By Karla L. Palmer – 

The Food and Drug Administration (FDA) announced earlier this week that it is seeking nominations for bulk substances that may be used by outsourcing facilities to compound drugs for use in animals.  FDA will ultimately include the listed substances in Appendix A to FDA’s guidance for “Compounding Animal Drugs from Bulk Substances.”  The draft of that guidance was released earlier this week (and blogged about here).  Bulk substance nominations should be submitted within 90 days after publication of the notice (or by August 17, 2015) to ensure FDA’s consideration (but FDA noted it cannot guarantee that all drugs nominated during the nomination process will be considered prior to initial publication of Appendix A).  After the comment period is closed, nominations to add or remove substances from the list may be submitted by citizen petition. 

FDA’s request for nominations notes there are “limited circumstances” where a drug compounded from bulk substances should be available for office use; FDA is proposing in its related draft guidance that outsourcing facilities compound animal drugs only from the bulk substances listed in Appendix A.  FDA will exercise enforcement discretion for those facilities that compound animal drugs using Appendix A’s listed bulk substances.  Although an outsourcing facility may fill an order for compounded animal drugs from bulk substances without obtaining an individually identified patient prescription, “outsourcing facilities cannot dispense a compounded drug to the owner or caretaker of an animal without a prescription for that individually identified animal patient.”  FDA specifically notes that Appendix A only applies to outsourcing facilities, and does not limit what bulk drug substances state-licensed pharmacies and veterinarians can use in compounding in accordance with the draft guidance.  In addition, the underlying draft guidance only addresses compounding from bulk substances; it does not apply to the compounding from approved animal or human drugs.

The list will be limited to bulk substances (but not inactive ingredients) that address all of the following criteria:

• There is no marketed approved, conditionally approved, or index listed animal drug that can be used as labeled to treat the condition;
• There is no marketed approved animal or human drug that could be used under FDCA section 512(a)(4) or (a)(5) and 21 CFR Part 530 (addressing extra-label use of approved animal and human drugs) to treat the condition;
• The drug cannot be compounded from an approved animal or human drug;
• Immediate treatment with the compounded drug is necessary to avoid animal suffering or death; and
• FDA has not identified a significant safety concern specific to the use of the bulk drug substance to compound animal drugs (under the listed conditions and limitations).

Concerning active ingredients, nominations must be for specific bulk substances that meet FDA’s definition of a bulk substance in 21 C.F.R. §207.3(a)(4).  As set forth in further detail in the notice, nominations must also include the following:

1. “Confirmation” that the nominated substance is a bulk substance including an explanation of why the substance is considered an active ingredient when it is used in the compounded product, citing to “specific sources that describe the active properties of the substance”;
2. A general background on the bulk drug substance;
3. Information on the animal drug products that will be compounded with the bulk drug substance (including dosage form, route of administration, strengths, etc.);
4. Information detailing the need for the animal drug products that will be compounded with the bulk drug substance.  FDA states that to be able to meaningful evaluate and review the substance, it needs more than a general explanation.

FDA adds that following information about “need” is necessary:

• A statement identifying the species and condition the drug is intended to treat;
• Bibliography of safety and efficacy data if available including peer reviewed literature;
• List of approved/index listed/conditionally approved  animal drug products for the condition that the compounded drug is intended to address;
• If there are approved drugs for the condition, why the compounded drug from the bulk substance is necessary, supported by  relevant literature;
• Review of veterinary literature to determine whether there are any approved or extralabel uses of the drug that could treat the condition in the species that the compounded drug is intended to address;
• If the bulk substance is an active ingredient in an approved animal or human drug, an explanation (with appropriate supporting scientific data) of why it cannot be compounded from the approved drug; 
• An explanation (supported by relevant veterinary literature) of why the animal drug product must be available to the veterinarian for immediate treatment to avoid animal suffering or death.  Nominations should include information documenting that “animal suffering or death will result if treatment is delayed until a compounded animal drug product can be obtained pursuant to a prescription for an individually identified patient”; and
• A discussion of safety concerning, including relevant literature.  Safety concerns must include an explanation with supporting literature of why those concerns should not preclude inclusion on the list. 

FDA warns that it will be unable to consider the bulk substance for Appendix A unless adequate information is submitted.  FDA encourages submission of nominations in a format that “explicitly addresses each item … listed in the order that they appear” in the notice.     

Hyman, Phelps & McNamara, P.C., the nation’s largest boutique food and drug regulatory law firm, seeks a junior to mid-level associate with substantive experience in medical devices and other areas of food and drug law and regulation to assist with a growing practice.  Strong verbal and writing skills are required.  Compensation is competitive and commensurate with experience.  HP&M is an equal opportunity employer.

Please send your curriculum vitae, transcript, and a writing sample to Jeffrey N. Wasserstein (jwasserstein@hpm.com).  Candidates must be members of the DC Bar or eligible to waive in.

By Kurt R. Karst –      

Each month we pore over the latest Orange Book Cumulative Supplement in an effort to keep our popular 180-Day Exclusivity Tracker as current as possible, and to look for interesting precedents.  Last month, one entry in particular caught our attention.  It was for ANDA 200828 for Lamotrigine Orally Disintegrating Tablets, 25 mg, 50 mg, 100 mg, and 200 mg, a generic version of GlaxoSmithKline LLC’s LAMICTAL ODT (NDA 022251).  The Orange Book Cumulative Supplement showed the addition of periods of “PC” exclusivity (i.e., 180-day patent challenge exclusivity) expiring on September 28, 2015 for all four strengths covered under the ANDA now owned by Impax Laboratories, Inc. (“Impax”) (formerly owned by Watson Laboratories, Inc. (“Watson”)).  What made the entry of 180-day exclusivity interesting is that FDA’s July 15, 2013 letter approving the ANDA included the Agency’s all-too-familiar 180-day exclusivity “punt” language:

With respect to 180-day generic drug exclusivity, we note that Watson was the first ANDA applicant for Lamotrigine Orally Disintegrating Tablets, 25 mg, 50 mg, 100 mg, and 200 mg, to submit a substantially complete ANDA with a paragraph IV certification.  Therefore, with this approval, Watson may be eligible for 180 days of generic drug exclusivity for Lamotrigine Orally Disintegrating Tablets, 25 mg, 50 mg, 100 mg, and 200 mg.  This exclusivity, which is provided for under section 505(j)(5)(B)(iv) of the Act, would begin to run from the date of the commercial marketing identified in section 505(j)(5)(B)(iv).  The agency notes that Watson failed to obtain tentative approval of this ANDA within 40 months after the date on which the ANDA was filed. See section 505(j)(5)(D)(i)(IV) (forfeiture of exclusivity for failed to obtain tentative approval).  The agency is not, however, making a formal determination at this time of Watson’s eligibility for 180-day generic drug exclusivity.  It will do so only if another paragraph IV applicant becomes eligible for full approval (a) within 180 days after Watson begins commercial marketing of Lamotrigine Orally Disintegrating Tablets, 25 mg, 50 mg, 100 mg, and 200 mg, or (b) at any time prior to the expiration of the listed patents if Watson has not begun commercial marketing. Please submit correspondence to this ANDA informing the agency of the date commercial marketing begins.

FDA’s Orange Book entry showing the addition of 180-day exclusivity could mean only one thing: that the Agency was forced into a position of determining whether or not eligibility for 180-day exclusivity was forfeited.  So we obtained a copy of FDA’s exclusivity determination to make sure.  And sure enough, FDA ruled on October 29, 2014 – just one day before tentatively approving Par’s ANDA 204158 for  Lamotrigine Orally Disintegrating Tablets, 25 mg, 50 mg, 100 mg, and 200 – that Watson (now Impax) maintained eligibility for exclusivity because of a change in the requirements for approval with respect to labeling. 

