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The rigors of regulatory approval Successfully navigating a pharmaceutical brand name through the global regulatory environment Beatrice Ellerin and John Breen


Introduction

The phase two trials of a new pharmaceutical compound are underway, and the clinical data looks promising. Product XX123 is generating excitement inside and outside the organization for its potential applications. While R&D and stockholders scrutinize the data anxiously, it is the marketers who are busy preparing the product for launch. Developing and securing a viable brand name is one of the most important of these pre-launch activities. Creating a pharmaceutical brand name is both exciting and challenging. Suddenly a compound that was once known as a strange code of letters and numbers (XX123), or referred to by its scientific name, will now have a real identity. Getting to this point requires a thoughtful strategy, the right tools, and a good deal of time. There are many aspects to the naming process from the creative output (the letters and syllables that make up this new piece of language), to securing trademark registration and regulatory approval. While each of these components is worthy of study, it is that last step - regulatory approval - that is the focus of this article. While government matters are generally not as sexy as other aspects of the naming process, they are arguably the most important. Ultimately, no matter how clever or groundbreaking the moniker for the drug, it is agency authorization – or lack thereof – that will determine the name’s final fate. A negative ruling can derail the entire launch process and force a company to go forward with a name that is sub-optimal, or worse non-existent. This is not a situation pharmaceutical companies desire, as it is both costly and embarrassing. The objective of this article is to help pharmaceutical marketers and brand managers better understand the steps necessary to obtain brand name approval with key regulatory bodies, specifically the Food and Drug Administration (FDA) in the United States and European Medicines Agency (EMEA) in Europe. It is meant to provide an overview of the regulatory process with both agencies, address the issues surrounding name approval, and lay out a framework for thinking about name validation and regulatory submission. In the case of rejection, we’ve provided guidance on evaluating the likelihood of success on appeal.

The rigours of regulatory approval – 1

Regulatory overview It is common knowledge that the Food and Drug Administration (FDA) in the United States and the European Medicines Agency (EMEA) in Europe must approve pharmaceutical compounds and biologics prior to public consumption. What is not as well known is that the trade names for these drugs must also be authorized and approved. The FDA began reviewing drug names beginning in the early 1990’s. However, it was a landmark report published in 1999 by the Institute of Medicine, linking drug name similarity to medication error, that led the FDA to increase its attention to and oversight of this part of the overall drug approval process. EMEA began examining “invented” names in 1995 and set up a specific working group to oversee the process in 1999. Both agencies initiated proprietary nomenclature assessment in the interest of public health and safety. This was based on the belief that names that sound alike or look alike can cause confusion, and in the worst cases, lead to medication error. Both FDA and EMEA share similar philosophies about proposed drug names. In general, they should not be: phonetically or visually similar to existing drug names or names pending approval, encode or be similar to generic/INN nomenclature, or convey promotional, misleading, unsubstantiated, or inappropriate claims Of course, there are many differences between the two agencies, particularly the type and amount of information that is documented and publicly available. Specifics related to each agency are discussed below. It is important to note that FDA and EMEA are not the only bodies that regulate pharmaceutical names. Japan’s Ministry of Health maintains its own set of guidelines for reviewing names. The process used in Japan warrants an article of its own, and will not be covered in this paper.


Food and Drug Administration (FDA) Within the vast bureaucracy that is the FDA, the responsibility for examining and approving new drug applications rests with the Center for Drug Evaluation and Research (CDER). Proprietary name reviews occur within the Office of New Drugs (OND), who request consultation from other divisions within the FDA, including the Division of Medication Errors and Technical Support (DMETS) within the Office of Surveillance & Epidemiology, and the Division of Drug Marketing, Advertising, and Communications (DDMAC), within the Office of Medical Policy (OMP) The one known about the name evaluation process is that there are many unknowns. The specific methodology used during the assessment has been gleaned from FDA articles, presentations, meetings, and the authors’ practical experience. However, although a recent recommendation from the Institute of Medicine suggested that the FDA should release guidelines in this area by early 2007, as of the writing of this article (January, 2007) there are no official FDA guidelines. In 2003, the FDA, in conjunction with the Pharmaceutical Research and Manufacturers of America (PhRMA) and Institute for Safe Medication Practices (ISMP), convened a workshop for industry, government, medicine, and academia to openly discuss the current methods and approaches used to screen proprietary drug names for similarities. Much of the information that follows is based on the meeting’s presentations and proceedings, as well as the authors’ practical knowledge of FDA procedures (Figure 1). The FDA’s trademark evaluation process can begin as early as the conclusion of Phase 2 for an investigational drug (IND) application or new drug application (NDA). It involves several steps and many people. The purpose of the review is to identify: Verbal (“sound-alike”) and/or visual (“look-alike”) likeness to: • Approved/marketed proprietary names • International non-proprietary names (INN) • Other medicinal products • Commonly used medical abbreviations • Medical procedures • Lab tests Embedded or implied promotional claims that are false or misleading and not supported by data including: • Superiority

