Tag: FDA

FDA Issues Final Rules to Implement FSMA Produce Safety, FSVP, and Third-Party Auditor Provisions

FDA has issued its long-awaited final rules to implement the produce safety, foreign supplier verification program (FSVP), and accredited third-party certification provisions under the FDA Food Safety Modernization Act (FSMA).  The rules are scheduled for publication in the Federal Register on November 27, 2015.  The general compliance dates for the Produce Safety rule are in January 2017 for covered activities involving sprouts and in January 2018 for covered activities not involving sprouts.  The general compliance date for the FSVP rule is in May 2017.  FDA must publish the final Model Accreditation Standards guidance and the final user fee rule before the third-party certification program may be implemented.

Below please find links to FDA’s rule overviews and the full text of the rules:

FDA also announced two upcoming webinars; a webinar devoted to significant provisions of the product safety final rule will take place on November 17, 2015, while FDA will address significant provisions of the FSVP and Third Party Auditors final rules on November 23, 2015.

Article By Melvin S. Drozen, Leslie T. Krasny, Evangelia C. Pelonis & Laura D. Venker of Keller and Heckman LLP
© 2015 Keller and Heckman LLP

Health Officials’ Latest Tool in Tool Box – Whole Genome Sequencing

In late October, the Food and Drug Administration (FDA), Centers for Disease Control and Prevention (CDC), along with state and local officials investigated an outbreak of E. coli infections linked to food served at a major fast-casual restaurant chain. Much of the underlying information documenting the outbreak has been derived from an advanced laboratory technique called “whole genome sequencing” (WGS). This is a fairly new instrument in the CDC toolbox. WGS reveals the complete DNA make-up of an organism, thereby enabling health officials to better understand variations both within and between potentially pathogenic species. Such information can then be compared with clinical isolates from sick patients, and, if they match, there may be a reliable link established between the illness and the pathogen. This new technique has the potential to define the scope of a foodborne illness outbreak more quickly and ideally will help to prevent additional cases. Traditionally, this analysis has been done via a process known as pulse-field gel electrophoresis (PFGE). But PFGE has a shortcoming in that it is unable to differentiate between related species of organisms, which can be critical when health officials are trying to delineate the specific source of the outbreak, and want to know whether to recall a product or not.

The FDA cites numerous examples of how it has used WGS: 1

  • To differentiate sources of contamination, even within the same outbreak;

  • To determine which ingredient in a multi-ingredient food harbored the pathogen associated with an illness outbreak;

  • To narrow the search for the source of a contaminated ingredient;

  • As a clue to the possible source of illnesses; and

  • To determine unexpected vectors for food contamination.

The use of techniques such as WGS reflects FDA’s shift toward a broader preventative-centric approach to food safety. This approach can be associated the Food Safety Modernization Act (FSMA), signed into law on January 4, 2011, which requires comprehensive, science-based preventive controls across the food supply.2 FSMA provides the FDA with new enforcement authorities designed to achieve higher rates of compliance with prevention-based and risk-based food safety standards, and to better respond to and contain problems when they do occur. Lastly, the law also gives the FDA important new tools to hold imported foods to the same standards as domestic foods and directs FDA to build an integrated national food safety system in partnership with state and local authorities.

WGS also has been employed in the context of recent illness outbreaks associated with products regulated by the Food Safety and Inspection Service (FSIS), which oversees the safety of meat and poultry. In some circumstances involving FSIS, the regulated industry has found itself on the receiving end of confusing scientific input, as regulatory recommendations based upon PFGE analysis were subsequently negated by WGS data.

A shift to WGS may allow health officials to more quickly and more precisely connect the dots during an outbreak, and use of this tool may also benefit the regulated community. The enhanced precision of WGS may provide the regulated community with a new ability to prevent being falsely labeled as the source of the outbreak. Under the prior testing regime, PFGE tests were often unable to differentiate between related species of organisms, and as a result, regulators were at times forced to cast an overly wide net to capture the source of an outbreak. The new WGS technique provides authorities with a more precise and accurate tool. But, as circumstances with FSIS suggest, companies may also encounter confusion over growing pains associated with the movement from one generation of technology to another. We will continue to monitor the development and use of new tools and techniques the FDA, FSIS, and other federal agencies are using to prevent and respond to food safety issues.

ARTICLE BY Robert G. Hibbert of Morgan, Lewis & Bockius LLP

1 Food and Drug Administration, Examples of How FDA Has Used Whole Genome Sequencing of Foodborne Pathogens For Regulatory Purposes, (last visited Nov. 9, 2015).
2 FDA Food Safety and Modernization Act, Pub. L. No. 111-353, 124 Stat. 3885 (2001). 