By way of background, under FDC Act § 505(j)(5)(D)(i)(IV), one of the six 180-day exclusivity provisions added to the FDC Act by Title XI of the 2003 Medicare Modernization Act (“MMA”), 180-day exclusivity eligibility is forfeited if:

The first applicant fails to obtain tentative approval of the application within 30 months after the date on which the application is filed, unless the failure is caused by a change in or a review of the requirements for approval of the application imposed after the date on which the application is filed.

The 2007 FDA Amendments Act (“FDAAA”) clarified FDC Act § 505(j)(5)(D)(i)(IV), such that if “approval of the [ANDA] was delayed because of a [citizen] petition, the 30-month period under such subsection is deemed to be extended by a period of time equal to the period beginning on the date on which the Secretary received the petition and ending on the date of final agency action on the petition (inclusive of such beginning and ending dates) . . . .” (FDC Act § 505(q)(1)(G)).  The 2012 FDA Safety and Innovation Act (“FDASIA”) made further changes with respect to the application of FDC Act § 505(j)(5)(D)(i)(IV) to certain ANDAs (see our previous post here).  Although the FDAAA provision did not come into play in the case of ANDA 200828, the FDASIA provision did, as noted below. 

For years – ever since the July 31, 2006 approval of ANDA 076969 for Metoprolol Succinate Extended-Release Tablets USP, 25 mg (see our previous post here) – FDA has been deciding not to decide on eligibility for 180-day exclusivity when there is no immediate need to do so.  It’s been rare that FDA has had to resolve 180-day exclusivity punts. 

The first punt resolution was made in the context of ANDA No. 200899 for Dutasteride Capsules, 0.5 mg.  As we previously posted, in that case, FDA ruled that eligibility for 180-day exclusivity was forfeited.  The second punt resolution was made in the context of ANDA 202608 for Methylphenidate HCl Extended-release Tablets, 27 mg, 36 mg, and 54 mg, as we previously noted.  Although FDA ruled that 180-day exclusivity was not forefeited (a punt return), it was a bit of an oddball case.  First, the drug at issue – a generic version of CONCERTA Extended-release Tablets – is a pre-MMA drug not subject to the failure-to-obtain-timely-tentative-approval forfeiture provision at FDC Act § 505(j)(5)(D)(i)(IV).  Second, FDA appears to have made the punt decision in the context of then-ongoing litigation that could have affected an exclusivity determination.  So the latest decision out of FDA concerning Lamotrigine Orally Disintegrating Tablets might be the first post-MMA punt return decision. 

Watson submitted ANDA 200828 to FDA on December 21, 2009.  But at the time of submission, the ANDA did not contain a Paragraph IV certification, and therefore, Watson was not a “first applicant” eligible for 180-day exclusivity.  First applicant status was conferred on April 14, 2011,when the ANDA was amended to include a Paragraph IV certification to U.S. Patent No. 7,919,115 listed in the Orange Book for LAMICTAL ODT.  That made ANDA 200828 an application subject to the later-enacted provisions in the 2012 FDASIA extending the 30-month deadline under FDC Act § 505(j)(5)(D)(i)(IV) to 40 months.  But as FDA noted in the Agency’s July 15, 2013 approval letter:

For applications submitted between January 9, 2010, and July 9, 2012, section 1133 of the Food and Drug Administration Safety and Innovation Act (FDASIA) (P.L. 112-144) extends this period to 40 months.  This includes applications such as ANDA 200828 “amended during such period to first contain [a PIV certification]…”  Watson therefore qualifies for 40 (not 30) months in the application of section 505(j)(5)(D)(i)(IV) (forfeiture of exclusivity for failed to obtain tentative approval).  However, this 40-month period dates from the date of receipt of the ANDA (December 21, 2009), not the date the paragraph IV amendment was received. [sic] (April 14, 2011), because this ANDA does not meet the terms of section 1133(b) of FDASIA.

But that’s all irrelevant now given FDA’s October 29, 2014 exclusivity determination.  After going through the relevant law, including FDA’s position rejecting “but-for” causation in analyzing FDC Act § 505(j)(5)(D)(i)(IV) (see our previous post here), FDA turned to the facts at hand.  And, specifically, to changes to the RLD (LAMICTAL ODT) labeling.  According to FDA:

A fifth labeling change was approved on August 1, 2012, approximately 8 months before the forfeiture date.  This labeling change provided for Agency-requested updates to the Use in Specific Populations/Nursing Mothers (section 8.3) and Patient Counseling information/Pregnancy and Nursing (section 17.6) section of the labeling, as well as corresponding changes to the Medication Guide.

FDA initially reviewed Impax’s labeling on May 11, 2010, and identified a number of deficiencies.  Impax submitted an amendment responding to FDA’s deficiencies on July 13, 2010.  FDA reviewed Impax’s amendment on October 23, 2011, and identified additional deficiencies.  One of the deficiencies asked Impax to update its package insert and medication guide labeling to be in accord with the August 4, 2011 approved labeling changes for the RLD.  Impax submitted an amendment responding to FDA’s deficiencies on April 2, 2012.  Before FDA reviewed lmpax’s April 2, 2012 amendment, Impax submitted another labeling amendment on September 10, 2012, to update their labeling to be consistent with the RLD labeling changes approved on August 1, 2012.  FDA reviewed Impax’s April 2, 2012 and September 10, 2012 labeling amendments and on April 24, 2013, three days after the 40-month forfeiture date of April 21, 2013, FDA notified Impax of additional labeling deficiencies.  Impax submitted an amendment on May 7, 2013.  FDA reviewed Impax’s amendment, and ultimately determined Impax’s labeling to be acceptable on May 30, 2013. . . .

We conclude that there were changes to the requirements for approval with respect to labeling, as outlined above.  We also find evidence that these labeling changes caused Impax's failure to obtain tentative approval by the forfeiture date.  Specifically, changes to the RLD labeling were approved on August 1, 2012, and Impax submitted a labeling amendment on September 10, 2012 to update their labeling.  At the 40-month date of April 21, 2013, Impax’s labeling amendment had not been reviewed by FDA, and the labeling deficiencies issued by FDA after the 40-month forfeiture date related to the changes to the RLD labeling that occurred after Impax submitted its ANDA.

So, there you have it – what seems to be the first true post-MMA 180-day exclusivity punt return.

By Jennifer D. Newberger –

In March 2012, FDA issued a guidance document, Factors to Consider when Making Benefit-Risk Determinations in Medical Device Premarket Approval and De Novo Classifications.  As we discussed in our blog post on that guidance, one important discussion in that guidance had to do with patient perspective of benefit-risk and how FDA might take that into consideration when deciding whether to approve premarket approval (PMA) applications or de novo submissions.  On May 13, 2015, FDA expanded this discussion with a 32-page draft guidance addressing how FDA might consider patient preference information, the types of data and information to include in a submission, and how to incorporate patient preference information into a product’s labeling.  See Patient Preference Information – Submission, Review in PMAs, HDE Applications, and De Novo Requests, and Inclusion in Device Labeling.  Note that the draft guidance applies only to PMAs, de novo petitions, and humanitarian device exemption (HDE) submissions.  It does not apply to 510(k)s, consistent with the Benefit-Risk Guidance.

FDA makes clear in the draft guidance that including patient preference information in a premarket submission is voluntary, but can be useful in the following ways: 

1) to help identify the most important benefits and risks of a technology from a patient’s perspective; 2) to assess the relative importance to patients of different attributes of benefit and risk, and clarify how patients think about the tradeoffs of these benefits and risks for a given technology; and 3) to help understand the heterogeneity or distribution of patient preferences regarding benefits and risks of various treatment or diagnostic options.

