Angie Drakulich was editorial director of Pharmaceutical Technology.

Angie Drakulich

FDA is collecting public comments on a series of studies that the agency plans to conduct on online direct-to-consumer (DTC) promotion of prescription drug products, according to an 

The studies are designed to test different ways of presenting benefits and risks in DTC prescription-drug websites. The three experimental studies to be conducted will investigate whether presenting risk information on branded-drug websites influences consumers' perception and understanding of the risks and benefits of the product; how special features, such as personal testimonial videos and interactive visuals, on branded-drug websites influence perception and understanding of the risks and benefits of the product; and whether links to and citations from external organizations referenced on the homepage of branded-drug websites influence consumer perception and understanding of the risks and benefits of the product.

FDA gives the following justification for the project in the aforementioned announcement: “Pharmaceutical products are launched and marketed in a number of new modalities and venues that did not exist a short time ago. Increasingly, prescription products are promoted to consumers online in such formats as banner ads, Web sites, and videos. The interactive nature of the Internet allows for features not possible with traditional media (i.e., print, radio, and television), such as scrolling information, pop up windows, linking to more information, and embedding videos.”

The agency is specifically asking for feedback on these topics, including whether the proposed collection of information is necessary for the proper performance of FDA's functions; the accuracy of FDA's estimate of the burden of the proposed collection of information; ways to enhance the quality, utility, and clarity of the information to be collected; and ways to minimize the burden of the collection of information on respondents.

Current FDA regulations require that prescription-drug advertisements include a “fair balance” of information about the products' benefits and risks of advertised products, and according to the 

 announcement, this balance must be clear in online DTC promotion. The research will therefore be “designed to test different ways of presenting prescription drug risk and benefit information on branded drug Web sites” and “will complement qualitative research we plan to conduct on issues surrounding social media,” says the announcement.

Details about the proposed studies are included in the 

 announcement. Comments are due June 27, 2011, and can be submitted at 

Articles

FDA is collecting public comments on a series of studies that the agency plans to conduct on online direct-to-consumer promotion of prescription drug products, according to an announcement in the Federal Register.

FDA to Study Online Drug Marketing

There are more than 250,000 over-the-counter (OTC) products on the market today with wide access to consumers. But after a series of major OTC drug recalls, regulators and standardsetting bodies seem to be taking a closer look at these readily available products.

Although industry is familiar with the process by which over-the-counter (OTC) products reach the shelves, many consumers may not fully understand the difference between regulatory approvals for prescription products and the majority of nonprescription products. They may not know, for example, that FDA does not perform a prereview of chemistry, manufacturing, and controls (CMC), labeling, or pharmacokinetics for products regulated under the OTC Monograph System. Unlike prescription products, OTC drug products may or may not require clinical studies, and manufacturers of OTC monograph drugs are not required to pay user fees (1). The fact is, OTC drug products have their own rules, and they are approved in various ways depending on when they are (or were) developed and submitted to FDA for marketing approval. 

Before the 1960s and 1970s, OTC drug sponsors were not required to demonstrate drug effectiveness. But in 1962, FDA required manufacturers to show effectiveness, and in 1972, the agency began what's known as the OTC Monograph System (also called the OTC Drug Review process), a project that is still underway today. The project involved reviewing in great detail the hundreds of compounds available to consumers in OTC form and developing FDA monograph requirements for drugs to be considered as generally recognized as safe and effective (GRAS/E). 

All drugs, including OTCs, for human use in the US market must: adhere to current compendial standards; meet labeling requirements called for in the 

and in the Federal Food, Drug, and Cosmetic Act; and be manufactured according to cGMPs, which are outlined in 21 

 Parts 210, 211, and 330 (2). GMP compliance is verified through FDA inspections. Any OTC drug that deviates from a final monograph is not recognized as GRAS/E and requires an approved application (i.e., a new drug or abbreviated new drug application, NDA or ANDA) before it can be marketed (3). OTC drugs that meet final monograph requirements do not require an application approval.  

