In a recently published white paper (registration required), Steven Richter, a former FDA official and President and Chief Scientific Officer of Microtest Labs, discusses the regulatory challenges facing combination products.  The market for combination products is growing such that it is estimated to reach approximately $9.5 billion in 2009, up from $5.9 billion in 2004, according to one analyst.  Another survey estimates that 30% of new products in development are combination products.  This increased interest is due in part to the unique therapeutic benefits of combining drugs and medical devices, which can, for example, deliver drug to specific areas of the body. 

FDA decides which center governs a combination product based on its primary mode of action (PMOA).  A product that has a pharmaceutical PMOA will be governed by the Center for Drug Evaluation and Research (CDER).  Likewise, a product with a device PMOA will be governed by the Center for Devices and Radiological Health (CDRH).  Different quality regulations, however, apply to each product:  good manufacturing practices (GMPs) (21 C.F.R. Parts 210, 211) apply to drugs, biologic product standards (21 C.F.R. Part 610) apply to biologics, and quality system regulations (QSR’s) (21 C.F.R. Part 820) apply to devices.  Richter maintains, however, that a combination product manufacturer’s “main regulatory foundation must be the drug GMP’s” and that the GMP system must “address[] some of the issues with the device QSR’s.”

Richter predicts that, as FDA continues to shift its regulatory focus from product to process, the largest challenge for combination product manufacturers will be “during the scale-up process.”  This is in part because “additional quality control (QC) measures are required to determine process scale-up parameter shift.”  Richter also expects FDA to issue guidelines specific to combination products that incorporate Process Analytical Technology (PAT) initiatives and design of experiments (DOE) requirements “regarding both small molecule and large molecule process design and scale-up.”  Moreover, Richter believes FDA will “increase[] cGMP regulatory action that affects both laboratory and manufacturing” as a result of its guidelines. 

By:  Carrie S. Martin

Earlier this month, the Supreme Court issued its unanimous decision in Long Island Care At Home, Ltd. v. Coke, a case concerning compensation for in-home caregivers and the Department of Labor’s (“DOL’s”) interpretation of the Fair Labor Standards Act (“FLSA”).  The Court’s decision, although anticipated, clarifies when an administrative agency’s “gap-filling” authority may be upheld as a permissible interpretation of the law.  FDA, like many federal agencies, frequently uses this authority to promulgate regulations.

Evelyn Coke, a 73-year-old home healthcare attendant, sued her employer, Long Island Care at Home, Ltd., alleging that the company did not pay her the minimum wage or overtime compensation.  The FLSA generally requires employers to pay the minimum wage and overtime, but has an exemption for “companionship services.” The DOL’s regulations (labeled as an “interpretation”) implementing the FLSA provide that the exemption applies to home health aides and similar employees who are “employed by an . . . an agency other than the family or household using the services” (i.e., third parties).  29 C.F.R. § 552.109(a).  The DOL’s “General Regulations” at 29 C.F.R. § 552.3, however, define the statutory term “domestic service employment” as “services of a household nature performed by an employee in or about a private home . . . of the person by or for whom he or she is employed.” 

The Supreme Court agreed to hear the case after the U.S. Court of Appeals for the Second Circuit overturned the DOL’s “interpretation” regulations.  (There, the court concluded that the regulations conflicted with congressional intent.)  The questions presented to the Supreme Court were:

1.         Whether the Second Circuit erred in refusing to give deference under Chevron, U.S.A., Inc. v. Natural Res. Def Council, Inc., 467 U.S. 837 (1984), to a thirty-year old [DOL] regulation –a regulation that has twice been upheld by the Tenth Circuit– on the ground that, even though it was promulgated under express grants of legislative authority and after full notice-and-comment rulemaking, the regulation was contained in a subpart headed “Interpretations.”

2.         Whether, in holding that a longstanding [DOL] regulation was not persuasive and thus undeserving of any deference under Skidmore v. Swift & Co., 323 U.S. 134 (1944), the Second Circuit erred by failing to address the governing provisions of the [FLSA] and by declining to give any weight to [DOL’s] interpretation of its own regulations.

Ms. Coke argued that “a thorough examination of the [third-party] regulation’s content, its method of promulgation, and its context reveals serious legal problems. . . .  In particular, . . . that the regulation falls outside the scope of Congress’ delegation; that it is inconsistent with another, legally governing regulation; that it is an ‘interpretive’ regulation not warranting judicial deference; and that it was improperly promulgated.”