FDA defines “patient preference information” as “qualitative or quantitative assessments of the relative desirability or acceptability of attributes that differ among alternative diagnostic or therapeutic strategies.”  One of the key ways in which this information may assist FDA during the review process is to help reviewers understand circumstances in which certain patient populations may be willing to accept a greater risk for a smaller benefit, for example, if there are no other treatment options available or a sub-group of patients may be more likely to benefit from a device even if the data do not support approval for use in the population as a whole.

The guidance discusses methods to elicit patient preferences.  While acknowledging that qualitative data may be sufficient at times, the guidance emphasizes the importance of quantitative data “to ensure that different outcomes are properly weighed in the same scale and therefore can be compared.”  It also states that while submission of patient preference information is voluntary, it may be particularly helpful where decisions about device usage are “preference-sensitive.”  This may occur, for example, when a patient may have multiple treatment options and none is clearly superior for all preferences, when the evidence supporting one option over others is uncertain or variable, or when patients’ views about the benefits and risks of a device vary considerably within a population.

In order to accept patient preference information provided in a premarket submission, the information must constitute “valid scientific evidence.”  FDA will make this determination based on the following study qualities:

• Representativeness of the sample and generalizability of results;
• Capturing heterogeneity of patients’ preferences;
• Established good research practices by recognized professional organizations;
• Patient centeredness;
• Effective communication of benefit, harm, uncertainty, and risk;
• Minimal cognitive bias;
• Logical soundness;
• Relevance;
• Robustness of analysis of results;
• Study conduct; and
• Comprehension by study participants.

Like other studies conducted to support a PMA, patient preference studies should be described in the device’s labeling upon approval.  The labeling should contain information to help patients understand:

• If they might benefit from use of the device;
• The potential benefits from use of the device;
• The potential risks or complications from use of the device, and the likelihoods of each;
• Any relevant contraindications, warnings, and precautions;
• If they share characteristics with the group of patients who view the benefits as outweighing the risks; and
• Any additional information about what is known and not known about patient outcomes (e.g., long-term outcomes, rare complications).

The information in the draft guidance has the potential to be helpful to sponsors of PMAs, de novo petitions, and HDEs, particularly for sponsors of new or novel devices.  While collecting patient preference data of a quality and quantity described in the guidance will pose an additional burden and expense on the sponsor, it may also allow for the possibility of device approval when such approval was previously unlikely.

By Ricardo Carvajal - 

The AP reports that USDA has developed a Process Verified Program (PVP) claim for non-GMO corn and soybeans, at the request of “a leading global company.”  The PVP claim was approved under a program operated by USDA’s Agricultural Marketing Service.  The program provides a framework for the verification of voluntary marketing claims that can address a range of product characteristics.  A company that obtains USDA approval of its PVP can market its product as USDA Process Verified and use this logo: 

USDA Secretary Vilsack lauded the development in a memo to staff:

Recently, a leading global company asked AMS to help verify that the corn and soybeans it uses in its products are not genetically engineered so that the company could label the products as such. AMS worked with the company to develop testing and verification processes to verify the non-GE claim.

While the Process Verified Program itself is not a new program, this is the first non- GMO/GE claim verified through USDA. It will be announced soon, and other companies are already lining up to take advantage of this service.

This is a great example of AMS employees working in partnership with stakeholders to respond creatively and adapt to changes in the market, monitor trends and consumer demands, and develop solutions that meet industry and consumer needs.

The option of obtaining a USDA-approved PVP claim for non-GMO foods could give companies an alternative to existing options such as the Non-GMO Project.   It might also come to play a role in litigation over Vermont’s new law requiring GMO labeling because the USDA approach timely illustrates the existence of alternatives to Vermont’s effort to compel speech – something that could prove relevant in the context of a First Amendment analysis of Vermont’s law.

A hat tip to Faegre Baker Daniels for making the USDA memo available on their website.

By James E. Valentine* & Alexander J. Varond –

After giving us a few months to shake our sticks at the nearly 400-page 21st Century Cures Act (the Cures Act) discussion draft, the House Energy and Commerce Committee (the Committee) dropped a 200-page version that was the subject of a Health Subcommittee hearing held on April 30, 2015.  Perhaps having found a happy medium, just two weeks later the Committee has issued a 300-page third version.  The Health Subcommittee advanced the bill by a vote during a mark-up held on May 14th.  

The two most recent versions of the 21st Century Cures Act are organized into three titles – DISCOVERY, DEVELOPMENT, and DELIVERY – reflecting the initiative’s initial goal to accelerate the pace of cures through all points during the innovation cycle.  Since the first draft, not only have a number of provisions been removed, but about a quarter of the provisions are new.  Many of those retained from the first version are heavily revised.  With the next step in the legislative process underway, here is an overview of some of these key changes these bloggers identified when reviewing these revised drafts (additional posts on other provisions may follow).

Discovery

Title I of the bill is almost completely focused on enhancements for the National Institutes of Health (NIH).  Of note, the bill includes reauthorization of the NIH (Sec. 1001) and the establishment of an NIH Innovation fund to be made available for precision medicine, young emerging scientists, and at least one other initiative that is to be determined (Sec. 1002).  In the April 30th Health Subcommittee hearing, Dr. Kathy Hudson, Deputy Director for Science, Outreach, and Policy at NIH,  delivered her thanks to the Subcommittee on Health for this increased funding after a number of years of diminishing funding resulting in the inability to fund good ideas.

Standardization of Eligibility Information in ClinicalTrials.gov:  A change to this provision on the standardization in the Clinical Trial Registry Data Bank, or ClinicalTrials.gov, on eligibility for clinical trials (Sec. 1102, the first draft’s Sec. 2081—see post on previous provision here) no longer requires eligibility criteria to be matched to diagnosis or procedure coding systems (e.g., the International Classification of Diseases or the Current Procedural Terminology) and integrated into electronic health records, but would have NIH make use of them to the extent possible.

Data on Natural History of Diseases:  This provision, first proposed in the second version and tweaked in the third, would have Health and Human Services (HHS) participate in public-private partnerships and award grants to patient advocacy groups to establish or facilitate the collection, maintenance, analysis, and interpretation of data on the natural history of diseases, with a particular focus on rare diseases (Sec. 1123).  The private-public partnerships would sponsor or maintain disease registries and registry platforms, develop or enhance a secure information technology system that builds on and cooperates with other disease registries, and provide advice on the design and conduct of natural history studies.  Support for and further development of disease registries and registry platforms would facilitate generations of natural history data valuable for use in drug development.  This would help to better understand disease progression and aid in the development of clinical trial protocols as well as the identification and development of outcome measurements (e.g., biomarkers, clinical outcome assessments), as a source of recruiting research subjects, for interpreting results, and as a historical control.

Development

Title II of the bill shifts the focus to medical product development activities regulated by the Food and Drug Administration (FDA or the Agency).  A concern voiced during the discussion at the April 30th hearing by FDA’s Dr. Janet Woodcock, the Director of the Center for Drug Evaluation and Research, and Dr. Jeff Shuren, Director of the Center for Devices and Radiological Health, was that there were a number of new responsibilities for the Agency, yet the draft legislation did not increase funding for the Agency to carry out the additional work.  Dr. Woodcock informed the Subcommittee that, to the extent the 21st Century Cures Act created statutory requirements and timelines, FDA would have to prioritize those activities.  She warned that there is a tradeoff between implementation and review work, citing Food and Drug Administration Amendment Acts as an example of when unfunded mandates impacted performance.  There was an appreciable dip in review time because of the burdens of implementing the law’s provisions without additional resources.   Dr. Woodcock urged the Subcommittee to not break what is fixed: the current drug review program.  A number of Subcommittee members echoed this concern and their desire to ensure that any new programs are adequately funded.  Meanwhile, the third version of the bill has included only a few small authorizations for appropriations.

