Cherie Paquette

The economics of follow-on drug research and development

AbstractObjectives: The development of so-called ‘me-too’, or ‘follow-on’, drugs by the pharmaceutical industry has been viewed by some as duplicative and wasteful, while others have argued that these drugs often provide needed therapeutic options and inject some price competition into the marketplace. This study examines data on the trends in the speed with which competitive entry has occurred in the pharmaceutical marketplace and the competitive nature of the industry’s development of these drugs. Data and methods: We examined data on the entry rates of drugs in a large number of therapeutic classes over time, as well as detailed survey information on the relative timing of the development of drugs in the classes. Classes were defined according to chemical structure or pharmacologic mode of action and similarity of clinical use. We determined average times to initial and subsequent entry in drug classes by period and examined the timing of development milestones achieved by what have turned out to be follow-on drugs in relation to the development and approval of the first drug in a class to be approved. Results: We found that the period of marketing exclusivity that the breakthrough drug in a new class enjoys has fallen dramatically over time (a median of 10.2 years in the 1970s to 1.2 years for the late 1990s). Approximately one-third of follow-on new drugs received a priority rating from the US FDA. The vast majority of the follow-on drugs for drug classes that were created in the last decade were in clinical development prior to the approval of the class breakthrough drug. Conclusions: The data suggest that entry barriers have fallen over time for new drug introductions. The increased competitiveness of the pharmaceutical marketplace was likely fueled by changes over time on both the supply and demand sides. The development histories of entrants to new drug classes suggest that development races better characterise new drug development than does a model of post hoc imitation. Thus, the usual distinctions drawn between breakthrough and ‘me-too’ drugs may not be very meaningful.

Comparing Patient Access to Pharmaceuticals in the UK and US

AbstractBackground: The debate on access to new drugs has focused on the time lag between applications for approval and granting of marketing authorisation. This delay was identified as the first barrier with respect to patient access to new drugs, encompassing the hurdles of safety, efficacy and quality. Additional barriers have since been identified. These pertain to reimbursement and pricing of approved drugs, the so-called fourth and fifth hurdles. Methods: We reviewed 38 National Institute for Health and Clinical Excellence (NICE) guidance appraisals carried out between April 1999 and April 2005. These appraisals included 71 recently approved drugs considered to have either high clinical or cost impact. For each drug we first determined its marketing approval date by the British Medicines Healthcare Products Agency (MHRA) or European Medicines Evaluation Agency (EMEA). Secondly, we determined if each drug was approved by the US FDA for marketing and, if so, the date when it was approved. Thirdly, we considered whether and when each drug was recommended for reimbursement and use by NICE, and whether conditions of reimbursement applied. Fourthly, for the subset of FDA-approved drugs, we examined formulary placement, cost sharing and conditions of reimbursement on three-tier formularies used by seven leading US third-party payers serving Medicare beneficiaries. Fifthly, we reviewed each NICE recommendation to determine if cost-effectiveness data were referred to either in the appraisal documentation or in the final recommendation. Sixthly, we asked a spokesperson from each US payer whether cost-effectiveness assessments or rebates played a role in determining formulary placement of drugs in our sample, and whether there was a lag between marketing approval and reimbursement for any of the covered drugs. Results: Of the 71 drugs contained in 38 NICE guidance appraisals, the US FDA approved 64. On average, the subset of 64 drugs received marketing authorisation in the US prior to the UK. On average, US plans covered 87% of the 64 drugs, the same percentage of drugs recommended for NHS reimbursement and use. Cost sharing in the US was significantly higher than in the UK, with wider variation across plans. On average, drugs covered in the US had fewer conditions of reimbursement (15%) than the percentage of drugs given conditions by NICE (46%). US plans were quicker to decide to reimburse drugs following marketing approval than NICE. Conclusions: The US provides faster, more flexible access to most, but not all, of the UK-approved pharmaceuticals in our sample. However, US patients have higher cost sharing than the UK and coverage is less evenly spread across the population. From a policy perspective, our study findings confirm the need to bolster the NICE fast-track initiative to decrease the amount of time it takes to appraise certain new pharmaceuticals. Also, the study findings point to the need in the US for careful monitoring of plan compliance with regulations pertaining to the Medicare drug benefit, particularly with respect to formulary restrictions and limits on cost sharing.

Interobserver variability in the application of a proposed histologic subclassification of endocervical adenocarcinoma.

