Parameters of Development - Drug Delivery Enabled/Enhanced Products (DDEP ) A Review (Chapter 9)

Transcription

1 CHAPTER 9 - PRODUCT EXCLUSIVITY Introduction This chapter examines the duration of market exclusivity enjoyed by drug delivery enabled/enhanced products in the period 1996 through All successful commercial products are subject to competition which can range from substitutable generic products, to functionally equivalent products, to products related only by the fact that they address the same therapeutic indication and patient population. The length of time a drug delivery product enjoys relative or absolute exclusivity can significantly impact its commercial prospects and net present value. This chapter looks at the two most important and relevant groups of competitors; substitutable generics and functional equivalents. By Substitutable Generic we are referring to a competitive product that in the USA can be substituted at the pharmacy for the originator or reference product. In terms of the FDA Orange Book these products are often approved with an AB (or AP, AN, ) designation permitting simple substitution. Often, but not always, these Substitutable Generics are approved on the basis of bioequivalence using the same quantity of active ingredient as the originator product in a similar, but not necessarily identical, dosage form. Substitutable Generics are not required to use a delivery technology identical to the originator so long as they are bioequivalent to the reference product according to issued FDA guidelines. These Substitutable Generics are generally, but not always, approved as ANDA products (505(j) approval). The second type of competitor we consider in this chapter is a drug delivery enhanced/enabled pharmaceutical (DDEP) competitor approved for the same indication, incorporates the same active in a similar or identical dosage strength, uses a comparable delivery format (Oral SR in the case of an Oral SR originator) but is not approved on the basis of bioequivalence to the originator. These Functional Equivalents are approved on the basis of their own clinical efficacy, safety, and tolerability studies. These DDEP are most often brought to market using the FDA s 505(b)(2) approval process. These products cannot be automatically substituted for the originator product at the pharmacy level. A physician might choose to prescribe the Originator or Functional Equivalent product based on his or her estimation of the relative therapeutic benefit of each product for any individual patient. In some cases a dispensing pharmacist may choose to call a physician to substitute one product for another based on his or her sense of therapeutic or financial benefits, but the pharmacist can only make a substitution with the approval of the physician. Either or both of the products may be included on a drug formulary, and subject to the same or separate co-pay levels. The bottom line is that while a Functional Equivalent may not be 9-1

2 freely substituted for another product it can be considered to provide a comparable benefit. An example might be two topical estrogen products approved for the treatment of menopausal symptoms. One might be a cream, the other a gel, and dosages might differ slightly, but a physician could freely choose to use one or the other for a patient based on their estimation of their relative benefits based on therapeutic or cost considerations. As we will see, DDEP in this time period have been more often subject to competition from Functional Equivalents rather than than Substitutable Generics. 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. Methodology The analysis of exclusivity was based on a review of 257 DDEP approved in the period 1996 through Each product was followed from its date of launch through the end of 2010 and coded as to if, and when, a Substitutable Generic or Functional Equivalent had been introduced. While Substitutable Generic and Functional Equivalents were evaluated separately, it should be recognized that Substitutable Generics are a subset of the Functional Equivalent group and are included in this larger group for the purpose of presentation and calculations. Additionally, DDEP that were subsequently withdrawn from the market were included in the analysis of Substitutable Generics. These products quite obviously were no longer being sold and enjoyed no relative or absolute market exclusivity. 9-2

