Parameters of Development - Drug Delivery Enabled/Enhanced Products (DDEP ) A Review (Chapter 7)

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1 CHAPTER 7 FDA DRUG APPROVALS, Introduction This chapter reviews drug delivery enabled/enhanced product approvals by the FDA over the period This is a simple analysis that provides some insight into the performance of the industry in terms of approved products. Unlike new pharmaceutical active products the barriers to new drug delivery enabled/enhanced products is much less impacted by safety concerns. The challenges in developing and gaining approval for DDEP are primarily related to identifying commercially and therapeutically meaningful product opportunities and then shepherding the products through the clinical development and regulatory approval process. A detailed definition of a DDEP is provided below. In summary, a DDEP is a pharmaceutical product that incorporates a drug delivery or formulation technology to alter the absorption, distribution, metabolism and/or excretion of pharmaceutical active with the intent of enabling and/or enhancing its therapeutic benefit. This definition excludes products that depend on technologies that are widely available and are considered simple toolbox formulation technologies. An example of a simple toolbox technology would be enteric coating as used to prevent stomach acid degradation of a pharmaceutical active. Defining DDEP This report uses the acronym DDEP for drug delivery enabled/enhanced product. We define a DDEP as a pharmaceutical product used for the treatment of humans that incorporates a drug delivery technology to alter the absorption, distribution, metabolism and/or excretion of a pharmaceutical active with the intention of enabling and/or enhancing its therapeutic benefits. DDEP are restricted to products that utilize non- toolbox formulation technologies. By non- toolbox we refer to drug delivery and formulation technologies that are proprietary, if not patented, and are not generally accessible to all companies. Examples of these non- toolbox technologies are PEGylation, Oral Dissolution Technologies (ODT) and Transdermal Patches, all of which in the period covered by this report are available from multiple sources but generally require certain proprietary materials or know- how. One technology not included in our definition of DDEP is enteric coating as used to avoid gastric degradation. Accordingly, products such as proton pump inhibitors are excluded from this analysis. The purpose of defining a DDEP in this manner is to provide a reasonable break between drug delivery and simple formulation impacted pharmaceutical products. This is a sliding definition. What was considered a breakthrough drug delivery technology when first introduced is often considered a toolbox or formulation technology a decade or two later. 7-1

2 For the purpose of this analysis we separate DDEP into two separate groups, Enhanced and Enabled products. The former products use drug delivery technologies to enhance the performance of the products, an example would be reducing the dosing frequency of an active; another would be improving the tolerability of an injectable. In contrast Enabled DDEP use drug delivery technology to permit the active to be used as a pharmaceutical. An example would be the use of a solubilization technology to increase bioavailability to the point that it makes the active suitable to be used as a drug. In general, enhanced DDEP are based on previously approved actives while enabled DDEP involve unapproved pharmaceutical actives, although there are exceptions where a technology is used to both enable and enhance. This analysis can be compared to other industry analyses of FDA approved drugs. The difference is that these industry reviews are focused on the approval of products containing new pharmaceutical actives and exclude drug delivery enabled/enhanced products unless the technology is incorporated into a product containing a new pharmaceutical/molecular entity. Methodology The methodology for this chapter involved reviewing all products approved by the FDA in the period 2000 through the end of 2010 and determining whether they were a DDEP and if they were, whether they were Enabled or Enhanced. The majority of these products are included in the analysis of clinical development and approval times presented in earlier chapters. DDEP approvals were also analyzed with respect to a variety of parameters including approved indication, delivery route and sponsoring company. 7-2