In the Court’s decision (written by Justice Stephen Breyer) holding the regulation (i.e., 29 C.F.R. § 552.109(a)) valid and binding, the Court summed up the case as follows:

[T]he ultimate question is whether Congress would have intended, and expected, courts to treat an agency’s rule, regulation, application of a statute, or other agency action as within, or outside, its delegation to the agency of “gap-filling” authority. Where an agency rule sets forth important individual rights and duties, where the agency focuses fully and directly upon the issue, where the agency uses full notice-and-comment procedures to promulgate a rule, where the resulting rule falls within the statutory grant of authority, and where the rule itself is reasonable, then a court ordinarily assumes that Congress intended it to defer to the agency’s determination. . . .  The three contrary considerations to which the Court of Appeals points are insufficient, in our view, to overcome the other factors we have mentioned, all of which suggest that courts should defer to the [DOL’s] rule. And that, in our view, is what the law requires.

Although this decision is important to those (i.e., employers, states, municipalities, and insurers) in the home-care industry, the decision also has significant implications for all regulated industries, and in particular, FDA-regulated industries, as it signals, among other things, greater judicial deference to agencies’ interpretations of their own regulations.

RELATED READING:

• SCOTUSblog post
• LawMemo post with case history and documents

On June 20, 2007, the United States Court of Appeals for the Eighth Circuit issued a decision in Washington University vs. Catalona affirming the District Court for the Eastern District of Missouri’s holding that neither the medical researcher nor the contributing patients have any ownership or proprietary interest in biological tissue samples collected for research.  Rather, Washington University — the institution to whom patients consented to donate their tissue samples — retained ownership.

Pharmaceutical and biotech companies routinely use banked biological tissue specimens for product development and other purposes.  This court case involves a hotly-contested dispute among a leading medical research institution, Washington University, a well-established prostate cancer researcher and former employee of the University, Dr. William Catalona, and his patients.  At issue was who owns biological tissue specimens, such as prostate, blood, and DNA samples, collected by Dr. Catalona (and other medical researchers) from study subjects and patients for use in prostate cancer research.  The specimens at issue comprise a very large and valuable biorepository.  The repository includes more than 4,000 prostate tissue samples and more than 100,000 blood samples.  The Court of Appeals upheld the District Court’s holding in favor of the University – that research participants retained no ownership in the biological specimens they contributed to the University’s repository. 

The Court of Appeals narrowly framed the question presented, and limited its holding to the facts of this case.  The Court held that individuals who make a voluntary and informed decision to contribute their biological tissues to a particular institution for medical research do not retain an ownership interest that would allow them to direct or authorize that the specimens be transferred to a third party.

This holding is not new, and is consistent with what little legal precedent is available.  Still, this case appears to be the first to address the ownership of biological specimens themselves, as opposed to some improvement or attempt at commercialization (e.g., a cell line or patented gene).  The decision underscores the importance of having clear documentation of the intent of study subjects to contribute their tissues.  It remains to be seen whether Dr. Catalona and his patients will petition the Eighth Circuit for rehearing or petition the United States Supreme Court for certiorari.

By:  Anne Marie Murphy

Our “blogfather” over at the Orange Book Blog already has a preliminary post up about the recent victory in the district court by Bristol-Myers Squibb and Sanofi-Aventis over Apotex relating to the enforceability and validity of the patent on the active ingredient in Plavix.  Long story short:  The patent is valid and Apotex is enjoined from further infringing the patent.

Aaron Barkoff, the blogmaster at OBB, always does a nice job summarizing the patent cases for those of us with liberal arts degrees whose eyes glaze over at the intricacies of patent law.  We look forward to his forthcoming detailed post on the topic.

In chemistry, enantiomers are stereoisomers that are non-superimposable complete mirror images of one another.  Enantiomers may be either “right-handed” (dextro-rotary) S(+)-isomers, or “left-handed” (levo-rotary) R(-)-isomers.  A racemic mixture is one that has equal amounts of “left- and right-handed” enantiomers of a particular chiral molecule.  For example, omeprazole (PRILOSEC) is a racemic mixture; esomeprazole, the “right-handed” enantiomer of the racemate, is approved under the brand name NEXIUM.

FDA has for decades treated single enantiomers of approved racemates as previously approved active moieties not eligible for 5-year new chemical entity exclusivity (but rather 3-year exclusivity).  In the preamble to FDA’s July 1989 proposed regulations implementing the Hatch-Waxman Act, the Agency stated this position:

FDA will consider whether a drug contains a previously approved active moiety on a case-by-case basis.  FDA notes that a single enantiomer of a previously approved racemate contains a previously approved active moiety and is therefore not considered a new chemical entity.