FDA’s Proposed Naming Convention for Biologics

On August 27, 2015, the Food and Drug Administration (FDA) released draft guidance on nonproprietary naming of biological products. The agency’s draft guidance proposes that the core nonproprietary name for originator biological products, related biological products, and biosimilar products be appended with a unique, four-letter suffix designated by the FDA in order to distinguish each product and minimize inadvertent substitution of products that are not interchangeable.

A New Naming Convention

The proposed framework for the naming convention includes the nonproprietary name — otherwise known as the proper name — of the originator biological product along with a designated four-letter suffix attached to the core name with a hyphen. Importantly, a related, biosimilar, or interchangeable product will share a core name with the originator biological product, but will also include a distinct four-letter suffix. This convention will indicate a relationship among the products while highlighting the unique identification of each product.

For example, two products sharing the core name of replicamab might have the following nonproprietary names:

  • replicamab-cznm

  • replicamab-hixf

The FDA has not yet decided whether the nonproprietary name for an interchangeable product should also include a unique four-letter suffix or whether it should be assigned the same proper name and suffix as its reference product. The draft guidance notes that the agency is seeking comment on these alternative approaches.

Which Products Are Covered?

The FDA’s proposed naming convention would apply both prospectively and retrospectively to biological products licensed under sections 351(a) and 351(k) of the Public Health Service Act, although the agency is still considering how the convention should apply to interchangeable products. As indicated in the draft guidance, the FDA believes that the designated suffix is warranted for both newly and previously licensed biological products in order to advance a number of goals, including (1) ensuring that patients only receive the biological products intended to be prescribed to them, (2) facilitating manufacturer-specific pharmacovigilance, (3) encouraging the routine use of designated suffixes, and (4) avoiding any inaccurate perceptions of the safety and effectiveness of biological products based on their path to licensure.

Designating a Suffix

Applicants and current license holders may propose their own suffix, which should consist of four lowercase letters devoid of any meaning. Proposed suffixes should not be promotional, include any abbreviations commonly used in clinical practice, contain or suggest the name of any drug substance, or look too similar to the name of a currently marketed product or another product’s suffix designation. The FDA will evaluate a proposed suffix and notify the applicant of its determination. Given the FDA’s previous selection of “sndz” for Sandoz’s Zarxio (filgrastim-sndz), it will be interesting to see the approach and development of these suffixes.

Comments and suggestions on the draft guidance are due by October 27, 2015, at www.regulations.gov. (Docket No. FDA-2013-D-1543).

Relatedly, the FDA issued a proposed rule to be published in the Federal Register on August 28, 2015, that would designate “the official names and the proper names” for six biological products that qualify as either a reference product, a related biological product, or a biosimilar product. As the agency explains, its proposed action with respect to the six products covered by the rule is meant to encourage the routine usage of designated suffixes.

Article By Nathan A. Beaver, David L. Rosen & Anna S. Ross of Foley & Lardner LLP

© 2015 Foley & Lardner LLP

FDA Flunks Mylan’s India Facilities, Finds cGMP Violations

When we open our medicine cabinet, we take for granted that the drugs we find there are safe and properly labeled. Many physicians privately worry, however, about the safety and efficacy of prescription drugs.

About 85% of the prescription drugs sold in the United States are manufactured offshore. Many of those offshore drugs are made by generic companies, foreign contract manufacturing companies and sometimes, offshore facilities owned by the so-called “big pharma” manufacturers themselves. Wherever manufactured, drugs distributed in the United States must meet certain current good manufacturing practices or cGMP standards.

Recently the Food and Drug Administration (FDA) began ramping up inspections of offshore manufacturing facilities and the results are shocking. Although cGMP violations have been found worldwide, experts are particularly worried about drugs made in China and India.

Earlier this month the FDA cited three facilities in Bangalore, India that manufacture drugs for Mylan. Headquartered in the U.K., Mylan is the second largest generic and specialty pharmaceutical company in the world. With approximately 30,000 employees worldwide and revenues of $7.72 billion (USD), Mylan certainly qualifies as big pharma.

The FDA says it inspected three of Mylan’s Indian plants between August of 2014 and February of this year. It found “significant” cGMP violations at all three facilities.

Worse, the FDA says that in all three instances Mylan’s response to the three inspections lacked “sufficient corrective actions.”

cGMP standards are in place throughout the manufacturing process to insure the potency and quality of the finished pharmaceuticals. The FDA wants to insure that there are no contaminants in the finished product as well as insuring the finished product is neither stronger nor weaker than advertised.

