New Drug Pipeline Monitor – July 2011

About the PMPRB

The Patented Medicine Prices Review Board (PMPRB) is an independent quasi-judicial body established by Parliament in 1987.

The PMPRB has a dual role: to ensure that prices at which patentees sell their patented medicines in Canada are not excessive; and to report on pharmaceutical trends of all medicines and R&D spending by patentees.

The PMPRB reports annually to Parliament, through the Minister of Health, on its activities, on pharmaceutical trends relating to all medicines, and on R&D spending by patentees.

The NPDUIS Initiative

The National Prescription Drug Utilization Information System (NPDUIS) provides critical analyses of drug price, utilization, and cost trends in Canada to support drug plan policy decision-making for participating federal, provincial, and territorial governments.

The NPDUIS initiative is a partnership between the PMPRB and the Canadian Institute for Health Information. It was established in 2001 by the federal/provincial/territorial Ministers of Health.

Acknowledgements

This report was prepared by the Patented Medicine Prices Review Board (PMPRB) under the provisions of the National Prescription Drug Utilization Information System (NPDUIS).

The PMPRB recognizes the contributions of the members of the NPDUIS Steering Committee for their expert oversight and guidance in the preparation of this report.

1. Introduction

This is the third edition of the New Drug Pipeline Monitor (NDPM), a publication that provides information on drugs currently under development that may have an impact on federal, provincial and territorial (F/P/T) drug plan expenditure. Each report contains a list of pipeline drugs identified as part of a search of a specialized database1 that provides information on over 20,000 drugs in clinical trials. The search is supported by a review of pharmacy literature, with a focus on Canadian studies.

Only drugs that meet a set of selection criteria are candidates for the NDPM. The selection criteria were prepared for the PMPRB in 2006 and include: the phase of development; indication; mechanism of action; and impact on clinical practice. A decision-tree algorithm was developed so that criteria could be applied in a consistent, step-wise manner. Once a preliminary list is screened in, an effort is made to include pipeline drugs from a diverse set of therapeutic classes covered by public drug plans. In particular, consideration is given to high-cost drugs and classes where a new drug could have a financial impact, along with classes with a high utilization share of generic drugs.

As this is the third edition of the NDMP, it provides an update of pipeline drugs identified in the two previous reports. Some drugs were removed from the list either because they have entered the Canadian market or because the manufacturer is no longer conducting clinical trials. Similarly, drugs were retained if ongoing trials supported the initial assessment for inclusion.

This edition is organized into five sections. Following the introduction, Section 2 gives an overview of the criteria for drug selection, while Section 3 describes the algorithm used to apply the criteria. Section 4 discusses the BioPharm Insight® database search and literature review, and provides a table of drugs identified for the 2011 pipeline report. Section 5 provides updates of the pipeline drugs identified in previous reports.

2. Criteria for Drug Selection

This section provides a brief description of the criteria used to select pipeline drugs.

2.1 Phase of Development

Only drugs in Phase III clinical trials are considered as potential candidates for the NDPM. Most drugs reaching this stage have a higher likelihood of proceeding to regulatory approval and marketing in the near future. Drugs in earlier phases of development may not necessarily progress beyond these stages.

2.2 Indication and Therapeutic Area

Drugs are considered to be potential candidates if they could be used to treat life-threatening conditions, conditions with unmet needs or rare diseases, or if they could potentially change clinical practice in a therapeutic area.

2.3 Drug Description

Drug description keywords that would flag that a new drug could potentially change clinical practice include: first drug in a class; different mechanism of action; novel technology; add-on therapy; targeted niche; or an existing drug with a new indication.

2.4 Clinical and Other Impacts

Drugs must demonstrate the potential to have a significant clinical impact or a significant impact on other sectors of the health care system. Examples include: increased efficacy versus existing drugs; impacts on patient health such as increased life expectancy or quality of life; new or redefined outcomes; or an improved safety profile.

3. Methodology for Applying Criteria

The main source of information for the NDPM is the BioPharm Insight database, which tracks drugs from pre-clinical discovery through clinical trials to market launch and subsequent sales.
The database is a comprehensive resource on investigational drugs and, at any one time, may contain more than 20,000 drugs. The database search capabilities allow drugs to be selected under various fields, including phase of development, therapeutic area, indication, drug mechanism, orphan drug, fast track and molecule type.

An algorithm developed for selecting drugs for the NDPM is illustrated in Figure 1. The algorithm combines the search capabilities of the BioPharm Insight database and the key criteria used to identify a potentially high-impact drug. Because the sources of information for this database are largely from the US, additional sources are used to determine whether the new drugs are in development in Canada.

