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Richard Klein, National Skills Building Conference

National Skills Building Conference, Atlanta, GA

HIV/AIDS Treatment

Issues and Research Institute

Oct 29, 1994

My name is Richard Klein - I am a Public Health Specialist at the FDA Office of AIDS and Special Health Issues. My office, which is located within the Office of the Commissioner, serves as the focal point for HIV and AIDS related issues at the FDA, performing an advisory and coordinating role within the Agency, and serving as liaison with the outside community.

I would like to talk about regulatory issues at the FDA, particularly as they pertain to HIV and AIDS. FDA has a variety of AIDS-related responsibilities. These include - the regulation of drugs and vaccines; the regulation of medical devices, including barrier products such as condoms, and gloves, and the regulation of diagnostic test kits for HIV. FDA also has responsibility to assure the safety of the nation's blood supply; and to protect HIV-infected individuals from health fraud.

What do I mean by regulation? The goal of FDA regulation is to ensure that products are designed properly, are safe, effective, properly manufactured, truthfully labelled, and have adequate directions for use. I will limit my remarks to just one of these areas, the drug approval process. I think it will be useful to briefly explain the statutory basis of the current scheme for testing and approval of drugs.

FDA's was given statutory authority in 1906 when Congress enacted the Food and Drug Act to address unhygienic conditions in Chicago's meat packing plants. The Act applied to drugs only to the extent that they could be removed from the market if the drugs could be shown to be adulterated or misbranded. But that law did little to control the sale of dangerous drugs and devices. It took a catastrophic incident, which occurred in the 1930's to propel further action. A common drug used by adults for treating bacterial infections at that time was sulfanilamide, a nearly insoluble powder. To make it more palatable for children, a chemist prepared an elixir by dissolving it in the only solvent he could find that would dissolve the powder. He used diethylene glycol - which is also used in antifreeze - and is a poison. There were no requirements in 1937 for testing the safety of drug products, and over 100 people died, most of them children. This scandal followed close on the heels of another drug-related tragedy during the 1930's. Dinitrophenol, promoted for weight reduction, caused serious injuries and deaths. These incidents lead Congress to the enact the Food, Drug, and Cosmetic Act in 1938. This statute expanded consumer protection by requiring the testing of new drugs for safety prior to marketing. It was this requirement for toxicological testing that spared the United States from the tragedy of Thalidomide that swept Europe during the sixties. You may recall that Thalidomide caused severe limb deformity in the offspring of the women who took it.

In 1962 Congress set in place the second cornerstone of our current public health and consumer protection efforts. Congress stated that before a drug product could go on the market, it had to be shown to be both safe... and effective.

Effectiveness had to be shown using adequate and well controlled investigations, which represented then, and still does today, the scientific standard for evidence.

I want to stress that while the laws that Congress set into motion required that the Food and Drug Administration review applications for new drugs, and set up certain standards by which the Agency must assess these applications... it did not give FDA the authority or the mandate to develop new drugs. Indeed, the agency does not fund or conduct the research to bring new drugs to market. Rather, the FDA acts as an unbiased third party to review the scientific work of drug developers, and measure their results against scientific standards to assure that the studies they submit show safety and effectiveness. The agency also inspects manufacturing facilities and reviews production records to assure that the products are produced under good manufacturing processes - specified standards that ensure that the product is pure, and of consistent quality.

So let me describe the drug testing and review systems currently in place. I want to stress that whether a product is mainstream or alternative, - synthesized in a state-of-the-art laboratory or found in a rain forest in Central America, the product is generally held to the same standards. It must be studied in properly controlled trials so that we can determine whether it works for a specific purpose.

For a drug thatès never been used in humans before, the first step a sponsor must take is to perform preclinical test-tube, (or In Vitro analyses), and/or animals studies for toxicity. FDA usually requires that dose toxicity be determined in at least two mammalian species. The toxicity information can then be used to make risk/benefit assessments and help determine the acceptability of the drug for testing in humans, and to estimate a safe starting dose.

Pharmacokinetic studies must be provided - showing the fate of the drug - absorption, distribution, metabolism and excretion. In addition, the company must provide information on chemistry, manufacturing and controls. This ensures the identity, purity quality and strength of both the active ingredient and the finished dosage form.

The sponsor, usually a drug company, develops a plan for testing the drug in humans, and submits it to the FDA, along with its animal testing data, information about the composition of the drug, manufacturing data, qualifications of its study investigators, and assurances for the protection of the rights and safety of the people that will participate in the trial. This information forms what is known as the Investigational New Drug Application - or IND. FDA reviews the information to make sure that study subjects will not be exposed to unreasonable risk of harm. If FDA finds no safety problems with the plan or product, it permits the study to begin.

Clinical trials are traditionally conducted in three distinct phases. The first exposure of humans to the drug, the Phase 1 study - usually takes place in a small number of healthy volunteers- although in the case of serious and life threatening conditions, volunteers who have the disease may be enrolled. These initial studies test the safety of the drug in humans and help to determine an appropriate dose for further investigations.