As a result of the inspections, the FDA concluded a likelihood that the finished drugs from all three plants were adulterated. Those findings are certainly bad news for consumers. It’s also bad for physicians as well. It’s hard for doctors to get dosages correct or monitor for side effects if a drug has inconsistent potency or the presence of contaminants.

In the case of Mylan’s Bangalore, India facilities, the violations were numerous and included:

  • gloves and sterile gowns for use in aseptic environments had holes and tears

  • personal sanitation violations

  • clean room violations

  • discolored injection vials

  • lots with failed assays or contaminants

At least one of the facilities had similar violations dating back to a 2013 inspection.

Overall, the FDA noted, “These items found at three different sites, together with other deficiencies found by our investigators, raise questions about the ability of your current corporate quality system to achieve overall compliance with CGMP. Furthermore, several violations are recurrent and long-standing.”

The FDA declared that continued noncompliance could result in drugs from these facilities being blocked from importation and distribution within the United States.

Mylan has had previous problems with U.S. regulators. In 2000 Mylan paid a $147 million fine to settle charges that the company raised the price of generic lorazepam by 2,6000% and generic clorazepate by 3,200%. The FTC had charged that the company raised the price of lorazepam, the generic equivalent of the brand name antianxiety medication Ativan, from $7 per bottle to $190. Although Mylan agreed to the payment of the fine, it denied any wrongdoing.

Only the FDA can punish drug companies for cGMP violations but if there is proof of an adulterated product entering the commerce stream, the federal False Claims Act can come into play. That law allows private individuals to file a lawsuit against a wrongdoer and receive a percentage of whatever is recovered by the government. Last year the Justice Department paid $635 million in whistleblower awards under the False Claims Act.

Whistleblowers in cGMP cases have received tens of millions of dollars. Dinesh Thakur, a former Ranbaxy executive, received $48 million for information about adulterated generic drugs.

To qualify for a whistleblower award, one must possess inside, “original source” information about a cGMP violation resulting in an adulterated drug or under / over potency medication being approved for sale by Medicaid, Medicare or Tricare. (Most drugs are approved.)

While we believe that contaminated drugs are relatively rare, industry sources tell us that potency issues are rampant. That means the drugs in your medicine cabinet may have little or no active ingredients.

Article By Brian Mahany of Mahany Law

© Copyright 2015 Mahany Law

Amarin Ruling Solidifies Off-Label Marketing Options but Raises Questions About False Claims Act Enforcement Action

The Southern District of New York recently ruled in Amarin Pharma, Inc. et al. v. Food and Drug Administration, et al. that a drug company may engage in “truthful and non-misleading speech” about off-label uses of an approved drug without the threat of a misbranding action under the Federal Food, Drug, and Cosmetic Act. No. 1:15-cv-03588 (S.D.N.Y., Aug. 7, 2015). This important decision—which arose out of Amarin’s constitutional challenge seeking to make certain statements about unapproved uses of a triglyceride-lowering drug, Vascepa—builds on recent Second Circuit precedent that allows drug makers more regulatory latitude, at minimum in the Second Circuit, to provide truthful and non-misleading scientific information about unapproved uses for their products. However, the ruling also serves as a reminder of potential False Claims Act (FCA) liability associated with off-label marketing of pharmaceuticals and devices.

Amarin filed its complaint against the Food and Drug Administration (FDA) after the company received a Complete Response Letter (CRL) from the FDA in connection with its application for approval of a new indication. The CRL indicated that, while clinical studies revealed that Vascepa reduced triglyceride levels, based on its data review, the FDA advised that additional clinical data would be needed before it could approve the drug for additional uses beyond the original approval for “very” high levels of triglycerides. Despite the fact that Amarin sought to make truthful and non-misleading statements about its product to “sophisticated healthcare professionals,” including the physicians who joined Amarin in the lawsuit, the FDA concluded there was insufficient support for approval of the supplemental application for a new indication and stated that any communications about off-label uses of Vascepa could result in enforcement action.