The Senate-passed version of the FDA Revitalization Act (“FDARA”), however, would provide sponsors the opportunity to elect 5-year exclusivity under certain circumstances.  The FDARA provision would also apparently put to bed a 1997 FDA notice in which the Agency requested comment on whether granting a 5-year period of exclusivity to enantiomers of previously approved racemates would encourage medically significant innovation.

Specifically, FDARA § 264 would amend the FDC Act to add § 505(t) –“Certain Drugs Containing Single Enantiomers”– to provide that:

if an application is submitted under [§ 505(b)] for a non-racemic drug containing as an active ingredient a single enantiomer that is contained in a racemic drug approved in another application under [§ 505(b)], the applicant may, in the application for such non-racemic drug, elect to have the single enantiomer not be considered the same active ingredient as that contained in the approved racemic drug . . . .

Thus, if a single enantiomer is not considered to be the same active ingredient as that contained in the approved racemic drug, FDA may consider it to be a new chemical entity eligible for 5-year exclusivity.  There are, however, several provisos . . . .

The election of 5-year exclusivity can only be made if:

(A)(i) the single enantiomer has not been previously approved except in the approved racemic drug; and (ii) the application submitted under [§ 505(b)] for such non-racemic drug –

(I) includes full reports of new clinical investigations (other than bioavailability studies) – (aa) necessary for the approval of the application under subsections (c) and (d); and (bb) conducted or sponsored by the applicant; and

(II) does not rely on any investigations that are part of an application submitted under [§ 505(b)] for approval of the approved racemic drug; and

(B) the application submitted under [§ 505(b)] for such non-racemic drug is not submitted for approval of a condition of use— (i) in a therapeutic category [(as identified in the list referenced at 42 U.S.C. § 1860D-4(b)(3)(C)(ii))] in which the approved racemic drug has been approved; or (ii) for which any other enantiomer of the racemic drug has been approved.

In addition to these requirements, which essentially necessitate the submission of a “full” 505(b)(1) NDA, FDARA § 264 also includes two significant limitations that may offset the incentive for electing 5-year exclusivity. 

First, FDA may not approve a single enantiomer of a previously approved racemate granted 5-year exclusivity for any condition of use in the therapeutic category in which the racemic drug has been approved “[u]ntil the date that is 10 years after the date of approval of a non-racemic drug described in [proposed FDC Act § 505(t)(1)].” 

Second, “the labeling of a non-racemic drug described in [proposed FDC Act § 505(t)(1)] and with respect to which the applicant has made the election provided for by such paragraph shall include a statement that the non-racemic drug is not approved, and has not been shown to be safe and effective, for any condition of use of the racemic drug.”

Whether FDARA § 264 (if enacted) will encourage the development of single enantiomers for new therapeutic uses remains to be seen.  Perhaps for this reason, FDARA § 264 is a trial balloon that Congress would need to reauthorize after it sunsets in 2012 (and once Congress evaluates its costs and benefits).

RELATED READING:

• FDA policy document on stereoisomeric drugs

The Supreme Court once famously characterized the risk-benefit analysis for approving new drugs as follows: “[A] drug is effective if it fulfills, by objective indices, its sponsor’s claims of prolonged life, improved physical condition, or reduced pain. . . .  [A] drug is unsafe . . . if its potential for inflicting death or physical injury is not offset by the possibility of therapeutic benefit.”  For the latter half of the 20th Century and the beginning of the 21st Century, attention was primarily focused on the drug efficacy component of this equation.  Beginning with the withdrawal of VIOXX (rofecoxib) from the market in 2004, and most recently, safety concerns raised about AVANDIA (rosiglitazone), however, there has been a seismic shift in FDA’s and Congress’ focus on drug safety and risk management.   

FDA recently announced plans to create a new Risk Communication Advisory Committee.  The committee will be designed to:

provide advice to the Commissioner or designee on strategies and programs designed to communicate with the public about both the risks and benefits of [FDA]-regulated products so as to facilitate optimal use of these products.  The committee also reviews and evaluates research relevant to such communication to the public by both FDA and other entities.  It also facilitates interactively sharing risk and benefit information with the public to enable people to make informed independent judgments about use of FDA-regulated products.

FDA also issued a Federal Register notice requesting nominations for membership on the committee.  FDA hopes that the committee will, among other things, “help FDA better understand the communication needs and priorities of the general public.”  Only time will tell, of course, if the creation of such a committee will have any long-lasting effect on minimizing drug product risk. 