Compendial drug quality monographs, or written standards, are published and maintained for the US marketplace by the US Pharmacopeial Convention (USP) and published in the 

. FDA monographs, which are for conditions for market entry, are published in the 

. An OTC drug monograph includes requirements for the active ingredient's dosage strength and form as well as for the product's labeling and final formulation testing (1).  

As part of the OTC Drug Review process, FDA ended up restricting in the 1970s the use of some 500 active ingredients that had previously been on the market because of a lack of sufficient demonstration of effectiveness or lack of general recognition of safety. To date, the agency has completed a review of more than three-fourths of the original monographs proposed at the inception of the program, according to FDA spokesperson Lisa Kubaska. Certain OTC medicines can be reviewed again when a monograph is amended or when a new question of safety or efficacy is raised.  

Since about 1984, most new OTC drug products have gone through the NDA/ANDA process for market approval, although companies can still submit applications to get into the monograph system. Figure 1 provides a full historical timeline of OTC drug regulation.  

Figure 1: More than 250,000 OTC products are available to consumers. The following timeline provides a detailed look at at the  history of OTC regulation (Adapted from an FDA online presentation, from Ref. 1.) 

Despite the differences in OTC monograph-drug reviews, NDAs and ANDAs for nonprescription products are examined in the same manner as prescription products. According to FDA, there are 774 OTC products on the market today that were approved by NDA or ANDA.  

Another mechanism by which a drug can enter the market as an OTC drug is to undergo a status switch from a prescription drug to a nonprescription drug. The labeling process for this type of switch is quite complex and described later in this article.  

USP is in the process of updating its compendial monographs and FDA applauds this change, which will help improve the standards companies follow when making drug products. In fact, the agency, along with the Consumer Healthcare Products Association (CHPA), is working closely with USP on the pharmacopeial convention's monograph modernization project, which began in 2010. The aim is to update key USP compendial monographs (to clarify, these are different from FDA's OTC monographs) to incorporate modern analytical methods and technologies. 

The most significant gaps reside in USP monographs that have relatively nonspecific identification and/or assay procedures and in monographs lacking procedures for impurities and degradants, says Karen Russo, vice-president for small molecules at USP.  In addition to these gaps, methods for certain procedures are outdated (e.g., packed column gas-chromatography and wet-chemistry techniques) and need updating.   

Furthermore, USP notes that only about 25% of the monographs targeted for revision are OTC-related. Although, says USP, it's important to note that the same product or active pharmaceutical  ingredient can be used in OTC and prescription form based on the dose or other FDA criteria.  

In February 2011, the standard-setting body said it would be focusing on a few specific OTC monographs based on an FDA request. The agency asked USP to make a priority the monographs for acetaminophen and diphenhydramine (as well as copovidone, crospovidone, povidone, and talc) based on potential health concerns with these drugs (4).  

"Acetaminophen- and diphenhydramine-containing drug products are two of the highest-volume selling OTC monograph drugs," explains FDA's Kubaska. "There are known impurities in both of these drugs that represent known (acetaminophen) and theoretical (diphenhydramine) concerns with respect to toxicity. So, the extent of exposure (using sales volume as a surrogate) and toxicity concerns played key roles in the selection of these drugs...."  

Adds Russo, "The challenge with diphenhydramine and acetaminophen are the many drug products, particularly those combined with other drugs, and the variety of dosage forms, such as tablets and oral liquids. For example, there are more than 25 acetaminophen-containing dosage form monographs in the 

Another challenge to the project overall, says Russo, is finding the replacement procedures for those monographs that need revision. "We encourage manufacturers to submit their procedures to USP so that the monograph can be revised to incorporate the new procedure(s).... USP is ... using its own laboratory resources to the extent possible to develop and validate procedures to serve as the basis for the monograph revisions; however, we are not able to accomplish this on our own." In addition, says Russo, USP has to find procedures that can accommodate all manufacturers of a given drug substance or drug product. 