3 Exclusivity Options The FDA currently provides some amount of regulatory exclusivity to most NDA approved pharmaceutical products. For products that incorporate a new molecular entity not previously approved the regulatory exclusivity is generally five years. Products incorporating a previously approved active in a new delivery format receive a three year period of regulatory exclusivity. This simply prohibits the FDA from approving a competitive product filed as an ANDA before the FDA exclusivity period has expired. And if a product addresses an Orphan Indication it is eligible for seven years of regulatory exclusivity. A company can secure extended exclusivity with issued patents that cover their DDEP. These patents can address a variety of critical parameters including the drug delivery system, the therapeutic active, the method of treatment, the serum plasma levels, an associated device, etc. In many cases these patents can extend exclusivity to more than a decade. In other cases, issued patents that are listed in the FDA s Orange Book have no practical impact on market exclusivity because a competitive product does not infringe these patents, for example uses a different delivery system, or the patents are found to be invalid. In other cases companies choose to settle with infringers even with valid and enforceable patents to avoid legal challenges and expenses. In some additional cases companies choose to enter into settlement agreements with potential infringers that permit the originator company to extend their market exclusivity in exchange for certain payments and the right for the infringer to enter the market under license from the originator earlier than the issued patents would have allowed. Securing FDA approval for any Substitutable or Functional Equivalent product depends on developing a product that does not infringe issued patents. For DDEP where the pharmaceutical active has no remaining patent protection this is becoming much less of an issue as more and more functionally equivalent drug delivery technologies are developed and validated. Exclusivity Period, Substitutable Generics Functional Equivalence The good news is that despite the fact many drug delivery enabled/enhanced products are based on approved actives and eligible in theory for only three years of exclusivity many DDEP enjoy a reasonably long period of exclusivity. The bad news is that most DDEP do not enjoy as much exclusivity as might be expected based on issued patents covering the product and underlying technology. 9-3

4 Chart 9-1 schematically summarizes the proportion of DDEP that retain exclusivity with respect to Substitutable Generics up to ten years after approval. There is a very slow erosion of exclusivity with respect to Substitutable Generics, with almost 75% of DDEP retaining exclusivity through ten years after approval. Chart 9-1: DDEP Exclusivity with Respect to Substitutable Generics ( ) % Without Generic Competitor Years Post Launch The situation with respect to Substitutable Generics is quite positive; we expect to see the first competitors being introduced after the third-year when the shortest FDA exclusivity period has expired. While there is a drop after the three-year post approval period it is only a little greater than the general trend over the first seven years post-approval. These generics almost always use technology not covered by the originator s intellectual property claims but are bioequivalent as defined by the FDA. In rare cases the underlying technology is the same as the originator product. This is the case where the originator drug delivery technology is older and the technology patents have lapsed. Even after 10 years only 25% of DDEP are subject to a Substitutable Generic. Optimistically this may imply that many of the drug delivery products being developed have sufficient intellectual property protection, or are so technically demanding, as to deter bioequivalent generics. Alternatively the situation may be that many of the products are of insufficient commercial importance to interest generic competition. In many cases though the parent active is still under patent protection if a DDEP formulation is introduced at first launch of the active or at an early stage of the brand s commercialization 9-4

5 Exclusivity Period, Functional Equivalence The situation with respect to Functional Equivalents, which include Substitutable Generics, is not quite so rosy but is still quite positive as seen in Chart 9-2. It is immediately apparent that after one year only 8 of products have retained their exclusivity with respect to functional equivalents. This does not mean competing DDEP have been introduced; rather these products are functionally equivalent to products already on the market. An example would be the early 2009 approval of Labopharm s sustained release oral tramadol product Ryzolt. This DDEP was approved on the basis of its own SR formulation and extensive clinical trial program and was functionally equivalent to Biovail s oral sustained release tramadol formulation Ultram ER. Thus Ryzolt had no effective exclusivity at launch, and is an example of this early 2 group. At the point of the Ryzolt introduction Ultram ER lost its Functional Equivalent exclusivity. In a similar fashion Roche s Pegasys (PEG-interferon alpha) had no functional exclusivity when it was launched as it followed Schering-Plough s PEG-Intron to the US market by about a year. At that point of course PEG-Intron similarly lost its functional exclusivity because it now competed with Pegasys. Both products though still retained exclusivity from substitutable generics. Chart 9-2: DDEP Exclusivity with Respect to Functional Equivalents ( ) % Without Generic or Functional Competitor Years Post Launch Functional equivalents do not include DDEP that address the same indication but incorporate a different active. A twice-daily oral morphine DDEP would not be a functional equivalent to a twicedaily oral oxycodone formulation. They may well compete for the same patient population but they are not functional equivalents for the purpose of this analysis. To further clarify this point, a oncedaily oral morphine DDEP is not considered functionally equivalent to a twice-daily oral morphine 9-5