While the FDA described Amarin’s First Amendment claims as a “frontal assault on the framework for new drug approval that Congress created in 1962,” the court rejected all of the government’s counterarguments. Relying on the Second Circuit’s decision in United States v. Caronia, 703 F.3d 149 (2d Cir. 2012), the court held that Amarin could engage in the following activity:

  • Distribute summaries and reprints of the relevant studies in a manner or format other than that specified by the FDA

  • Articulate, in connection with Vascepa, the off-label claim permissible for use on chemically similar dietary supplements

  • Make proactive truthful statements and engage in a dialogue with doctors regarding the off-label use

While the Amarin decision is welcome news for the industry, drug manufacturers must still take care to analyze promotional statements to ensure that the content can be successfully defended as “truthful” and “non-misleading” speech. As the Amarin court acknowledged, manufacturers not only face potential criminal exposure for “false” or “misleading” misbranding, but the promotion of off-label use can give rise to civil claims under the FCA. FCA enforcement in off-label cases—which proceed on a theory that a company caused false claims to be submitted to government health care programs for non-covered and non-FDA-approved uses—have been a huge source of FCA recoveries in recent years. In FY2014, for example, the Department of Justice (DOJ) recovered over $2.2 billion in FCA actions against pharmaceutical and medical device companies stemming from off-label promotion. Regulatory enforcers and qui tam whistleblowers will not hesitate to allege FCA violations where circumstances, for example, allow the inference that narrowly couched promotional statements may have been “truthful” but still factually incomplete and, thus, misleading. The Amarin decision highlights the fact-specific nature of the risk analysis. Amarin relied on truthful statements about Vascepa’s off-label use that were largely derived from an FDA-approved study and writings from the FDA itself on the subject. Rather than shooting from the marketing “hip,” Amarin appears to have invested in building a defensible factual scientific record and preemptively sought an FDA opinion regarding the off-label use of Vascepa before engaging in those communications.

While it remains unclear whether the FDA will appeal the Amarin decision to the Second Circuit, the agency’s decision to let Caronia stand without further appeal suggests that there may be reluctance on the part of regulators to risk a higher court expanding the reach of the Caronia holding across the country. Pharmaceutical and device manufacturers should still proceed cautiously as the FDA determines how it will respond following the Amarin ruling. For example, the FDA updated its draft guidance regarding the dissemination of scientific and medical journal articles following the Caronia decision in February 2014 and agreed in June 2014 to conduct a “comprehensive review [of its] regulatory regime governing communications about medical products,” with the intent of issuing new guidance by June 2015. As the Amarin court noted, this revised guidance is still forthcoming and may be further revised in light of this decision.

ARTICLE BY T. Reed Stephens & Amandeep S. Sidhu of McDermott Will & Emery

© 2015 McDermott Will & Emery

Scrutiny of Nail Salon Chemicals Raises Mass Tort Risk

Recent reports purport to link certain chemicals used in nail salon products to serious health problems such as cancer, asthma, respiratory disease, and miscarriages.  Though past efforts to impose stricter regulations on these chemicals have been largely unsuccessful, a recent slew of New York Times articles have drawn significant attention to the issue. 126504560 In response, New York Governor Andrew Cuomo issued a number of emergency regulations to protect salon workers, and New York City mayor Bill de Blasio has announced his own efforts to address the issue.  These responses could indicate a willingness on the part of lawmakers to revisit the laws regulating the cosmetics industry.

The Food, Drug, and Cosmetics Act of 1938, bans harmful chemicals from cosmetics.  The law is over 75 years old and, many believe, outdated.  It does not require FDA preapproval before chemicals are marketed, and does not mandate that chemical companies test the effects of the chemicals.  Nor does the law require cosmetic chemical manufacturers to share safety information with the FDA.  Senators Diane Feinstein (D-CA) and Susan Collins (R-ME) recently introduced a bipartisan bill that would expand FDA oversight of cosmetics.  But critics say that the bill does not go far enough because it allows the cosmetic industry to essentially continue regulating itself.  The bill may also preempt states’ ability to implement stricter regulations.

OSHA has identified at least twelve chemicals it says causes serious health problems for salon workers.  Three of these, dibutyl phthalate, formaldehyde, and toluene, which some have dubbed the “toxic trio,” have been purportedly linked to the most serious problems, such as cancer, lung and kidney failure, birth defects, and miscarriages.  These chemicals have been banned in several countries and, in others, require labels indicating the potential consequences of exposure.  No such rules currently exist in the United States.

[S]alon workers can be exposed to levels of chemicals that are legal according to OSHA but are still dangerous . . . .

In response to recent New York Times articles highlighting the working conditions of nail salon employees, Governor Cuomo issued emergency regulations to address the potential health hazards these workers face.  Thenew rules, which require manicurists to wear gloves and masks and mandate ventilation at salons, are expected to become permanent in the coming months.  NYC Mayor Bill de Blasio has also announced steps to address this issue.  In addition, NYC’s Department of Consumer Affairs has been visiting salons to collect and test products.  The Department indicated it would issue subpoenas to the manufacturers of products labeled free of a certain toxin if the product is found to contain that toxin.  The Department has also started a petition directed at the Personal Care Products Council, the cosmetic chemical industry’s main trade group, to urge its members to stop using ingredients linked to certain ailments.  The agency has sent similar letters to the FDA and OSHA.  David Michaels, the labor secretary who heads OSHA, believes OSHA’s standards are outdated and has said that salon workers can be exposed to levels of chemicals that are legal according to OSHA but are still dangerous to the workers.