Confusion caused by names that contain letters that could be misinterpreted as a dosing schedule, e.g. QD (every day), BID (twice a day) The assessment begins when the reviewing division for a drug requests a consult from the Office of Surveillance and Epidemiology. From there, DDMAC will first evaluate the name for communicating false promotional or misleading claims. If DDMAC finds a problem with the name they will make a recommendation to the OND to reject the name. If the OND agrees with DDMAC’s findings they will notify the product’s sponsor. If a name passes the DDMAC review it is sent on to DMETS for a safety evaluation. A panel of internal experts (who all work for the FDA) reviews the trademark against a number of FDA, pharmaceutical, medical, and trademark databases from which they compile a list of potentially confusing names. The trademark goes through a proprietary FDA-developed tool called Phonetic Orthographic Computer Analysis (POCA) to further hone in on similar drug names. A group of FDA volunteers (approximately 120-130) participates in handwriting and verbal order prescription simulation studies. Then, safety evaluators review the data amassed from the steps above and consider additional factors such as labeling, packaging, category, dose, dosage form, regimen, and route of administration. The safety evaluator issues an overall risk/benefit analysis and sends the recommendation to the project leader and the Deputy Division Director of DMETS. This opinion is forwarded to OSE for final review and sign-off, and sent on to OND. The OND notifies the product sponsor (pharmaceutical company) whether the name is acceptable or not acceptable. The last data published by DMETS covered its activities during 2004. That year the office received 338 name applications, of which it rejected 36%. The denial rate in 2004 was higher than in both 2003 (29%) and 2002 (31%). Although there is no recent data, it is likely that the rejection rate may be increasing based on the authors’ knowledge of the market. What is clear is that the lack of transparency can lead to unpredictable outcomes. This is as true today as it was in 2003 when one of the meeting’s participants opined, “If we can build predictability and validation into our model, it will help us to understand what level of evidence is necessary to achieve FDA clearance because right now…I’m not even sure I could say that we have 75 percent assurance that we’re going to actually achieve that name at the end of the day.”

• Efficacy • Safety The rigours of regulatory approval – 2


European Medicines Agency (EMEA) EMEA established a distinct committee, the (Invented) Name Review Group (NRG), in 1999 to consider proposed pharmaceutical trade names. The NRG is part of EMEA’s Committee for Medicinal Products for Human Use (CHMP), the body that evaluates the safety of medical products. Representatives from EU Member States participate in the NRG as do members of the European Commission and the EMEA Secretariat. NRG is chaired by an EMEA representative. Unlike the FDA, EMEA clearly details the NRG’s criteria and procedures for reviewing proposed pharmaceutical trade names in the “Guideline On The Acceptability Of Invented Names For Human Medicinal Products Processed Through The Centralized Procedure.” Since 1999, EMEA has introduced multiple revisions of the document as they continue to refine and improve their process. The NRG meets monthly, concurrent with the CHMP plenary meeting, to consider whether a proposed proprietary name “could create a public health concern of potential safety risk.” According to the NRG, a potentially acceptable name will not: 1. Express misleading therapeutic or pharmaceutical connotations 2. Misinform with respect to the composition of the product 3. Have the potential to cause confusion verbally or visually with the invented name of an existing medicinal product 4. Be liable to cause confusion with or be derived from international non-proprietary names (INNs) and/or reserved INN Stems 5. Convey promotional messages (e.g. Plus) 6. Appear to have an offensive connotation in any of the official EU languages. When considering the potential for confusion with another marketed product EMEA will consider the product’s indication, form, route of administration, and other relevant dispensing characteristics. Sponsors may submit an invented name (or names – up to three are permitted) up to one year in advance of submission of the drug’s marketing authorization application (MAA), but are encouraged to do so no more than four to six months prior to applying. The process proceeds as follows. EMEA assigns a Product Team Leader to the review. The proposed name(s) is sent to the National Competent Authorities (NCA’s) of all E.U. Member States, the European Commission (EC) and the World Health Organization (WHO), after which the reviewers have 30 days to advise EMEA of comments, concerns or issues regarding the name(s). During the next monthly NRG meeting, the committee members discuss all objections, comments, and other issues raised, and consider them against The rigours of regulatory approval – 3

