Important note: Information in this article was accurate in 2004. The state of the art may have changed since the publication date.
Food and Drug Administration - May 17, 2004
Richard Klein, HIV/AIDS Program Director - Office of Special Health Issues
DETAILS OF FDA'S GUIDANCE
FDA's Guidance for Industry Fixed Dose Combination and Co-Packaged Drug Products for Treatment of HIV provides simplified pathways for submitting clinical safety and efficacy data, virology, chemistry and bioavailability information for combination therapy products for HIV. The guidance states that applicants for co-packaged or FDC products may provide clinical efficacy (as measured by the drug's effect on viral load) and safety information by one of the following mechanisms:
*reference to their own relevant NDA or IND submission
*cross-reference to another applicant's submission for which they have been given right of reference
*submission of peer-reviewed literature of relevant clinical studies and other scientific information and a summary that synthesizes the information and provides rationale for the combination
The guidance describes how applicants can submit chemistry data to FDA to show that the drugs used in the combination, as well as any other ingredients, do not interact or cause other problems when used together, that the product is stable in the packaging that will be used, to establish specifications for the final drug product, and describe how a bioavailability study should be conducted to show that blood levels of the drugs, when used in combination, are the same as those needed to achieve efficacy when the drugs are used alone.
While a marketing application cannot be approved to permit sale in the United States until applicable patents or exclusivity protections expire, FDA can grant "tentative approval," showing that a product has met all FDA scientific standards for safety, efficacy, and quality. Such tentatively approved products would then be available for procurement under the President's Emergency Plan for AIDS Relief - a program that would provide $15 billion over five years - with the goal of preventing 7 million new infections, treating 2 million HIV infected people, and caring for 10 million HIV infected individuals and AIDS orphans.
Link to the Federal Register Notice, Availability of Guidance: http://www.fda.gov/OHRMS/DOCKETS/98fr/cd0466.pdf (PDF 25 KB)
Link to the draft Guidance Document: http://www.fda.gov/oc/initiatives/hiv/hivguidance.html (PDF, 295 KB)
BACKGROUND ON TODAY'S ACTION
*Co-packaged or fixed-dose combination HIV treatments can best deliver antiretroviral therapies in developing countries with large previously untreated populations infected with HIV because the simplified dosing facilitates distribution and may improve patient adherence.
*Many combination HIV treatments have been studied and the results have been described in product labels or peer reviewed literature. Where these products are to be made available in combined form, FDA review of safety, efficacy, and manufacturing data can be completed quickly, so that co-packaged or fixed dose combination treatments can be made available in significantly less time than would ordinarily be required.
*To encourage sponsors to obtain FDA approval of fixed dose combination and co-packaged HIV therapies, FDA has issued guidance clarifying what regulatory requirements would be applied to such applications, what issues might be of concern, and how these could be addressed.
Some questions and answers about FDA's fixed dose combination guidance
For What Drugs Does the Guidance apply?
It applies to proposed fixed dose combination (FDC) antiretroviral products and proposed co-packaged antiretroviral products for which there is adequate evidence of safety and efficacy for the treatment of HIV and is aimed primarily at those combinations of individual drugs for which the combination has already been evaluated and established.
This guidance does not specifically apply to FDCs or co-packaged products to treat diseases other than HIV/AIDS.
How many drugs are needed to treat HIV the virus that causes AIDS?
In general three antiretroviral drugs are required to treat HIV/AIDS when initiating therapy. This is called combination antiretroviral therapy or HAART (highly active antiretroviral therapy). Most of the time it consists of two drug from one class of drugs (nucleoside reverse transcriptase inhibitors) and a third drug from another class (either an HIV protease inhibitor or non-nucleoside reverse transcriptase inhibitor) More than three drugs may be needed for HIV-infected patients who have resistant virus or who have previously experienced loss of virologic control on antiretroviral therapy
What is a FDC (fixed dose combination)?
A fixed-dose combination product is one in which two or more separate drug and/or biological active ingredients are combined in a single dosage form.
What is a co-packaged product?
A co-packaged product consists of two or more separate drug and/or biological products in their final dosage form, packaged together.
Why are FDCs or co-packaged drugs important for HIV treatment?
Such products may allow for easier distribution and help to simplify regimens, leading to improved patient adherence, particularly in resource poor settings. Combination antiretroviral therapy is essential to effectively treat HIV/AIDS, and improved adherence to combination antiretroviral therapy may help to slow the rate of development of drug resistant HIV.
What kind of combinations should be co-packaged or put in an FDC?
Proposed combination products should be relatively well tolerated and easy to administer, while providing adequate potency and sufficient barrier to the emergence of drug resistance. They should have proven safety and efficacy in patients initiating HIV treatment.
Why does FDA have requirements for Fixed Dose Combinations and Co-Packaged Drugs?
Combining drugs in one formulation (pill) can potentially change the amount of drug the gets into the bloodstream (its bioavailability). When treating HIV low blood levels of drugs could lead to drug resistance in people taking them and could even lead to the spread of drug resistance. Changes in bioavailability could be due to problems with manufacturing several drugs into one pill or could be due to interactions between the drugs in the product. Even co-packaging drugs into new containers or blister packs could change the potency of a drug when stored over a period of time especially in severe climates (very hot or humid). All of these factors are important because the amount of drug that eventually gets into the bloodstream is very important for controlling HIV.
Richard Klein
HIV/AIDS Program Director
Office of Special Health Issues
Food and Drug Administration
040517
FD040501
SOURCE: Food and Drug Administration (FDA).
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