Speeches & Testimony

WORKSHOP ON ULTRA-ORPHAN GENETIC DISEASE THERAPEUTICS FOR CLINICAL DEVELOPMENT AND REGULATORY APPROVAL: SURROGATE MARKERS &RELATED ISSUES

Abbey S. Meyers
President
National Organization for Rare Disorders (NORD)


Washington, DC May 8-9, 2003

I want to thank you for convening this meeting to discuss critically important issues that affect development of treatments for rare "orphan diseases." The National Organization for Rare Disorders (NORD) is the not-for-profit consumer health agency that advocated for passage of the Orphan Drug Act of 1983, and we continue to monitor its implementation and encourage international efforts to eradicate these disorders.

As you know, NIH estimates that there are 6,000 rare disorders affecting approximately 25 million Americans. Most of these are serious, crippling, or life-threatening disorders that pose a desperate need for therapeutic advancements. However, the expectation that orphan drugs can be studied in the same manner as drugs or biologics for prevalent diseases sometimes defies common sense. I want to outline some of these problems for you, with the hope that our discussions today and tomorrow can begin the search for solutions.

It is also important to say from the outset that the Orphan Drug Act is a series of financial incentives designed to entice companies into developing treatments for diseases with small populations of patients. The evidence of safety and effectiveness that FDA expects and accepts is a regulatory matter, not governed by the Orphan Drug Act. Patients with rare diseases want the same assurances of safety and efficacy that people with common diseases expect. However, the FDA uses the same tools to analyze and measure clinical data no matter how prevalent or rare a disease is. Thus, for example, the critical importance of a "P value" never seems to vary, whether you are developing a treatment for very rare genetic disorders that affect only a few dozen people, or hypertension, or arthritis, which affects millions.

Let me touch on some of the unique problems that affect clinical trials for rare disorders:

• There is a serious and painful lack of historical controls for rare disorders. Therefore, the FDA usually requires placebo controls even for untreatable and fatal diseases, although most experts question the ethics of placebos in this regard. But there is no funding for historical control research, so the academic experts who are in the best position to pursue these studies don't do them. In fact, academic experts become experts because they publish journal articles about a disease, and that publication draws more patients to them. These experts have followed some families for several generations. However, there is no funding available to help them organize their data or to create registries to track patients over long periods of time. As a consequence, families of people with life-threatening diseases who feel that placebos are unethical discover they have no other options, and they cannot avoid them. But without historical control groups, sponsors have no choice and they must use placebos.
  
  
• For rare diseases, it is sometimes impossible to find enough patients, and when it is possible, it usually requires multi-site studies due to wide geographic disbursement of patients. In fact, they often have to be multi-national studies. FDA requires a sufficient number of patients to participate in each clinical trial in order to prove "statistical significance." All of this means extra time and money is needed to get patients to the clinical sites, over and over again for months and even years. It also means approval by multiple IRBs, and multiple informed consent documents that rarely use the same wording. Any deviation from the protocol at any individual site can ruin the entire study, so close supervision is required. For small companies, this can be very difficult.
  
  
• Both the IRBs, and the FDA review sections, are not required to have expert members, or even to call in external consultants who know the disease that they are reviewing. This can lead to inadequate protocols and selection of inappropriate endpoints.
  
  
  It is standard practice for investigators and sponsors to set the endpoints before they launch a clinical trial. When they omit experts on the disease in question, they can easily miss an important endpoint, or name an irrelevant primary, secondary or even surrogate endpoint. In fact, even if they discover an amazing unanticipated beneficial effect of a treatment during the study, FDA may not recognize it as important if it was not specifically targeted in advance as a primary or secondary endpoint, or a surrogate marker.
  
  
• How does one create a surrogate marker? There are groups of orphan diseases that are extraordinarily difficult to study because they don't have clear-cut biological markers. For example, neurological diseases that often wax and wane on their own; you cannot simply get a brain biopsy to prove that an experimental treatment has changed brain chemistry, or prevented further neurodegeneration. For many neurological disorders, neuroscience has no set biological markers, no less surrogate markers; and how does one prove "prevention", or "delay of progression" in a six-month or one-year clinical trial for a chronic disease that has slowly evolving symptoms?
  
  
• FDA will not accept clinical data if they are not "well controlled". Unfortunately, because of the unique funding streams associated with rare disease research, many years can be wasted on academic clinical research that is unacceptable to FDA. Academic research facilities are where the patients are referred, and that's where the research is done. NIH focuses most of its funding on basic research, and seed money for clinical research often comes from the voluntary health sector or independent foundations. By the time a corporate sponsor gets involved, they may have to start from ground zero again because they cannot use the data generated by academic clinicians if they were not "well controlled" studies.
  