The increased regulatory and media focus on the health threats facing salon workers suggests the potential for lawsuits arising from cosmetic chemical exposure.   As in other mass or “toxic tort” claims, salon worker lawsuits may involve a large number of defendants, since workers often use a variety of products made by different manufacturers.  In states that impose strict product liability on anyone in a product’s chain of distribution, nail salon lawsuits may implicate not only manufacturers, but also wholesale and retail distributors of chemical products.  As in other “toxic tort” cases, nail salon lawsuits would likely involve competing expert testimony from toxicologists, industrial hygienists, and epidemiologists regarding a numerous issues not that least of which being general and specific causation.

ARTICLE BY Jamie Lynn Lanphear & Yakov P. Wiegmann of Schiff Hardin LLP
© 2015 Schiff Hardin LLP

FDA Issues Draft Guidance on Mandatory Food Recalls Under the Food Safety Modernization Act

The Food and Drug Administration (FDA) recently issued a draft guidance titled, “Questions and Answers Regarding Mandatory Food Recalls.” FDA was given general mandatory food recall authority by the Food Safety Modernization Act (FSMA). The guidance is notable for its brevity, coming in at a total of seven pages including the cover. Although much of the content will be familiar to those with experience in food recalls, the guidance does discuss the procedure for FDA to order a mandatory food recall and the assessment of user fees for those subject to such a recall.

With respect to the procedure, the guidance states after FDA finds that the criteria for a mandatory recall have been met, it must first provide the responsible party with an opportunity to perform a voluntary recall of the food. FDA will provide this opportunity in writing using an expeditious method. If the responsible party does not voluntarily cease distribution and recall the food within the time and manner prescribed by FDA, FDA may order the responsible party to cease distributing the article of food, order the responsible party to give notice to certain other persons to cease distributing the article of food, and give the responsible party an opportunity for an informal hearing. After these steps are completed, FDA may order a recall if it determines that the removal of the food from commerce is necessary. Only the FDA Commissioner has the authority to order a recall.

As to user fees, the guidance observes that the FDA has the authority to collect fees from a responsible party for a domestic facility and an importer who does not comply with a food recall order. The fees would cover time spent by FDA conducting food recall activities, including technical assistance, follow-up effectiveness checks, and public notifications. FDA defines noncompliance to include (1) not initiating a recall as ordered by FDA, (2) not conducting the recall in the manner specified by FDA in the recall order, or (3) not providing FDA with requested information regarding the recall, as ordered by FDA. FDA publishes a Federal Register notice of fees for non-compliance with a Recall Order no later than 60 days before the start of each fiscal year.

Given that most parties will voluntarily recall food when the statutory conditions are satisfied to avoid a public relations disaster and harsh FDA action, it seems unlikely that FDA will have to resort often to the exercise of its mandatory recall authority or assessment of fees. The fact that FDA has this authority, however, helps ensure FDA will not have to exercise it.

A copy of the draft guidance document can be found here.

ARTICLE BY Hae Park-Suk & Lynn C. Tyler, M.S. of Barnes & Thornburg LLP
© 2015 BARNES & THORNBURG LLP

Are Cosmetics Gaining Higher Congressional and FDA Scrutiny?

Currently, FDA regulates cosmetics to ensure they are not adulterated or misbranded, but does not have the authority to order cosmetic recalls or require adverse event reporting.  Senators Dianne Feinstein (D-CA) and Susan Collins (R-ME) seek to change that.

On April 20, 2015, they introduced the Personal Care Products Safety Act (S.1014). The Act, if passed, would modify Chapter VI of the Federal Food, Drug, and Cosmetic Act (FDCA) to strengthen FDA’s oversight of, and regulatory authority over, cosmetic products.

Title I of the Act (“Cosmetic Safety”) gives FDA authority to order cosmetic recalls, as well as require manufacturers to:

  1. Report adverse events,

  2. Label ingredients not appropriate for children,

  3. Post complete label information (including ingredients and product warnings) online, and

  4. Register their facilities with FDA.

In addition to this significant new authority over manufacturers, the Act also requires FDA to work with industry and consumer groups to annually select and review at least 5 ingredients or non-functional constituents.