3 Benchmarks NME and BLA Approvals A number of sources provide an analysis of trends in the FDA approval of new molecular entity drugs. This is considered by many to be a valid benchmark of pharmaceutical industry productivity, more must mean better. These audits almost never include new formulations of previously approved actives, i.e., drug delivery enabled/enhanced products (DDEP), even if they provide significant therapeutic benefits or define new indications. We will use the Nature Reviews article (Nature Reviews Drug Discovery 10, (February 2011) as a reference for FDA new molecular entity approvals. This analysis includes new molecular entities and biologicals approved annually since The results are presented in Chart 7-1. A total of 275 products classified as new molecular entity (NME) or Biologicals (BLA) were approved in this period. As others have commented there has been a steady drop in approved new molecular entity small molecule products over the 2000 to 2010 period that is partially offset by a reasonably constant stream of therapeutic biological product (BLA) approvals. Table 7-1: NME and BLE Approvals by Year, Annual Approvals NME BLA

4 DDEP Approvals Chart 7-2 provides a graphical overview of Enabled and Enhanced DDEP approvals for the period 2000 to Over this period a total of 235 DDEP were approved by the FDA, for an annual average of about On average 19.4 Enhanced DDEP, and 2.0 Enabled DDEP were approved annually. This total includes 30 products that were also classified as NME or BLA products by the FDA. These products include NME delivered by the pulmonary route and covalent conjugate products such as Pegasys and Vyvanse. The total number of DDEP is total would be higher if we were to include products using relatively generic toolbox formulations such as enteric coating, a standard formulation approach used with many of the proton pump inhibitors. Table 7-2: DDEP Approvals by Year, Enhanced Enabled Annual Approvals On a combined basis the FDA approved a total of 480 new products in the period of (This total does not double-count those products that were both an NME or BLA and a DDEP.) The approval trend in terms of NME (including BLA) and DDEP (Enhanced and Enabled) approvals over this period is presented in Chart 7-3. The slight uptick in DDEP approvals over this period has countered in part the downward trend seen in the traditional NME approvals. 7-4

5 Table 7-3: NME, BLE and DDEP Approvals by Year, Annual Approvals DDEP NME All Products 7-5

6 DDEP Approvals Parameter Analysis It is possible to further analyze the DDEP approvals in terms of a number of product specific parameters. These parameters are presented in Table 7-1 with a short description. Table 7-1: Analysis Parameters, DDEP Approvals Parameter Description 1. Company Type Big Pharma, Specialty or Drug Delivery 2. Company Leaders Leading Companies with Approved DDEP 3. Indication DDEP by Therapeutic Indication 4. Route DDEP by Delivery Route 5. Technology Suppliers DDEP by Technology Providers DDEP Approvals by Company Type It s worth considering who is responsible for the 235 DDEP approved over the past 11 years. We define the responsible company as that organization primarily responsible for the financing and execution of product development and approval. This means a product such as Exubera is considered a Pfizer product because Pfizer was a very early product partner and provided the largest proportion of financial and clinical development resources to bring Exubera through development and approval. This is not to minimize the considerable Nektar contribution but without Pfizer there would not have been a product. In a similar fashion a Big Pharma or Specialty Pharma company that commissioned a DDEP from a Drug Delivery company (DDCo) was credited with the approval of this product. An example might be GSK working with Flamel for a sustained release formulation of Coreg. There are examples of DDCo, for example DepoMed, that developed their products through to NDA filing or approval before licensing the DDEP to a partner. These products are credited to the DDCo. Confusion may arise with respect to the definition of Big Pharma, Specialty Pharma and Drug Delivery companies. Big Pharma, including Big Bio, are considered in the context of 2010 to have had annual sales in excess of $7 billion. Specialty Pharma have reported sales less than $7 billion and a marketing and sales operation. Drug Delivery includes companies without a sales and marketing resource. In many cases these DDCo provide the technology and resources for a Big Pharma or Specialty Pharma company to develop their own DDEP. The assignments were considered at the time a DDEP was filed with the FDA. Often a Specialty Pharma or Drug Delivery 7-6