A histologic pattern-based system of risk stratification for endocervical adenocarcinoma has been recently proposed on the basis of tumor-stroma interface and lymph-vascular invasion. The key utility of the system lies in separating cases with very low risk for nodal metastases (pattern A) from those with higher risk (patterns B and C), which may alter the treatment approach. In this study, we determine the reproducibility of applying this system among gynecologic pathologists from 2 institutions using blinded review of 49 adenocarcinomas from 2003 to 2013. &kgr; values and pairwise differences are calculated for the proposed 3-tier system (patterns A, B, and C) as well as a modified version comparing pattern A versus patterns B and C combined (2-tier system). Consensus diagnosis for the 3-tier system is reached in 50% of cases, with majority of &kgr; values indicating fair to almost perfect agreement (range, 0.24 to 0.84). When condensed to 2 tiers, consensus is reached in 81.3% of cases with &kgr; values showing modest improvement (range, 0.33 to 0.92). Pairwise difference analysis reveals diagnosis trends for specific pathologists on the 3-tier system that decrease with 2 tiers. Interpretive variability may be of practical significance in application of the proposed 3-tier pattern–based approach to endocervical adenocarcinoma. Additional studies with larger patient cohorts are needed to confirm the negligible risk for lymph node involvement seen in pattern A patients and to further evaluate the applicability of this new classification system.

Risk stratification by p16 immunostaining of CIN1 biopsies: a retrospective study of patients from the quadrivalent HPV vaccine trials.

Previous studies of p16 immunohistochemistry (IHC) on CIN1 have suggested the likely utility of p16 in stratification of women at risk for subsequent CIN2/3. But those studies had limitations in statistical power, histologic diagnosis, and disease ascertainment. We conducted a retrospective study of p16 IHC on adjudicated CIN1 tissue diagnosed in young women participating in the placebo arm of the quadrivalent human papillomavirus (HPV) vaccine trials. Tissue sections were stained with p16 IHC and hematoxylin and eosin. p16 IHC was scored using LAST criteria, and hematoxylin and eosin–stained sections were reviewed for concordance with the adjudicated diagnosis. p16 IHC, antecedent high-grade cytology, review diagnosis, and HPV16 detection were assessed as independent risk factors for subsequent CIN2/3. Five hundred twenty-four patients with CIN1 biopsies and complete data were identified, 63 (12.0%) of whom developed CIN2/3 in follow-up. p16 positivity (P=0.06), review diagnosis of CIN2/3 (P=0.04), HPV16 positivity (P=0.01), and antecedent high-grade cytology (P=0.02) were (marginally) associated with CIN2/3. In a logistic regression model, the associations with CIN2/3 (vs. other), expressed as odds ratios (95% confidence intervals), were 1.6 (0.91-2.8) for p16, 2.0 (1.0-3.7) for HPV16, and 2.2 (1.1-2.4) for antecedent high-grade cytology. The mean risks for CIN2/3 estimated from the model ranged from 7.6% for negative for all markers to 36.3% for positive for all 3 markers. p16 IHC does not risk stratify CIN1 patients in a manner that would alter recommended management for CIN1. This reinforces the LAST recommendations that p16 should only be used selectively for problematic scenarios, such as CIN2 because of its inherent lack of reproducibility, cases in which one is struggling between CIN1 and CIN2, and benign mimics of CIN3.

Predictive Value of Cytokeratin 7 Immunohistochemistry in Cervical Low-grade Squamous Intraepithelial Lesion as a Marker for Risk of Progression to a High-grade Lesion.

The squamocolumnar junction (SCJ) cell population of the uterine cervix is a discrete epithelial area and the putative source of the majority of high-grade squamous intraepithelial lesions (HSIL). The SCJ cells can be identified by immunohistochemical (IHC) stains including cytokeratin 7 (CK7). Others have theorized that an SCJ marker–positive low-grade squamous intraepithelial lesion (LSIL) has a higher risk for future HSIL compared with an SCJ marker–negative LSIL. This study has 2 aims: first, to refine the definition of a positive CK7 immunostaining pattern in cervical lesions, and, second, to test the hypothesis that CK7 positivity in LSIL indicates higher risk for future HSIL, with both questions addressed using a data set with consensus diagnoses. One hundred cases each of LSIL, moderate HSIL (CIN2), and severe HSIL (CIN3) were stained for CK7, with positivity defined as a diffuse cytoplasmic staining pattern (>5 to 6 contiguous cells); all others were considered negative. Using this model, 34% of CIN1, 45% of CIN2, and 60% of CIN3 were CK7 positive. With follow-up, CK7-positive LSILs were more likely to progress to HSIL compared with CK7-negative LSIL (32% vs. 11%, P=0.05), in concordance with the results of other researchers. This study simplifies cervical CK7 IHC grading into a reproducible system and supports the thesis that CK7 positivity in LSIL is associated with increased risk for future HSIL. Larger cohorts using consensus-diagnosed LSIL are needed to confirm these results before CK7 may be considered for clinical validation.

