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U.S. Department of Health and Human Services

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Expanded Access and Expedited Approval of New Therapies Related to HIV/AIDS

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.

Expediting Review and Approval of New Therapies

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.

There have been a number of efforts to speed the availability of new therapeutics for HIV infection, involving both the way that potential therapeutics are developed and studied by product sponsors, and how they are analyzed and reviewed at FDA.

Expanded Access 

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, and cannot enter a clinical trial. Expanded access refers to access to investigational medical products outside of a clinical trial, where the intent is a potential treatment, rather than research.

More about Access to Investigational Drugs

Questions and Answers about treatment of serious and life threatening illnesses, and use of investigational drugs 


Breakthrough Therapies (2013)

The Food and Drug Administration Safety and Innovation Act (FDASIA) includes a provision that allows sponsors to request that their drug be designated as a Breakthrough Therapy.  A breakthrough therapy is a drug: 

  • intended alone or in combination with one or more other drugs to treat a serious or life threatening disease or condition and
  • preliminary clinical evidence indicates that the drug may demonstrate substantial improvement over existing therapies on one or more clinically significant endpoints, such as substantial treatment effects observed early in clinical development.
If a drug is designated as breakthrough therapy, FDA will expedite the development and review of such drug.  All requests for breakthrough therapy designation will be reviewed within 60 days of receipt, and FDA will either grant or deny the request.  
 
Guidance for Industry: Human Immunodeficiency Virus-1 Infection: DevelopingAntiretroviral Drugs for Treatment (2013)

Replacing an earlier guidance from 2002 (Antiretroviral Drugs Using Plasma HIV-RNA Measurements — Clinical Considerations for Accelerated and Traditional Approval), a new Guidance for Industry: Human Immunodeficiency Virus-1 Infection: DevelopingAntiretroviral Drugs for Treatment provides recommendations for the development of antiretroviral drugs for the treatment of HIV infection that reflect FDA's current thinking regarding overall development and clinical trial design for antiretroviral drugs to support an indication for the treatment of HIV-1 infection.

Significant changes from the 2002 version include:
  1. more details on nonclinical development of antiretroviral drugs;
  2. a greater emphasis on recommended trial designs for HIV-1-infected heavily treatment-experienced patients (those with multiple-drug resistant virus and few remaining therapeutic options);
  3. use of a primary endpoint evaluating early virologic changes for studies in heavily treatment­ experienced patients; and
  4. use of the traditional approval pathway for initial approval of all antiretrovirals with primary analysis time points dependent on the indication sought instead of an accelerated approval pathway followed by traditional approval. 
 
Fast Track Drug Development Programs (1997)

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:

  • Improved effects on serious outcomes of the condition that are affected by alternate therapies
  • Effects on serious outcomes of the condition not known to be affected by the alternatives
  • Ability to provide benefits in patients who are unable to tolerate or are unresponsive to alternative agents, or ability to be used effectively in combination with other critical agents that cannot be combined with available therapy
  • Ability to provide benefits similar to those of alternatives, while avoiding serious toxicity that is present in existing therapies, or avoiding less serious toxicity that is common and causes discontinuation of treatment of a serious disease
  • Ability to provide benefits similar to those of alternatives but with improvement in some factor, such as compliance or convenience, that is shown to lead to improved effects on serious outcomes.
 
Priority Review Policies (1997)

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 designations 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, breakthrough therapies development programs, priority review policies), while one (treatment INDs) provides early access to investigational therapies.

A priority review designation is intended to direct overall attention and resources to the evaluation of applications for products that, if approved, would be significant improvements in the safety or effectiveness of the treatment, diagnosis, or prevention of serious or life-threatening conditions, as compared to standard applications.

 
Accelerated Approval Regulations (1992)

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 314.510 and 21 CFR 601.41).

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.

 

Parallel Track (1992) 

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. 

While the Parallel Track policy is still technically available, it has not been used since stavudine was approved in 1994. Treatment INDs have proven to be a more practical mechanism to provide treatment access. 

 
Subpart E Regulations (1988)

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.

 
AA Priority (1987)

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.

 
Treatment IND (1987/revised 2009)

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. The regulation was revised and expanded in 2009, effective October 12, 2009. 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 312.305(a), the investigational drug can only be used for this purpose if the following criteria are met:

  • The patient or patients to be treated have a serious or immediately life-threatening disease or condition, and there is no comparable or satisfactory alternative therapy to diagnose, monitor, or treat the disease or condition;
  • The potential patient benefit justifies the potential risks of the treatment use and those potential risks are not unreasonable in the context of the disease or condition to be treated; and.
  • Providing the investigational drug for the requested use will not interfere with the initiation, conduct, or completion of clinical investigations that could support marketing approval of the expanded access use or otherwise compromise the potential development of the expanded access use.

Further, in accord with 21 CFR 312.320, FDA must determine that:

  • The drug is being investigated in a controlled clinical trial under an IND designed to support a marketing application for the expanded access use, or all clinical trials of the drug have been completed;
  • The sponsor is actively pursuing marketing approval of the drug for the expanded access use with due diligence; and
  • When the expanded access use is for a serious disease or condition, there is sufficient clinical evidence of safety and effectiveness to support the expanded access use. Such evidence would ordinarily consist of data from phase 3 trials, but could consist of compelling data from completed phase 2 trials; or 
  • When the expanded access use is for an immediately life-threatening disease or condition, the available scientific evidence, taken as a whole, provides a reasonable basis to conclude that the investigational drug may be effective for the expanded access use and would not expose patients to an unreasonable and significant risk of illness or injury. This evidence would ordinarily consist of clinical data from phase 3 or phase 2 trials, but could be based on more preliminary clinical evidence.
 
What Drugs are approved for treatment of HIV/AIDS and its complications?

Antiretrovirals Currently Approved for use in the treatment of HIV infection

Approved therapies for the treatment of complications of HIV/AIDS

 

 

Historical Examples of Expanded Access Enrollment

 

DrugDates# Enrolled
AZT1986-874,804
trimetrexate1988-94753
pentamidine1989728
ddI1989-91>21,000
ddC1990-926,705
atovaquone1991-931,054
rifabutin1992-932,506
d4T1992-9412,551
3TC1993-9529,430
saquinavir19952,200
indinavir19951,500