The Food and Drug Administration: The Process of Approval

Fall 2004

This article is part of The Body PRO's archive. Because it contains information that may no longer be accurate, this article should only be considered a historical document.

For every dollar the typical American spends, approximately 25 cents goes to products that are regulated by the U.S. Food and Drug Administration (FDA). We're talking about everything from food, to drugs, to radiation-emitting products like cell phones, to cosmetics. With respect to drugs used for medical conditions, the regulatory role of the FDA reflects the sometimes paradoxical needs of consumers: facilitating rapid access to new therapeutics that show promise for patients, while also protecting them from products that are ineffective, unsafe, and marketed using unproven claims.

When it comes to the approval and regulation of drugs used to treat HIV and AIDS, the role of the FDA and its various regulations can be extremely complex. Confusing matters further, the role of the FDA is continually being shifted and reshaped in accordance with new, sometimes conflicting laws designed to protect consumers and the pharmaceutical industry. In fact, many FDA regulations in place today -- such as expanded access and accelerated approval of promising drugs for life-threatening conditions -- arose in response to the HIV/AIDS epidemic.

In order to highlight the most important information about the Byzantine activities of the FDA as they relate to HIV and AIDS drugs, ACRIA Update asked ACRIA's treatment education team and Community Advisory Board to come up with a list of frequently asked questions about the FDA and its activities.

Who Decides Whether the FDA Approves a Drug?

Once clinical trials have been completed, the approval process begins with a pharmaceutical company filing a New Drug Application (NDA) with the FDA's Center for Drug Evaluation and Research (CDER). The NDA contains volumes of paper describing everything that has been learned about the drug, including data from test tube studies, animal studies, initial dosing studies in HIV-negative and HIV-positive people, along with the results of all safety and effectiveness studies that have been completed to-date.

If CDER finds the NDA to be in order -- meaning that it contains complete and sufficient information to review -- the FDA usually passes the NDA on to an advisory committee made up of non-FDA experts. When it comes to antiretroviral agents, it is the Antiviral Drugs Advisory Committee (ADAC) that reviews the NDA. ADAC is made up of researchers and clinicians with significant experience in the field of HIV research and care. At least one community representative -- usually a knowledgeable treatment activist/educator working for an AIDS service organization -- also serves as a voting member of ADAC.

In reviewing the NDA, ADAC often holds a public meeting with the pharmaceutical company and members of the FDA to hear oral arguments in support of -- and sometimes against -- the drug's approval. At the close of the meeting, the ADAC members take a vote, deciding whether or not to recommend approval of the drug. If ADAC votes to recommend approval, the FDA usually grants it -- in the form of a letter sent to the pharmaceutical company -- typically within days or weeks of the ADAC committee meeting.

Why Does One Drug Get Approved and Not Another?

For much of its early history, the FDA was primarily concerned with one thing when deciding whether or not to approve an investigational drug: safety. In 1962, Congress drafted and passed the Kefauver-Harris Drug Amendments to the Food, Drug, and Cosmetic Acts in response to the horrifying birth defects caused by thalidomide, a sleeping pill approved at the time in Europe. The FDA strengthened its safety requirements and began requiring companies to prove that their investigational drug was also effective for the disease it was meant to treat.

Almost all of the anti-HIV drugs that have made their way to the FDA for review have been approved. All except one: adefovir dipivoxil. While this drug is now approved for the treatment of chronic hepatitis B (under the brand name Hepsera), it was originally studied as a treatment for HIV. At the dose needed to effectively suppress HIV (40 mg a day), clinical trials found that it was associated with a high rate of kidney problems, with 214 patients participating in these studies requiring dialysis. The ADAC reviewing the NDA for adefovir dipivoxil also felt that there was "insufficient proof of the drug's effectiveness."

Essentially, the heart of all FDA activities is a judgment about whether a product's benefits to users will outweigh its risks. In the case of adefovir, the risks appeared to outweigh the benefits. Given the high cost of developing a new drug, pharmaceutical companies are usually quick to pull the plug on an investigational candidate before an NDA is filed if the drug appears to be ineffective or too toxic in early clinical trials.

A little pressure from community activists can go a long way as well. There have been instances in which the FDA has been provided with an NDA containing limited convincing data. If it weren't for community support for the drug -- including public testimony from patients who benefited from the drug in clinical trials -- some medications used today to treat HIV-related problems may not have been approved.

How Long Does it Take for a Drug to Become Available After the FDA Approves it?

Even before the FDA officially reviews an NDA, the sponsoring pharmaceutical company is usually hard at work producing mass quantities of a drug in anticipation of approval. This is, undoubtedly, a risky business decision -- beginning production of a drug, along with the costly development of advertising and sales materials, before the FDA has given the company an official green light.

Fortunately, this decision usually pays off and HIV-positive people in need of the drug can sometimes look forward to its widespread availability within just days of approval. Post-approval access isn't always this easy, however. Sometimes it can take several weeks or months for a pharmaceutical company to have enough drug available for widespread distribution after its approval.