There is no set deadline for completing the monograph project, according to USP, although a general target is to finish before the 2010–2015 convention cycle ends. USP is hosting an OTC workshop in September 2011 to discuss with industry and FDA some of these compendial issues. (For more details on the monograph modernization project, see the Inside USP 

 in this issue "Monograph Makeover Requires Industry Input".)   

Meeting regulatory requirements and safety standards is only half of the battle for OTC drug manufacturers.  As FDA's Kubaska points out, "Like prescription drugs, OTC drugs can cause serious adverse events." And the fact that there is no healthcare provider between a consumer and an OTC drug means that "the consumer must be able to self-diagnose the condition and safely self-medicate," explains Kubaska. For this reason, OTC product labels and information leaflets must be even more clearly identifiable, readable, and understandable to the average consumer than those for prescriptions.   

According to David C. Spangler, senior vice-president of policy, and general counsel and secretary for CHPA, "the labeling standards that we have today [for OTCs] have been gone over in painstaking detail by FDA. When putting together a category monograph, the biggest thing FDA is focusing on, in addition to effectiveness and safety of the ingredients, is getting the labeling right. There is always room for improvement, but labeling reviews have been going on for decades."  

In terms of improvement, in August 2010, FDA released an OTC guidance for industry on label-comprehension studies (5). These studies determine how well a consumer can read and understand a label. "FDA felt the need to publish this guidance to help industry conduct well-designed studies that provide meaningful data," says Kubaska. Although the guidance is not expected to require major changes in industry practice, it demonstrates that regulators are concerned about making sure OTC manufacturers provide the most clear and accurate information to consumers.  

The guidance targets companies planning a label-comprehension study to evaluate a new label or a labeling change, but also applies to drug sponsors trying to switch their already approved prescription drugs to nonprescription status, a trend that seems to be on the rise, says CHPA's Spangler. (See a list of prescription to nonprescription switches at 

http://chpa-info.org/media/resources/r_4620.pdf

.) This type of marketing switch has to be done extremely carefully, not just from a manufacturing and business perspective, but also from the consumer's perspective.  

Caution is especially important when considering a complex drug status switch, such as those for cholesterol-lowering products. According to Spangler, these types of status switches involve intense labeling reviews because the products they are based on are generally for asymptomatic conditions. Without obvious symptoms, it is more difficult for a consumer to self-diagnose and self-treat, and so the product labels must be extremely detailed. "We are already seeing this type of switching activity in the UK, and it's more likely for the US in the future." 

Across the Atlantic, the European Medicines Agency (EMA) is taking another look at OTC product labels as well. In April 2011, the agency released quality review recommendations for nonprescription-drug packaging design and labeling that would apply across the European Union (6). The new recommendations add to already existing requirements in the European Commission's Directive 2001/83/EC and in the 2009 EMA guideline on the readability of the labeling and package leaflet of medicinal products for human use (7). The new document aims to better harmonize OTC labels across Europe, especially where certain descriptions may use symbols or pictograms. Fonts, colors, text size, and information to be included on the labels and leaflets are addressed. Comments on the recommendations are due to EMA by June 30, 2011. 

FDA aims to inspect prescription and nonprescription drug-manufacturing facilities every two years (8). OTC facility inspectors focus on verifying drug-monograph compliance (3).  Many of the drug recalls that have occurred during the past 18 months are not tied to FDA approval or labeling, but rather to the manufacturing and supply-chain management of these products, points out Jonathan M. Lewis, a principal at Advanced Biomedical Consulting.  "Many OTC drugs are less 'risky' in FDA's eyes," he says, "so these facilities often are not inspected nearly as frequently or with as much focus as compared with prescription products, such as injectables."  

Lewis suggests that preapproval inspections, which he says are rarely required for OTC drug products, be implemented. "These inspections would help assess manufacturing conditions and regulatory compliance prior to marketing of these products," he says. 