The first 5 ingredients, if the law is passed, will be:

  1. Diazolidinyl urea

  2. Lead acetate

  3. Methylene glycol/methanediol/formaldehyde

  4. Propyl paraben

  5. Quaternium-15

Title II of the Act (“Fees Related to Cosmetic Safety”) outlines the costs associated with enforcement of the new standards. With an annual implementation cost estimated at $20.6 million, it is to be funded by annual fees from all registered owners or operators of cosmetic facilities engaged in manufacturing or processing in the United States.

The Act has wide industry support, including the Personal Care Products Council (a 600+ member company trade association), large cosmetics manufacturers, and consumer groups.  Since it was introduced, it has gained two co-sponsors, Senators Barbara Boxer (D-CA) and Amy Klobuchar (D-MN).

The Act is consistent with FDA’s current priorities related to cosmetics.  Two of these priorities have been reporting of adverse events (with the majority of issues seen in hair care products), and maintaining a distinct line between over-the-counter drugs and cosmetics, because cosmetics need not currently undergo the additional scrutiny that OTC drugs must.

More information on the Personal Care Products Safety Act can be found in Senator Feinstein’s statement upon its introduction.

ARTICLE BY Michelle Gillette & Katherine Fox of Mintz, Levin, Cohn, Ferris, Glovsky and Popeo, P.C.
©1994-2015 Mintz, Levin, Cohn, Ferris, Glovsky and Popeo, P.C. All Rights Reserved.

FDA Issues Final Guidance on Biosimilars

Shortly after approving the first biosimilar under the abbreviated approval pathway created by the Biologics Price Competition and Innovation Act of 2009 (“BPCIA”), the FDA has recently issued 3 final guidances regarding biosimilars. Biological products, or “biologics,” are pharmaceutical products created from biological sources. Unlike chemically synthesized pharmaceuticals, biologics are isolated from natural sources, and are typically more complex than conventional pharmaceutical drugs.

The BPCIA provides abbreviated pathways for the FDA to approve two types of follow-on biologics: biosimilar and interchangeable biological products. Similar to the 1984 Hatch-Waxman Act’s abbreviated pathway for pharmaceuticals, the BPCIA allows a sponsor to seek approval of a “biosimilar” product under section 351(k) of the Public Health Service Act (“PHS Act”) by relying on certain existing scientific knowledge about the safety, purity, and potency of the reference product. The BPCIA defines “biosimilar” as (1) “highly similar to the reference product notwithstanding minor differences in clinically inactive components” and (2) having “no clinically meaningful differences between the biosimilar product and the reference biological product in terms of the safety, purity, and potency of the product.” To meet the higher standard of “interchangeability,” the application must further show (1) the biosimilar is expected to produce the same clinical result as the reference product and (2) a patient can switch back and forth between the biosimilar and the reference product with no adverse effects.

The BPCIA provides abbreviated pathways for the FDA to approve two types of follow-on biologics

The FDA has been slow to accept and approve biosimilar applications, which has left open questions about how to establish biosimilarity and interchangeability under the statutory definitions. On April 28, 2015, the FDA finalized three draft guidances originally published in 2012:

  • Biosimilars: Questions and Answers Regarding Implementation of the Biologics Price Competition and Innovation Act of 2009

  • Scientific Considerations in Demonstrating Biosimilarity to a Reference Product

  • Quality Considerations in Demonstrating Biosimilarity of a Therapeutic Protein Product to a Reference Product

The new guidances provide insight into the FDA requirements for establishing biosimilarity.

Biosimilars: Questions and Answers Regarding Implementation of the Biologics Price Competition and Innovation Act of 2009

This final guidance addresses three categories of commonly asked questions regarding FDA implementation of the BPCIA: (1) biosimilarity or interchangeability; (2) definitions relevant to the BPCIA; and (3) exclusivity. With regard to biosimilarity or interchangeability, the guidance states that a proposed biosimilar may have a different formulation, delivery device, or container closure than the reference product under certain circumstances. Additionally, the guidance discloses conditions permitting an applicant to obtain licensure for fewer than all routes of administration, presentations, and conditions of use for which the reference product is licensed. Further, the guidance describes conditions in which a sponsor may support biosimilarity using comparative data with a non-U.S.-licensed product or extrapolated clinical data designed to support a different condition of use. The guidance additionally instructs applicants how to describe the “strength” of a proposed injectable biosimilar. Finally, the guidance states that a biosimilar product that cites a reference product subject to the Pediatric Research Equity Act must include a pediatric assessment unless the applicant initially seeks approval as an interchangeable biological product.

With regard to the BPCIA’s definition of “biological product,” the guidance discloses the FDA’s regulatory definitions of “protein” and “chemically synthesized polypeptide.” Additionally, it defines when a proposed biological product is considered to be within the same “product class” as previously approved protein products.