7 company might file a product and then license it out to a Big Pharma company, or a company was acquired later by Big Pharma. In both cases the product was assigned to the smaller entity as it really was responsible for the DDEP development. The leading company group in receiving FDA approval for DDEP was Specialty Pharma with a total of 123 products, (52% of all DDEP), approved in the period Big Pharma lagged behind with 93 (40%) approved DDEP while Drug Delivery was a distant third with 19 (8%) DDEP. In terms of where these companies sourced the underlying drug delivery technology, Big Pharma sourced technology internally for 70% of their products, with their remaining products using externally sourced technology. In the case of Specialty Pharma, 55% of the technology was sourced internally. For DDEP developed by Drug Delivery companies, 100% of the technology was internally sourced. Results are summarized in Table 7-2. Table 7-2: Company DDEP Approvals and Technology Sourcing, Approved DDEP (%) Internal Technology (%) External Technology (%) Big Pharma 93 (40%) 70% 30% Specialty Pharma 123 (52%) 55% 45% Drug Delivery 19 (8%) 100% 0% DDEP Approvals by Company Big Pharma A total of 80 companies were responsible for the 235 DDEP approved over the last 11 years. The leading company in terms of approved DDEP was GlaxoSmithKline with a total of 13 approved DDEP. The largest part of this portfolio was related to internal projects initiated through one or more of their subsidiaries. Pfizer was a close second with 12 FDA approved DDEP. This figure may surprise some as Pfizer is not usually associated with a major drug delivery initiative and DDEP portfolio. The answer is that many of these DDEP have been contributed by companies acquired over the last decade, notably Pharmacia & Upjohn and Wyeth. This total does not include DDEP that were added to their portfolio as a result of the acquisition of Specialty Pharma companies. A full list of Big Pharma companies with three or more DDEP is presented in Table 7-3. Abbott and J&J, companies known for their drug delivery capabilities are tied for 3 rd. Lilly and Roche are notable in being lower in the list with 3 and 2 approved DDEP respectively. 7-7

8 Table 7-3: Big Pharma Company Approvals, (>2 DDEP) Company Approved DDEP Share of All DDEP GlaxoSmithKline 13 6% Pfizer 12 5% Merck 10 4% Abbott 8 3% Johnson & Johnson 8 3% AstraZeneca 7 3% Novartis 7 3% Sanofi-Aventis 7 3% Boehringer-Ingelheim 4 2% Bristol-Myers Squibb 4 2% Eli Lilly 3 1% 7-8

9 DDEP Approvals by Company Specialty Pharma The top Specialty Pharma companies in terms of approved DDEP were UCB (8), Valeant (8), Shire (7) and Watson. Valeant, which includes the Biovail portfolio, and Shire are not a surprise as leading companies in this area. UCB is a little surprising. Much of their DDEP portfolio came from the acquisition of smaller Specialty Pharma companies that had profitable DDEP. The Watson DDEP include only those approved as NDA products, all ANDA products are excluded. A list of Specialty companies with 3 or more approved DDEP is presented in Table 7-4. Table 7-4: Specialty Pharma Company Approvals, (>2 DDEP) Company Approved DDEP Share of All DDEP UCB 8 3% Valeant 8 3% Shire 7 3% Watson 7 3% Endo 4 2% Allergan 3 1% Dey 3 1% Forest 3 1% Purdue 3 1% Reckitt Benckiser 3 1% Sunovion 3 1% 7-9

10 DDEP Approvals by Company Drug Delivery There were no Drug Delivery companies able to bring more than two DDEP to the market in the period Several companies that one might imagine having done so, notably Alkermes, Nektar and SkyePharma, most often were involved in providing a partner with a product or technology to meet the larger partner s requirements. There were five Drug Delivery companies able to gain FDA approval for more than a single internal product. These companies are, with the exception of SkyePharma and perhaps DepoMed, smaller players with very niche oriented products. The Drug Delivery companies with more than a single approved DDEP are listed in Table 7-5. Table 7-5: Drug Delivery Company Approvals, (>1 DDEP) Company Approved DDEP Share of All DDEP Cipher 2 1% DepoMed 2 1% NovaDel 2 1% SkyePharma 2 1% Tris 2 1% 7-10