Qualification of Drug Development Tools:  The new version of the legislation provided a revised section (Sec. 2021) that replaces Sections 1021-1024 of the first discussion document.  The revised section is broader, as it now addresses biomarkers, surrogate endpoints, and other drug development tools; the first discussion draft focused primarily on surrogate endpoints.  On the other hand, it is narrower because it does not affect devices. The section also removes many of the formal procedures and timelines from the first discussion draft and provides FDA with more discretion in the development of the program. 

The revised section would add Section 507 to the Federal Food, Drug, and Cosmetic Act (FD&C Act), which would call upon FDA to facilitate the availability of qualified biomarkers, including surrogate endpoints, and other drug development tools (e.g., clinical outcome assessments, patient reported outcomes).  FDA would be required to develop guidance with respect to standards for qualification and establish a process for qualifying biomarkers and other drug development tools.  Such a drug development tool would be qualified only for “its proposed context of use,” which would be specified by the requestor. 

Accelerated Approval Development Plans:  One provision, first proposed in the second version of the bill (Sec. 2022) and modified in the third version, would establish a process for a sponsor of a drug eligible for accelerated approval to voluntarily submit, and for FDA to agree to, an “accelerated approval development plan” for purposes of facilitating early interactions and agreement between sponsors and FDA on designing studies to generate evidence for purposes of accelerated approval.  An accelerated approval development plan would need to include (1) a surrogate endpoint to be assessed under the plan, (2) the design of the study that will utilize the surrogate endpoint, and (3) the magnitude of the effect of the drug on the surrogate endpoint that would be sufficient to form the primary basis of a claim that the drug is effective. 

These plans would create an opportunity earlier in development for sponsors and FDA to consider the appropriateness of accelerated approval for each new therapy, as well as for sponsors to receive advice on how an accelerated approval could be achieved.  If an accelerated approval development plan is pursued, like a Special Protocol Assessment, it would provide a means for sponsors and FDA to come to an agreement, thereby reducing regulatory uncertainty.  

Precision Medicine:  Congress finally provided some detail about precision medicine in the second version of the 21st Century Cures Act (Sec. 2041).  While the second version of the bill provided a definition of precision medicine, the latest version would have FDA define the term.  The revised provision would require FDA to issue a guidance document to assist sponsors in the development of such drugs. 

This provision also allows for applications of a precision medicine that has been designated “for a rare disease for a serious condition” to rely upon data or information previously developed by the sponsor for a prior approved drug or indication in order to expedite clinical development of a precision medicine or indication that is using the same or similar approach as that of the prior approved drug.  In addition, the provision specifies that applications for precision medicines should be considered as to whether they are eligible for accelerated approval.     

Broader Application of Bayesian Statistics and Adaptive Trial Designs:  A provision retained from the first version (Sec. 2061, the first draft’s Sec. 3021), no longer requires the establishment and implementation of a framework through which sponsors could submit to FDA a proposal for the incorporation of adaptive trial designs, Bayesian methods, or alternative statistical methods into proposed clinical protocols and marketing applications.  The requirements for FDA to issue guidance and host a public meeting, however, were retained.

Utilizing Evidence from Clinical Experience:  Yet another provision added in the second draft (Sec. 2062) would require FDA to establish a program to evaluate the potential use of evidence from clinical experience (i.e., data derived from sources other than randomized controlled trials, including observational trials, registries, and therapeutic use) to help support the approval of a new indication for a drug and to help support or satisfy post-approval study requirements.  While it is unclear what the standards for such evidence will be, this provision would result in an expansion of the types of safety and effectiveness data that can support an approval, creating new opportunities for the development of new drugs.  The section would also expand the type of safety and effectiveness data that could be used to satisfy post-approval study requirements. 

Facilitating Responsible Communication of Scientific and Medical Developments:  Completely new in the latest version of the 21^st Century Cures Act is a provision (Sec. 2102) that would have FDA issue draft guidance within 18 months of enactment on “facilitating the dissemination of responsible, truthful, and non-misleading scientific and medical information not included on the label of drugs.”  This provision is consistent with continued pressure on FDA, especially in light of the Caronia decision (see previous coverage here) and the recent Amarin suit, to update its interpretation of the drug promotion regulations to permit drug manufacturers to share truthful and non-misleading information with healthcare professionals that would be considered off-label.

The Orphan Product Extensions Now (OPEN) Act:  The text of the OPEN Act, which was removed in the second draft of the bill, was reinserted in the latest draft (Sec. 2151, the first draft’s Sec. 1261).  This provision would provide an extension of exclusivity periods for a drug approved for a new indication for a rare disease or condition (see our previous post on the OPEN Act here).  This provision is intended to increase the number of rare disease therapies and address many off-label reimbursement problems faced by rare disease patients.

Reauthorizing the Rare Pediatric Disease Priority Review Voucher Program:  Completely new in the latest version of the 21st Century Cures Act is a provision to reauthorize the Rare Pediatric Disease Priority Review Voucher incentive program (Sec. 2152).  With the 1-year sunset clause for this program was triggered with the issuance of the third rare pediatric disease priority review voucher on March 17th (see our previous post here), it is not surprising that Congress would take the opportunity to extend this program.  The reauthorized program would extend through June 30, 2022.  We view this proposal to be better than Representative Butterfield’s “Advancing Hope Act of 2015” since it does not make a potentially counterproductive change to the Tropic Disease Priority Review Voucher program (see our previous post here).

Keeping 21st Century Cures Alive

While NIH, FDA, CMS, and others will have quite of few new programs and functions to implement (if even a fraction of the 70+ current provisions make it through mark-up and into an actual bill), the Energy & Commerce Committee added another provision to the 21st Century Cures Act (Sec. 1141) that would keep this multi-stakeholder, cross-discovery-development-delivery conversation going through a public-private partnership called the “Council for 21st Century Cures.”  The Council would be required to submit an annual report to Congress and would be slated to terminate on September 30, 2023.

After the bill makes it through mark up by the Health Subcommittee, it would likely move up to the full committee by next week for a vote.  The bill will also be referred to multiple House Committees for review for 30 days, as per the standard procedure.  The final bill should come up for a vote on the floor of the full House of Representatives sometime in June.

* Admitted only in Maryland.  Work supervised by the Firm while D.C. application pending.

By James C. Shehan –

Of the three FDA final guidances that FDA recently released (here, here and  here), the Questions and Answers guidance has received the most attention (see our previous post here).   But our perusal of the ScientificConsiderations in Demonstrating Biosimilarity to a Reference Product guidance also revealed a number of changes that will significantly affect how sponsors collect the data needed to support a biosimilar approval.  Below is a review of our choices for the most significant of these changes, first touching on those that seem to make approval easier and then turning to those that potentially make it more difficult.  And at the end, we discuss major changes made to the guidance that do not fit into the category of scientific data needed to support approval – the scarlet letter referred to above.

The first significant change in the guidance relaxes the requirement that a sponsorcompare its proposed biosimilar product directly with U.S.-licensed reference product.  FDA added the qualifier “unless it can be scientifically justified that such a study is not needed,” thereby opening the door to using product sourced from outside the US.  Another possible boon to biosimilar developers appears when FDA discusses approaches to developing evidence of biosimilarity.  FDA reiterates its preference for a step-wise approach but notes that sometimes tests may be conducted “in parallel.” 

Some animal toxicity study requirements are also relaxed.  For example, FDA notes that “if comparative structural and functional data … provide strong support for analytical similarity to a reference product, then limited animal toxicity data may be sufficient to support initial clinical use.”  FDA deleted a sentence recommending additional comparative in vitro testing if animal toxicity studies are not warranted. 