With regard to exclusivity, the guidance instructs applicants and sponsor to search an online database to identify whether the reference product is subject to unexpired orphan exclusivity. The FDA will not approve a biosimilar during the 7-year exclusivity period.

Scientific Considerations in Demonstrating Biosimilarity to a Reference Product
This final guidance provides an overview of the FDA’s recommendations for establishing biosimilarity and discusses in detail relevant scientific principles for designing data and information to show biosimilarity. The FDA stresses that it will apply a totality-of-the-evidence approach in its assessment of biosimilarity and will use a risk-based approach to evaluate all data and information submitted. The FDA further emphasizes that the information sufficient to demonstrate biosimilarity will be determined on a product-specific basis.

The BPCIA requires an application to include analytical, animal, and clinical studies demonstrating that the biological product is “biosimilar” to a single reference product. As discussed above, the application must establish the product is “highly similar” to the reference product and has “no clinically meaningful differences.” Although the reference product must be U.S.-licensed, the application may rely on data from comparative studies with a non-U.S. licensed comparator product if the data is scientifically relevant. Because the FDA has discretion to determine what data is required to establish biosimilarity in a particular application, it encourages sponsors of the application to meet with the FDA early during product development to discuss adequate scientific justifications.

The FDA encourages sponsors to use a three step approach to develop evidence necessary to establish biosimilarity.

First, the sponsor should characterize the structural and functional aspects of both the proposed product and the reference product to identify potentially clinically relevant safety or efficacy risks. Structural analyses must use “state-of-the-art technology” to analyze multiple representative lots and show the proposed product will encode the same primary amino acid sequence as the reference product. Any minor modifications must be explained by the sponsor. The structural analyses for all relevant characteristics of the protein product (such as primary, secondary, tertiary, and quaternary structure; posttranslational modifications; and biological activities) must also be included. The FDA further recommends structural analysis of the finished dosage form to assess the effect of excipients or any other formulation effects. In vitro and/or in vivo functional assays must also be used to evaluate the pharmacologic activity of protein products.

Second, the sponsor should demonstrate safety and biosimilarity through animal studies. These studies generally do not establish safety, but are relevant to support the demonstration of biosimilarity through evidence of PK and PD measures. Nevertheless, animal toxicity and immunogenicity studies may be useful where uncertainty about safety remains after the initial structural and functional characterization.

Third, the sponsor should conduct comparative human PK and PD studies and a clinical immunogenicity assessment of the two products in an appropriate study population. The sponsor should discuss study proposals and overall clinical development plan with the FDA before initiating such studies. A sponsor should provide adequate scientific justification for choices in study design, population, endpoints, and other parameters. Human PK and PD measures comparing the proposed product to the reference product are typically fundamental to demonstrate biosimilarity. Even where relevant PD measures are not available, sensitive PD endpoints may be assessed. The FDA further expects at least one comparative clinical study regarding immunogenicity in order to assess the safety and effectiveness of the proposed product. The overall immunogenicity assessment should consider the nature of the immune response, the clinical relevance and severity of consequences, the incidence of immune responses, and the population being studied. Generally, the FDA expects studies to present statistical evidence that the proposed product is neither significantly inferior nor superior to the reference product. An applicant may provide sufficient scientific justification to extrapolate clinical data to support a determination of biosimilarity for various indications.

If there is uncertainty at each step, the sponsor should evaluate the uncertainty and consult with the FDA to adequately address it.

Quality Considerations in Demonstrating Biosimilarity of a Therapeutic Protein Product to a Reference Product

This guideline relates to the biosimilarity of therapeutic protein products and describes nine factors that are relevant in developing analytical studies to show a proposed product is “highly similar” to a reference product.

1. Expression System. The application should seek to minimize differences between the proposed and referenced expression systems. The FDA expects the expression construct for a proposed product encodes the same primary amino acid sequence as its reference product. However, minor modifications (such as N- or C- terminal truncations) that are not expected to change the product performance may be justified.

2. Manufacturing Process. The application should demonstrate its manufacturing process does not result in significant differences between the proposed product and its reference product.

3. Assessment of Physiochemical Properties. Physicochemical assessments are designed to maximize the potential for detecting differences between the proposed and reference products. The sponsor should consider all relevant characteristics of the protein product and design tests to account for the heterogeneity of the proposed product and the reference product as well as the ranges of variability for each.

4. Functional Activities. Functional assays are designed to complement physicochemical analyses and evaluate the function of the protein product. Sponsors should perform appropriate assays to evaluate the range of relevant functional activities for a product.

5. Receptor Binding and Immunochemical Properties. Sponsors should analyze specific binding or immunochemical properties when they are part of the activity attributed to the protein product.

