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  1. FDA Voices

FDA’s Comprehensive Response to HIV — Part I

A multidisciplinary approach helps spur the development of effective treatments and approval of an expanding number of HIV drugs and drug combinations.

young male patient conversing with doctor in examining room while looking at iPad

By: Ned Sharpless, M.D., Acting Commissioner

Our nation has been engaged in a battle against the HIV/AIDS epidemic since the early 1980’s. Over the past 37 years, we have learned a great deal about the virus, made important progress in the development of treatments and diagnostic tests, and remain resolute in our efforts to eradicate this disease.

For those engaged in the field of public health, the AIDS crisis is a particularly instructive example of some of the ways such crises and responses to them evolve, particularly because this response coincides with our own medical training, development, and professional experience. In 1990, I took time off from medical school to work in an HIV lab at the National Institutes of Health, studying what was then called “AIDS dementia.” My subsequent medical residency and fellowship occurred at the height of the AIDS epidemic, prior to the advent of many of our most important therapies for HIV infection, and I cared for many desperate patients dying from the disease.

Photo of Norman E. "Ned" Sharpless, M.D.
Ned Sharpless, M.D.

We have made incredible progress since then. Thanks to the power of groundbreaking medical research and the dedication of scientists, doctors, nurses, epidemiologists, researchers, government regulators, and, most importantly, people living with HIV and their advocates, we have shifted the prognosis for HIV from a death sentence to a chronic and manageable illness. We’re working to build on this success, through efforts like the president’s plan for Ending the HIV Epidemic: A Plan for America, which seeks to provide the hardest hit communities with the additional expertise, technology, and resources required to address the HIV epidemic in their communities. Moreover, we’ve been working collaboratively across government through efforts like the Presidential Advisory Council on HIV/AIDS, which includes regional “Ending the HIV Epidemic” initiatives.

The U.S. Food and Drug Administration (FDA) has played a significant role in generating this changing outlook for HIV patients, both domestically and internationally. Across the agency, our medical product centers are engaged in important work spanning the entire spectrum of HIV research and product development. FDA experts employ a multidisciplinary review and oversight program to help spur the development of effective treatments and approve expanding numbers of HIV drugs and drug combinations. Beyond therapeutics, FDA’s work has also led to the development of more accurate diagnostics tests, reliable blood donor screening, and rigorous public education programs, all of which reflect areas of continued focus.

This two-part FDA Voices addresses many of these issues and discusses some of the ways that FDA is addressing the continuing challenges posed by HIV. The first part of the article will focus primarily on our response domestically; the second will address global issues.

Developing New Drug Treatments

Since the start of the HIV epidemic, the FDA’s Center for Drug Evaluation and Research (CDER) has approved 29 anti-retroviral drugs (ARVs) to treat the disease. This includes multiple drug classes and many fixed dose combinations of these drugs. This includes our approval last year of the first monoclonal antibody for HIV intended for the 5,000 to 10,000 U.S. patients who have developed resistance to multiple existing therapies.

Science is constantly making new advances, thanks to ongoing research. This not only leads to the development of new products, but also to determinations of what combinations of existing and new products are effective.

Until recently, for example, it was thought that three ARVs were needed to initiate and sustain treatment. Two years ago, FDA approved the first two-drug regimen [Juluca] for maintenance therapy in virologically-suppressed patients, and, just a few months ago, we approved Dovato (dolutegravir and lamivudine), a two-drug combination for adults with no previous history of being treated with antiretrovirals and no known or suspected resistance to the individual components of Dovato.

FDA experts are also reviewing and providing drug development advice on new formulations such as injectables and implants for HIV treatment or prevention. These could stretch dosing to a week, a month, or even longer, which means greater convenience for patients, greater compliance with therapy and, optimally, greater effectiveness. Work is also underway to develop microbicides that would prevent vaginal and/or rectal transmission of HIV. No matter what the regimen, one thing we know with certainty is that these products don’t work unless patients take them, on schedule and as prescribed.

