clinical superiority over the approved drug that formed the basis for designation.2⁰

Pharmacy Compounders Undercut Orphan Drug Exclusivity

In general, FDA attempts to protect companies with an ODE from those seeking to undermine such exclusivity. However, a company should not look to the agency as its guardian angel. As an example, K-V Pharmaceuticals found that pharmacy compounders were undercutting the ODE for its Makena drug product. FDA chose not to take action, exercising its enforcement discretion; K-V sued the agency. FDA argued successfully in court that it is under no legal obligation to take enforcement action against pharmacy compounders that might undermine a drug company's ODE.2¹

It's Not Exclusivity Until FDA Says So

In September 2012, Depomed Inc. sued FDA, seeking a court order requiring the agency to grant an ODE for its Gralise (gabapentin) prescription drug product.2² The agency approved the drug in 2011 and had granted orphan drug designation to Gralise. A major focus of the case is the standard for obtaining designation, which is different from the standard for obtaining exclusivity when clinical superiority is at issue ("plausible hypothesis of clinical superiority" in the designation stage versus demonstration of clinical superiority at the time of drug approval). In the case of Gralise, FDA granted orphan drug designation based on a plausible hypothesis of clinical superiority. However, to date, the agency has not granted an ODE.

Sign of Things to Come

While the aforementioned examples are unusual and fact-specific, they demonstrate a continued evaluation and evolution of FDA's policies, views and interpretations of orphan drug law. This is not to suggest that we are seeing a tidal wave of change with the ODE. FDA continues to encourage orphan drug development and, in fact, the Food and Drug Administration Safety and Innovation Act, signed into law in July 2012, includes provisions to accelerate the development of "breakthrough therapies" that demonstrate early promise and faster patient access to new medical treatments and expand the priority review voucher program to include pediatric rare diseases.2³ To quote Little Orphan Annie, "the sun'll come out tomorrow" (yes, it's a stretch, but you knew it was coming). Rather, the orphan drug area is constantly changing, and any company with orphan drug designation, exclusivity or both, or considering the orphan drug approach, should continue to monitor regulatory developments.

References

FDA, Response to CSL Behring Citizen Petition (Aug. 8, 2012). Elsevier Business Intellience website., www.elsevierbi.com/~/media/Supporting%20Documents/The%20Pink%20Sheet%20DAILY/2012/FDA%20response%20to%20CSL%20Behring%20citizen%20petition.pdf. Accessed 5 February 2013.
21 CFR 316.3. GPO website. www.gpo.gov/fdsys/pkg/CFR-2009-title21-vol5/pdf/CFR-2009-title21-vol5-sec316-3.pdf. Accessed 5 February 2013.
21 CFR 316.20(b)(5). FDA website. www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?fr=316.20. Accessed 5 February 2013.
21 CFR 316.3(b)(3). GPO website. www.gpo.gov/fdsys/pkg/CFR-2009-title21-vol5/pdf/CFR-2009-title21-vol5-sec316-3.pdf. Accessed 5 February 2013.
Op cit 1, p. 2.
21 CFR 316.20(a). FDA website. www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?fr=316.20. Accessed 5 February 2013.
21 CFR 316.25(a)(3). GPO website. www.gpo.gov/fdsys/pkg/CFR-2012-title21-vol5/pdf/CFR-2012-title21-vol5-sec316-25.pdf. Accessed 5 February 2013.
Op cit 1, p. 13..
76 FR 64868, 64868 (October 19, 2011). GPO website. www.gpo.gov/fdsys/pkg/FR-2011-10-19/pdf/2011-27037.pdf. Accessed 5 February 2013.
FDA Leaves an Orphan Out in the Cold. AGG website. www.agg.com/files/Publication/7551b990-58c8-428c-a548-bfae4d4ee461/Presentation/PublicationAttachment/862613a1-0b8e-4732-b11e-c05f7f529a67/Minsk-Nduom-FDA-Leaves-an-Orphan-Out-in-the-Cold%5b1%5d.pdf. Accessed 5 February 2013.
21 U.S.C. 360bb(a)(2)(A). Cornell University Law School website. www.law.cornell.edu/uscode/text/21/360bb. Accessed 19 February 2013.
21 CFR 316.20(b)(8)(i). FDA website. www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?fr=316.20. Accessed 5 February 2013.
21 CFR 316.20(b)(6). www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?fr=316.20. Accessed 5 February 2013.
Op cit 4.
Op cit 6.
Op cit 3.
Op cit 6.
Op cit 7.
21 CFR 316.3(b)(3)(i) and 316.3(b)(3)(ii). GPO website. www.gpo.gov/fdsys/pkg/CFR-2009-title21-vol5/pdf/CFR-2009-title21-vol5-sec316-3.pdf. Accessed 5 February 2013.
76 FR at 64879 (emphasis added). Federal Register website. www.federalregister.gov/articles/2011/10/19/2011-27037/orphan-drug-regulations. Accessed 5 February 2013.
K-V Pharmaceutical Company v. United States Food and Drug Administration (D.D.C. 2012). GPO website. www.gpo.gov/fdsys/pkg/USCOURTS-dcd-1_12-cv-01105/pdf/USCOURTS-dcd-1_12-cv-01105-0.pdf. Accessed 5 February 2013.
Depomed v. Health and Human Services, 1:12-cv-01592 (D.D.C. Sep. 25, 2012). Justia.com website. http://dockets.justia.com/docket/district-of-columbia/dcdce/1:2012cv01592/156194/. Accessed 5 February 2013.
Pub. L. 112-144. , 126 Stat. 993 (2012). GPO website. www.gpo.gov/fdsys/pkg/PLAW-112publ144/html/PLAW-112publ144.htm. Accessed 5 February 2013.

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