FDA Lawyers Blog

Yesterday, FDA issued two new items to help clarify combination products: 1) a Final Rule published in the Federal Register entitled, "Current Good Manufacturing Practice Requirements for Combination Products" and 2) a Draft Guidance entitled, "Guidance for Industry and FDA Staff:
Submissions for Postapproval Modifications to a Combination Product Approved Under a BLA, NDA, or PMA", also announced in the Federal Register.

The Final Rule is intended to clarify which good manufacturing practice ("CGMP") requirements apply when drugs, devices, and biological products are combined to create combination products. The Rule also provides a mechanism that FDA describes as "transparent and streamlined regulatory framework" for companies to use when demonstrating compliance with CGMP requirements for "single-entity" and "co-packaged" combination products. "Single-entity" combination products are two or more regulated components, e.g., drug/device, biologic/device, drug/biologic/device, which are physically, chemically, or otherwise combined or mixed and produced as a single-entity. Two or more separate products packaged together in a single package or as a unit and comprised of two or more regulated products is a "co-packaged" combination product. The Final Rules started as a Draft Guidance announced on October 4, 2004 (69 FR 59239), entitled "Current Good Manufacturing Practices for Combination Products." Based on comments and FDA's own internal review, FDA decided that "rulemaking was warranted" and issued Proposed Rules on September 23, 2009 (74 FR 48423).

Written by Brian J. Malkin

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The concept behind the CGMP Rule is simple for parts that are separately manufactured and marketed: each of the constituent parts of a combination product are subject only to the CGMP regulations applicable to that part, e.g., drug, biologic, or device. The two categories of combination products mentioned above, however, "single-entity" and "co-packaged" are slightly different due to the possibility for overlapping CGMP requirements for the different regulated components. Companies have two basic options for these types of products: 1) demonstrate compliance with the specifics of all CGMPs to each of the parts, or 2) demonstrate compliance with the specifics of either the drug CGMPs at 21 C.F.R. Parts 210 and 211 or the quality system ("QS") regulation at 21 C.F.R. Part 820 rather than both, for drug/devices under certain conditions. For combination products including biologics, the specific regulations are 21 C.F.R. parts 600 through 680, and for product including any human cell, tissue, and cellular tissue-based products, the regulations are 21 C.F.R. Part 1271.

Purchasing of pharmaceuticals through on-line pharmacies is on the rise and gives rise to many potential problems. Crucially the most important issue is whether the medicinal product is genuine, contains the correct ingredients, and is an approved product in the relevant regulatory jurisdiction. Medicines supplied via on-line links can come from anywhere in the world, and this method of distribution is more open to fraudulent activity.

In Europe, the European Parliament passed Directive 2011/62/EU, which relates to medicinal products for human use, and is in regard to the prevention of the entry into the legal supply chain of falsified medicinal products. The European Commission ("EC") has put some thought into how on-line pharmaceutical purchases can be made safe and to comply with the Directive. To that end, they have released a Concept Paper for public consultation on the introduction of a "common logo" for websites of legally-operating
on-line pharmacies/retailers.

Written by Howard E. Rosenberg, Ph.D.

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The requirements are that the logo is recognizable throughout the EU and identifies the Member State in which the on-line pharmacy/retailer is established. There is also an obligation for each Member State to set up a dedicated website providing a national list of all legally-operating on-line pharmacies/retailers. The entries in these lists must have a hyperlink to the respective on-line pharmacies/retailer's website and a reciprocal link from the logo on the on-line pharmacies/retailer's website back to the national list. The point being that a customer can go to either the national list to find approvable pharmacies and vice versa to the on-line pharmacies/retailer's website and link back to the national list via the logo thus assuring authenticity.

A research letter published online in the Journal of the American Medical Association ("JAMA") last Tuesday reports findings that pharmaceutical advertisements have a tendency to minimize potential adverse effects when the products they promote become available over-the-counter ("OTC"). The researchers attribute this shift in content to the differences in prescription drug advertising standards, governed by FDA, and those for OTC advertising, governed by the Federal Trade Commission ("FTC"). FDA requires that ads present a "fair balance" of the risks and benefits of a drug, a requirement that is absent from FTC's "reasonable consumer" standard. Commentators note that the FDA regulations are better equipped to ensure against "active deception."