As clinical studies progress, additional animal studies continue to be carried out out so that the safety of ongoing human studies can be ensured to the greatest extent possible. These include reproductive toxicity studies to examine the effects of the drug on fertility, reproduction, teratogenicity, and mutagenicity.

I might mention that until last year women were often excluded from early phase studies pending the analysis of this information. Under FDA's 1977 guidelines, sponsors were discouraged from including women of child bearing potential in studies until animal trials provided data sufficient to determine the possible risk to the fetus. While women of childbearing potential, and even pregnant women have always had access to investigational drugs in the case of life threatening diseases, FDA's new guidelines on analysis of gender-related differences strongly encourage inclusion of women in most early phase trials, as long as they are adequately informed of the potential risks.

The next phase, phase 2 studies, not only continue to evaluate the safety profile of the drug, identifying the most common side effects that might result from its use, but also begin to assess itès activity for a particular indication. Phase 2 studies usually involve a few dozen to a few hundred people.

I would like to note that almost 80 percent of all drugs tested are abandoned by their sponsors after either phase 1 or 2 because of excessive toxicity or lack of substantial benefit.

By the time phase 2 is completed, the drug developer knows quite a lot about the safety and activity of the drug. If the results are promising, the sponsor moves to phase 3. FDA strongly encourages sponsors to work closely with the Agency to optimize the design of their phase 3 trials to be sure they fulfil the regulatory requirements for demonstrating safety and effectiveness.

The large, controlled phase 3 studies often involve thousands of people with the target condition. The studies may examine additional uses for a drug, or consider additional population subsets, but are primarily aimed at obtaining the necessary effectiveness data. The phase 3 studies also continue to generate valuable safety data, including long term effects.

Once phase 3 testing is completed, the sponsor submits the test results to the FDA in the form of a New Drug Application, or NDA. FDA's scientists [medical officers, pharmacologists, chemists, microbiologists, and statisticians] review the application to validate the data and determine if they do, in fact, show that the drug is both safe and effective. The manufacturing facility is evaluated to ensure that a consistent and high quality product can be produced. Finally, the safety and effectiveness data itself is usually audited by the FDA to verify any questionable data.

Once the drug developer has completed testing the drug, it submits proposed labeling for its drug, which must be reviewed and approved by the FDA. (Labeling is generally reflective of the conditions of the trial in terms of indication and population, but once the drug is approved, under the practice of medicine, which is not regulated by the FDA, a physician may use the drug in any way he or she deems therapeutically appropriate.) Use of a drug product for other than its labeled indication is called an "off label use."

The traditional drug development process I've just described is a lengthy one. On the average, it takes about 10 years to complete. It is certainly expensive. But it is an effective system that does accomplish what is was designed to do. And that is...to protect the public from ineffective and dangerous drugs and assure that the risks associated with drugs are in acceptable ratio to the benefits to be derived.

Over the years, people have argued that this process does not address the needs of people faced with life threatening diseases for which there are no practical alternative therapies. People with life threatening illnesses have argued that the process takes too long - that they are willing to accept greater risks and unknowns for the sake of access to promising drugs.

To meet the needs of this population, the agency has made some substantial changes in the drug review process over the years.

Generally, these changes fall into two major categories -

First those designed to permit treatment access to promising products before they are approved, and secondly, those designed to speed the review process, getting products to market sooner. The changes made in the past few years reflect an evolving institutional philosophy that supports greater risk-taking in the pursuit of effective agents for patients with serious diseases.

FDA has looked at various approaches to making promising therapeutic agents available earlier without compromising the thoroughness and scientific integrity of the development process or the review, or the protections afforded study subjects.

Since the data on safety and effectiveness accumulate gradually during laboratory and animal testing, and during the course of human trials, it is the FDA's challenge to determine when public health needs are best met by permitting access to a new therapy. Remember... that drugs undergo these testing procedures because we don't know if they really work, and because we really don't know if they are safe. If we did, they would be approved - rather than in clinical trials! In determining whether the evidence favors making a drug available, the FDA must consider 1) the quality and the extent of the data available, 2) the potential value of the new agent to a specific patient population, 3) the risk of toxicity, 4) the length of time necessary to obtain more conclusive answers, and 5) whether the risk of allowing broader access will ultimately impede the ability to learn more about how the therapy works. As we know, there is inevitably a tradeoff between speed and certainty. The sooner a drug is made widely available, the less is known about it. And it becomes more difficult to answer the unanswered questions once a product is approved because people are less apt to participate in controlled clinical trials once a drug is available on the open market. Unanswered issues might include optimizing the effective dose, when to begin use of a product, and how long to use it.

Over the years FDA has nevertheless implemented a variety of programs to make promising therapies more widely available to people with serious and life threatening illnesses.