Figure 1. Algorithm to select drugs for the NDPM

As a first step in identifying potential candidates for the NDPM, the BioPharm Insight database is searched for drugs currently in Phase III development. Phase III trials may have just been initiated for these drugs, or some Phase III results may be available. Drugs in Phase III development are then screened by therapeutic area and indication. Drugs are considered as potential candidates for the NDPM if they have been identified by the US Food and Drug Administration (FDA) as orphan drugs, which treat rare diseases, or fast track drugs. The FDA considers drugs for fast track development if they are intended to treat serious or life-threatening conditions or if they demonstrate the potential to address unmet medical needs.

For drugs that are neither fast tracked nor designated as orphan drugs, the drug profiles are searched for keywords relating to specific drug descriptions, such as first in class, different mechanism, novel technology, add-on therapy, targeted niche or existing drugs with a new indication. If the drugs have these key descriptors, Phase III results are scanned to further validate the drug characteristics identified in the profile, such as a significantly increased efficacy or increased safety. At this point, drugs just entering Phase III trials are screened out, since there is insufficient information to make a scientific assessment.

Next, Canadian sources are consulted to determine whether there is information on any Canadian development. The main source of information is Pharmacy Practice, which publishes an annual list of promising new drugs in the later stages of development (Phase III or beyond) in Canada. The next step in identifying potential drugs for the NDPM involves the scientific assessment of all drugs for which preliminary Phase III results suggest an efficacy/safety impact.

Finally, to confirm the selection of new drugs for the NDPM, consideration is given to the likelihood of coverage by F/P/T public drug plans, based on indication and form.

4. Identification of Candidates for the NDPM

4.1. BioPharm Insight database search

The first step in identifying potential candidates for the pipeline monitor was a search of the BioPharm Insight database. As in previous analyses, only drugs currently in Phase III development or under review by the FDA (i.e., New Drug Application/Biologic License Application, NDA/BLA, filed) were screened in for the first step. The search was done on the week of March 7, 2011, and so is current for that period.

Table 1 summarizes the results of this search by therapeutic area. The database profile for each of these drugs was reviewed, with particular attention given to the drug description field. Specific keywords were sought, such as first in class or different mechanism. If these keywords

Table 1. BioPharm Insight search results by therapeutic class

were identified, the next step was to determine the results, if any, of Phase III clinical trials. Under the development history field of the drug profile, details of the Phase III results were scanned to further validate drug characteristics, such as increased efficacy or safety. If this scan revealed a lack of effect or a safety issue, the drug was screened out.

Table 2 is a working list of drugs that were screened in at this stage. All of these drugs were checked against the most recent pipeline list in Pharmacy Practice2 to determine if there was information on any Canadian development. From this working list, all drugs for which preliminary Phase III results suggested an efficacy or safety impact on the disease therapy were added to a draft table of potential candidates.

The next step was a scientific assessment of this preliminary list. For this assessment, details of the Phase III results from the BioPharm drug profiles were reviewed, specifically looking for significant improvements in efficacy and safety outcomes. In addition, a search of the MEDLINE® database was done to gain a sense of how the drug was viewed in the published literature.

Table 2. Specific drugs screened in by therapeutic area

As part of the final screening, an effort was made to include pipeline drugs from a diverse set of therapeutic classes covered by public drug plans. The potential financial impact on public drug plans was also taken into consideration. New drugs entering a class with high utilization (e.g., cardiovascular) or costly drugs (e.g., cancer) can be expected to increase the overall expenditure for a drug plan. The same logic can be applied to drugs entering therapeutic classes with a high utilization share of generic drugs. As an example, numerous high-expenditure drugs to treat high cholesterol (atorvastatin, simvastatin and pravastatin) have recently lost patent protection and have been replaced with less expensive generics. If a new drug enters this market, it has the potential to be an important cost driver.

4.2 Drugs Added to the New Drug Pipeline Monitor

Table 3 lists new candidates for the NDPM. Each drug met the selection criteria discussed in Section 3. The table lists the drug's trade name, company, therapeutic area and rationale for inclusion in the NDPM.

Table 3. Drugs added to the New Drug Pipeline Monitor

5. Status Updates

5.1. Drugs Retained in the Pipeline List

Table 4 lists the drugs from the first and second editions of the New Drug Pipeline Monitor that remain as pipeline candidates. A status update based on recent scientific literature is provided, along with a rationale for retaining the drugs on the pipeline list.

Table 4. Drugs retained in pipeline list

5.2 Drugs Removed from Pipeline List

Tables 5 and 6 provide a list drugs from the first and second editions of the New Drug Pipeline Monitor that have been removed from the pipeline list. Drugs in Table 5 were removed because the manufacturer was granted authority to market the drug in Canada. Health Canada grants that authority in a Notice of Compliance (NOC). Table 5 also provides information on recommendations made by CADATH's Canadian Expert Drug Advisory Committee on whether public drug plans should list the drug, as well as rulings of the Patented Medicine Prices Review Board (PMPRB) on whether a drug was priced within its excessive price guidelines. Table 6 lists the drugs that have been removed because a scientific assessment no longer supports retention on the pipeline list. Reasons cited include lack of information or subsequent clinical trials that cite insufficient efficacy or safety.