FDA has also been at the forefront of HIV prevention. In 2012, FDA approved a preexposure prophylaxis drug (PrEP), Truvada, intended for those adults who are not HIV-infected but are at a high risk of infection. Initially approved for adults, the drug’s label has since been expanded to include adolescents age 15 to 17. On July 1, 2019, the FDA released the REMS (Risk Evaluation and Mitigation Strategy) for Truvada. Although the FDA determined that while safety risks for Truvada still exist, the requirements of the REMS program are no longer necessary to ensure that the benefits of the drug outweigh the risks. REMS assessments have shown that prescribers and consumers have consistently demonstrated an understanding of the potential risks associated with the daily use of Truvada, and educational materials and treatment guidelines are readily available from the Centers for Disease Control and Prevention (CDC), state and local health departments and other public health entities.

An important and related focus of FDA’s work involves balancing our support for innovation with enhancing competition to increase the production of new and less expensive drugs, especially generic versions of important older medical products on which many patients rely. FDA’s Office of Generic Drugs (OGD) plays a key role in this work, including reducing cost and increasing access to antiretrovirals for the treatment of patients with HIV. OGD does this through its review of Abbreviated New Drug Applications (ANDAs) and providing other support to assist with the submission of applications.

Another important area of therapeutic focus involves pediatric patients. Fewer than half of the approximately 2.1 million children in the world living with HIV have received an HIV drug treatment. In March of 2019, FDA issued a final guidance to industry to provide general recommendations on the development of antiretroviral (ARV) drugs to treat children living with HIV. Our intent is to help sponsors understand when it is appropriate to initiate pediatric formulation development and to begin pediatric studies.

Developing Vaccines to Protect Individuals Against HIV Infection

One of the key areas of scientific investigation of HIV protection is the development of vaccines to protect people from infection with HIV. The complexities of how HIV interacts with the human immune system have required novel approaches to the design of HIV vaccines and vaccine regimens, including some that combine different vaccine candidates administered over time.

Much of the work at FDA’s Center for Biologics Evaluation and Research (CBER) is designed to support the development of safe and effective vaccines by advancing and promoting scientific innovation. Research is fundamental to CBER’s ability to provide effective scientific and regulatory evaluation of vaccines. CBER conducts its research activities in conjunction with its regulatory activities, which provides the Agency a unique perspective on both fronts that facilitates interactions with vaccine developers. CBER plays a critical role in evaluating rapidly evolving technical and scientific issues concerning the safety, potency, and effectiveness of vaccines, including potential HIV vaccines. The FDA continues to play an important role in identifying vaccine evaluation strategies that may provide preliminary evidence of effectiveness.

Over the years, CBER has engaged its external expert advisory committee and a variety of stakeholders on HIV vaccines on a range of issues relating to clinical trial design and endpoints, and appropriate preclinical testing strategies for HIV vaccines made in new cell types. Many HIV vaccines have entered into clinical trials, and CBER is evaluating vaccines at all stages of clinical development, forging FDA’s role in the scientific community and with industry in developing testing strategies and identifying appropriate endpoints for HIV vaccine studies. For example, we developed a diagnostic known as HIV Selectest, which can detect HIV breakthrough infections in individuals enrolled in HIV vaccine trials.

Empowering the Public to Get Tested

One of the most critical steps in fighting the HIV epidemic is through voluntary and routine testing and knowing one’s HIV status. According to the CDC, more than one million people in the United States are living with HIV infection and about 15 percent of them don’t know they’re infected. Although HIV tests are very accurate, no test can detect the virus immediately after infection. The primary testing methods are:

Lab-based Test: Blood is drawn by a health professional and tested in a lab, and results are returned in as little as an hour to several days.

Point-of-Care Test:

  • Oral (mouth) Fluid Test: Oral fluid is collected with the use of a swab by a health professional and results are returned in 20 minutes.
  • Blood Test: Blood is collected following a finger prick or through oral swabbing and results take about 10 minutes.
  • Home Use Test: Rapid oral fluid test is performed at home with results in approximately 20 minutes.