The research endeavor, sponsored by CVS Caremark, considered four drugs that transitioned from prescription to OTC status within the last ten years: Claritin® (loratidine), Prilosec® (omeprazole), Xenical®/Alli® (orlistat), and Zyrtec® (cetirizine). It examined 133 total television and print advertising materials from twenty-four months prior to, through six months after, each transition, and found that the percentage of advertisements that referenced side effects plummeted from 70% while prescription only to 11% once available OTC. Conversely, the proportion describing drug benefits jumped from 83% to 97%. The study further reports that OTC advertisements frequently omit the generic names of drugs, "a powerful tool for the patient as a consumer in that it helps tie together scientific information on the drug from different places." Roughly 50% of the OTC ads mentioned the generic name, while over 95% had when the drugs were available by prescription only.

"In many, many cases information about risks simply disappeared from the ads once the drugs became [OTC]," remarked head researcher Dr. Jeremy Greene. This likely contributes to erroneous consumer beliefs that relocation out from behind the pharmacy counter automatically indicates a safer product. With 106 ingredients, indications, or dosage strengths having made the Rx-to-OTC switch since 1976, it is unlikely that this is always the case. Greene highlighted the danger of this situation given the frequency of overdoses on some of the most commonly used OTC drugs, such as acetaminophen (Tylenol®) and ibuprofen (Advil®). A 2006 study, for example, estimated over 450 acetaminophen overdose-related fatalities each year.

This research raises the question of where consumers can turn to obtain important information on potential side effects, if they are not receiving it from product ads or prescribers/suppliers. While some information is available online (such as at otcsafety.org or webmd.com), tracking it down requires active effort. Consumer Healthcare Products Association (CHPA) policy does note that the OTC label "is the most important element of a nonprescription drug," and "clearly lists a product's active ingredient, purpose, uses, warnings, directions, other information, and inactive ingredients." In an age dominated by electronic media, however, consumers are inevitably paying more attention to television and online/print advertising than drug labels. Also of note is that current OTC labeling requirements were promulgated by FDA, not FTC.

The Caremark study findings indicate that reform may be necessary to ensure transparency of consumer risks in the OTC pharmaceutical market, whether it be FDA oversight of OTC drugs or FTC adoption of stricter advertising criterion. With 240 million Americans currently using OTC medicines, according to a January 2012 CHPA report, it is a matter that deserves serious consideration.

The Pediatric Committee ("PDCO") of the European Medicines Agency ("EMA") is tasked with identifying the needs for children in a variety of therapeutic areas and aims to encourage the research and development of pediatric medicinal products. The first Inventory, which is now open for discussion and public consultation, covers medicines for cardiovascular diseases. The EMA points out that it will be releasing similar lists for other therapeutic areas for public consultation during 2012 and 2013.

According to the EMA, the Inventory aims to enable:

• Companies to identify opportunities for business development;

• The PDCO to judge the need for medicines and studies when assessing draft pediatric investigation plans, waivers and deferrals; and

• Healthcare professionals and patients to have an information source available to support their decisions as to which medicines.

Written by Howard E. Rosenberg, Ph.D.

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The Inventory is based on a report on the survey of all pediatric uses of medicinal products in Europe completed by the PDCO in December 2010.

On July 2, the much heralded new European Pharmacovigilance legislation came into operation. This new piece of legislation is aimed at promoting and protecting public health by strengthening the existing Europe-wide system for monitoring the safety and benefit-risk balance of medicines and provides regulators with a range of new or improved tools to ensure that patients are not exposed to unnecessary risks when taking medicines.

Highlights of the new legislation include:

• The establishment of a new scientific committee, the Pharmacovigilance Risk Assessment Committee ("PRAC").


• A clarification of the roles and responsibilities leading to more robust and rapid European Union ("EU") decision-making.


• The engagement of patients and healthcare professionals in the regulatory process.