Ravi Harapanhalli, principal consultant and late-stage services lead at Parexel Consulting, agrees. "Over the counter drugs approved 

 an NDA/ANDA process don't need anything beyond what is currently applied with regard to ensuring product quality. However, for monograph drugs, a requirement for cGMP inspection prior to marketing should be mandated to ensure appropriate product quality and postmarketing recalls. If FDA cannot have the resources to do inspections, it should consider third-party audits as an alternative for OTC drugs marketed under monographs. A system of third-party audits is already accepted for certain low-risk devices." 

Also, says Harapanhalli, "OTC drugs approved under an NDA or ANDA pathway seem to have fewer concerns of product quality compared with the OTC drugs marketed under monographs. Because monograph drugs are neither pre-reviewed nor approved, a manufacturer takes full responsibility to attest that their product meets the quality guidelines and requirements described in an OTC monograph."  

This responsibility can be more difficult for smaller manufacturers of OTC products, adds Lewis. These smaller firms often turn to outsourcing and do not have the finances or staff to audit their contract manufactures and suppliers. They end up taking "more risk, often at the cost of quality, to produce these products domestically," says Lewis.  

Resources are a constant challenge for FDA as well. Harapanhalli points out that many cGMP inspections of OTC sites uncover manufacturing problems and that unfortunately, FDA does not have the resources it needs to perform all of its targeted biennial inspections.  As a result, consumer complaints and other triggers often prompt the agency to inspect OTC manufacturing sites.  

On the positive side, FDA recently released a guidance for industry on adverse-event reporting that requires manufacturers of OTC monograph drugs to provide safety updates to the agency (9). But until FDA's budget sees a massive increase, inspections of facilities, and seemingly low-risk facilities, may be put on the back burner. 

Many of the ongoing efforts described herein are aimed at improving OTC drug safety for consumers, and says CHPA's Spangler, "It doesn't take a whole lot of sophistication to observe that we're in an era of greater enforcement." These changes are good, he says, because industry ultimately wants to reassure consumers that products on the market are safe and meet quality standards.  

That said, it is not official that OTC drug manufacturers will face higher levels of enforcement going forward. According to FDA, the agency's "standards that a marketed drug must have a favorable benefit-to-risk profile remain unchanged."  

At the end of the day, consumers play a crucial role in OTC drug safety by their decisions to select and use these products properly. "Consumers should read the product labels carefully and should not throw away the boxes that have the Drug Facts information," points out FDA's Kubaska. Together, consumers, industry, and the authorities can make the drugstore shelf not just an easily accessible place, but a safer place. 

 1.  FDA, "Regulation of Nonprescription Drug Products," presentation 

www.fda.gov/downloads/AboutFDA/CentersOffices/CDER/UCM148055.pdf

, Title 21, Food and Drugs (Government Printing Office, Washington, DC), Part 330. 

 3.  FDA, "Compliance Program Guidance Manual," 

 4.  USP, Letter to USP from FDA, February 2011, 

Guidance for Industry: Label Comprehension Studies for Nonprescription Drug Products 

 6.  EMA, EMA/275297/2010 3/9 (Apr. 1, 2011). 

Guideline on the Readability of the Labeling and Package Leaflet of Medicinal Products for Human Use (

 8.  FDA, "Compliance Program Guidance Manual for FDA Staff: Drug Manufacturing Inspections Program," Document 7356:002. 

Regulators and standard-setting bodies are re-examining over-the-counter drugs.

Up Close and Personal

User-Fee Waivers, Reductions, and Refunds for Drug and Biological Products

, that offers recommendations to applicants seeking such actions under the Federal Food, Drug, & Cosmetic Act (FD&C Act). A similar draft guidance was issued in July 1993. The new document clarifies the types of waivers, refunds, and reductions available under the user-fee provisions of the FD&C Act as well as the procedures for handling these requests, including how to appeal an FDA decision. 

The guidance is tied to the Prescription Drug User-Fee Act (current version IV), which allows FDA to assess and collect user fees from applicants for certain human drug and biological products. In addition, FDA can assess annual product fees for certain approved drug and biological products, as well as annual establishment fees for the facilities in which those products are made in final dosage form, states the draft guidance. However, the amount FDA collects in total from these fees is “independent of the number of waivers or reductions in fees that are granted… Therefore, the more waivers or reductions are granted, the more fees must be increased the following year for applications, products, and establishments subject to fees to meet the annual statutory revenue targets.” 