Therapeutic cancer vaccines on trial

Therapeutic cancer vaccines offer hope for patients for whom traditional treatments have failed, but various obstacles may impede the launch of these new agents.

Impact of Schwartz enhanced visualization solution on staging colorectal cancer and clinicopathological features associated with lymph node count.

BACKGROUND: Stage-specific survival for colon cancer improves when more lymph nodes are reported in the surgical specimen. This has led to a minimum standard of identifying 12 lymph nodes as a quality indicator. OBJECTIVE: The aim of this study was to determine whether the addition of Schwartz solution increases node yield and impacts pathologic staging. DESIGN: This is a prospective cohort study. SETTING: The study was conducted in an academic medical center. PATIENTS: Included were 104 consecutive patients with colorectal cancer. MAIN OUTCOME MEASURES: Lymph node counts before and after specimen treatment with Schwartz solution and incidence of upstaging were measured. RESULTS: An additional 20 minutes (interquartile range, 15–40 minutes) was spent searching for lymph nodes, increasing the median number of nodes from 22.5 to 29.0 nodes. However, only 1 patient was upstaged. Schwartz solution decreased the number of specimens with less than 12 lymph nodes from 15 to 6. The following factors were associated with Schwartz solution leading to the detection of additional nodes: number of nodes detected initially with formalin only (p < 0.000), mesenteric fat volume (p < 0.000), mesenteric fat weight (p < 0.000), length of specimen (p < 0.016), tumor greatest dimension (p < 0.016), patient body surface area (p < 0.034), and patient age (p < 0.003). LIMITATIONS: Clinical data for this study were obtained retrospectively and were not available for all of the patients. CONCLUSIONS: Although Schwartz solution increased the number of nodes detected in 95% of patients and improved compliance with the 12-node standard for colon resection, there was minimal impact on cancer staging. Upstaging is unlikely to explain the increase in overall survival in patients with higher lymph node counts, casting doubt on the validity of this process measure as a meaningful quality indicator. Rather, the lymph node count may be a reflection of inherent tumor biology or host-related factors.

CK7 Immunohistochemistry as a Predictor of CIN1 Progression: A Retrospective Study of Patients From the Quadrivalent HPV Vaccine Trials

Cervical high-grade squamous intraepithelial lesion (CIN2-3) is thought to arise from a distinct population of cells at the squamocolumnar junction (SCJ). Immunohistochemical (IHC) biomarkers that characterize the SCJ phenotype, including CK7, have been proposed as tools to separate the subset of low-grade squamous intraepithelial lesions (LSILs) (CIN1) that will progress to high-grade squamous intraepithelial lesion from the majority of cases, which will resolve without further intervention. We conducted a retrospective study of CK7 IHC on adjudicated CIN1 tissue from women in the placebo arm of the quadrivalent human papillomavirus (HPV) vaccine trials. Tissue sections were stained with CK7 IHC and scored as negative, patchy, gradation (ie, top-down), or full-thickness pattern. Results were assessed for the prediction of future diagnosis of CIN2-3/AIS (eg, CIN2+ progression) along with p16 IHC, antecedent high-grade cytology, and HPV16 status. A total of 517 patients with CIN1 biopsies and complete data were identified, 12% of whom showed CIN2+ progression on follow-up. Full-thickness CK7 staining showed the highest correlation with CIN2+ progression (odds ratio [OR] 2.8, P=0.021) relative to the other risk factors (HPV16: OR 2.0, P=0.035; antecedent high-grade cytology: OR 2.2, P=0.028; p16 IHC: OR 1.5, P=0.16). Inclusion of the gradation/“top-down” CK7 pattern resulted in a less robust association with progression (CIN2+: OR 2.0, P=0.028; CIN3+: OR 1.3, P=0.74). Interobserver variability ranged from slight to substantial and was not contingent on gynecologic pathology training experience (&kgr;=0.7078 for negative/patchy vs. gradation/full thickness; &kgr;=0.5672 for negative/patchy/gradation vs. full thickness). These data support the theory that SCJ-derived LSILs are precursors to a potentially aggressive subset of cervical SILs and that CK7 staining may inform risk stratification for LSIL (CIN1). However, clinical utility is significantly tempered by the relatively low amplitude of the risk increase, interpretative variability, and limitations of colposcopic sampling.