In the clinical studies section, after providing a list of issues that sponsors need to assess in scientifically justifying extrapolation across indications, FDA added that “Differences between conditions of use with respect to the factors described above do not necessarily preclude extrapolation.  A scientific justification should address these differences in the context of the totality of the evidence supporting a demonstration of biosimilarity.”  FDA now also advises sponsors that in choosing which indication to extrapolate form, they should choose one that is adequately sensitive, as opposed to the draft guidance’s “most sensitive” admonition.  And there is a key change to the FDA recommendation on study populations, a shift from recommending similar study populations as “essential” to FDA now advising biosimilar sponsors that “there are cases where a study population could be different from that in the clinical studies that supported the licensure of the reference product.”

As for possible heightened standards, in the structural analyses section, FDA added that formulation changes and product related impurities should be considered when comparing biosimilars to reference products.  When conducting structural analyses, sponsors also are now asked to consider characterizing lots during process development and to conduct analytical similarity assessments when they make changes in the manufacturing process.  In addition, a suggestion that sponsors might use a stand-alone instead of a comparative animal toxicology study was deleted.   

Most of the changes that may make approval more difficult to achieve occur in the clinical studies section.  FDA added a paragraph that notes that it expects a sponsor to conduct comparative human PK and PD studies, a clinical immunogenicity assessment, and “if residual uncertainty about biosimilarity remains after conducting these studies,” a comparative clinical study or studies.  In discussing PK and PD studies, the agency added a recommendation that sponsors use a population, dose, and route of administration that are “adequately sensitive to allow for the detection of differences in PK and PD profiles.”

The requirements for immunogenicity studies also appear to have been beefed up considerably, e.g., new recommendations for use of a comparative parallel design in treatment-naïve patients and evaluation of a subset of patients to assess whether a single cross-over from the reference product to the proposed biosimilar would result in a major risk in terms of hypersensitivity, immunogenicity, or other reactions.  Sponsors are now also asked to consider the impact of antibodies on pharmacokinetics.  FDA even added that certain immunogenicity safety risks may need to be evaluated through postmarketing surveillance or studies.

The section on comparative clinical safety and effectiveness studies was substantially rewritten by FDA.  New headings on endpoints, study population, sample size and duration of study and study design and analyses, have been added.  These changes add a good deal of clarity.

So what are the labeling changes referenced at the beginning of this blog that we deem to be so significant?  It’s the deletion of the draft guidance’s requirements that the labeling of biosimilars indicate that they are biosimilars and also call out whether or not they are interchangeable.  While such designations may not have made a biosimilar feel like Hester Prynne, it does seem that mandating such terms be present may have led to some shunning in the marketplace that is today’s town green.    

By James E. Valentine* –

In late April 2015, FDA’s Bioresearch Monitoring (“BIMO”) Program released its annual report on inspections from the previous fiscal year.  BIMO is FDA’s multi-center compliance program for on-site inspections and data audits to monitor all aspects of FDA-regulated research, domestically and abroad.  The BIMO Program assesses sponsor, investigator, and institutional review board (“IRB”) compliance with FDA regulations governing the conduct of clinical trials.  The program also verifies the accuracy and reliability of clinical trial data submitted to FDA in support of research or marketing applications.  The most common FDA enforcement activity concerning potential violations that FDA has documented during BIMO inspections is the issuance of Warning Letters.  Here are the trends and highlights of BIMO’s activities in 2014.

Domestic Inspections

In FY 2014, there was a modest 8% increase in the total number of BIMO inspections from FY 2013, up from 1,224 to 1,326 inspections.  Table 1 provides a breakdown of the number of inspections conducted by Center.  Both the Center for Biologics Evaluation and Research (“CBER”) and the Center for Drug Evaluation and Research (“CDER”) saw increases of greater than 15% from the previous year; the Center for Food Safety and Applied Nutrition (“CFSAN”) also conducted its first BIMO inspections since reorganizing the program.  Meanwhile, the Center for Devices and Radiological Health (“CDRH”) had a modest decrease in BIMO inspections, and the Center for Veterinary Medicine (“CVM”) has less than half as many inspections.

Table 1. BIMO Inspections by Center: FY 2013 vs. FY 2014

*CFSAN’s BIMO program was under reorganization in FY 2013.

The BIMO program conducts inspections of clinical investigators, IRBs, sponsors, monitors, contract research organizations (“CROs”), Good Laboratory Practices (“GLPs”), and bioequivalence.  In FY 2014, FDA had a marked increase in inspections of clinical investigators, increasing by 139, or about 20%.  This increase is consistent with FDA’s renewed focus on clinical quality and data integrity at clinical trial sites.  There was also an increase in the number of inspections of sponsors, monitors, and CROs.  On the other hand, IRB, GLP, and bioequivalence inspections all decreased from FY 2013.  See Table 2 for a breakdown of the number of inspections by category.

Table 2. BIMO Inspections by Category: FY 2013 vs. FY 2014

Across the board, the most common deficiencies for each category remained nearly the same from FY 2013 to FY 2014.  A list of the most common deficiencies by category can be found in the annual report.  In addition, the proportions of inspections classified as No Action Indicated (“NAI”), Voluntary Action Indicated (“VAI”), or Official Action Indicated (“OAI”) remained similar in FY 2014.  In most inspectional categories, there appeared to be a slight decrease in OAIs and a corresponding increase in VAI and/or NAI classifications.  The exception was GLP inspections, which saw a 23% decrease in NAI classifications, an 18% increase in VAI classifications, and a 5% increase in OAI classifications.

International Inspections

International BIMO inspections, while small in number compared to domestic inspections, also saw a modest increase from FY 2013 to FY 2015.  Table 3 provides a breakdown of the number of international inspections conducted by Center.  CDER and CDRH conducted slightly more inspections in FY 2014, while CBER conducted essentially the same number of inspections.

Table 3. BIMO International Inspections by Center: FY 2013 vs. FY 2014 

Enforcement Actions

In calendar year 2014, FDA issued 12 warning letters citing violations related to the conduct of FDA-related research (violations of 21 C.F.R. Part 312 Subpart D, 21 CFR Part 50, and/or 21 CFR Part 56).  Eight warning letters were sent to clinical investigators, three to sponsors/monitors/CROs, and one to an IRB.  Generally, the cited violations included failure to comply with study protocol requirements, or to keep appropriate records.  Table 4 provides a breakdown of the violations cited in these 12 warning letters, as well as examples of the type of activities cited to justify the violation.

Table 4. Warning Letters Citing Violations Relating to FDA-Regulated Clinical Research: CY 2014

* Admitted only in Maryland. Work supervised by the Firm while D.C. application pending.

By Riëtte van Laack –

The Court of Appeals for the Eleventh Circuit overturned a contempt order against Hi-Tech, Jared Wheat, Stephen Smith, and Dr. Terrill Mark Wright (“Hi-Tech”) because, according to the Court, the order was incorrectly premised on collateral estoppel. 

As we discussed in a previous post, since 2004, Hi-Tech has been involved in a lawsuit by the Federal Trade Commission (FTC) regarding Hi-Tech’s advertising claims for certain weight loss dietary supplements.  Pursuant to a 2008 permanent injunction, Hi-Tech was prohibited from making claims about weight-loss products unless they “possess[] and rel[y] upon competent and reliable scientific evidence that substantiates” the claim.  According to FTC, Hi-Tech continued to promote weight loss products without having the required substantiation.  In 2011, the FTC moved the district court to order Hi-Tech to show cause why they should not be held in contempt for making unsubstantiated claims. 

