 |
|
 |
FDA Home Page | Search
FDA Site | FDA A-Z Index | Contact
FDA
Human Immunodeficiency
Virus and
Acquired Immunodeficiency Syndrome
FDA has taken significant steps, primarily in response to the HIV/AIDS crises, toward making experimental drugs intended to treat life-threatening diseases more widely available to severely ill patients, as well as toward speeding the review and approval of the applications for these products.
Marketing approval of new drugs, based on scientific evidence of safety and effectiveness for the drug's intended use is the best way to make the product available to the largest number of people, and to permit third-party (insurance, medicaid, etc) reimbursement for their use.
FDA created a "AA" priority category to classify all applications for potential AIDS therapies to ensure that these products receive the highest priority in the review process.
The Agency's procedures in subpart E of 21 CFR part 312 (the Investigational New Drug Application regulations), which expedite the development, evaluation, and marketing of promising therapies to treat individuals with life-threatening and severely debilitating illnesses, reflect that the Agency must make a medical risk-benefit judgment in deciding whether to approve a drug or biological product. As part of this risk-benefit analysis, the Agency will "take into consideration the severity of the disease and the absence of satisfactory alternative therapy" (21 CFR 312.84). Under the Subpart E regulations for investigational new drugs, drug development is considered a continuum from early preclinical and clinical studies through submission of a marketing application. The regulations emphasize the critical nature of close early communication between the Agency and a sponsor, outline procedures such as pre-IND and end of phase 1 meetings as methods to improve the efficiency of preclinical and clinical development, and focus on efforts by the Agency and the sponsor to reach early agreement on the design of the major clinical efficacy studies that will be needed to support approval.
FDA's accelerated approval procedures and restricted distribution provisions in 21 CFR subpart H are available for new drug and biological products (1) that have been studied to treat serious or life-threatening illnesses and (2) "that provide meaningful therapeutic benefit to patients over existing treatments (e.g., ability to treat patients unresponsive to, or intolerant of, available therapy, or improved patient response over available therapy)" (21 CFR 314.500 and 601.40).
Under these procedures FDA may approve drugs based on surrogate endpoints that reasonably predict that a drug provides clinical benefit. This clinical benefit is then confirmed through additional human studies that will be completed after marketing approval. The accelerated approval approach provides for removal of the drug from the market if further studies do not confirm the clinical benefit of the therapy.
FDA's fast track drug development programs are designed to facilitate the development
and expedite the review of drug and biological products that are intended to
treat serious or life-threatening conditions and that demonstrate the potential
to address unmet medical needs (FDA guidance for industry on Fast Track Drug
Development Programs: Designation, Development, and Application Review). In
the guidance, the Agency defined an unmet medical need as a "medical need
that is not addressed adequately by an existing therapy."
As described in the guidance, where there is no available therapy for a condition
(or the only available therapy is approved under the accelerated approval regulations),
a product in a drug development plan designed to evaluate the drug's potential
to address the condition would meet the factors to address an unmet medical
need. Where there is available therapy for the condition, the drug development
program would address unmet medical needs if it evaluated any of the following:
Section 112 of the Food and Drug Administration
Modernization Act of 1997 (P.L. 105-115) amended the Federal Food, Drug,
and Cosmetic Act by adding new section 506 (21 U.S.C. 356), authorizing FDA
to take actions appropriate to facilitate the development and expedite the review
of new drugs that are intended to treat serious or lifethreatening conditions
and that demonstrate the potential to address unmet medical needs (fast track
products).
The Center for Biologics Evaluation and Research (CBER) and the Center for Drug
Evaluation and Research (CDER) have established review classifications and review
policies and procedures for new drug applications (NDAs), biologics license
applications (BLAs), and efficacy supplements to prioritize and speed their
review. Most of these Agency policies and procedures are intended to encourage
the development and expedite the review of innovative drug products (i.e., subpart
E regulations, accelerated approval regulations, fast track drug development
programs, priority review policies), while one (treatment INDs) provides early
access to investigational therapies.
A priority designation is intended to direct overall attention and resources
to the evaluation of applications for products that have the potential for providing
a significant treatment, preventive or diagnostic therapeutic advance, as compared
to standard applications. Products regulated by CDER are eligible for priority
review if they provide a significant improvement compared to marketed products
in the treatment, diagnosis, or prevention of a disease. Products regulated
by CBER are eligible for priority review if they provide a significant improvement
in the safety or effectiveness of the treatment, diagnosis, or prevention of
a serious or life-threatening disease.
Expanded access mechanisms are designed to make promising products available as early in the drug evaluation process as possible to patients without therapeutic options, either because they have exhausted or are intolerant of approved therapies.
Expanded access mechanisms include Treatment IND protocols and parallel track protocols. In addition, the ordinary development of drugs under an IND includes a variety of open studies that also provide access to drugs. FDA monitors each of these access programs on an ongoing basis.
Final regulations were issued in May of 1987 establishing conditions under which promising new drugs and biologics that have not yet been approved or licensed for sale may be made available to persons with serious and life threatening illnesses, for whom no comparable or satisfactory alternative drug or therapy is available. Treatment IND regulations allow the treatment use of an investigational drug for treatment under a treatment protocol, or treatment investigational new drug application (IND), outside of the clinical trial.
Treatment INDs have generally been granted when the product is well into clinical trials, or when clinical trials have been completed, after the accumulation of adequate safety data, and there is evidence of likely effectiveness.
According to regulations, 21 CFR 312.34(b), the investigational drug can only be used for this purpose if the following criteria are met:
Eleven treatment IND protocols for promising AIDS-related products have been allowed to proceed since the Treatment IND regulations became effective. Additionally, treatment use of therapeutic products still in stages of clinical trial investigation have been achieved through Open Label Safety Protocols, and Parallel Track.
The final PHS policy statement on the parallel track mechanism was published in the Federal Register on April 15, 1992. The purpose of the parallel track policy was to expand the availability of promising investigational drugs to those persons with AIDS and HIV-related diseases who are without satisfactory alternative therapy and who cannot participate in controlled clinical trials.
The policy differs from the treatment IND primarily in that it applies only to AIDS and HIV-related diseases, and that investigational drugs could be made available earlier in the development process.
Stavudine (d4T) is the only drug that was submitted for consideration under the parallel track policy. The protocol was allowed to proceed on October 5, 1992. Approximately 12,000 patients received Stavudine through the parallel track mechanism. An accelerated new drug application for stavudine was approved June 17, 1994. The application received full marketing approval on December 21, 1995.
| Drug | Dates | # Enrolled |
|---|---|---|
| AZT | 1986-87 | 4,804 |
| trimetrexate | 1988-94 | 753 |
| pentamidine | 1989 | 728 |
| ddI | 1989-91 | >21,000 |
| ddC | 1990-92 | 6,705 |
| atovaquone | 1991-93 | 1,054 |
| rifabutin | 1992-93 | 2,506 |
| d4T | 1992-94 | 12,551 |
| 3TC | 1993-95 | 29,430 |
| saquinavir | 1995 | 2,200 |
| indinavir | 1995 | 1,500 |