• An improved collection of key information on medicines, e.g., through risk-proportionate, mandatory post-authorization safety and efficacy studies.


• More transparency and better communication.

Written by Howard E. Rosenberg, Ph.D.

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The first meeting of the new key committee, PRAC, will be on July 19 and 20, 2012. PRAC's mandate includes, among other things, "All aspects of the risk management of the use of medicinal products including the detection, assessment, minimization and communication relating to the risk of adverse reactions, having due regard to the therapeutic effect of the medicinal product, the design and evaluation of post-authorization safety studies and pharmacovigilance audit".

On May 11, FDA reportedly told attendees of the Consumer Healthcare Product Association's Regulatory & Scientific Conference in Washington, D.C. to be patient while FDA implements its "new paradigm" for prescription to over-the-counter ("Rx-to-OTC") switch applications (The Tan Sheet (May 21, 2012). Andrea Leonard-Segal, M.D., Director, Division of Nonprescription Clinical Evaluation, Office of Nonprescription Products, Center for Drug Evaluation and Research, said that FDA's anticipated, revised Rx-to-OTC regulations will allow for expanded conditions of safe nonprescription use.

Leonard-Segal acknowledged, however, that the process will take time, warning "if you submit [a new drug application] where we don't have the regulations to support the switch, if you're ahead of your time compared to the regulations, then I think the project won't go where you want it to go." While waiting for FDA to final the regulations, Leonard-Segal suggested that firms make business decisions about initiating switch programs that employ new diagnostic technologies and other measures, according to their internal estimate project timelines. Leonard-Segal, however, sympathized with sponsors that had failed to meet FDA's current, less flexible regulations that only permit OTC conversions where the Drug Facts label has full comprehension. An example of failed Rx-to-OTC switches cited was statins to lower cholesterol, but other categories of products that may benefit from the new regulations are sleep aids and triptans to treat migraines.

Written by Brian Malkin

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Commenting further, Leonard-Segal said at the Conference: "One of the frustrations of being in the switch business . . . has been watching the regulations interfere with, what in my perspective have been some very interesting and very innovative ideas, but that just can't move forward because the regulations don't allow us to go there." Leonard-Segal further noted that a priority for the new regulations will be to consider how diagnostic devices could work together with OTC drugs, which is currently a complex approval process involving multiple centers and considerations.

by Brian Malkin

On March 7, FDA announced in a Request for Comments in the Federal Register a two-day public hearing to obtain feedback and suggestions regarding ways that FDA can modernize its regulations, policies, and practices that apply to the conduct of clinical trials for FDA-regulated products. FDA hopes that with this input it can modernize the regulatory framework that govern clinical trials and form approaches for good clinical practice ("GCP") providing for greater effectiveness and efficiencies in the process.

FDA explained in its Request for Comments that FDA's clinical trial regulations are now more than twenty-five years old and has been showing its age. In the past years, clinical trial management has changed dramatically, including increased size and complexity of clinical trials, increased number of clinical trials performed globally, greater use of contract research organizations ("CROs"), increased participation of "vulnerable" populations (children, individuals with orphan-designated diseases, others), and numerous scientific and technological advances, including increased use of the Internet. FDA has learned in various forums that FDA's current regulations and compliance policies may not facilitate the use of innovative methods to improve clinical trial quality, the Request for Comments observes. For example, CROs or other clinical investigators may continue to use older data collection methods given the uncertainties involved in using new procedures that may not be aligned with FDA's older guidances and recommended procedures.

FDA said that its focus is on good clinical practice, including enhanced clinical protocol design to take advantage of newer technologies to ensure reliability of data, safety surveillance reporting, quality control processes including auditing, data integrity, and human subject protection. FDA is interested in workshops or strategic alliances that may help to encourage the implementation of innovative methods in clinical trials including risk-based methods in the design, oversight, and conduct of clinical investigations.

by Scot B. Pittman

FDA's Center for Veterinary Medicine ("CVM") announced last week that it was restricting the use of certain antibiotics in farm animals. On January 6, 2012, CVM published a final rule in the Federal Register that prohibits certain uses of cephalosporin drugs in food-producing animals. The rule is a modification of FDA's 2008 order banning all extralabel uses of cephalosporins in food producing animals. The roughly 170 comments in response to the 2008 proposal convinced FDA that the ban was too broad.