The Agency for Healthcare Research and Quality (“AHRQ”) also recently published a report, titled “Registries for Evaluating Patient Outcomes: A User’s Guide.”  A summary of the report is available here.  The document is “a handbook that [serves] as a reference for establishing, maintaining, and evaluating the success of registries created to collect data about patient outcomes.”  FDA defines a patient registry as:

an organized system for the collection, storage, retrieval, analysis, and dissemination of information on individual persons exposed to a specific medical intervention who have either a particular disease, a condition (e.g., a risk factor) that predisposes [them] to the occurrence of a health-related event, or prior exposure to substances (or circumstances) known or suspected to cause adverse health effects.

Registries are an important risk minimization tool, and are highlighted in FDA’s risk minimization plan announced in March 2005.  There, FDA commented that “[t]hrough the creation of registries, a sponsor can evaluate safety signals identified from spontaneous case reports, literature reports, or other sources, and evaluate factors that affect the risk of adverse outcomes, such as dose, timing of exposure, or patient characteristics.”  Given the focus on the development of Risk Evaluation and Mitigation Strategies (so-called “REMS”) in the Senate-passed version of the FDA Revitalization Act, and if such legislation is enacted, the use of patient registries will likely increase.  As such, the AHRQ handbook could be a very valuable tool for industry.

RELATED READING:

• FDA, Guidance for Industry: Establishing Pregnancy Exposure Registries
• FDA Presentation on Patient Registries

In a previous post, we reported on an assessment conducted by the Analysis Group, Inc. on the effects of authorized generics on paragraph IV patent certifications.  There, the authors concluded that “[t]here is no evidence to suggest that authorized generic entry causes delayed generic entry.” 

In a new study published in the May/June 2007 issue of Health Affairs, most of the same authors also conclude (not surprisingly) that authorized generics tend to enhance competition and work to the benefit of consumers.  According to the authors:

Although reliable long-run data are not yet available, we posit that authorized generic entry will disproportionately deter what otherwise would be unsuccessful paragraph IV certifications.  Even when a successful certification is deterred, generic entry is delayed by anticipated authorized generic entry only if all timely and successful certifications for a drug are deterred. In the absence of extensive data on paragraph IV filings, [there are] reasons why, in our judgment, anticipated authorized generic entry is unlikely to delay independent generic entry for most drugs and why any impact on consumer prices from delayed entry is likely to be small.

We also find that should anticipated authorized generic entry reduce the long-run number of generic entrants for a drug, it still might have little effect on long-run generic prices and shares. Our analysis of recent data demonstrates that additional generic entrants after the first four or five do not appear to significantly affect long-run generic-to-brand price ratios. Furthermore, although our analysis is preliminary, we find that 180-day exclusivity does not appear to lower long-run generic-to-brand price ratios or increase long-run generic penetration. Hence, any effect of authorized generics on the incentives created by 180-day exclusivity is unlikely to greatly affect consumers through delayed generic entry or higher long-run generic prices.

Although there is pending legislation in the U.S. Senate and House that would, if enacted, prohibit the marketing of authorized generics during a generic applicant’s 180-day exclusivity period, Congress has not yet included (and may not include) any such legislation as part of its omnibus FDA reform and user fee bill, the FDA Revitalization Act.  Instead, Congress may wait to see if there is a need for such legislation based on the results of a study of the use, and likely short- and long-term competitive effects, of authorized generics proposed by the Federal Trade Commission in March 2006. 

There is a wise political maxim, “Fool me once, shame on you; fool me twice, shame on me.”  Not to be fooled a second time, the U.S. Senate has passed legislation that would, if enacted, make significant changes in the way FDA handles so-called “generic blocking” citizen petitions.  The measure is part of the FDA Revitalization Act (“FDARA”) passed by the U.S. Senate in May 2007.

Fool me once . . . .

In November 1999, FDA issued a proposed rule to revise the Agency’s citizen petition regulations at 21 C.F.R. § 10.30.  At that time, FDA stated that “[q]uestions have [] arisen whether a citizen petition can be used for improper purposes, such as delaying competition . . . or delaying agency action,” and noted that there was a citizen petition backlog.  As such, FDA proposed several options intended to reduce the backlog, to facilitate and improve FDA interactions with petitioners, and to avoid frivolous petitions, including limiting petitions to “request that the agency: (1) Issue, amend, or revoke a regulation; (2) amend or revoke an order that the agency has issued or published; or (3) take an action as specifically authorized by another FDA regulation.”

In April 2003, FDA withdrew the proposed rule.  In taking this action, FDA stated:

As we evaluated the comments [submitted in response to the proposed rule, such as the Federal Trade Commission’s [http://www.ftc.gov/be/v000005.pdf]], we continued efforts to improve our handling of citizen petitions.  These efforts have led to a marked increase in the number of citizen petition responses, and our current annual response rate is equal to, and sometimes even exceeds, the number of citizen petitions that we receive.  Given this progress, we believe that a revision of the citizen petition regulations is not warranted at this time. 