Hi-Tech submitted evidence and an expert declaration in support of the challenged representations.  However, this evidence did not include randomized placebo controlled double blind studies (RCTs), and the district court refused to consider this evidence.  According to the district court, the doctrine of collateral estoppel applied.  It reasoned that because it previously had determined that nothing but RCTs would be sufficient to support claims, it need not review evidence that fell short of that standard. 

However, the Court of Appeals concluded that this was incorrect; and the district court misapplied the doctrine of collateral estoppel.  The Court explained that  the 2008 permanent injunction order  involved different representations, different products, and the interpretation of a different legal standard.  According to the Court, the level of substantiation required for the representations at issue in the contempt proceedings was not “identical” to any issue the district court decided in the earlier litigation and, thus, collateral estoppel did not apply.  Accordingly, the Court of Appeals vacated the order and remanded for further proceedings.

Although the ruling appears a win for Hi-Tech, the reversal does not mean that Hi-Tech is out of the woods. The reversal is a procedural, not a substantive victory.  The Court of Appeals merely determined that the district court should have considered the evidence of substantiation.  It did not consider or rule on whether the evidence constituted competent and reliable scientific evidence.  In fact, the Court of Appeals specifically stated that, on remand, the district court is “to determine the admissibility of any evidence offered by [the FTC] and by [Hi-Tech] and make findings about whether any evidence of substantiation, if admissible, satisfies the standard of the injunctions for ‘competent and reliable scientific evidence.’”

By Karla L. Palmer - 

Earlier this week, the GAO released the Testimony of Marcia Crosse, Director, Health Care, before the Senate Caucus on International Narcotics Control.  The statement, titled, “Controlled Substances: DEA Needs to Better Manage its Quota Process and Improve Coordination with FDA,” provides a summary of key portions of a relatively scathing and detailed GAO report on the DEA quota process dated February 2, 2015 (but  released on March 4, 2015), and blogged on here.  The statement also provides selected updates concerning steps that DEA and FDA have taken since the issuance of that February  2015 report.  The statement highlighted two significant issues discussed in the report:

(1) DEA’s failure to maintain appropriate staffing and timeliness in administration of the quota process: 

Ms. Crosse emphasized that, notwithstanding yearly quota applications, DEA has not responded to annual bulk manufacturing or procurement quotas within time frames required by regulations for any year from 2001 through 2014.  GAO further found that DEA does not have adequate protocols, policies, training, or internal controls to ensure reliability of data (in DEA’s YERS/QMS system) it uses to track applications and record decisions.  DEA attributed this shortfall to, among other things, inadequate staffing, stating specifically that the Agency has been unable to find qualified candidates who are able to pass the necessary background checks, and, in addition, qualified candidates have declined job offers.  DEA stated, however, that they “ensure consistency in their [quota] decision-making by having the Deputy Assistant Administrator in the Office of Diversion Control review and authorize every quota decision that is made.”  GAO noted that, given the volume of applications in a given year (i.e., 3000 in 2012), it is “unreasonable to assume that one senior manager can devote sufficient time to review these decisions…” DEA’s lack of written guidance also “poses a risk to the continuity” of quota operations should responsible DEA personnel leave or be reassigned. 

Manufacturers cited DEA’s late quota decisions as causing or exacerbating some shortages of their drugs.  GAO stated that, although (since 2012) FDASIA requires DEA to respond to supplemental quota applications within 30 days, DEA responded to only 21 percent of supplemental applications within 30 days, suggesting that this 30-day requirement could “pose a challenge during a drug shortage.”  DEA asserted to GAO that quotas cannot cause shortages because the Agency authorizes quota at the basic class level of a substances (e.g., amphetamine, morphine), and not by specific drug product.  GAO disagreed that actions DEA takes in setting quotas at the class level would have no bearing on the drug products manufactured with such substances.  Specifically, “while the manufacturers are ultimately responsible for what the manufacturer with the quota authorized by DEA, their decisions are made within the confines of the amount and timing of the quota granted by DEA.”  GAO noted that, “because of concerns with the reliability of DEA’s data, among other things, we could not confirm whether DEA’s lack of timeliness in establishing quotas has caused on exacerbated shortages.”  Ms. Crosse’s statement noted that DEA  indicated that it has already taken steps consistent with GAO recommendations in the February 2015 report, but no further information was provided.      

(2) Lack of Coordination of activities between DEA and FDA to prevent and mitigate shortages of drugs containing controlled substances.

The GAO report also cited several barriers that may hinder DEA and FDA from coordinating effectively on quota-related drug shortages.  For example, DEA and FDA’s definitions of a drug shortage differ.  FDA considers supply and demand for the drug, and whether there is enough supply to meet demand by evaluating potentially interchangeable substitutes for the particular drug.  DEA believes there is no shortage as long as there is quota available to manufacture a given controlled substance, regardless of manufacturer, strength or available formulation.  Although GAO notes there has not been a reported shortage of a controlled substance since passage of FDASIA in 2012, that law requires the agencies to coordinate on what exactly is a drug shortage.  GAO states it is unclear whether the two agencies will be able to do so successfully.  It also asserts that another barrier to collaboration is DEA’s lack of compatible policies and procedures should FDA notify DEA of a shortage.  Although FDA established such policies and procedures concerning coordination on shortages in 2014, DEA has not, and does not plan to address this issue.  Notwithstanding, on March 24, 2015, FDA and DEA finalized a Memorandum of Understanding to facilitate sharing of proprietary information between the agencies, which GAO recommended in its February 2015 report.  However, contrary to  its recommendation, GAO noted that the MOU failed to specifically outline what information they will share and the timeframes for sharing information in response to a real or potential shortage. 

By Andrew J. Hull* - 

On April 14, 2015, a federal judge in Iowa imposed a three-month term of imprisonment on two food executives, describing the period of imprisonment as “relatively small.” 

After a major Salmonella outbreak in August 2010 that left thousands of people sickened across the United States, the federal government traced the outbreak to an Iowa-based company, Quality Egg, LLC (“Quality Egg”).  As a result, Quality Eggs voluntarily recalled hundreds of millions of eggs from the market.  In United States v. Quality Egg, LLC, No. C 14-3024, (N.D. Iowa),  the government pressed charges against the company in the Northern District of Iowa (see criminal information here), alleging that the company engaged in 1) bribery of a public official, 2) introduction of misbranded food into interstate commerce with intent to defraud or mislead, and 3) introduction of adulterated food into interstate commerce. 

The government also charged Austin DeCoster, the owner of the company, and his son, Peter DeCoster, the company’s chief operating officer, under the Responsible Corporate Officer Doctrine, also known as the Park Doctrine, for introduction of adulterated food into interstate commerce.  Specifically, the government alleged that the eggs produced and shipped by Quality Egg containing Salmonella were adulterated within the meaning of the Federal Food, Drug & Cosmetic Act (“FDCA”).  Despite the fact that the government acknowledged that they did not have knowledge that the eggs sold by Quality Egg were contaminated, both DeCosters, by virtue of their respective responsibilities as Quality Egg executives, were charged under section 303(a)(1) of the FDCA, a strict liability misdemeanor offense punishable by no more than one year of imprisonment, a $100,000 fine, or both per count. 

Under the Park Doctrine, not only may a company be held strictly liable for the unintentional violations of the FDCA, but this liability also extends to include unassuming corporate officers whose companies engage in unlawful activities under the FDCA.  As such, the government can seek to obtain misdemeanor convictions of a company official for alleged violations of the FDCA – even if the corporate official was unaware of the violation – if the official was in a position of authority to prevent or correct the violation and did not do so.  (For a more in-depth discussion of this doctrine, see some of our past posts here, here, here, and here).