Specifically, the new rule prohibits certain extralabel uses of cephalosporin drugs in cattle, swine, chicken, and turkey. Included among the prohibitions are:

• Using cephalosporin drugs at unapproved dosage levels, frequencies, durations, or routes of administration;
• Using cephalosporin drugs in cattle, swine, chickens, or turkeys that are not approved for use in those species; and
• Using cephalosporin drugs for disease prevention.

• Extralabel use of approved cephapirin products in food-producing animals;
• Use to treat or control an extralabel disease indication, provided that the use adheres to a labeled dosage regimen approved for that particular species and production class; and
• Extralabel use in food-producing minor species (e.g. ducks and rabbits).

by Scot B. Pittman

On January 3, FDA released proposed amendments to its regulations governing submitting citizen petitions and petitions for stay of action ("PSAs") that involve requests for FDA to take action regarding pending abbreviated new drug applications ("ANDA") or 505(b)(2) new drug applications ("NDAs"). The changes are meant to execute provisions in the Food and Drug Administration Amendments Act of 2007 ("FDAAA") (Pub. L. 110-85).

Citizen Petition Regulation Amendments

Specifically, the proposed changes are meant to address Section 505(q) of FDAAA (21 U.S.C. § 355(q)) and codify certain aspects of FDA's thinking presented in its Guidance on 505(q) citizen petitions, which we reported on here. Enacted in September 2007, section 505(q) governs how FDA handles certain citizen petitions and PSAs that call for any form of action related to pending ANDA or 505(b)(2) NDAs. FDA notes that it receives many petitions asking it to delay approving an ANDA or 505(b)(2) NDA until certain criteria in the petition have been met. While many of these petitions, especially if submitted early in the approval process, can aid FDA, some, especially those submitted late in the review process raising minimally valid scientific or legal issues, can improperly delay the approval of an application.

by Brian Malkin

On December 16, a group of Senators sent FDA a letter urging FDA to prohibit the use of flavorings in cigars. The letter was signed by Senator Frank Lautenberg (D-N.J.) joined by Senators Dick Durbin (D-Ill.), Sherrod Brown (D-Ohio), Jeff Merkley (D-Ore.), and Richard Blumenthal (D-Conn.).

According to the letter, more than 13 million Americans smoke cigars, including an estimated 1.8 million high school students and 475,000 middle school students. Unlike cigarettes, which FDA regulates under the 2009 Family Smoking Prevention and Tobacco Control Act ("the Act"), FDA has so far chosen not to regulate cigars as "tobacco products."

Cigars and little cigars or "cigarillos" are like cigarettes because they contain tobacco and are intended to be smoked, so they arguably contain the same ingredients that were described in the Act as "inherently dangerous and cause cancer, heart disease, and other serious adverse health effects" and are addictive because they contain nicotine, "an addictive drug." Another purpose of the Act was to reduce smoking by "young people," including minors, who may be tempted to smoke, particularly when tobacco products contain non-tobacco-type flavors.

by Brian Malkin

Whose seafood is your seafood, or, more appropriately, how do you know the fish you ordered is the fish you ordered? In October, FDA approved a new DNA barcoding system that can identify fish species similar to a supermarket scanner to prevent mislabeling of locally produced and imported seafood in the United States. Reportedly, other national regulators are considering adopting similar measures, which are described as fast, reliable, and cost-effective.

In most cases, the DNA barcoding system should prevent restaurant patrons from consuming inferior fish from the one that they thought they were consuming. In other cases, it may prevent unwanted health consequences for individuals who may be allergic to specific types of seafood, including exotic species that are banned. Just in 2007, several individuals became seriously ill following consumption of illegally imported toxic pufferfish from China that had been mislabeled as monkfish to circumvent U.S. import restrictions.