Can Medicare Draw Lessons from Dutch Experience with a National Formulary

Objective: Using seven therapeutic subclasses of cardiovascular drugs as a case study, we investigated how different systems of formulary practice have an impact on access to prescription drugs, as well as the likely repercussions of the recently passed Medicare legislation on Medicare beneficiaries. We identified four dimensions of access: availability, coverage, equity, and flexibility. We examined a fifth item, transparency, unrelated to access but relevant to the formulary decision-making process as a whole. Study Design and Methods: Drawing from public data from the US and Dutch drug regulatory agencies, three leading US managed care plans participating in the Medicare Advantage program, Michigans Medicaid agency, and the Dutch board of insurers, we determined for the period 1991–2004 (1) which cardiovascular drugs were approved for marketing in the United States and the Netherlands and approval dates; (2) formulary status of the approved drugs; and (3) copayments for on-formulary drugs. For each insurer, we determined whether an appeals mechanism is in place for obtaining nonformulary drugs and if so the estimated appeals success rate. Finally, on the basis of publicly available documentation as well as personal communications with officials at the managed care plans, we determined the degree of transparency underlying the formulary decision-making processes. Results: For each dimension identified, we give an ordinal ranking of the selected US and Dutch systems of formulary management. In terms of availability, the number of cardiovascular drugs approved between 1991 and 2004 by the respective drug regulatory agencies was the same (37), while on average the Dutch agency approved this subset of drugs faster than the United States. The Dutch system affords better coverage as 84% versus 68% of approved drugs are on formulary, and there are nominal out-of-pocket costs for beneficiaries across all therapeutic subclasses of cardiovascular drugs. We observed that the Dutch system is more equitable as formulary coverage applies to virtually the entire population, while copayments are practically equal across the population. However, it is less flexible, with little or no choice in drug benefit, and has an underutilized, difficult-to-navigate appeals mechanism for nonformulary drugs. Finally, we observed that both the US and Dutch systems of formulary management lack transparency. Conclusions: The Dutch formulary shows how, from a beneficiarys perspective, a national formulary can succeed in achieving a high degree of (universal) coverage. The United States is unlikely to establish a single formulary for Medicare, yet it is implementing regulations sponsored by the Centers for Medicare and Medicaid Services that are designed to minimize inadequacies in and undue variation between formularies to ensure adequate coverage and a high rate of beneficiary participation.

The economics of follow-on drug research and development: Trends in entry rates and the timing of development — The authors’ reply

Hollis[1,2] discusses so-called ‘me-too’ drug deconsequence of the incentives and disincentives invelopment and comments on our paper,[3] recently herent in institutional and policy structures. It makes published in this journal, which presented evidence sense to examine the incentive and market entry on the entry rates and development histories of effects of a particular policy change, but general first-in-class and follow-on1drugs in therapeutic statements claiming that multiple entrants to a marclasses defined by mechanism of action or chemical ket increase or decrease innovation incentives are similarity. While the discussions by Hollis are internot particularly useful. esting and provocative, we believe that to some The empirical results in our paper[3] are not tests extent he mischaracterises our views and the releof hypotheses about innovation incentives. Howevvant literature. We also believe that his strong coner, our discussion did remark on some of the potenclusions are neither the inevitable implications of tial implications of a proposal to use drug registraeconomic theory as he seems to suggest, nor are they tion authorities to erect entry barriers for follow-on supported by empirical evidence. DiMasi[4] offers a drugs in therapeutic subclasses.[5]2 DiMasi[4] excomprehensive critique of the antecedent[1] to Holpands on that discussion in relation to claims in lis’ comment[2] in PharmacoEconomics. Our comHollis’ earlier posting.[1] The basis for Hollis’ claim ments here will be brief, but we refer the reader to about incentives was made in his earlier posting in DiMasi’s posting[4] for a more detailed discussion of the context of a model that, in its starkest form, many of our points. makes extreme assumptions. Specifically, the unHollis[1,2] maintains that follow-on drugs dederlying explicit and implicit behavioural and marcrease innovation incentives, and that we claimed ket assumptions for the model are that firms in the that they increase innovation incentives. We never current environment seek to develop drugs that are made such a claim, and framing matters in this way perfect substitutes for one another, there is no price makes little sense to us. Institutional and policy competition among the perfect substitutes (other environments, interacting with scientific and ecothings being equal, relaxing this assumption will nomic conditions, determine innovation incentives. strengthen his argument about private incentives if The level and type of entry into a market is a demand is inelastic), marketing among competitors