6 DDEP, even though they would be competitive products. If one were to include this potentially larger definition of a Functional Equivalent, it is obvious that the slope would be much steeper. After the first year functional exclusivity is lost slowly, so that after about seven or eight years only half of drug delivery enabled/enhanced products have some sort of functional equivalent in the market. There is a slight but obviously larger drop in Functional Exclusivity after three years. This coincides with the lapse in the three year exclusivity offered by the FDA for novel formulations of a previously approved active. The slight increase in Year 9 and drop in Year 10 seems to be an anomaly of the data set. Each year had a slightly different population set depending on the year the product was launched. An examination of those DDEP that incorporate a previously approved active does not reveal a faster rate of functional equivalent introduction in comparison to the full DDEP population. This effect may be disguised by the fact that the majority of the DDEP included in this survey, and actually all those approved in the past fifteen years, incorporate previously approve actives. Among those products that attracted early AB Generics we find a half dozen DDEP that share common features. All are oral sustained release products genericized since 2003, and all had sales greater than $150 million annually. Two of these products had sales in excess of $1 billion. The other DDEP subject to early AB Generics were Oral ODT products. These were effectively genericized even when their annual sales were less than $20 million. Exclusivity Period Evolution, Functional Equivalence and Parameter Analysis It s worth looking at how the exclusivity period for DDEP is evolving. A snapshot on the situation is provided by looking at the rate of first five-year functional equivalent exclusivity for DDEP first approved in the periods , and pre The results are presented in Chart 9-3. There appears to be a trend towards a quicker loss of exclusivity for drug delivery enhanced/enabled pharmaceuticals. This is consistent with increasing competition in the pharmaceutical area, the quicker introduction of generics, the increasing availability of functionally similar drug delivery technologies, and the drop in approval of new small molecule chemical entities. The reduced number of NME small molecule approvals requires companies developing DDEP to increasingly return to the same pool of previously approved actives and try to improve upon previously approved DDEP, or find a new therapeutic twist consistent with their particular platform technology. The increased relative exclusivity seen in year 5 with the group seems to be an anomaly related to the relatively small number of DDEP included. 9-6

7 Chart 9-3: DDEP Exclusivity with Respect to Functional Equivalents ( ) % Without Generic or Functional Competitor Approvals Approvals <2001 Approvals Exclusivity Period, Parameter Impact on Functional Equivalence One might imagine there could be a difference in the rate of the introduction of functionally equivalent products depending on the type of DDEP being considered. One obvious parameter which might be subject to variable rates of functionally equivalent DDEP is delivery route. It would seem that DDEP for which there are multiple technology platform options should see a faster drop in exclusivity. To this end three general platforms were examined; Inhalation, Oral SR, and Oral ODT. These platforms were chosen because they were sufficiently well populated to permit reasonable analysis and perhaps allow for some conclusions. Exclusivity Period, Inhalation DDEP Drug delivery enabled/enhanced product based on inhalation platforms seem to have a remarkable longevity in terms of market exclusivity. This is due in part to US-FDA regulations that do not provide for a simple pathway for the approval of generic inhalation products. This means that companies wishing to develop a substitutable inhalation DDEP are required to conduct full clinical trials to demonstrate efficacy and safety in the absence of accepted bioequivalence metrics (for which there may be no accepted standards). This is a challenging requirement for most companies without the resources of Big Pharma or the very largest Specialty Pharma companies. And these DDEP when approved are at best functional equivalents and non-interchangeable with the originator product. But the numbers do not readily support this hypothesis as seen in Chart 9-5. Even with inhalation DDEP there is a 9-7

8 steady drop in products retaining exclusivity. Part of this can be explained by the crop of functionally equivalent metered dose inhalation bronchodilators approved in the early 2000 s as regulatory requirements mandated a change to the use of non-cfc propellants. And jet nebulized DDEP are treated pretty much as injectables with regard to regulatory approval, requiring only the demonstration that the nebulization solutions contain the same dose and volume as the reference drug. The performance of these DDEP are dependent on the performance of the jet nebulized to a much greater extent than the formulation. Nonetheless, inhalation based DDEP can enjoy prolonged regulatory exclusivity because of the absence of simple bioequivalence guidelines and the idiosyncrasies of proprietary inhalation devices. Chart 9-4: Inhalation DDEP Exclusivity with Respect to Functional Equivalents ( ) 10 % Without Generic or Functional Competitor Years Post Launch Exclusivity Period, Oral SR DDEP There is a long history with Oral SR products, it has been more than 25 years since the approval of Procardia XL and the rush to develop long acting formulations. This is born out by the numbers, Chart 9-5. Starting out with some 2 of Oral SR enjoying no exclusivity with respect to functional equivalents the number rises to 5 by Year 6. So unlike Inhalation DDEP that never drop below the 6 exclusivity level, Oral SR DDEP drop to below by Year