Most HIV tests, including most rapid tests and home tests, are antibody tests that can’t detect infection until the body makes enough antibodies, a process that takes about 3 to 12 weeks. Combination antibody/antigen tests have a window between infection and detection of 2 to 6 weeks. These tests are now recommended for testing done in labs, although one FDA-approved rapid combination test is also available. Nucleic Acid Tests, which measure and detect HIV DNA or RNA, have window periods as short as one week after infection.

HIV diagnostics currently come to market in the U.S. through the premarket approval pathway. Today there is one FDA-approved HIV test for home use, eight FDA-approved point-of-care diagnostic tests, 12 FDA approved lab-based diagnostic tests and six supplemental tests that are used to confirm screening test results.

The FDA is considering reclassifying HIV diagnostic, supplemental, and viral load monitoring tests from class III (PMA submissions) to class II (the 510(k) pathway). Provided there is sufficient information to establish special controls, in addition to general controls, to provide reasonable assurance of the safety and effectiveness of these tests, the 510(k) pathway is a less-burdensome pathway to market that generally results in shorter premarket review times and may also provide more timely access to new tests, while still providing reasonable assurance that these are safe and effective.

The FDA is also focusing on two additional areas where more diagnostic development is needed: tests to differentiate HIV-1 and HIV-2 antibodies and tests to diagnose HIV infection in infants born to HIV-positive mothers, because antibody tests cannot distinguish between infant and maternal antibodies and there is not a Nucleic Acid test available for early infant diagnosis. These are important next steps in the development of rigorous and reliable diagnostics as part of advancing patient care.

The Role of Blood Screening in HIV Prevention

The FDA plays an important role in ensuring the safety of the nation's blood supply by minimizing the risk of HIV transmission to patients through blood transfusion. In the U.S., all donors of blood and blood components are screened with a donor history questionnaire and each donation is tested for HIV and other transfusion-transmitted infections. Blood collection establishments must register with FDA and are inspected routinely to help prevent blood infected with HIV and other infectious diseases from entering the blood supply.

Our Office of Blood Research and Review (OBRR) in CBER is responsible for ensuring the safety and efficacy of blood and blood components intended for transfusion and further manufacturing use, as well as related medical devices used to test and manufacture blood products. OBRR is also responsible for the regulation of HIV retroviral diagnostic tests.

Factoring in the Patient Personal Perspective

Photographers documenting a crowd of people outside FDA headquarters protesting the agency's lack of action in response to HIV/AIDS epidemic in 1988.
In 1988, the AIDS Coalition to Unleash Power (ACT-UP) organized a demonstration at FDA headquarters in Rockville, Maryland, to protest for greater access to investigational drugs to help treat AIDS patients.

One of the most important aspects of our work in HIV/AIDS has been to engage and work with the patient community and ensure their voices are heard and their experiences inform our guidances and policy. It was in part, in response to the AIDS Coalition to Unleash Power (ACT UP), who gathered outside FDA headquarters in 1988 to call for greater access to experimental treatments and faster approval of AIDS drugs, that we invited greater patient engagement in the policy-making process. We will continue to stress the importance of patient engagement in our ongoing work.

The FDA also has an e-mail list serve that has more than 55,000 subscribers, and “HIV Email Updates” provide up-to-date information on product approvals, labeling changes, safety warnings, notices for upcoming meetings and proposed regulatory guidances.

As we mark National HIV/AIDS and Aging Awareness Day, a time to highlight the growing number of people living long and full lives with HIV, and to bring much needed attention to aging-related challenges of HIV prevention, testing, treatment, and care, the FDA will continue to do its part to develop new treatments and diagnostic tests with the longstanding vision of curing this disease.

Tomorrow, in part II, I will take a look at FDA’s global impact on HIV.

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