The new draft guidance explains how an applicant may qualify for a waiver or reduction in user fees. Three potential qualifications for applicants are available to protect the public health; to avoid a barrier to innovation (i.e., the assessment of the fee would present a significant barrier in developing the product because of limited resources); or to maintain a small business (i.e., the applicant is a small business submitting its first drug application for review). The guidance goes into detail about each potential qualification for a waiver or reduced fee, and provides examples of how a company might meet the requirements. 

For example, if a company is requesting a waiver because its drug product protects the public health, the company might explain to FDA how the drug product offers a significant improvement compared with other marketed products, including other dosage forms or routes of administration and nondrug products or therapies; whether the drug is designated as a priority drug (e.g., fast-track status, new molecular entity); and whether the drug product demonstrates an increased effectiveness in the treatment, prevention, or diagnosis of disease. Additional considerations for applicants provided in the draft guidance document regarding barriers to innovation and costs for small businesses are provided in the draft guidance document.

The draft guidance also provides clarification of timing for when to request a waiver or reduced fee (i.e., no later than 180 calendar days after the fee is due). The consequences of not paying the application fee, and when to submit a request for a waiver or reduced fee to avoid paying the application fee (about three to four months before submitting an application) also are addressed. Finally, the document provides information about the content and format of such requests, and about how to handle refund requests as well as appeals or requests for reconsiderations should FDA deny an application.

Industry and public comments on the draft guidance are due within 90 days of the document’s publication date.

FDA issued a draft guidance for industry on Mar. 11, 2011, titled User Fee Waivers, Reductions, and Refunds for Drug and Biological Products, that offers recommendations to applicants seeking such actions under the Federal Food, Drug, & Cosmetic Act (FD&C Act). A similar draft guidance was issued in July 1993. The new document clarifies the types of waivers, refunds, and reductions available under the user-fee provisions of the FD&C Act as well as the procedures for handling these requests, including how to appeal an FDA decision.

FDA Issues Draft Guidance on User-Fee Waivers, Reductions, and Refunds

  FDA announced on Mar. 2, 2011, that it is taking action against companies that manufacture, distribute, or market certain unapproved prescription oral cough, cold, and allergy products, according to an agency 

  FDA’s Office of Compliance Director Deborah M. Author explained in a press briefing that the legal requirements for evaluating and approving prescription drugs have changed over the past century, including the enactment of the Food, Drug, & Cosmetic Act, and that, still, many drugs have remained on or entered the market illegally.

  This class of drugs is of particular concern because many of these products are labeled as “timed release,” which are complicated to manufacture. It is important, said Author, that FDA review these types of drugs to ensure that the release of the active ingredient is occurring at the right time and in the right dosage. This class of drugs is also important because many of the products are labeled for children age 2 and under. In 2008, the agency called for the relabeling of over-the-counter cough, cold, and allergy medications for children under age 2 because of potential serious side effects.

According to the agency press release, “Unapproved prescription cough, cold, and allergy drug products have not been evaluated by the FDA for safety, effectiveness, and quality. People may be at greater risk when using these products than when using FDA-approved prescription drugs or drugs that are appropriately marketed over-the-counter.” 

  The action, which is part of FDA’s 2006 unapproved drugs initiative, calls for companies that have previously listed products subject to FDA’s action to stop manufacturing the products within 90 days and to stop shipping the products within 180 days.  In addition, companies that have not previously listed products subject to today’s action with FDA are asked to stop manufacturing and shipping their products immediately. The overall initiative has prompted the removal of 550 unapproved products from the market in the past five years. This latest action affects 500 unapproved prescription products.

FDA announced on Mar. 2, 2011, that it is taking action against companies that manufacture, distribute, or market certain unapproved prescription oral cough, cold, and allergy products, according to an agency release.