9 The reason for the 8 figure in Year 1 is related to the fact that many Oral SR DDEP are variations on a previously approved theme, for example Oral SR formulations of tramadol, bupropion and methylphenidate. But even if we ignore these DDEP that are launched without any exclusivity from functional equivalents the drop for Oral SR DDEP is precipitous. Oral SR DDEP need to make their money early in their launch cycle because of the all too pressing challenge of imminent substitutable and functionally equivalent formulations. Chart 9-5: Oral SR DDEP Exclusivity with Respect to Functional Equivalents ( ) 10 % Without Generic or Functional Competitor Years Post Launch Exclusivity Period, Oral ODT DDEP Another delivery platform that seems to be a candidate for generic and functionally equivalent competition is Oral Dissolve Technology (ODT) formulations. There are many companies offering these technologies and the approval demands are minimal; a requirement to provide the same therapeutic serum levels as the oral immediate release reference product. The data seems to be at odds with this hypothesis, Chart 9-6. While 2 of Oral ODT formulations enjoy no real exclusivity on launch, the drop in exclusivity is relatively mild with between 5 and 6 of these DDEP enjoying exclusivity at Year 10. There biggest reason for the extension of this exclusivity may be that unlike some other DDEP, ODT formulations of new chemical entities are often introduced to the market early in the product lifecycle, rather than at the end as part of a lifecycle extension strategy. This allows the Oral ODT products to enjoy the market exclusivity of the new chemical entity rather than the three-year FDA awarded exclusivity or any patent associated with the ODT formulation. Patents on ODT formulations tend to be weak and rarely prevent functionally equivalent competitors. (Note: the 9-9

10 inconsistent trends after Year 6 my be accounted for by the fact that the database of Oral DDEP consists of 28 products, only 10 of which have been on the market for more than 6 years.) Chart 9-6: Oral ODT DDEP Exclusivity with Respect to Functional Equivalents ( ) 10 % Without Generic or Functional Competitor Years Post Launch 9-10

11 Reflections Despite the very obvious possibility of functional equivalence and substitutable generics it seems this has not been a major commercial issue for drug delivery products in the period The situation is different if we look at drug delivery products with higher sales, especially if these are simple oral extended release products for which patent protection is limited to the drug delivery technology but not the drug delivery enhanced product or active. In these cases, with the general availability of comparable delivery technology, the availability of AB Generics after expiration of the FDA three-year exclusivity is almost guaranteed. A good example of this is the once-daily formulation of bupropion (Wellbutrin XL) first approved by the FDA in August 2003, and where the first AB Generic launched a little more than three years later. In contrast products such as Toprol XL, Duragesic and OxyContin each enjoyed more than a dozen years of market exclusivity, suffering neither Functional Equivalent nor AB Generic competition. In these cases the sponsoring companies established a sophisticated intellectual property position that precluded simple generic competition. (It should be noted of course that Purdue Pharma was required to go to court to remove generic competitors from the market that infringed their issued patents for OxyContin.) It s getting harder to see how a product that is a simple dose schedule enhanced version of an approved oral product can secure more than three years of exclusivity from AB Generic competitors if it does not possess patent protection for the pharmaceutical active. This is especially true for products with significant sales. Preparing a once-daily dosing formulation of an approved pharmaceutical is obvious and unlikely to support patent protection, and with multiple sustained release technologies readily available the prospect of exclusivity must be found elsewhere. Gaining durable exclusivity will increasingly depend on developing and validating a drug delivery enhanced product that goes beyond the obvious and addresses opportunities for which conventional technologies perform poorly. It is likely that the period of functional exclusivity, FE50, will drop in the decade ahead, from the current eight years to something more on the order of five or six years. That s enough time to provide for good profitability and a strong business case, but only if the plan is well thought out and properly executed. 9-11