11 DDEP Approvals by Indication, Central Nervous System Disease indications as a group, which included DDEP for anxiety, insomnia, depression, ADHD, pain and drug and alcohol abuse, was the top therapeutic class accounting for 27% of all approved DDEP. This was followed by Cardiovascular, Endocrinology and Respiratory DDEP each with about an 11% share. Infectious Disease and Neurology focused DDEP each had an 8% share. Results are summarized in Table 7-6. Table 7-6: DDEP Approvals by Indication (>3 DDEP) Number % of Total Total Allergy 11 5% Cancer 10 4% Central Nervous System 64 27% Cardiovascular 27 11% Endocrinology 25 11% Infectious Disease 18 8% Inflammation 4 2% Neurology 18 8% Respiratory 25 11% Urology 10 4% 7-11

12 DDEP Approvals by Delivery Route, Oral delivery was by far the most common DDEP delivery route accounting for 54% of all approved DDEP in the period Oral delivery included Oral SR, Oral IR, and ODT formulations. This was followed by Inhalation and Injection based DDEP each with an 11% share. Combined Transdermal/Topical DDEP were next with a 10% share. Nasal and Buccal/Lingual DDEP each accounted for 5%. In terms of trends, delivery by Oral and Injection routes remained as popular on average at the end of the decade as it was at the start. Inhalation DDEP accounted for smaller share of approvals as the decade progressed ranging from a high of 19% in 2000 to a low in the 4-5% range in 2007, 2008 and 2009, with an increase to 9% in Transdermal/Topical DDEP approvals hit a peak in the years accounting for an average of 18% of all approvals. This has dropped to the 10% over the last couple of years. The results are summarized in Table 7-7. Table 7-7: DDEP Approvals by Delivery Route (>5 DDEP) Number % of Total Total Buccal/Lingual 12 5% Implant/Insert/IUD 6 3% Inhalation 26 11% Injection 27 11% Nasal 11 5% Oral % Transdermal/Topical 24 10% 7-12

13 DDEP Approvals by Technology Supplier As noted earlier the majority (65%) of the approved DDEP were developed using internal drug delivery technology. The use of internal technologies ranged from a high of 100% for Drug Delivery companies, to a low of 55% for Specialty Pharma companies. Big Pharma used internal technologies for 70% of their approved DDEP. For drug delivery technologies sourced externally the most important suppliers were Elan, Cima and 3M accounting for a combined 12% of all approved DDEP, or a third of all in-licensed technologies. These companies were followed by a number of other well known companies each providing the technology for 4 to 5 approved DDEP. Results are summarized in Table 7-8. It should be remembered that this table summarizes only FDA approved prescription products that required in-licensed technologies and excludes any internally developed DDEP by these same companies and any generic and OTC products using in-licensed drug delivery technology. Table 7-8: DDEP Approvals by External Technology Supplier, (2+ DDEP) Number % of Total Elan 11 5% Cima 10 4% 3M 7 3% Eurand 5 2% Nektar 5 2% SkyePharma 5 2% Catalent 4 2% CyDex 3 1% Debiopharm 3 1% Pari 3 1% Besins 2 1% Monosol 2 1% Supernus 2 1% All Other External 21 9% Internal Technology % 7-13

14 Reflections What is to be made of the figures and analysis provided in this chapter? Unlike earlier chapters which provided information on success rates and development timelines, this chapter simply provides an overview without offering any clear guidelines and recommendations. Unsurprisingly, oral drug delivery enhanced/enabled pharmaceuticals proved to be the most popular/common. This is not a surprise considering the large number of oral agents, the availability of sustained release and ODT technologies, and the accepted lifecycle strategy benefits of reducing dosing frequency. Perhaps more surprising is Big Pharma s reliance on internal, rather than third party, drug delivery and formulation technologies. This is a change from the decade earlier where Big Pharma were largely reliant on the drug delivery pioneers, Elan and Alza, to provide them with products and technologies to extend the usefulness of their own actives. Big Pharma s current reliance on internally developed, or non-proprietary technologies, may be largely responsible for the increasing focus of drug delivery companies to develop their own pipeline of products for eventual commercialization or later stage outlicensing. 7-14