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Development of Opioid and Adjuvant Fixed Combination Dosage Forms for the Treatment of Chronic Pain with Reduced Addiction Potential (R41/R42)

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Agency: Department of Health and Human Services
Program/Year: STTR / 2014
Solicitation Number: PA-13-388
Release Date: November 7, 2013
Open Date: March 5, 2014
Close Date: January 7, 2017 (closing in 868 days)
001: Funding Opportunity Description
Description:

Purpose

This Funding Opportunity Announcement seeks small business organizations to develop opioid and adjuvant drug combinations within a single dosage form for treatment of a pain condition. The drug combination should provide improved analgesia when compared with the same dose (morphine equivalents) of opioid monotherapy. Such dosage forms should minimize opioid exposure while optimizing analgesia, in order to reduce risk of addiction and limit severity of other opiate adverse effects.

Background

Opioids are one of the two main classes of analgesic prescribed, even though they induce significant adverse effects such as addiction and withdrawal, insomnia, depression, cognitive impairment and constipation. The National Institute on Drug Abuse has an interest in promoting the use of combination opioid and adjuvant combination therapies in order to limit the risk of addiction by minimizing the dose of opioid required for optimal analgesia.

Pain management specialists are familiar with several classes of FDA-approved drugs that can improve opioid analgesia when used as adjuvants, the most well-known coming from antidepressant, anticonvulsant and antihypertensive drug classes. Long-term opioids are more frequently prescribed as a monotherapy than with an adjuvant, possibly because of concern about the risk of drug-drug interaction problems, lack of familiarity with adjuvant use and reluctance to add to the burden of pharmaceuticals a patient must remember to take each day. Pre-formulated, FDA-approved opioid-adjuvant combinations would reduce physician concerns about drug interactions; for example, physicians are seldom concerned about the safety of FDA-approved acetaminophen and hydrocodone combinations. Similarly, substitution of an opioid-adjuvant combination instead of an opioid monotherapy would improve analgesia / reduce opioid exposure without increasing the number of pills the patient must remember to consume, thereby simplifying pain management for elderly patients and those for whom pain is a symptom or comorbidity. Finally, marketing of fixed combination dosage forms would shift the task of ensuring physician awareness of opioid-adjuvant therapeutics from Continuing Medical Education providers to manufacturers of combination dosage forms, many of whom excel in messaging effectiveness.

Research Objectives and Considerations

When designing this new product, investigators should consider FDA guidance (21 CFR 300.50) and address the following issues. Both of the agents contained in the proposed new product should currently have at least one existing FDA-approved indication, as well as some existing clinical evidence to support the use of the chosen adjuvant : opioid combination and a reasonable expectation that the combination will present minimal drug-drug interaction concerns. The application should emphasize available evidence that the chosen drugs and doses in the combination will allow a substantial patient population to gain sufficient analgesic value from the contained opioid dose while the adjuvant dose remains within a safe and effective "therapeutic window". One example of a potentially viable adjuvant is gabapentin, a drug known to reduce neuropathic pain and to which patients typically exhibit no more than mild adverse effects. Gabapentin does not typically induce substantial drug interactions because it is eliminated as parent drug by renal excretion and does not extensively bind to blood proteins.

The adjuvant should be chosen for a capacity to increase overall analgesia, rather than an ability to reduce opioid adverse effects. For example inclusion of a poorly absorbed opioid receptor antagonist, with the intent of reducing constipation, would not be considered of high programmatic interest..

The combination dosage form proposed by the application should provide sustained relief when it is the only analgesic used and is administered no more than three times in a 24 hour period. The formulation should be such that a patient with reasonable mobility is able to self-administer the drug (eg oral dosage form).

The application should propose late-stage drug development-oriented studies that significantly drive the project towards an ultimate aim of a New Drug Application [505(b)(1or2)] or Abbreviated New Drug Application [505(j)] for the treatment of a long-term pain condition.

Studies planned for Phase1 of the project should focus on issues that concern feasibility of the project. The exact nature of such studies will differ depending on the proposed drug combination project.

Studies that might be appropriate for Phase1 STTR applications include, but are not limited to:

  • Development of a formulation that safely delivers the desired amount of both agents over an appropriate dosing interval.
  • Preclinical studies demonstrating additive or synergistic analgesia with the opioid-adjuvant combination.
  • Studies to provide data for an Investigational New Drug (IND) submission such as short term stability studies,
  • Pre-IND consultations with an FDA project management group and development of the IND documentation.

Examples of projects appropriate for the Phase2 of an STTR award might  include:

  • Pharmacokinetic absorption and disposition studies to demonstrate the bioequivalence between approved dosage forms and the proposed product
  • Proof of concept clinical studies. Appropriate outcome measures might aim to detect and distinguish value added by an opioid adjunctive therapy, whether due to improved analgesia or reduced required opioid dosage.