Seafood mislabeling is notorious. For example, a a pair of high school students in New York found 25% of the fish that they sampled around New York was incorrectly labeled as higher-end-type seafood.

by Erin A. Lawrence

On November 9, 2011, U.S. District Court for the District of Columbia, Judge Richard Leon, ruled that it is likely that tobacco companies will succeed in their lawsuit to block the new graphic warning labels proposed by FDA. Tobacco companies were supposed to begin distributing cigarettes with the FDA's graphic package warnings on October 22, 2012. However, pursuant to Judge Leon's decision, the companies will no long have to meet this requirement at least until the lawsuit is decided. (See our most recent blog on this topic here).

The tobacco companies did not challenge FDA's proposed textual warnings; they only opposed the graphical warnings. The tobacco comanies argued that the warnings are unconstitutional, because they do not simply convey facts to inform people's decision whether to smoke. Instead, the labels force the companies to display the government's anti-smoking advocacy and, therefore, violating their first amendment rights by compelling speech.

FDA argued that the public interest in conveying the dangers of smoking outweighs the companies' free speech rights. FDA said Congress gave it the authority to require the new labels because existing warnings dating to 1984 were going unnoticed and, therefore, health warnings were not being conveyed effectively.

by Brian Malkin

On November 8, the Institute of Medicine ("IOM") released a report, "Health IT and Patient Safety: Building Safer Systems for Better Care". The IOM Committee had been charged with summarizing existing knowledge of the effects of health information technology ("IT") on patient safety, making recommendations to the Department of Health and Human Services ("HHS") regarding specific actions federal agencies should take to maximize the safety of health IT-assisted care, and making recommendations concerning how private actors can promote the safety of health IT-assisted care, and how the federal government can assist private actors in this regard.

The IOM Committee concluded that current market forces are not adequately addressing the risks associated with the use of health IT. No federal agency is currently charged with monitoring the safety of health IT, i.e., the software, hardware, and systems that record and manage patients' health information. The Report recommended that HHS should publish an action and surveillance plan within twelve months that includes a schedule for working with the private sector to asses the impact of health IT on patient safety and minimizing the risk of its implementation and use. The Report also recommended that HHS fund a new Health IT Safety Council, which would operate within an existing voluntary consensus standards organization, to evaluate criteria for assessing and monitoring the safe use of health IT to enhance safety. All health IT vendors should be required to publicly register and list their products with the Office of National Coordinator for Health IT ("ONC"), the Report continues, and HHS should establish a mechanism for reporting health IT-related deaths, serious injuries, or unsafe conditions.

by Brian Malkin

On October 19, FDA published in the Federal Register proposed amendments to its 1992 Orphan Drug Regulations. According to the notice, the amendments "are intended to clarify regulatory provisions and make minor improvements to address issues that have arisen since those regulations were issued." FDA said it has reviewed over 3,350 orphan-drug designation requests since the 1992 regulation became final. This proposed rule follows FDA's announcement of boosting its orphan drug program, as we reported here. Comments are due by January 17, 2012 on the proposed rule.

The specific issues addressed in the proposed rule include:

(1) Demonstration of an appropriate "orphan subset" of persons with a particular disease or condition that otherwise affects 200,000 or more people in the United States, for the purpose of designating a drug for use in that subset;

(2) Eligibility for orphan-drug designation of a drug that is otherwise the same orphan-drug indication as a previously-approved drug;

(3) Eligibility for multiple orphan-drug exclusive approvals when a designated orphan drug is separately approved for use in different subset of the rare disease or condition;

(4) Requirement for demonstrating clinical superiority for the purpose of orphan-drug exclusive approval;

(5) Requirement for submitting the name of the drug in an orphan-drug designation request;

(6) Required drug description and scientific rationale in a designation request;

(7) Required information in a designation request relating to the sponsor's interest in the drug;

(8) Timing of a request for orphan-drug designation;

(9) Responding to a deficiency letter from FDA on an orphan-drug designation request;

(10) FDA publication of information regarding designated orphan drugs;

(11) FDA recognition of orphan-drug exclusive approval;

(12) Miscellaneous terminology changes; and

(13) An address change.