Table 5. Drugs removed from pipeline list: market authority granted by Health Canada

Table 6. Drugs removed from pipeline list: scientific assessment

6. References

1 The BioPharm Insight® database was accessed the week of March 7, 2011, for this report. The web address is: http://www.infinata5.com/BioPharm/AccessPoint.aspx?action=Login.ShowLogin&datakey=BioPharm

2 Murdoch LA. Promising drugs in the late stages of development in Canada. Pharmacy Practice Dec 2010/Jan 2011. Available online at: www.CanadianHealthcareNetwork.ca.

3 White H. Editorial: why inhibition of lipoprotein-associated phospholipase A2 has the potential to improve patient outcomes. Curr Opin Cardiol. 2010; 25(4):299–301.

4 Steg PG, James S, Harrington RA, Ardissino D, et al. Ticagrelor versus clopidogrel in patients with ST-elevation acute coronary syndromes intended for reperfusion with primary percutaneous coronary intervention: A Platelet Inhibition and Patient Outcomes (PLATO) trial subgroup analysis. Circulation. 2010; 122(21):2131–41.

5 McHutchison JG, Manns MP, Muir AJ, et al; PROVE3 Study Team. Telaprevir for previously treated chronic HCV infection. N Engl J Med. 2010; 362(14):1292–303.

6 Brodie MJ, Lerche H, Gil-Nagel A, et al; for RESTORE 2 Study Group. Efficacy and safety of adjunctive ezogabine (retigabine) in refractory partial epilepsy. Neurology. 2010; 75(20):1817–24.

7 Hodi FS, O'Day SJ, McDermott DF, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med. 2010; 363(8):711–23.

8 Robinson BG, Paz-Ares L, Krebs A, Vasselli J, Haddad R. Vandetanib (100 mg) in patients with locally advanced or metastatic hereditary medullary thyroid cancer. Clin Endocrinol Metab. 2010; 95(6):2664–71.

9 Green B. Focus on agomelatine. Curr Med Res Opin. 2011; 27(4):745–9.

10 Hale A, Corral RM, Mencacci C, Ruiz JS, Severo CA, Gentil V. Superior antidepressant efficacy results of agomelatine versus fluoxetine in severe MDD patients: a randomized, double-blind study. Int Clin Psychopharmacol. 2010 ; 25(6):305–14.

11 Riedl M, Campion M, Horn PT, Pullman WE. Response time for ecallantide treatment of acute hereditary angioedema attacks. Ann Allergy Asthma Immunol. 2010; 105(6):430–6.

12 Mizuno Y, Hasegawa K, Kondo T, Kuno S, Yamamoto M; Japanese Istradefylline Study Group. Clinical efficacy of istradefylline (KW-6002) in Parkinson's disease: a randomized, controlled study. Mov Disord. 2010; 25(10):1437–43.

13 Factor S, Mark MH, Watts R, Struck L, Mori A, Ballerini R, Sussman NM;Istradefylline 6002-US-007 Study Group. A long-term study of istradefylline in subjects with fluctuating Parkinson's disease. Parkinsonism Relat Disord. 2010; 16(6):423–6.

14 Spagnolo P, Del Giovane C, Luppi F, et al. Non-steroid agents for idiopathic pulmonary fibrosis. Cochrane Database Syst Rev. 2010; (9):CD003134.

15 Kessans MR, Gatesman ML, Kockler DR. Plerixafor: a peripheral blood stem cell mobilizer. Pharmacotherapy. 2010; 30(5):485–92.

16 Sternberg CN, Petrylak DP, Sartor O, et al. Multinational, double-blind, phase III study of prednisone and either satraplatin or placebo in patients with castrate-refractory prostate cancer progressing after prior chemotherapy: the SPARC trial. J Clin Oncol. 2009; 27(32):5431–8.

17 Kantoff PW, Higano CS, Shore ND, et al; for IMPACT Study Investigators. Sipuleucel-T immunotherapy for castration-resistant prostate cancer. N Engl J Med. 2010; 363(5):411–22.

18 CADTH recommendations available at the agency's Common Drug Review (CDR) online database: http://www.cadth.ca/index.php/en/cdr/search. PMPRB rulings available at web address: http://www.pmprb-cepmb.gc.ca/english/home.asp?x=1 Only publicly available recommendations/rulings are cited.

19 Olson JJ, Paleologos NA, Gaspar LE, et al. The role of emerging and investigational therapies for metastatic brain tumors: a systematic review and evidence-based clinical practice guideline of selected topics. J Neurooncol. 2010; 96(1):115–42.

20 Ferrer E. Tolvaptan for the treatment of hyponatremia and congestive heart failure. Drugs Today (Barc). 2010; 46(3):163–71.