FDA’s withdrawal notice, however, did not address the lingering concern raised in the proposed rule about “generic blocking” petitions.  Indeed, a few years later, in 2005, FDA continued to express concern:

The citizen petition process is in some cases being abused.  Sometimes, stakeholders try to use this mechanism to unnecessarily delay approval of a competitor’s products. … [we’ve] already seen several examples of citizen petitions that appear designed not to raise timely concerns with respect to the legality or scientific soundness of approving a drug application, but rather to delay approval by compelling the agency to take the time consider arguments raised in the petition, whatever their merits, and regardless of whether the petitioner could have made those very arguments months and months before.

Fool me twice? . . .  Not a Chance . . .

Recognizing that an overhaul of the citizen petition process would be necessary to prevent the type of abuse about which FDA expressed concern, and that the Agency would likely be unable to carry through to completion the type of proposal made in November 1999, a cadre of Senators, led by Sen. Debbie Stabenow (D-MI), spearheaded an initiative to include a provision in FDARA to require swift FDA action in response to citizen petitions with the ability to stall or block generic competition.

Specifically, FDARA § 506 (which is similar to a provision in Sen. Stabenow’s “Lower PRICED Drug Act” introduced earlier this year) would amend the FDC Act to add § 505(s) – “Citizen Petitions and Petitions for Stay of Agency Action.”  Under new (if enacted) FDC Act § 505(s):

[T]he receipt and consideration of a petition [(including a citizen petition, petition for stay of action, or other request) to delay consideration or approval of an ANDA or a 505(b)(2) application] shall not delay [such] consideration or approval . . . unless [FDA] determines, not later than 25 business days after the submission of the petition, that a delay is necessary to protect the public health. . . .  Notwithstanding [such] a determination . . . [FDA] shall take final agency action with respect to a petition not later than 180 days of submission of that petition unless [FDA] determines, prior to the date that is 180 days after the date of submission of the petition, that a delay is necessary to protect the public health.

In cases where FDA determines that a delay is necessary to protect the public health, FDARA § 506 would require FDA to promptly provide a detailed and publicly available statement with the reasons underlying the Agency’s determination, and to provide the affected generic applicant with an opportunity to meet with appropriate FDA staff to discuss the Agency’s determination. 

In addition, FDARA § 506 would require persons submitting petitions and comments to make certain written verifications, including the following: “I received or expect to receive payments, including cash and other forms of consideration, from the following persons or organizations to file this petition [(or for commenters – to submit this information or its contents): _______.”  Thus, while today companies can submit petitions and comments anonymously via, for example, a law firm, if the Senate-passed version of FDARA § 506 is enacted, it will be more difficult for companies to cloak their activities and interests.   

We previously reported that Pfizer submitted a citizen petition (2007P-0110) and a petition for stay of action (2007P-0111) requesting that FDA take certain action with respect to Novartis’s LOTREL (amlodipine besylate; benazepril HCl) subsequent to Pfizer’s decision to revoke (as of midnight March 25, 2007) the right of reference granted to Novartis to rely on data supporting the approval of Pfizer’s NORVASC (amlodipine besylate).  The right of reference Pfizer granted permitted Novartis to submit a “stand alone” 505(b)(1) NDA instead of a 505(b)(2) application. 

Specifically, Pfizer’s petition requests that FDA deem the LOTREL NDA a 505(b)(2) application subject to Pfizer’s pediatric exclusivity for amlodipine besylate (expiring on September 25, 2007), rescind final approval of the LOTREL NDA and reclassify it as a tentative approval, and withhold final approval of any NDA supplement for LOTREL.  Pfizer’s petition for stay of action requests that FDA stay the approval of any LOTREL NDA supplements concerning amlodipine besylate until September 25, 2007.

On May 18, 2007 (the same day that FDA approved the first generic version of LOTREL), FDA denied Pfizer’s citizen petition and petition for stay of action.  FDA’s response states that the “threshold issue in this matter is whether the termination of a right of reference to data that was necessary for approval of an NDA requires that the Agency withdraw approval of the NDA,” but notes that the “plain language of the FDCA does not address this question,” and that Pfizer “asserted no basis on which [FDA] may withdraw approval of the Lotrel NDA.”  “In the absence of such authority, [FDA] will not withdraw the Lotrel approval . . . .  Because we are not withdrawing the final approval of the Lotrel NDA, as either a 505(b)(1) application or a 505(b)(2) application, we do not need to address the issue of whether the Lotrel NDA is subject to Pfizer’s pediatric exclusivity for amlodipine.”

