John Orloff

The future of drug development: advancing clinical trial design

Declining pharmaceutical industry productivity is well recognized by drug developers, regulatory authorities and patient groups. A key part of the problem is that clinical studies are increasingly expensive, driven by the rising costs of conducting Phase II and III trials. It is therefore crucial to ensure that these phases of drug development are conducted more efficiently and cost-effectively, and that attrition rates are reduced. In this article, we argue that moving from the traditional clinical development approach based on sequential, distinct phases towards a more integrated view that uses adaptive design tools to increase flexibility and maximize the use of accumulated knowledge could have an important role in achieving these goals. Applications and examples of the use of these tools — such as Bayesian methodologies — in early- and late-stage drug development are discussed, as well as the advantages, challenges and barriers to their more widespread implementation.

Evaluation of compliance and health care utilization in patients treated with single pill vs. free combination antihypertensives.

Abstract Objectives: To compare compliance/persistence, health care resource utilization, and costs associated with single-pill combination (SPC) vs. free-combination (FC) therapies among adult hypertension patients at the national and state level. Combination therapies with angiotensin receptor blocker (ARB) + calcium channel blocker, ARB + hydrochlorothiazide, and angiotensin-converting enzyme inhibitor + hydrochlorothiazide were evaluated. Methods: Patients initiated on SPC or FC were identified in the MarketScan Database (2006–2008). Multivariate regression models were used to compare the health care outcomes of SPC vs. FC use during the 6-month study period. National- and state-level outcomes were analyzed and reported. Compliance was measured by medication possession ratio (MPR), and persistence was assessed based on treatment discontinuation (i.e., a lapse in therapy exceeding 30 days). Utilization and cost outcomes included frequencies of inpatient and emergency room (ER) visits and changes in health care costs from baseline. Results: Adjusting for baseline characteristics, SPC patients (N = 382,476) demonstrated significantly higher MPR than FC patients (N = 197,375) (difference = 11.6%; 95% confidence interval [CI]: 11.4%, 11.7%). SPC patients had fewer all-cause hospitalizations (adjusted incidence rate ratio [IRR] = 0.77; 95% CI: 0.75, 0.79) and ER visits (adjusted IRR = 0.87; 95% CI: 0.86, 0.89) than FC patients. Results for cardiovascular-related utilization were similar to all-cause results. Compared to FC, SPC patients showed significantly greater reductions post-therapy initiation in all-cause medical costs by −

Innovative approaches to clinical development and trial design

208 (95% CI: −

Copayment level, treatment persistence, and healthcare utilization in hypertension patients treated with single-pill combination therapy

302, −

Compliance, Persistence, Healthcare Resource Use, and Treatment Costs Associated with Aliskiren plus ARB versus ACE Inhibitor plus ARB Combination Therapy

114), but larger increases in hypertension-related prescription costs by

Chart review of patients on valsartan-based single-pill combinations vs. ARB-based free combinations for BP goal achievement

53 (95% CI:

Cardiovascular safety of lumiracoxib: A meta-analysis of all randomized controlled trials ≥1 week and up to 1 year in duration of patients with osteoarthritis and rheumatoid arthritis

51,

Recommendations for an update of the current (2001) regulatory requirements for registration of drugs to be used in the treatment of osteoporosis in postmenopausal women and in men

55). State-level results were generally consistent in magnitude and direction for comparisons of compliance and utilization, with greater regional variation in costs. Limitations include the possibility of residual confounding from factors not observable in claims. Conclusion: SPC use was associated with significantly better compliance/persistence and fewer hospitalizations and ER visits than FC in hypertensive patients at the national level and in almost all states. Larger reductions in medical costs with SPC use more than offset higher drug costs within most states.

Recommendations for the Registration of Agents to be Used in the Prevention and Treatment of Glucocorticoid-Induced Osteoporosis: Updated Recommendations from the Group for the Respect of Ethics and Excellence in Science

Pharmaceutical innovation is increasingly risky, costly and at times inefficient, which has led to a decline in industry productivity. Despite the increased investment in R&D by the industry, the number of new molecular entities achieving marketing authorization is not increasing. Novel approaches to clinical development and trial design could have a key role in overcoming some of these challenges by improving efficiency and reducing attrition rates. The effectiveness of clinical development can be improved by adopting a more integrated model that increases flexibility and maximizes the use of accumulated knowledge. Central to this model of drug development are novel tools, including modelling and simulation, Bayesian methodologies, and adaptive designs, such as seamless adaptive designs and sample-size re-estimation methods. Applications of these methodologies to early- and late-stage drug development are described with some specific examples, along with advantages, challenges, and barriers to implementation. Because they are so flexible, these new trial designs require significant statistical analyses, simulations and logistical considerations to verify their operating characteristics, and therefore tend to require more time for the planning and protocol development phase. Greater awareness of the distinct advantages of innovative designs by regulators and sponsors are crucial to increasing the adoption of these modern tools.

Communicating With the FDA: The “Third Rail” of a New Model for Drug Development

Abstract Objectives: To evaluate the relationship between drug copayment level and persistence and the implications of non-persistence on healthcare utilization and costs among adult hypertension patients receiving single-pill combination (SPC) therapy. Methods: Patients initiated on SPC with angiotensin receptor blocker (ARB) + calcium channel blocker, ARB + hydrochlorothiazide, or angiotensin-converting enzyme inhibitors + hydrochlorothiazide were identified in the MarketScan Database (2006–2008). Multivariate models were used to assess copayment level as a predictor of 3-month and 6-month persistence. Three levels of copayment were considered (low: ≤