Improving and Accelerating Therapeutic Development for Nervous System Disorders Workshop Summary (2014) / Chapter Skim
Currently Skimming:
2 Drug Development Challenges
2 Drug Development Challenges
Pages 9-24
The Chapter Skim interface presents what we've algorithmically identified as the most significant single chunk of text within every page in the chapter.
Select key terms on the right to highlight them within pages of the chapter.
From page 9... ...
Animal models often cannot recapitulate an entire disorder or disease. Challenges related to heterogeneity of the patient population might be alleviated with increased clinical phenotyping and endotyping.
|
From page 10... ...
To better understand how these challenges create bottlenecks in the development pipeline, William Potter, senior advisor in the Office of the Director of the National Institute of Mental Health, began with an overview of current practices. DRUG DISCOVERY AND DEVELOPMENT PATHWAY Potter described the process of drug discovery and development beginning with target identification and validation (see Figure 2-1)
|
From page 11... ...
.1 Potter noted that a typical POC clinical trial is a small controlled study conducted at fewer than 4 sites with less than 100 subjects/patients. If the drug succeeds at POC, clinical trials then proceed to larger Phase II and Phase III trials, which consist of randomized, usually placebocontrolled arms, to ensure safety and efficacy (see Table 2-1)
|
From page 12... ...
CURRENT DRUG DEVELOPMENT CHALLENGES Christopher Austin, director of the National Center for Advancing Translational Science (NCATS) , highlighted underlying challenges behind translational failures that need to be addressed to improve the drug development pipeline for nervous system disorders (Wegener and Rujescu, 2013)
|
From page 13... ...
In addition, identifying biomarkers is essential, not only to provide proof of mechanism but also to refine targets, provide POC, and evaluate whether an early intervention focused on a single target can prevent or forestall disease (IOM, 2011, p.
|
From page 14... ...
Translational Failures Using Animal Models Many participants discussed the inability of animal models to accurately predict efficacy as a challenge to drug development. Although animal models work reasonably well to prioritize reagents for a clinically validated target, they are not as useful to prioritize reagents aimed at
|
From page 15... ...
; and inability of drugs found efficacious in animal models to translate to clinical trials. Wayne Drevets, scientific vice president and disease area leader in mood disorders at Janssen Pharmaceutical Companies of Johnson & Johnson, echoed similar comments for depression (Banasr et al., 2011; Manji et al., 2001; Savitz et al., 2013)
|
From page 16... ...
From an investment standpoint, stated Kiran Reddy, principal at Third Rock Ventures, the heterogeneity of patient populations necessitates larger, more complex, and thus more expensive clinical trials. Patient populations with depression and bipolar disorder, for example, are highly heterogeneous, and segregating patients based on phenotypes may serve as a useful method of patient stratification when conducting clinical trials.
|
From page 17... ...
Because most drug testing fails in Phase IIa and because the negative results are usually not shared, the field is potentially wasting resources (e.g., time and money) , said Bountra.
|
From page 18... ...
Multiple challenges can impact the drug development pipeline, originating with the lack of understanding of underlying biological mechanisms of nervous system disorders. Lawrence Goldstein suggested that the field identify key bottlenecks in the pathway and become better at
|
From page 19... ...
Speakers emphasized that IND applications are reviewed on a case-by-case basis and that researchers can use pre-IND meetings as a resource to answer technical questions prior to submission. To begin the conversation, Imran Khan, pharmacologist and toxicologist in the Office of New Drugs, Center for Drug Evaluation and Research of FDA, provided an overview of the review process for IND applications; common inadequacies that could put applications on clinical hold, an FDA-ordered delay or suspension of clinical trials3; and how issues can be mitigated.
|
From page 20... ...
For example, new safety pharmacological data are not needed if adequately documented safety data with previous human experience are included. However, the intended duration of drug administration must be supported with comparable or longer repeat-dose toxicity studies.
|
From page 21... ...
Inadequate studies might lack sufficient documentation, test too few animals, not assess standard parameters or not provide data, study inadequate doses, use a route of administration other than that proposed for the humans without justification, and have had an insufficient duration. Another common reason for a clinical hold is that a no-effect dose for serious toxicity was or could be determined.
|
From page 22... ...
When asked to explain the animal rule for IND applications, Bastings explained that animal studies are needed only when human efficacy trials are neither feasible nor ethical. In some cases, a risk–benefit analysis is needed for protocols in which animal efficacy models may be needed.
|
From page 23... ...
A participant stated that there has been a transition from traditional efficacy studies using animals to select efficacy studies when there are sufficient safety data and a plausible mechanism. The field is developing tools to better understand the molecular level of a disease and move toward a patient-stratified approach with the goal of developing compounds with less toxicity.
|
From page 24... ...
Nervous system disorder drugs in particular face a number of challenges that complicate drug development even further. Although regulatory processes are not intended to hinder drug development, many investigators are unclear of the specific requirements for INDs and request comprehensive guidance.
|
Key Terms
This material may be derived from roughly machine-read images, and so is provided only to facilitate research.
More
information on Chapter Skim is available.