Food Drugs and Devices Update – September 2010

Topic of the Month: Medical products development would be improved under a joint pilot program between the FDA and the Centers for Medicare and Medicaid Services.  Citing inefficient use of agency resources in product approvals, as well as general confusion to developers, the parallel development would potentially reduce the time to market and national coverage determination.
I. Agency Developments

Parallel developments of medical products, public comments sought
Comments are being sought on the development of a process, as well as a pilot program, to conduct overlapping evaluations of premarket FDA review and national coverage decisions by the Centers for Medicare and Medicaid Services (CMS) for regulated medical products when the product sponsor and both agencies agree that such parallel review would be proper for a particular product. The process would reduce the time between FDA marketing approval or clearance decisions and CMS national coverage determinations and accelerate consumer access to new, particularly innovative, safe and effective medical products. Parallel review could also create incentives for venture capitalists and companies to increase their investment in innovative medical products by reducing the time to return on investment for those products eligible for parallel review.
The regulatory standards and evidentiary standards used by the FDA and CMS for decision-making would not change; under any review scenario, each agency would continue to make its decision under its respective authority and with its own standards, independent of the other. The agencies are also establishing a docket to receive information and comment from the public on: (1) what products would be appropriate for parallel review by the two agencies; (2) what procedures should be developed; (3) how a parallel review process should be implemented; and (4) other issues related to the effective operation of the process. The pilot program will begin after both agencies have reviewed the public comments. FDA Notice, ¶43,940

Schedule I and II production quotas revised for 2010
Revised calendar year 2010 production quotas for various controlled substances in Schedule I and II were adjusted by the Drug Enforcement Administration (DEA) for alfentanil, amphetamine, carfentanil, dihydromorphine, diphenoxylate, marihuana, morphine, as well as other controlled substances, because of insufficiency for research and industrial needs. Regarding codeine (for conversion), codeine (for sale), dextropropoxyphene, gamma hydroxybutyric acid, and other controlled substances, the DEA determined that the proposed revised 2010 aggregate production quotas were sufficient to meet the current 2010 estimated medical, scientific, research, and industrial needs of the United States and to provide for adequate inventories. DEA Notice, ¶43,939
2011 production and import quotas for List I chemicals announced
Production and import quotas for the List I chemicals ephedrine, pseudoephedrine, and phenylpropanolamine were proposed by the Drug Enforcement Administration (DEA) in accordance with the Combat Methamphetamine Epidemic Act of 2005. The annual needs quantity for 2011 was developed after consideration of: (1) submitted applications for 2010 import, manufacturing, and procurement quotas; and (2) import and export declarations from DEA-registered manufacturers and importers. The proposed quotas represent the quantities of each chemical that may be manufactured domestically or imported into the United States to provide adequate supplies of each chemical for the estimated medical, scientific, research, and industrial needs of the United States, lawful export requirements, and the establishment and maintenance of reserve stocks. The proposed values for 2011 are: (1) ephedrine (for sale) at 3,400 kg; (2) phenylpropanolamine (for sale) at 4,700 kg; (3) pseudoephedrine (for sale) at 190,000 kg; (4) phenylpropanolamine (for conversion) at 8,100 kg; and (5) ephedrine (for conversion) at 18,600 kg.FDA Notice, ¶43,933

II. Drug and Biologics Developments

Design of OTC label comprehension studies
A draft guidance to assist sponsors on all phases of development of direct-acting antiviral agents (DAAs) (agents that interfere with specific steps in the hepatitis C virus (HCV) replication cycle) was published by the FDA. Titled “Draft Guidance for Industry on Chronic Hepatitis C Virus Infection: Developing Direct-Acting Antiviral Agents for Treatment; Availability,” the guidance recommends the types of nonclinical studies and clinical trials recommended throughout the drug development process to support the approval of treatments for chronic hepatitis C (CHC). Nonclinical combination studies should be conducted to support clinical trials for combination drugs.
However, similar to the approach used for HIV and oncology, it is not recommend that these nonclinical studies be conducted routinely for the following reasons: (1) in clinical practice, DAAs are likely to be used with multiple hepatitis C drugs, including interferon and RBV and other DAAs, in multiple different combinations; it would not be feasible to conduct animal studies for all potentially relevant combinations; (2) given the difficulty of conducting combination toxicologic studies that may require multiple different drugs and multiple dose combinations, it is believed that nonclinical studies would be more interpretable and may offer more useful data by looking at individual agents at multiple and higher doses; and (3) single- and multiple-dose drug-interaction trials in humans and in vitro metabolic studies can screen for potential pharmacokinetic (PK) drug interactions that may lead to safety issues.
To support clinical trials evaluating two or more  investigational DAAs for up to 90 days, the FDA recommends a minimum of 3 months repeat-dose nonclinical toxicity studies in a rodent and nonrodent species for each individual agent. Longer term data on individual agents (6-month rodent, 9-month nonrodent) can support longer duration combination clinical trials, depending on the toxicity profile. Until the DAAs are approved, the recommended design for initial registration of a DAA is demonstration of superiority as an add-on to SOC (standard of care), Peg Interferon/RBV, in a blinded comparison to placebo plus SOC. The FDA also recommends consideration of (1) clinical virology; (2) PK/PDs  (pharmacokinetics/pharmacodynamics); (3) special populations; and (4) early access/treatment investigational new drug applications. FDA Notice, ¶42,060

Vaccine bar code label requirements draft guidance issued
A draft guidance titled “Guidance for Industry: Bar Code Label Requirements –Questions and Answers (Question 12 Update)” with compliance recommendations for manufacturers of licensed vaccines on bar code label requirements was published by the FDA. According to the draft document, while vaccines are subject to bar code requirements by virtue of being prescription drugs, the FDA declined to require the inclusion of lot number and expiration date information in a vaccine’s bar code information because the costs associated with encoding lot number and expiration date information appeared to exceed the benefits.
The draft guidance answers were revised to allow an alternative regulatory program, comprised of alternative technology such as two dimensional symbology, that could render the use of linear bar codes unnecessary for patient safety and could enhance health care providers’ ability to comply with the National Childhood Vaccine Injury Act of 1986 (PubLNo 99-660). The FDA will now also consider requests from vaccine manufacturers who request to use alternate coding technologies for an exemption pursuant to 21 CFR §201.25(d)(1)(ii) to the linear bar code requirement. FDA Notice, ¶42,058