In 1987 FDA finalized regulations that allowed a "treatment IND." This rule formalized the procedures that allow thousands of patients to have access to investigational drugs for treatment of serious and life threatening diseases for which there is no satisfactory alternative treatment - PRIOR to general marketing. The regulation allows for a treatment protocol, separate and distinct from the study protocols, either while clinical studies are still under way or completed, but the sponsor must actively be pursuing marketing approval. There must be sufficient data to show that the substance "may be effective," and that there are not unreasonable risks. These treatment uses generally donèt provide data about effectiveness, but useful safety data is collected.

In the 7 years since the treatment IND procedures were developed, there have been 30 treatment INDs. Nine of these have been for AIDS or AIDS-related conditions, all of which were subsequently approved for marketing.

In 1992 the Public Health Service published a policy statement permitting expanded availability of investigational drugs for AIDS through a "parallel track" mechanism. This policy outlines how promising new drugs can be made available early in the development process, once there is evidence of probable efficacy based on laboratory and available clinical data, evidence that the drug is reasonably safe, and enough data to recommend an appropriate starting dose. It serves people without satisfactory alternatives who cannot tolerate or derive no benefit from the available therapies, and cannot participate in clinical trials because they do not meet the entry criteria, are too ill to participate, or because it would cause undue hardship, such as travel - or because the trials are fully enrolled. The drug is distributed by the patient's personal physician.

How does parallel track differ from the treatment IND? First, parallel track applies only to AIDS-related therapies - and secondly, it makes drugs available earlier in the study process. Where the treatment IND can make drugs available in late phase 2 or in phase 3 - parallel track drugs can be made available as early as late phase 1 or early phase 2.

Drugs are distributed under a study protocol so that data, particularly side effects and safety data, can be collected. This protocol runs èparallelè to the ongoing controlled clinical trials that provide the data essential to learning about the drug for marketing approval.

Another approach to increasing access to promising therapies is to get new products onto the market as quickly as possible.

To help speed the approval process for promising products that affect the survival of patients, FDA's IND regulations formally identify a proactive role for FDA in helping to design definitive trials at the earliest possible stage to evaluate effects on mortality and morbidity. The provisions of Subpart E, under the IND regulations, focus on the entire drug development and evaluation process - from early preclinical and clinical testing through FDA evaluation of controlled clinical trials and marketing applications, and up through post-marketing surveillance - treating the entire process as a coherent and continuous operation to significantly increase the overall efficiency. The process allows FDA to work closely with sponsors to assist in designing the studies needed to gain marketing approval, and helps prevent false starts and wasted effort that could result from flawed study designs. If data looks promising, FDA may suggest a Treatment IND to make the drug available until final marketing approval. Subpart E allows FDA to work with a sponsor to complete studies by the end of phase 2 that would give FDA enough data to weigh known and potential risks of the drug against known benefits, and to make a decision on marketing approval based on a medical risk-benefit analysis. If FDA grants this earlier phase approval, it may seek an agreement from the sponsor to conduct certain post-marketing studies to reveal additional information about the drugès risks, benefits, and optimal use.

Later in 1992, FDA also published regulations outlining a new procedure for accelerating approval based on demonstrated effect by the drug on a surrogate endpoint that would be reasonably likely to predict effectiveness of the product. In other words, effectiveness could be demonstrated on a laboratory or clinical measurement that could be expected to indicate a probable corresponding clinical benefit.

Like Subpart E, accelerated approval allows FDA to grant full marketing approval to a drug earlier than would normally be possible, allowing full access and third party reimbursement - using evidence of an effect on a marker that can be expected to correspond to a tangible clinical benefit. For example viral burden may be useful in predicting onset of symptoms and disease progression. A sponsor might propose demonstrating that itès drug lowers viral burden, as measured by PCR, for example, to correlate with a delay in disease progression - and the surrogate marker, reduction of viral burden would have to be validated in further studies, conducted after approval of the drug, to show that there was a correlation to prevention or delay of disease progression.

In the case of accelerated approval, the sponsor is required, as part of the approval agreement, to conduct continuing adequate and well controlled studies to validate the surrogate. These post-marketing study commitments are negotiated with sponsors, and are usually underway at the time of the approval. The regulation specifically permits FDA to withdraw approval if the post-marketing studies fail to verify a clinical benefit, if the sponsor fails to complete the required studies with due diligence, if the promotional materials are false of misleading, or if other evidence comes to light to show that the product is not safe or effective under itès labelled conditions for use. FDA is obtaining agreements from sponsors to withdraw products form the market if they cannot verify clinical benefits.

As with all approved drugs, labelling is required to provide information about the safe and effective use of the product, including any necessary warnings, and reflect the nature of the data supporting the productès approval.

Accelerated approval applies to products that are for life threatening or serious illnesses, and provide meaningful therapeutic effects not available through existing treatments. ####