Under the framework of this doctrine, both DeCosters pled guilty to the two FDCA misdemeanor offenses.  (The company also pled guilty to all three counts).  On April 13, 2015, the District Court sentenced father and son to three months of imprisonment.  At the sentencing hearing, the DeCosters argued that a sentence involving imprisonment under a strict liability offense was unconstitutional on due process grounds.  The District Court rejected this argument.  Specifically, the District Court held that imprisonment for a strict liability misdemeanor offense does not violate the Eighth Amendment’s prohibition against cruel and unusual punishment, and it recognized the Supreme Court’s repeated determinations that section 301(a) can be used to impose criminal penalties for violations of the FDCA, even absent proof of intent.  See United States v. Park, 421 U.S. 648 (1975); United States v. Dotterweich, 320 U.S. 277 (1943).

Of particular interest, the District Court noted that the DeCosters:

created a work environment where employees not only felt comfortable disregarding regulations and bribing [Department of Agriculture] officials, but may have even felt pressure to do so.  Because the offending parties were never disciplined for their actions, according to the record, it does appear that their conduct was condoned.

Additionally, in weighing the three-month prison sentence against the public welfare, the District Court found that the defendants knew about the insanitary conditions at Quality Egg.  The District Court also stated:

Given the defendants’ careless oversight and repeated violations of safety standards, there is an increased likelihood that these offenses, or offenses like these, could happen again.  The punishment will also serve to effectively deter against the marketing of unsafe foods and widespread harm to public health by similarly situated corporate officials and other executives in the industry.

There are several significant takeaways from the Quality Egg decision.  First, this case demonstrates what we believe is a possible resurgence of the use of the Park Doctrine by the government (see our past post here).  Indeed, it is one of the few true strict liability cases brought under this doctrine by the government.  Second, both of the executives in Quality Egg were charged with shipping adulterated product that actually contained a harmful substance (i.e., Salmonella).  Third, it is important to highlight that the District Court found the harm to the public significant enough to weigh in favor of sentencing the DeCosters to actual prison time in lieu of merely slapping them with a fine. 

* Admitted only in Virginia.  Work supervised by the Firm while D.C. application pending.

By Ricardo Carvajal & JP Ellison –

Last week, the federal district court judge presiding over industry’s challenge to Vermont’s law requiring GMO labeling issued a complex decision arising out of dueling motions.  The State of Vermont had asked the court to dismiss the plaintiffs’ complaint, arguing that it failed to state a claim on which relief could be granted.  The plaintiffs has asked the court to enjoin the law pending resolution of the case.  The court’s ruling gave no party a complete victory.  The effect of the decision is that it allows some parts of the challenge to proceed (a partial victory for the plaintiffs), but also allows implementation of the law to go forward on the timetable favored by Vermont (a partial victory for the state).  For that reason, advocates of the law were quick to paint the decision as a victory.  However, it is clear that at least some aspects of the law face tough sledding, and it appears somewhat unlikely that the law will survive intact.  Provisions of the law prohibiting “natural” labeling of GMO foods appear particularly vulnerable, but the heart of the law – the GMO disclosure requirement – is not out of the woods. 

Much of the decision focused on the question of what level of scrutiny should be applied in considering whether the GMO disclosure requirement violates the First Amendment.  Although the court concluded that it was appropriate to apply a lower level of scrutiny (referred to as Zauderer scrutiny after the Supreme Court decision by that name), the court acknowledged that reasonable minds may differ – and that the final outcome is by no means certain at this early stage in the proceedings:

Because the State has established that Act 120's GE disclosure requirement is reasonably related to the State's substantial interests, under Zauderer, Act 120's GE disclosure requirement is constitutional. Nonetheless, because the appropriate level of scrutiny is a contested question of law and because the factual record is undeveloped, the court does not dismiss Plaintiffs' First Amendment challenge to Act 120's GE disclosure requirement under Zauderer at this time. [(Emphasis added)]

Regardless of how this key issue is ultimately resolved, there will doubtless be fodder for an appeal on one side or the other, which suggests that an ultimate resolution could be years away.  That uncertain panorama should give pause to other states contemplating following in Vermont’s footsteps.  If not, then the passage of additional measures in additional states will almost certainly usher in federal legislation creating a national, uniform standard for GMO labeling.  Indeed, Vermont’s law standing alone may have a sufficiently profound commercial impact to trigger that outcome. 

In the interim, the science moves on.  In some quarters, focus is turning to gene-editing as a way of developing desired traits without the need for transgenesis (the introduction of external genes). Developers are hoping that the new techniques will be less controversial, but at least some critics view gene editing as just another form of genetic engineering – and presumably one that should be disclosed in the labeling of foods derived from gene-edited plants.  

By Riëtte van Laack –

Continuing its broad application of  the consent decree in the action by the National Resource Defense Council against FDA (see our previous post here), FDA issued a proposal to amend the Tentative Final Monograph for Topical Antimicrobial Drug Products for Over-the-Counter Human Use. At this stage, FDA proposes to amend the 1994 TFM for the over-the counter (OTC) health care antiseptic drug products.  These health care antiseptic products include health care personnel hand washes, health care personnel hand rubs, surgical hand scrubs, surgical hand rubs, and patient preoperative skin preparations.  FDA previously proposed to amend the portion of the 1994 TFM that applies to consumer antiseptics.

Referring to  modern standards for effectiveness and safety, FDA proposes to reclassify all active ingredients that in 1994 were classified as category I (i.e., shown to be safe and effective) or category III (i.e., additional data are needed for safety or effectiveness), as category III for both safety and effectiveness.  In short, FDA has determined that it currently has insufficient data to conclude that any of the health care antimicrobial active ingredients are generally recognized as safe (GRAS) and effective (GRAE) under FDA’s updated standards.  Unless additional data are submitted to support GRAS and GRAE under the updated standards, FDA will declare them non-monograph ingredients in the final monograph.

In contrast to the Agency’s tone in announcing the proposal regarding consumer antiseptics [link to dec. 2013 blog post], FDA this time stresses that health care professionals should continue to use the current products while additional safety and efficacy data are being obtained.  For example, in the press release, FDA states that “[t]he FDA’s request for more safety and effectiveness data for health care antiseptic active ingredients should not be taken to mean the FDA believes that these products are ineffective or unsafe.”

Also in contrast to the consumer antiseptics proposal, the Agency does not propose requiring clinical data to support GRAE status for the health care antiseptic products.  Instead, FDA continues to propose the use of surrogate endpoints (bacterial log reductions) combined with in vitro testing to characterize the antimicrobial activity of the ingredient as evidence of the effectiveness for health care antiseptics.  However, the log reduction standards have been revised to require an instant reduction upon a one-time use/application.  (See table below).  These updated criteria are based on published literature and have been used in review of antiseptics approved under the NDA process.

Table: Clinical Simulation Testing Bacterial Log Reduction Effectiveness Criteria in This Proposed Rule and in the 1994 TFM 

Because this standard is different from what FDA proposed in 1994, the Agency has no evidence that any of the ingredients meet the updated standard. 

As discussed in the proposal regarding consumer antiseptic drug products, several scientific developments that affect the safety evaluation of antimicrobial ingredients have occurred since FDA’s 1994 evaluation of the safety of health care antiseptic active ingredients.  Not surprisingly, FDA does not have data to address some of these concerns.  Among others, FDA now requires data regarding antimicrobial resistance, human safety studies (e.g., maximal use trials), nonclinical safety studies (e.g., developmental and reproductive toxicity studies and carcinogenicity studies), and data to characterize potential hormonal effects.  For each category III health care antiseptic ingredient, FDA discusses what data are available and what data are missing.  For example, for alcohol, only data regarding human pharmacokinetics are incomplete, whereas for benzalkonium chloride, data regarding human and animal pharmacokinetics, dermal carcinogenicity, reproductive toxicity, and hormonal effects, are missing.

