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A look at the FDA from the MS point of view.

In recent months, the Federal Food and Drug Administration (FDA) has come under increasing fire because of perceived delays in the drug approval process which some believe slow access to new therapies by patients. While the greatest outcry has come from the AIDS support community, it is a matter of concern to everyone -- and, perhaps, particularly those involved with multiple sclerosis research and treatment, because now, more than ever, new drugs are being systematically tested for safety and efficacy in MS.

As our understanding of MS increases, and as biomedical research and drug development technologies become more sophisticated, the number of rational treatment possibilities has increased markedly. The NMSS, the National Institutes of Health (NIH) and pharmaceutical companies here and abroad are currently supporting many experimental studies to test safety and efficacy of new therapies for multiple sclerosis. One or more of these may ultimately provide new safe and effective treatments.

Is the FDA moving too slowly to keep up with this surge of investigation both in our field and in others? Should there be changes in the FDA drug review and approval process?

Before we can attempt to answer these questions, it is important to take a look at where the FDA comes from and what its drug approval process involves.

The drug approval process in the United States is one of the world's most highly complex. It serves to protect American citizens not only from exposure to unacceptably toxic agents, but also from economic and medical fraud resulting from the sale of unproven remedies. The FDA, born in 1906, is responsible for scientifically evaluating the efficacy and safety of therapeutic agents before they can be advertised and marketed to physicians and the general public. It meets this responsibility through a series of steps carefully designed to provide the mandated safeguards.

Initial Research Steps

Before Approaching the FDA

Even before the FDA is called upon to evaluate new therapies, years of research, from the most basic to the most applied, are required to develop new agents. This effort is dictated not only by FDA procedures, but even more importantly, by the scientific and medical procedures required to test safety and efficacy of new therapeutic agents for diseases like MS. Such studies are complex, time consuming and expensive.

For any disease, a basic understanding of the underlying disease process must be obtained so that new drug development can proceed against a background of a strong scientific rationale. This understanding entails considerable work in the laboratory using test tubes and tissue culture, and, when possible, work with laboratory animal disease models of the relevant human disorder.

A good model system for MS is an animal disease found in mice, rats and guinea pigs called experimental allergic encephalomyelitis (EAE). Because of some similarities between EAE and MS (such as the immuno-logical nature of the diseases, lesion formation and clinical symptoms), scientists often test new drugs for safety and efficacy in EAE before even considering a clinical trial in MS on humans. Many of the agents currently being tested for MS, such as monoclonal antibodies and Copolymer I, were shown to be relatively safe and effective in EAE before human trials began.

After basic research 1) suggests that a new drug has a reasonable scientific rationale for use in a human disease; 2) shows evidence of biological activity through lab and animal studies; and 3) has at least acceptable levels of toxicity, an investigator or pharmaceutical company may apply to the FDA for an Investigational New Drug (IND) permit. The IND permit allows limited use of the agent in humans, under a regulated research plan.

Once the permit has been granted, three phases of study are generally undertaken before final presentation can be made to the FDA for analysis.

Phase I Studies

After IND Permit Has Been

Granted: Safety and Dosing

The first studies usually done are called Phase I or preliminary clinical trials. A relatively small number of volunteers will be given the drug, and signs of safety and toxicity will be carefully monitored. If the FDA allows such studies to be done with people who have the target disease, usually only the most severely affected individuals will be selected, individuals whose opportunities to benefit from the drug will outweigh the unknown risks of using an agent never before tried on humans. However, the FDA often requires that only non-affected volunteers be allowed in first-level toxicity studies.

Phase I studies can be quite short, often taking less than a year. They are aimed primarily at determining the proper dose, schedule, and route of delivery to ensure zero or acceptable toxicity of a drug. Results from such studies, presented to the FDA along with a research plan for a first test of efficacy, can lead to a Phase II study.

Phase II Studies

After IND Permit Has Been

Granted: First Formal Test for

Effect

Phase II or pilot studies vary in size, duration and study design. They are planned to assess continuing safety and address the question of efficacy.

For MS, it has been concluded that the best design of an efficacy study will include controls (sham treatment group or treatment group with alternative generally acceptable therapy), randomization (to ensure that experimental and control groups are both representative of the study population), and blinding where possible (to minimize the influence of a placebo effect). Rather stringent inclusion and exclusion criteria are set, depending on the known toxicity or complications of the agent and on the target population for treatment.

While some Phase II studies are run at a single clinical center, others may be "multicenter," and run simultaneously at several clinics. Agents which show positive results in Phase II studies will be subjected to more extensive studies, called Phase III.

Phase III Studies

After IND Permit Has Been

Granted: Close to the End

Phase III or full clinical trials are large in scope, requiring hundreds or even thousands or subjects. Phase III trials are also rigorously designed and controlled, as they are aimed at collecting the definitive data required by the FDA for a new drug application (NDA) which would allow marketing of the agent to physicians and the public. These clinical studies may last several years depending on the disease being studied and the questions being asked.

After the Studies are Completed

When all these studies are completed, the data are gathered and presented to the FDA for analysis to determine whether trials have met FDA criteria.

Up to this point, the lengthiness of the process is understandable. All the clinical studies described are necessary to determine efficacy and safety for use in MS.

However, once the studies have been concluded and forwarded to the FDA, it becomes that agency's responsibility to review and then to grant or deny permission to market as expeditiously as possible.

This is where serious problems come in. Currently, this review process is taking on the average of three years.

So -- we return to our original questions: 1) Should there be changes in the FDA drug review and approval process? 2) Is the FDA moving too slowly to keep up with this surge of investigation?

Conclusions

From the MS point of view, the answer to the first question is "No," we should not be seeking to change the review and approval process. At present there is no shortcut to a complete cycle of clinical trials for new agents in MS. The FDA drug approval process, although lengthy, has not thus far unnecessarily delayed the availability of new agents for MS, and it has provided and will continue to provide significant protection.

On the other hand, report after report has indicated that the FDA is an "agency under stress": between 1979 and 1987 the Fda experienced a 15% cut in personnel, from 8200 to under 7000; because of lack of competitive salaries there is an attrition of mid-level and senior level scientists; and the agency's suffering from a crumbling infrastructure. All of this while 15,000 application on products, devices and drugs were referred for evaluation each year -- not to mention the 23 recent laws Congress has passed adding new responsibilities to the FDA, but not providing new resources to carry them out.

Therefore, the answer to question number two is "Yes," in general the FDA is moving too slowly to keep up with the demands being made on it. What should take about three months generally takes three years.

Can anything be done to help the agency speed up the approval process once the applications are in its hands?

A coalition was formed in 1988 to strengthen the infrastructure of the FDA. The Society is a founding member of the FDA Council and is taking an active role in fighting to obtain the resources the FDA so badly needs: consolidated space, equipment and instrumentation, more personnel and training. The FDA Council is already making a difference: it helped achieve a 14.9% increase in the 1991 appropriation for the Food and Drug Administration -- the highest percent increase in 12 years.

Although this is only the tip of the iceberg, it is good news for those of us involved in MS research. The FDA is the nation's oldest consumer protection agency; it is unique in the world. It merits our support to bring it to full strength.
COPYRIGHT 1991 National Multiple Sclerosis Society
No portion of this article can be reproduced without the express written permission from the copyright holder.
Copyright 1991, Gale Group. All rights reserved. Gale Group is a Thomson Corporation Company.

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Title Annotation:includes related information on investigational new drug; Food and Drug Administration, multiple sclerosis
Author:Reingold, Stephen
Publication:Inside MS
Date:Jan 1, 1991
Words:1549
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