This is what happened with Crixivan (indinavir), Merck's protease inhibitor, when it was approved in 1996, resulting in limited distribution through a single mail-order pharmacy. This was also the case with Fuzeon (enfuvirtide), Hoffmann-La Roche's entry inhibitor. Given the complexities and time-consuming process associated with the manufacturing of this drug, the company predicted that it would only have enough drug supply for 15,000 people worldwide during the first several months after approval. Initially, this created anxiety and panic among AIDS activists working to secure Fuzeon access for everyone who needed it. But in reality, the limited demand for Fuzeon -- because of its cumbersome injectable dosing and its high cost -- ended up being more of a problem than the limited supply of the drug.

How Much Safety Can a Clinical Trial for an Experimental Drug Assure?

Generally speaking, most experimental anti-HIV drugs reviewed by the FDA today have been tested in at least one study that was conducted for at least 48 weeks (approximately one year). When a drug is first approved, it is reasonable to say that we know a lot about its short-term complications: toxicities and side effects that may arise during the first year of treatment.

Many people rightfully argue that this is too limited of a snapshot given that some long-term side effects may occur after several months or years of continued use. Unfortunately, this has been the case with a number of anti-HIV drugs. For example, long after they were approved for use, we learned that nucleoside analogues such as Zerit and Videx -- if used for long periods of time -- can cause damage to mitochondria, the tiny powerhouses inside cells. Similarly, we learned that long-term protease inhibitor use is associated with increases in cholesterol, triglycerides, and glucose levels, along with abnormal body-shape changes. Because the clinical trials needed to approve these drugs were only 24 to 48 weeks in duration, these long-term side effects weren't documented until after the drugs were approved.

Some pharmaceutical companies collect long-term follow-up data from studies that continue well after the drug is approved, allowing for continual updates of a drug's package insert to document both short- and long-term side effects. All package inserts, including revisions, are reviewed by the FDA before they can be distributed. Package inserts are the accordion-folded pieces of paper that accompany packaged medications reviewing their effectiveness, safety, and dosing requirements.

What is Expanded Access? Compassionate Use? Treatment IND? Parallel Track?

These are all programs that helped set the stage for accelerated approval. They are still used today to help make promising experimental treatments available to people with life-threatening diseases who aren't benefiting from approved treatments and don't qualify for clinical trials. Expanded access is the general term for any program that allows doctors and their patients to gain access to medications outside of controlled clinical trials before the FDA officially approves them.

Prior to the activism surrounding HIV/AIDS drug development, expanded access usually came in the form of compassionate use allowances, which were often quite cumbersome. First, a doctor had to get permission from a company to use its experimental agent in a desperately ill patient (lots of paperwork). If permission was granted, the doctor then had to request authorization from the FDA to use the drug in his or her patient (even more paperwork). This process sometimes took weeks or months.

In response to the activism aroused by the limited availability of Retrovir (AZT) when it was being developed, the FDA created treatment investigational new drug (treatment IND) regulations, which went into effect on June 22, 1987. These regulations allowed pharmaceutical companies to set up programs to help doctors and patients gain access to investigational drugs in a much more efficient manner, usually in exchange for regular reports tracking the patients' progress (and problems) while receiving the treatment. Before being allowed to open a treatment IND program, the company had to provide the FDA with data indicating that the drug was both safe and effective. Within months, however, community activists protested that treatment INDs weren't likely to be useful, given that the safety and effectiveness data requirements were too stringent. This, they argued, only shaved six months off the time that the drug would otherwise be made available through the usual approval process.

Soon, regulations were published announcing a new expanded access approach: parallel track. As its name implies, this program would be provided on a track that ran parallel to the needed safety and effectiveness clinical trials of the drug. Parallel track was designed specifically with investigational anti-HIV drugs in mind. It made investigational drugs available much earlier in the development process, after reasonable safety -- but not necessarily effectiveness -- had been determined in clinical trials. Parallel track programs usually take the form of a large national study (sometimes called an open-label safety study), designed to collect safety data until the drug is approved (and sometimes thereafter), in which any doctor treating needy HIV-positive patients can participate.

While these expanded access programs seemed ideal in terms of rapidly making new treatments available to the sickest HIV-positive people, they were also problematic. One problem was fairness. Because of all the initial and follow-up paperwork involved in expanded access programs, many doctors didn't have the time or resources to enroll patients. Patients who had private health insurance -- and were being seen by private medical doctors with flexible schedules and support staff -- were most likely to benefit from these programs. HIV-positive patients receiving care through public clinics, where doctors have enormous caseloads and little assistance, were often left out of the process. In turn, the focus shifted away from expanded access programs to initiatives to make new drugs widely available by prescription by speeding up the FDA drug approval process.

What Is Accelerated Approval? Which Drugs Get it? Why? How Does it Work?

The best way to ensure that all HIV-positive patients had access to promising anti-HIV drugs was to focus on getting them through clinical trials and the FDA approval process as quickly as possible. In short, accelerated approval would benefit everyone: HIV-positive people in desperate need of new treatments, doctors without the time or resources to participate in expanded access programs, and pharmaceutical companies attracted to the idea of being able to cash in on their product much earlier in the drug development process.