the criteria above. Once the committee reaches a determination regarding adoption or rejection of the proposed name(s), it is presented at the plenary CHMP meeting for adoption. The EMEA Product Team Leader notifies the product sponsor of the outcome. EMEA began publishing monthly statistics from its NRG meetings in 2006. The committee reviewed 305 brand name applications (first submissions, not appeals), of which it rejected 152 or 50%. Perhaps this is due to the expansion of member states into the European Union, as an objection in a single country can lead to name rejection for the entire E.U. (Figure 2). Creating a successful validation program As outlined above, there are many hurdles a drug name must overcome to secure regulatory approval. It is, therefore, prudent to identify and explore any issues that may lead to rejection well in advance of a regulatory submission. Currently, there is no single scientifically proven method for identifying a safe drug name or pharmaceutical trademark. Therefore, the best strategy is one that incorporates multiple methodologies to test the viability of a proposed name, and casts the net broadly enough to highlight potential problems. Research should mirror the methods employed by the reviewing agencies, – to the extent possible – looking for visual and verbal similarity to marketed products, potential for dispensing error, compliance with regulatory guidelines, and cultural/linguistic suitability. Many pharmaceutical companies work with outside agencies or consultants to design and conduct name validation research. Selecting a partner with extensive trademark validation experience in healthcare is a good idea because they are in an excellent position to comment on the severity of issues that surface. Effective research will help marketers optimize name selection and generate the right data to support regulatory submissions. Below are issues to consider when devising or evaluating a name validation program. 1. Number of Names to Test Once the brand team has winnowed its list of preferred candidates from hundreds of possibilities to a small number of promising ones, it is appropriate to begin name assessment and validation. While there is no magic minimum or maximum, it is important to go into testing with enough names so that the team has a group from which choose at the end of the process. Based on the experience of the authors, a reasonable number would be ten to twelve names. Assuming the quality of the creative and corresponding legal viability is high, a typical yield post-validation would be three to five names. Testing with fewer candidates leaves the company open to the possibility of no survivors, which is clearly not a good situation to be in.


2. Sample Size While there is no published guidance regarding minimum respondent numbers in name validation research, it is important to recruit a robust and compliant sample. This typically includes anywhere from 130 to 200 healthcare professionals for the United States and 150 to 250 for Europe. Within Europe, researchers will often seek respondents from three to seven major markets. The sample is typically comprised of prescribers (general practioners and/or target specialists) and dispensers (hospital pharmacists, retail pharmacists and nurses). 3. Study Timeline A good research process takes time to design and execute. Allow at least eight to 12 weeks to execute a comprehensive name validation program for the United States and Europe. 4. Prescription Simulation Exercises Both FDA and EMEA place great emphasis on the belief that medication error is more likely to occur when a name sounds like or looks like another marketed product. Prescription simulation exercises are often used to test verbal and visual similarity to an existing or investigational drug. Typically, this research is conducted with prescribers (primary care physicians and/or target specialists) and dispensers (retail pharmacists, hospital pharmacists, nurses) who are asked to spell the name following a simulated verbal or written order. Most of this work is conducted online, particularly in markets like the United States and Europe where Internet penetration is high. As an example of the exercise, a research respondent will listen to a sound file of the name being spoken and then type in what he/she thought was communicated. Another respondent will review a written file with the name scripted by a physician (or physicians) and spell the word. It is best if different segments of professionals participate in each exercise to avoid bias that might result from seeing or hearing the name previously. An experienced consultant or agency can assist in determining which candidate misspellings are problematic and could lead to potential confusion in a healthcare setting. 5. Associations/Name Similarity Primary research with prescribers and dispensers is often helpful in identifying potentially confusing drug names, INN names, therapeutic connotations, medical products, and abbreviations. Through a series of open-ended questions, the respondents will comment on the names and provide specific associations. This often yields a generous number of drug and medical citations, some of which will be relevant, and others of which will be superfluous. An experienced consultant or agency can assist in determining those of a meaningful and serious nature.