FDA’s decision, however, is not a total win for Novartis.  Pfizer’s decision to revoke the right of reference granted to Novartis may have significant implications on future submissions to the LOTREL NDA.  FDA’s May 18th response states:

As of March 25, 2007 . . .  FDA may not rely on data and information contained in the Norvasc NDA to approve supplements to the Lotrel application.  Therefore, the approval of any section 505(b)(1) supplement to the Lotrel NDA must be based on data owned by Novartis, or to which Novartis has a right of reference.  A section 505(b)(2) supplement would require appropriate patent and exclusivity certifications, and approval of such supplement could be delayed by patent or exclusivity protections.

Earlier this week, FDA announced the availability of a draft guidance for industry, titled “Bioequivalence Recommendations for Specific Products.”  The draft guidance describes a new process by which FDA will provide, via the Internet, recommendations on how to design product-specific bioequivalence (“BE”) studies to support Abbreviated New Drug Applications (“ANDAs”). Under this new process, FDA will make product-specific BE study recommendations available in draft form on its web site and seek public comment.  In addition to the guidance document, FDA made available the first group of about 180 product-specific draft recommendations.  Comments on the draft BE recommendations are due by September 28, 2007. 

Among other things, a generic sponsor must demonstrate that its proposed product is bioequivalent to the reference listed drug (“RLD”) (i.e., the brand product).  Two drug products are bioequivalent if there are no significant differences in the rate and extent of absorption of the drug products’ active ingredient.  BE studies are designed and conducted by ANDA applicants to demonstrate bioequivalence.  Previously, applicants could obtain recommendations on the design of BE studies by submitting a letter requesting the information from FDA’s Office of Generic Drugs.  Responding to such requests was time consuming for the Agency.  Responses came slowly, if at all.    

Under the new procedure, FDA will post recommendations for BE studies in draft form at http://www.fda.gov/cder/guidance/bioequivalence/default.htm, and seek public comment.  Users will also be able to search the web site for recommendations on specific drug products.  New draft and final BE recommendations will be announced in the Federal Register and listed monthly on FDA’s web site.  The draft guidance indicates that, as under the old procedure, BE study recommendations will be based on FDA’s understanding of the characteristics of the RLD as well as information from the scientific literature and FDA’s own research.  FDA will also consider public comment on the draft BE study recommendations in order to finalize them. 

A question left unanswered by the draft guidance is how applicants can affirmatively request BE study recommendations on specific products that have not yet been addressed by FDA through this new process.  Comments on the draft guidance must be submitted by August 29, 2007.

By Anne Marie Murphy

On May 22, 2007, the Competitive Enterprise Institute (“CEI”), a self-described non-profit public policy organization dedicated to advancing the principles of free enterprise and limited government, published a report, titled “Healthy Competition: The Case for Generic and Follow-On Biologics.”  The report, authored by Gregory Conko, states:

[M]any groups have sought the creation of a new abbreviated regulatory pathway for generic—or what the FDA calls “follow-on”—biopharmaceuticals.  It may be possible for FDA to establish such an abbreviated approval process on its own, and the agency’s initial attempt to create such a process for generic conventional drugs may serve as a useful model. That effort was frustrated, however, by a variety of inefficiencies, so new statutory authority is probably necessary to make the approval process for follow-on biopharmaceuticals efficient and effective. . . .  [Some] observers note that, because the research and development costs for biopharmaceuticals are significantly greater than for conventional drugs, and because the biotechnology industry is considerably less mature, Congress should enact special provisions—such as additional patent life or data exclusivity protections—that will help the industry remain viable. Indeed, Congress should consider certain limited incentives for innovation. However, once the patent and data exclusivity protections expire, there should be a simple and proficient method for getting approval of follow-on biopharmaceuticals.

The report also cites several FDA drug approval actions, including the Agency’s May 2006 approval of a 505(b)(2) application for OMNITROPE (somatropin [rDNA origin]) for injection, as an indication that “FDA has begun to reconsider the ‘process is the product’ philosophy that has governed biologics regulation since 1902 —at least so far as small and relatively well-characterized protein products are concerned.”  Indeed, FDA has been departing from the “process is the product” philosophy ever since the mid 1990s when the Agency accepted “bioequivalence data” to compare the monoclonal antibody produced at an original manufacturing site to the monoclonal antibody submitted to FDA as VERLUMA (nofetumomab). This change was further signaled in 1996 when FDA issued its comparability guidance document, “Demonstration of Comparability of Human Biological Products, Including Therapeutic Biotechnology-derived Products,” which permits reliance on clinical data from a “precursor product” if there is evidence of comparability.