6. Impurities. Sponsors should characterize, identify, and quantify impurities in the proposed product and reference product. Sponsors should further perform a risk-based assessment regarding any differences in process-related impurities between the proposed and reference products.

7. Reference Product and Reference Standards. Sponsors should provide a broad comparison of the proposed product to the reference product that is not strictly limited to analysis of each product in isolation. For example, the biosimilarity analysis may further consider applicable reference standards and relevant publicly available information.

8. Finished Drug Product. Product characterization studies should be performed on the most downstream intermediate best suited for each analytical procedure. Thus, sponsors should analyze the finished drug product if it is best suited for a particular analysis. If the analysis is performed on an earlier intermediate, sponsors should provide additional information. Additionally, sponsors should clearly identify excipients used in the proposed product that differ from those in the reference product.

9. Stability. Sponsors should include comparative studies conducted under multiple stress conditions to establish degradation profiles of the proposed and reference product.

Conclusion

The recently issued final guidances provide insight into how the FDA will evaluate biosimilarity and directions for sponsors throughout product development. However, many additional questions surrounding the BPCIA remain. For example, the currently issued guidances do not address how the FDA will determine “interchangeability.” Interchangeable drugs are likely to be more profitable than mere biosimilars because they can be sold in place of the reference drug without a prescribing doctor’s approval.

Upcoming draft guidances plan to provide additional information regarding the required scientific requirements for establishing biosimilarity and interchangeability as well as naming and labeling requirements for approved biosimilars. In January, the FDA’s Center for Drug Evaluation and Research (CDER) announced plans to publish five draft guidances on biosimilars in 2015:

  • Biosimilars: Additional Questions and Answers Regarding Implementation of the Biologics Price Competition and Innovation Act of 2009

  • Considerations in Demonstrating Interchangeability to a Reference Product

  • Labeling for Biosimilar Biological Products

  • Nonproprietary Naming for Biological Products

  • Statistical Approaches to Evaluation of Analytical Similarity Data to Support a Demonstration of Biosimilarity

ARTICLE BY Imron T. Aly, Sailesh K. Patel, John K. Hsu and Helen H. Ji of  Schiff Hardin LLP
© 2015 Schiff Hardin LLP

FDA Finalizes Guidance Documents on Biosimilarity

On Tuesday, and over three years after the initial guidance documents were released, the US Food and Drug Administration released final versions of three guidance documents discussing how FDA will evaluate applications for regulatory approval of biosimilar products:

•Scientific Considerations in Demonstrating Biosimilarity to a Reference Product

•Quality Considerations in Demonstrating Biosimilarity of a Therapeutic Protein

•Questions and Answers Regarding Implementation of the Biologics Price Competition and Innovation Act of 2009

Draft versions of the guidance documents were originally released by FDA for public comment in February 2012. In general, the final versions released Tuesday track the draft versions fairly closely, with a few noteworthy differences.

The guidance documents reiterate that the FDA will use a totality of the evidence approach to review applications for biosimilar products, and encourages a stepwise approach to demonstrating biosimilarity which with rare exceptions will include a comparison of the proposed biosimilar product with the reference product in terms of structure, function, animal toxicity, human pharmacokinetics (PK) and pharmacodynamics (PD), clinical immunogenicity, and clinical safety and effectiveness. This stepwise approach is intended to better address residual uncertainty about biosimilarity that might remain at each step of the approval process.

The final guidance documents contain a few changes from the draft versions that are noteworthy:

•Most of the discussion of issues related to demonstrating the heightened standard for interchangeability was removed from the guidances with a note that it will be the subject of a separate guidance document that is forthcoming.

•The final guidances reiterate that, in most instances, a sponsor will need to provide information to demonstrate biosimilarity based on data directly comparing the proposed biosimilar product to FDA-approved reference product. However, they elaborate on the type of bridging data needed when a biosimilar applicant seeks to use a non-US licensed comparator product to support a demonstration of biosimilarity.

•Specific comments have been provided for biosimilar developers considering manufacturing/process changes after completing the initial analytical similarity assessment including a requirement to demonstrate comparability between the pre- and post-change proposed product.

•More detailed comments regarding animal toxicity studies were added.

•Previous Q and As relating to what constitutes the “publicly-available information” that should be included in a 351(k) application and whether an applicant can include a request for reference product exclusivity in its 351(a) application were deleted – an indication that the FDA is still considering its position on these points.

Authored by: Paul A. Calvo, Ph.D. and Timothy J. Shea, Jr., PhD. by Sterne Kessler

© 2015 Sterne Kessler