6. Implied Name Communication As noted in the regulatory section, both the FDA and EMEA will reject names that embed or imply claims not supported by the data, such as those that convey superiority, efficacy, or safety. Ask your research panel to uncover these in much the same way they assist in identifying associations and similar drug names. If an overt, or even subliminal, message comes through, the panel members will likely point it out. An experienced consultant or agency can assist in determining which messages could lead to a regulatory rejection. 7. Letter String Analysis and Supplemental Desk Research In 2003, FDA developed its own screening tool, Phonetic Orthographic Computer Analysis (POCA), to help identify drug names and medical terminology that are visually and verbally similar to each other. POCA is not publicly available so it is impossible to mimic the software program exactly. However, there are a number of established approaches that can lead to the identification of similar drug names. As such, letter string analysis is often implemented in name validation research. A combination of automated and human searches can be conducted in comprehensive resources such as IMS Health (which tracks pharmaceutical sales across global markets), DRUGS@FDA and the USAN/WHO databases (to gauge conflicts with established generic nomenclature). Search strategies are developed to identify potential drug conflicts with similar prefixes, infixes and/or suffixes, visual and/or phonetic similarities and similar letter placements or letter combinations. Often times up to 900 variations are considered when searching a single trade name candidate. An experienced consultant or agency will conduct a review of the citations identified to determine conflicts of serious nature. 8. Linguistic/Cultural Analysis Testing for cultural suitability and linguistic nuance is yet another aspect of the overall name validation process. Marketers must avoid language that communicates an inappropriate or offensive message. What could have a positive or neutral meaning in one culture can easily be offensive or taboo in another. From a regulatory stance, a name that conveys a misleading promise or negative message (in an official E.U. language) is not acceptable. When pursuing trademark approval in the United States or European Union, it is good practice to test the name with linguists or translators in the major languages of North America and Europe. They will be able to identify any linguistic or cultural issues would make the name unsuitable for use as a trademark.

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Introduction

Preparing your regulatory submission After the name validation process is complete, a handful of possible trademarks remain, and the team narrows its selection to a final group of one to three names. The name(s) is ready to be submitted to the FDA for U.S. approval and/or the EMEA for E.U. approval. The FDA does not publish formal submission guidelines or preferred format, so it is up to drug’s sponsor to determine which information to include in support of the proposed name. The FDA will accept up to two names per review and suggests that the sponsor submit the names in order of preference. A request can take the form of a simple letter that includes the drug’s scientific name, the proposed proprietary name(s), a product profile, and any proposed product packaging and inserts. Examination of a proprietary name at the FDA is conducted on a first-come, first-serve basis with a target completion time of 60 days, although the process often takes much longer. Although the product sponsor may request early read on a name (starting at the end of Phase 2), the final determination is not made until 90 days prior to drug approval. Thus, positive feedback received prior to that threemonth window may not survive if similar names have been approved during the interim. As John Jenkins of CDER noted during the 2003 meeting, “I like to remind people that your proprietary name is not approved until it’s approved. So until you get the approval letter from the agency, we have not approved your proprietary name.” EMEA publishes a simple “Proposed Invented Name(s) Request Form” that requires the applicant to supply basic information including the drug’s INN name, proposed name(s), the intended indication(s), strength, pharmaceutical form and route of administration. Up to three names can be submitted at one time, although the sponsor should clearly identify which is the preferred trade name, and which are the back-ups. A draft Summary of Product Characteristics (SPC) or a product profile should accompany the request form. Companies are eligible to apply for NRG review up to one year in advance of submission of the drug’s marketing authorization application (MAA); however they are encouraged to do so between 4-6 months prior. Historically, product sponsors did not submit name validation research data to the regulatory bodies since it was neither requested nor required. Today, however, that position has changed. Many product sponsors proactively include portions of the research results to demonstrate that the proposed name does not present any significant safety problems. The hope is, that if they address any potential issues first – and provide data to support their rationale that the issues do not present a public health or safety concern – then the reviewing Agency will take this into consideration during the assessment. The rigours of regulatory approval – 5