Meanwhile, the U.S. House of Representatives is considering two competing bills that would create a biogeneric approval pathway.  The first bill, H.R. 1038 (“Access to Life-Saving Medicine Act”), was introduced by Rep. Henry Waxman (D-CA) earlier this year, and is generally backed by supporters of generic biologics.  The bill would amend the Public Health Service Act (“PHS Act”) to authorize FDA to approve applications for products that are “comparable” to and “interchangeable” with an innovator product.  A generic applicant may elect to establish that its product can be substituted for the innovator product.  To encourage the development of interchangeable products, the first generic applicant to obtain approval would be awarded a 180-day exclusivity period during which no other interchangeable version may be approved.  However, FDA may approve a comparable version if the product has not been shown to be interchangeable.

The second bill, H.R. 1956 (“Patient Protection and Innovative Biologic Medicines Act of 2007”), was introduced by Rep. Jay Inslee (D-WA) in April 2007.  The bill would, among other things, amend the PHS Act to authorize FDA to approve “similar biological products,” but would prevent interchangeability.  In addition, the bill would provide marking exclusivity to innovator drug companies.

RELATED READING:

• Orange Book Blog post on BioGeneric Approval Pathway
• Pharmalot post on Inslee Biogenerics Bill

On May 10, 2007, FDA announced the availability of a draft guidance for industry –“Protecting the Rights, Safety, and Welfare of Study Subjects – Supervisory Responsibilities of Investigators.”  The draft guidance document is intended to help investigators meet their responsibilities with respect to protecting human subjects and ensuring the integrity of the data from clinical investigations, and clarifies FDA’s expectations concerning the investigator’s responsibility for supervising a clinical study in which some study tasks are delegated to employees of the investigator or to outside parties. 

Under FDA’s Investigational New Drug and Investigational Device Exemption regulations, clinical study investigators have significant responsibilities. They are responsible for ensuring that a clinical investigation is conducted according to the signed investigator statement, the investigational plan, and for protecting the rights, safety, and welfare of study subjects under the investigator’s care.

In assessing the adequacy of supervision by a study investigator, FDA’s draft guidance focuses on four major points:  (1) whether there is appropriate delegation of study-related tasks; (2) whether study staff received adequate training; (3) whether there was adequate supervision and involvement in the ongoing conduct of the study; and (4) whether there was adequate supervision or oversight of any third parties involved in the conduct of the study. 

The draft guidance also provides recommendations for investigators for protecting the rights, safety, and welfare of clinical study subjects.  In particular, clinical investigators should provide a reasonable standard of medical care for study subjects for medical problems arising during participation in the trial, reasonable access to medical care, and attention to protocol violations that can expose study subject to unreasonable risks.

By Noelle C. Sitthikul

Last Friday, FDA announced the Agency’s plans to take enforcement action against firms marketing unapproved drug products in timed-release dosage forms containing guaifenesin, a commonly used expectorant drug.  On May 29, 2007, FDA published a Federal Register notice to this effect.  FDA’s latest action is at least the fourth in 2007 –a year FDA in which the Agency has promised to be particularly aggressive in enforcement actions concerning marketed unapproved drugs.  (FDA’s  previous enforcement actions concerned the drug products ergotamine and trimethobenzamide, and the firm PharmaFab.) 

FDA first took enforcement action with respect to unapproved timed-release guaifenesin drug products in October 2002, when the Agency issued scores of Warning Letters to firms marketing unapproved products competing with Adams Respiratory Therapeutics’ FDA-approved Over-the-Counter (“OTC”) drug MUCINEX (guaifenesin) Extended-Release Tablets, also marketed under the trade name HUMIBID. (You know, the drug product in those ubiquitous “Mr. Mucus” commercials.)  However, that enforcement action was limited to single-ingredient timed-release guaifenesin drug products.  Since then, Adams has obtained FDA approval for 2 other OTC timed-released drug products containing guaifenesin – MUCINEX DM (dextromethorphan HBr; guaifenesin) Extended-Release Tablets (approved in April 2004), and MUCINEX D (guaifenesin; pseudoephedrine HCl) Extended-Release Tablets (approved in June 2004). 