Comments are due October 28, 2015.  FDA explains that it provides a longer comments period (i.e., 180 days) because of the complexity of the proposed rule.  In addition, new data or information may be submitted to the docket via regulations.gov until May 1, 2016, and comments on any new data or information may then be submitted for an additional 60 days.  The Agency also states that it will consider requests to defer further rulemaking with respect to a specific active ingredient so that additional new safety or effectiveness data can be submitted.  The Agency does not commit to a date for the final rule, although the consent order sets a date for the publication of the final monograph on triclosan of January 15, 2018.  Because the proposed rule only addresses the GRAE and GRAS status of active ingredients and no other amendments to the TFM, e.g., tests for the final product, finalizing the TFM will involve further amendments. 

By James C. Shehan –

On April 28th, FDA finalized the three biosimilar guidances that it issued in 2012.  Covering the topics of questions and answers regarding BPCIA implementation, scientific considerations in demonstrating biosimilarity, and quality considerations in demonstrating biosimilarity of proteins to reference products, the final guidances make a few significant changes to the drafts but the bulk of the draft guidances remain unchanged.  This posting will discuss the significant changes to the Q&A guidance and later ones will review the other two.  For a review of the draft Q&A guidance, see our post here.

After an introductory section, the questions and answers are grouped into three major categories: Biosimilarity and Interchangeability, What is a “Biological Product” and Exclusivity.  About three-quarters of the questions are related to the first category, Biosimilarity and Interchangeability. 

In that category, the largest changes have been made to the answer regarding use of non-US-licensed versions of reference product to generate biosimilarity data.  The draft guidance required that analytical studies, at least one clinical pharmacokinetic study and at least one pharmacodynamic study (if required), use US-licensed reference product.  The final guidance repeats that general rule but adds a possible exception – “unless it can be scientifically justified that such a study is not needed.” 

This answer in the final guidance also delves heavily into the topic of bridging studies.   FDA states that if non-US data is relied upon, analytical, PK and PD studies should directly compare all three products (biosimilar, US reference product and non-US comparator product).   FDA also added to the final guidance that the analytical studies should include  “degradation profiles under stressed conditions.” 

FDA lists a large number of factors that may affect the amount of bridging data needed:

• higher order structure;
• post-translational modifications (e.g., glycosylation);
• degree of heterogeneity;
• whether the formulations, dosage forms, strengths and routes of administration of the US-licensed reference product and the non-US-licensed comparator products are the same;
• the design of the physicochemical and biological/functional assessments and the use of multiple orthogonal methods with adequate sensitivity to detect differences among the products; and 
• the scientific justification for the selection of the non-US-licensed comparator lots used to establish the scientific bridge and how the selected lots relate to the material used in the nonclinical and clinical studies.  The scientific bridge should include a sufficient number of lots of non-US- licensed comparator product to adequately capture variability in product quality attributes. When possible, the non-U.S.-licensed comparator lots used in the nonclinical or clinical studies should be included in the assessment performed to establish the analytical bridge.

Given this level of complexity, it is unsurprising that in this answer FDA encourages sponsors are encouraged to discuss bridging with FDA during the development process.  It is also unsurprising that, as in its draft guidance, FDA notes that comparisons to non-US product are unlikely to be able to support an interchangeability determination.

FDA also significantly expanded its answer on how to extrapolate clinical data on one indication to support approval in another indication.  Immunogenicity of the biosimilar in different patient populations was added to the list of issues that should be addressed in justifying extrapolation.  In gathering the clinical data that will be extrapolated, sponsors are urged to choose a use that “would be adequately sensitive to detect clinically meaningful differences between the two products.”  And in perhaps the most significant change, FDA recommends that sponsors do not try to extrapolate from indications approved under Subpart E, accelerated approval.  Considering the “potential complications in the event that postmarketing trials fail to verify the clinical benefit of the reference product for the condition of use,” this seems to be a prudent addition to the guidance.

In its answer to the question discussing whether applicants can request licensure for fewer routes of administration than those approved for the reference product, the draft guidance noted that FDA may require studies using a route of administration for which the biosimilar sponsors is not requesting approval.  The final guidance adds that such an FDA request will be made only “in a limited number of circumstances.” 

Four biosimilarity\interchangeability Q&As from the draft guidance are not in the final guidance, but FDA promises to finalize them in the future and add them to the guidance.  These Q&As deal with (1) the need for biosimilars to perform cardiac repolarization and drug-drug interaction studies;
(2) the length of the retention period for samples from PK and PD studies; (3) what constitutes “publicly available information” that a reference product is safe, pure and potent; and (4) how to obtain a determination of interchangeability.  Reinforcing its intent to answer these questions, FDA did not renumber Q&As in the final guidance.  The precise timing of finalization is not provided. A chart in the guidance states that revisions to #s 1 & 2 are “forthcoming,” but does not do so for #s 3 & 4.  This may be a typographical error. 

In the second category, of Q&As, FDA retained its proposed definition of a “protein” as an amino acid polymer of more than 40 amino acids in size. It amended this definition however, by noting that the amino acids do not need to be in a contiguous sequence for a product to be a protein.  FDA slightly changed the wording justifying the basis for its 40 amino acid test, referencing a lack of clear scientific consensus for distinguishing proteins from peptides.  Given the potential consequences of this issue, it would not surprise this author if FDA sees future challenges on this point.

In the last category, Exclusivity, FDA removed a Q&A addressing how a sponsor may request 12 year reference product exclusivity. The afore-mentioned chart promises that a revision of this question is also forthcoming.  A separate draft guidance from 2014, covered in our post here, deals exclusively with biologics exclusivity. 

Additional guidances on interchangeability, biosimilars naming and statistical approaches to proving biosimilarity are expected later this year.

On April 27, 2015 the Drug Information Association journal, Therapeutic Innovation and Regulatory Science, published the findings of a study conducted by HP&M Attorneys Frank J. Sasinowski and James E. Valentine*, along with co-author, Erika B. Panico, RAC, head of U.S. Regulatory Affairs for Chiesi Pharmaceuticals Inc.  This study serves as a follow-up to a March 2012 analysis conducted by Frank J. Sasinowski that reviewed the quantum of effectiveness evidence that is required to secure FDA approval of therapies for rare diseases, or orphan drugs, from the 1983 enactment of the Orphan Drug Act through June 30, 2010.  This current study was designed to determine, over the 4 years since the original study, how frequently FDA has required marketing applications of drugs for rare diseases to provide the conventional level of proof of effectiveness that is ordinarily expected for most drugs for prevalent diseases.

This study employed methods similar to the original analysis, identifying the noncancer orphan drugs approved as new chemical entities by relying on FDA’s publicly available documents for drugs approved by FDA from July 1, 2010, to June 30, 2014. These materials were used to identify the basis for each drug’s approval, and each approval was analyzed and classified.

The results of this study show that for just over two-thirds of all noncancer orphan drugs approved between July 1, 2010, and June 30, 2014, FDA did not require the orphan drug applications to provide the conventional level of proof of effectiveness that is ordinarily expected for drugs for prevalent diseases. This is consistent with the results of the 2012 analysis (see Table below).

Table. Update to Analysis of Orphan Drug Efficacy Evidence 

* January 1, 1983 to June 30, 2010. ** July 1, 2010 to June 30, 2014.

The findings further support that FDA has demonstrated extraordinarily reasonable flexibility in its review of certain applications for orphan drugs and reinforce the need for FDA and drug companies to better understand and discuss the various types of flexibility.

*Admitted only in Maryland. Work supervised by the Firm while D.C. application pending.