As discussed above, both the FDA and the EMEA will consider more than one name during the review. Sponsors share mixed views on this. Some believe submitting more than one name decreases the chances of securing the one most desired, while others see it as a prudent way to increase the likelihood of a successful outcome for at least one of the names. Ultimately this is a judgment call, so the sponsor must consider, and be prepared, to accept the risks involved in selecting either option. The name is rejected: when to consider an appeal Recall that the EMEA’s rejection rate in 2006 was nearly 50% and the FDA’s last published rate in 2004 was 36%. No matter how thoroughly the sponsor prepares, there is clearly a chance that the proposed name will be rejected, at least initially. Given these realities, smart marketers can prepare for rejection as part of the name submission process. One strategy is to submit more than one name (discussed above) to spread the risk and increase the likelihood that at least one name passes muster. Another tact is to appeal the negative regulatory ruling. Increasingly, companies are prepared to lobby against a rejection to secure the trade name they desire. And there is good reason to consider this option, because both the FDA and the EMEA have overturned initially negative rulings. Each situation is different, so it is important to weigh the risks and benefits of pursuing an appeal. The sponsor must carefully consider a host of factors including: • What were the circumstances surrounding the rejection? • Is there a suitable back-up name for the company to consider? • If look-alike and/or sound-alike issues were cited, was it one drug that caused the conflict or multiple drugs? Are there enough differences between the drug(s) in question to mitigate the actual potential for dispensing confusion? • What data captured during the validation process are available to specifically address the Agency’s objections? • Is additional research needed to build a case? If so, is it possible to collect enough credible evidence to refute the rejection? • Will the expense involved in capturing new data be a worthy expenditure? • Internally, what is the team’s appetite for yet another rejection if the appeal is not successful? If the sponsor chooses to go forward with an appeal, the best course of action is to consult with experts who have already successfully navigated the process.


Conclusion

Securing regulatory approval for a brand name is a rigorous, timeintensive process. It is one that requires a well-crafted strategy and commitment of resources. A few final thoughts on best practice: • Begin thinking about regulatory matters early. Devise your plan of action by close of Phase 2 or early in Phase 3. • Don’t skimp on name validation research, particularly in terms of uncovering potentially similar drug names. It is important to let issues surface before, not after, regulatory submission. • Incorporate multiple research methodologies (primary, secondary, quantitative, qualitative) into your process. • If you choose to work with an outside consultant or agency, select one with extensive healthcare name validation expertise. And make sure they have recent approvals to talk about. • Have back-up names available in case of Agency rejection. • When appealing a negative ruling, work cooperatively with the Agency to address and resolve issues. Ultimately, companies face a number of challenges in the process of developing and securing a name for global brand: a creative challenge, to develop a unique and compelling name; a linguistic and cultural challenge, to ensure the name will be applicable across global markets; a legal challenge, to ensure the name is registrable as a trademark; and finally, the challenge of securing regulatory approval. We hope to have demonstrated, in this paper, the value of paying as much attention to the regulators, as to the other stages of the name development process. Although not exactly the sexiest of topics, it is arguably one of the most important.

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Beatrice Ellerin Beatrice Ellerin, known as Bunny, is the Managing Director of InterbrandHealth, in the New York office. Bunny leads the research division and is responsible for all facets of the business including operational performance, business development, client management, and staffing. Bunny is known throughout the industry for her work founding and leading the Harvard Business School Health Industry Alumni Association.

www.interbrandhealth.com

John Breen John Breen is Research Director for rxmark, the research division of InterbrandHealth. He is responsible for managing all global qualitative and quantitative branding research services for Interbrand Health. Over his eight plus years with the company, John has worked extensively with healthcare clients to design, implement, and report on trademark evaluation studies. In addition, John has consulted with clients to navigate the unsettled regulatory environment and develop documentation to support trademark submissions to both the FDA and EMEA.

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InterbrandHealth: Rigors of Regulatory Approval