  
• We could probably cut years off the development process if we could solve this problem, particularly for biologics. FDA insists that every biologic is "different", and therefore a biologic that was manufactured in an academic laboratory and used in initial clinical trials is considered "different" from a commercial grade biologic that is later made by a company in a GMP facility. Therefore, the commercial sponsor may have to do the research all over again if FDA believes the initial compound is not the "same" as the manufactured biologic.
  
  
• Long-term chronic illnesses often have to be studied over long periods of time. It is much easier to study a medicine for headaches, where efficacy can be proven in a matter of days or weeks, rather than months or years. Many orphan diseases are long-term illnesses with long-term chronic complications. Manufacturers want to see a return on their investment quickly, and therefore they hesitate to adopt products that must be studied for long periods of time. Furthermore, patients with degenerative diseases don't have enough time to wait.
  
  
• Patients and parents of children with serious and life-threatening orphan diseases are often desperate. They may feel they lack a voice in their medical care, as well as the FDA approval process, and they may believe they have an inherent right to access to any promising new treatment. Companies should plan on Expanded Access Programs for any investigational drug for an untreatable serious or life-threatening disease. However, FDA must do more to educate the public about the nature of investigational therapies, and the fact that they are not safe or effective until clinical trials prove otherwise. Both the FDA and the industry must understand that Wall Street generates much of the information about experimental therapies that reaches the public. Investment information is entirely too positive and misleading to patients who look at new scientific discoveries through the perspective of drowning people grasping at straws, and not through the perspective of investment bankers.
  
  
• For the purpose of orphan drug designations, sponsors must show prevalence and incidence statistics. However, the statistics often do not exist because there are usually no funds available to support epidemiological studies on rare disorders. And when statistics do exist, they are often inaccurate primarily because some support groups are known to exaggerate their population statistics. Even when researchers have published data indicating a certain genetic defect is "common", one has to ask what their definition of "common" is, and how many people actually have been diagnosed with the disease and are being treated? For example, there are disorders such as sleep apnea and hemochromatosis that are presumed to be fairly common, but how many people are actually diagnosed and know that they have it? And will FDA accept a presumption that although a specific defect may be common, fewer than 200,000 patients in the United States are actually being treated?
  
  
• Sometimes it is impossible to do double-blind clinical studies. FDA has to recognize this and find reasonable alternatives. For example, a therapy may be unusually smelly, or it can cause a specific side effect such as diarrhea, making it obviously different from the placebo. If the patient or physician can tell the real drug from the placebo, it may be impossible to do a true double-blind trial. Should this mean that the treatment will never be developed? Moreover, placebos are becoming more unacceptable to the general public, and particularly patients with life-threatening diseases who volunteer for clinical trials with an expectation that they may personally benefit. It is time for scientists and the FDA to find an alternative for studies of life-threatening diseases with no treatment alternatives. However, it is also time for clinicians to be frank with research volunteers about their unrealistic expectations for investigational therapies. Volunteers need to know that they should not expect to personally benefit from investigational therapies, but the knowledge gained from such studies may benefit other patients in the future.
  
  
• Unfortunately, the human toll has not yet been recognized as part of the research equation. For example, at a recent FDA advisory committee meeting, two families, each having two children affected, spoke about their excitement when they heard about an experimental therapy for their children's untreatable and life-threatening genetic disease. Each family brought both of their children to the clinical center hoping that they would be able to get them into the trial. But in both cases the investigators chose one child. If you remember the movie, "Sophie’s Choice", one can only imagine the agonizing decision these families had to make about which child would get the drug. This is what I mean by "human toll".

So I want to leave you with these thoughts, because after you finish debating P-Values, epidemiological data, surrogate endpoints and the like, I want you to remember those families. If you had to choose which one of your children would have a chance of living a long productive life, and which would lose his ability to control his own body and mind as he slips off to a vegetative state, which one would you chose? As a parent and a grandparent, I can tell you it would be unacceptable for me to make that choice, and it is unacceptable for the FDA or a sponsor to put that restriction on access.

I want to thank the American College of Medical Genetics, Society for Inherited Metabolic Disorders (SIMD), and the Office of Rare Diseases for convening this conference. We all look forward to hearing the experts address these important topics, and even more so, to finding solutions to these problems so that people with rare disorders will have a fair chance of benefiting from cutting edge scientific advancements. After 20 years of remarkable progress through the Orphan Drug Act, we have an opportunity to propel research forward in the next 20 years by eliminating the regulatory potholes that have plagued our path through clinical trials for decades. Orphan diseases are the exceptions for which some rules should be broken. We just need to work harder to find a better way to move orphan drugs from the laboratory bench to the patient's bedside.

Many patient organizations believe that FDA should be working more closely with academic scientists, companies, and consumer representatives to tear down the barriers to progress on orphan disease research. The human toll must be measured in any research equation. Only those who can identify with human suffering should design research protocols. Working together, we can find new methodologies to prove that a treatment is safe and effective, while respecting the sanctity of patients who participate in clinical trials.

Thank you.