Typically, an investigational drug for a life-threatening disease needs to show that it actually helps people live longer lives with less illness -- clinical markers of effectiveness -- than people taking either a placebo (a dummy pill) or a currently available treatment. Studies to test this are usually very large and often need many months or years of follow-up data to yield the necessary results. Fortunately, around the time activists and doctors were clamoring for the rapid release of new therapies, researchers found that certain laboratory parameters -- surrogate markers of effectiveness -- could be used to determine if a new therapy was likely to work without having to conduct time-consuming clinical marker studies. The first surrogate marker was the CD4+ cell count, whereby a sustained increase in CD4+ cells was found to be associated with longer survival. Then came viral load, whereby low or undetectable HIV levels in the blood translated into a higher likelihood of CD4+ cell recovery and longer, healthier living. The availability of these surrogate markers has enabled the FDA to review and approve investigational anti-HIV drugs on an accelerated basis.

When the accelerated approval guidelines went into effect in April 1992, a pharmaceutical company was technically allowed to file an NDA after the completion of Phase II studies that showed a positive effect on CD4+ cell counts in patients failing available options at that time. However, in exchange for accelerated approval, the company still had to conduct Phase III clinical trials to demonstrate fewer AIDS-defining illnesses and fewer deaths.

Today, the FDA rarely requires data from clinical trials employing clinical markers when reviewing investigational anti-HIV therapies given the overwhelming evidence that improvements in CD4+ cell counts and reductions in viral load are associated with longer, healthier survival. The agency -- and ADAC -- usually like to see at least 48 weeks of CD4+ cell count and viral load data from a sizeable study involving patients who desperately need new treatment options before they will grant accelerated approval. Phase III studies must also be well underway before an NDA seeking accelerated approval is reviewed. And while the FDA may no longer require Phase III studies to look for differences in death rates or the number of new AIDS-related illnesses, the accelerated approval guidelines permit the FDA to demand additional data from the company, such as longer-term safety and effectiveness research (longer Phase III follow-up or the addition of Phase IV studies, for example).

What About "Standard" and "Priority" Review? Is This the Same as Accelerated Approval?

No. With accelerated approval, the drug company begins working with the FDA early on in the development process so that an NDA can be submitted for review after the completion of Phase II or early in Phase III. For some drugs, the FDA requires completed data from Phase II or III studies before the NDA will be reviewed. However, there is still a way to accelerate the process: request that the FDA grant a priority review.

A standard review is given to drugs that provide only minor or no improvement over currently available options. A priority review can be granted to drugs that are likely to provide a significant advantage over currently available options. A standard review means that the FDA can take as long as 12 months after the NDA is submitted to review the data and grant approval. With a priority review, the FDA calls on a larger number of staff to review the NDA, reducing the approval time to less than six months.

What's the Deal With FDA Regulation of Herbs, Vitamins, and Complementary Therapies?

Herbal products, vitamins, and other complementary therapies are classified as dietary supplements in the eyes of the FDA. They are not considered drugs and, therefore, are not regulated by CDER. These products are regulated by the FDA's Center for Food Safety and Applied Nutrition (CFSAN), using guidelines stemming from the Dietary Supplement Health and Education Act (DSHEA) of 1994.

Generally speaking, dietary supplements -- a catch-all term for any vitamin, mineral, herb, botanical, amino acid, or other dietary substance (such as enzymes or tissues from organs or glands) -- are largely unregulated. Manufacturers do not need to obtain approval from the FDA or prove that their product is safe or effective before selling it to the public. The FDA can only intervene in the sale of dietary supplements under two conditions: 1) if the drug is found to be toxic or unsafe, relying on reports filed with the agency by doctors or consumers; and 2) if the manufacturer makes claims that the product has medicinal value (meaning that it can be used to diagnose, cure, mitigate, treat, or prevent a disease). Unfortunately, many manufacturers do make unsubstantiated marketing claims -- untested supplements to cure or treat HIV remain popular -- which has contributed to the ongoing debate as to whether the FDA should have more power, not less, in regulating the sale of these products.


The activities of the FDA since the beginning of the AIDS epidemic a little more than 20 years ago have been nothing short of amazing. The regulatory role of the agency has been tugged in all directions -- by politicians, by researchers, by the pharmaceutical industry, by activists, and by consumers. But through it all, the FDA still has a lot to show for itself: the approval of 26 anti-HIV medications, including 19 unique agents, three prodrug/extended-release formulations of older drugs, and four fixed-dose combinations. Not to mention numerous drugs for AIDS-related conditions. No other disease has ever seen this number of FDA approvals in such a short period of time. This may not have been possible without the flexibility the FDA has shown. And it definitely wouldn't have been possible without the dedicated individuals -- AIDS activists, healthcare providers, and people with HIV -- who worked tirelessly, both with and often against the FDA, to make this a reality.

Tim Horn is Executive Editor of The PRN Notebook, published by Physicians' Research Network in New York. He is also the head medical writer for

This article was provided by AIDS Community Research Initiative of America. It is a part of the publication ACRIA Update. Visit ACRIA's website to find out more about their activities, publications and services.


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