Adams has been trying to get FDA to take enforcement action against firms marketing unapproved timed-release multiple-ingredient guaifenesin drug products ever since MUCINEX DM and MUCINEX D were first launched.  FDA’s delay of enforcement action until 3 years after Adams’ approvals is curious.  FDA’s Federal Register notice simply states that in accordance with the Agency’s June 2006 Compliance Policy Guide:

[t]he agency is taking action at this time against these products because the agency has approved applications to market timed-release drug products containing guaifenesin, alone and in combination with other active ingredients, for relief of cough, cold, and allergy symptoms; thus the continued marketing of unapproved timed-release guaifenesin is a direct challenge to the drug approval process.       

FDA’s “Question and Answer” document accompanying this enforcement action is no more illuminating:

Why is FDA taking this action?  When drugs lack required FDA approval, consumers and health care providers cannot be assured that those drugs are safe, effective, accurately labeled, and properly manufactured. For products in timed-release form, FDA approval is also necessary to ensure that the product is made so that the active ingredients are released at the correct rate. Improperly manufactured timed-release products may release the active ingredients too quickly, too slowly, or not at all, making the product unsafe or ineffective. FDA has stated in a regulation since 1959 that drugs in this form need to be reviewed and approved by the FDA.

Whatever reasons FDA might have had for delaying enforcement action, Adams is clearly pleased.  Adams’ President and CEO, Michael Valentino, commented in a press release that:

We are extremely pleased with the FDA announcement today. We have always believed that the FDA would take enforcement action against the unapproved prescription versions of our Mucinex DM and Mucinex D and remove them from the market in due course. Our initial review of this regulatory action is underway and we expect to be able to serve the additional market demand for our products as it develops.

Firms currently marketing unapproved timed-release guaifenesin drug products must cease manufacturing them by August 27, 2007.  The products may not shipped in interstate commerce after November 25, 2007.  In addition, FDA’s Federal Register notice “cautions firms against reformulating their products into guaifenesin-free unapproved new drugs that are marketed under the same name or substantially the same name (including a new name that contains the old name) . . . .  Depending on the circumstances, these products may be considered misbranded . . . .”

In a recently-released report on the pharmaceutical, biotech, and medical device industries’ relationship with FDA, a significant number of representatives surveyed responded that user fees have not succeeded in decreasing approval times.  The report, “Improving America’s Health IV: A Survey of the Working Relationship between the Life Sciences Industry and the FDA,” summarizes the results of a 2006 survey of industry conducted by PricewaterhouseCoopers and BIOCOM, a Southern California regional trade association.  The report is the fourth in a series.  Previous reports were based on surveys conducted in 1995, 1997 and 1999. 

Of the 66 companies that responded to the survey, approximately one-third of pharmaceutical and biologic companies, and nearly one-half of medical device companies indicated that user fees have not resulted in decreased approval times for products under consideration by FDA.  The report notes that this finding may become significant as Congress considers whether to reauthorize the Prescription Drug User Fee Act and the Medical Device User Fee and Modernization Act.  The report suggests that FDA may need “to explain how staff increases speed up reviews,” and that “[g]reater transparency may be needed about how the user fees are being employed, especially by [the Center for Biologic Evaluation and Research].”  The report urges consideration of “a structural review of the product approval process resourcing model . . . to help ensure a proper balance of resources.”

In addition, among the “most worrisome findings” of the survey is that approximately half of the responding companies reported that goal timeframes caused FDA to reject products because reviewers have not been able to resolve questions within those timeframes.  The report suggests that the availability of additional reviewers may help to alleviate this problem.

The news is not all bad, however.  The report notes that “[i]n the nearly ten years since the passage of [the FDA Modernization Act], both FDA and life sciences companies have met somewhere in the middle, both making great strides to improve communication and effectiveness of their working relationship.”  Indeed, a majority of surveyed companies “agreed that FDA promptly facilitated requests for clarification from the reviewers, the Agency contact was extremely knowledgeable about their submission status and promptly responded to requests.”  With respect to FDA’s risk mitigation and product lifecycle management initiatives, 88% of surveyed companies “agreed that new FDA guidance . . . has enhanced their comprehension of submission requirements,” and a significant majority of respondents “agreed that FDA is making better decisions because of these guidance tools.”   

By Brian J. Wesoloski

Our colleague John Fleder has just written an article for FDLI Update that outlines the agencies and offices that get involved in decisions to commence FDA enforcement actions, such as Warning Letters, seizures, injunctions (consent decrees), and criminal prosecutions.  Mr. Fleder, who used be the Director of the office in the Justice Department that represents FDA in court proceedings, sets forth both FDA’s published and unpublished policies on these matters.  We believe that this article is the first published or otherwise public statement that presents an overview of the way that enforcement actions weave their way through the government bureaucracy.  It is a roadmap for companies and their counsel to determine the people they need to speak with to influence decisions to bring or not bring enforcement actions.