FDA Removes from Market Unapproved Cough and Cold Prescription Products

If you haven't seen it yet, FDA has a Facebook page. In fact, as of this writing, the agency had nearly 4000 "friends" and more than 150 related links on its page (

). Among the agency's "favorite pages" are the CDC, the White House, Aids.gov, and Healthcare.gov. FDA and the US government as a whole are trying to be more transparent and open about the way they do things, but it's unclear whether a Facebook page is the right approach, or garnering the right audience. 

For example, one friend of the FDA page located outside the US asks on the agency's Facebook wall, why he can't send a carton of cigarettes to his friend in New Jersey for his birthday. Others have used the site to post negative comments about regulatory policies and initiatives. 

The agency has online supporters, too. One friend comments that people would not be able to trust drugs, food, cosmetics, medical devices, and more if it weren't for FDA's activities. He writes, "I would love to see how this country would operate with no FDA and no regulations." Others use the page to ask questions about drug approvals or to lobby for their own pharma or healthcare causes. 

To date, FDA does not seem to be responding to these comments or questions. Instead, the agency  uses the page to make announcements about new initiatives, to post press releases, and so forth.  FDA also has a more serious LinkedIn page and a Twitter account, the latter of which it has used to release recall alerts to the public rather quickly. 

 would like to hear your thoughts on FDA's use of social media tools and how you use them in your day-to-day work. 

Social media tools have taken over many aspects of our lives, now including regulatory info.

Is Facebook the Place for FDA?

The United States Pharmacopeial Convention (USP) launched a 12-month pilot Technical Assistance Program (TAP) to provide developing countries in sub-Saharan Africa with greater capacity to test the quality of medicines, according to a Feb. 8, 2011, USP 

. Under TAP, participating countries (Ethiopia, Ghana, Kenya, Senegal, and Sierra Leone) will receive a comprehensive package of pharmaceutical reference standards, documentary standards, and technical training. The goal is to improve these countries' efforts to ensure drug quality for their citizens. 
 
 Each of the participating countries has committed to improving public health, says the USP release. Several of the sub-Saharan African nations participating in TAP have also been part of USP’s Promoting the Quality of Medicines (PQM) program, which is funded by the US Agency for International Development and focuses on removing substandard and counterfeit medicines from the market. TAP will complement and reinforce PQM’s work.
 
 “I am very pleased that USP is able to launch this important pilot program in support of vulnerable populations,” said Roger L. Williams, MD, USP’s chief executive officer, in the press announcement. “The ability to test essential medicines using good quality standards is a crucial component of efforts to improve public health. The countries in this pilot are committed to strengthening drug quality and lack of key resources should not stand in their way. As a physician, I’m particularly interested in the broadest possible access to high quality, affordable medicines.”
 
 The fact that the USP standards will be provided at no cost to the participating TAP countries is unique. Traditionally, reference and documentary standards are sold to pharmaceutical manufacturers and quality-control laboratories, leaving organizations with few resources unable to purchase the most current standards.
 
 Patrick Lukulay, PhD, director of the PQM program, points out that, “Without good reference standards, test results produced by laboratories are questionable at best. USP’s Technical Assistance Program will increase the extent and scope of quality control and regulators will be able to exercise better oversight of medicines quality in their markets,” he said in the release. 
 
 At the end of the pilot program, USP and the five participating countries’ quality-control laboratories will assess progress in areas such as number and variety of drug samples tested, number of substandard or counterfeit drugs detected, and improved access to quality medicines. According to the pharmacopeia’s press announcement, “USP is emphasizing the need to measure, evaluate, and document activities and outcomes resulting from TAP projects. If the pilot is successful, support may be renewed or expanded with the initial participants, and the program also may be extended to other countries and include additional features.” 
 
 See related PharmTech articles
 

Recent Regulatory Efforts in Africa Aim to Fight Counterfeit Drugs

The United States Pharmacopeial Convention (USP) launched a 12-month pilot Technical Assistance Program (TAP) to provide developing countries in sub-Saharan Africa with greater capacity to test the quality of medicines.