Saving Amanda and the Anatomy of A Compassionate Use Drug Program for Medarex

Amanda a 22 year old young lady who suffers from Hodgkin's Lymphoma, a form of cancer, has had recurrences after it was diagnosed in 1998 when a mass the size of a submarine sandwich was found behind her heart in the thoracic cavity (www.tinyurl.com/9ukyk). Initially treated with chemotherapy and after a recurrence she underwent a bone marrow transplants. In spite of this state of the art treatment which has saved so many cancer victims she subsequently had a recurrence. However, there is one last promising possibility to combat this tenacious form of Hodgkin's. CD 30 a drug currently in Phase II clinical trials being run by the Pharmaceutical company Medarex www.medarex.com could be this last chance. New approaches involving the use of antibody-based agents have produced promising results in experimental Hodgkin's lymphoma models. Early clinical trials using immunotoxins, radioimmunotherapy (RIT), bispecific molecules and monoclonal antibodies (mAbs), have demonstrated some clinical efficacy in patients with advanced refractory Hodgkin's Lymphoma. Although it seems unlikely that these approaches alone will cure chemotherapy-resistant patients with larger tumor masses, combination with conventional chemotherapy may help to overcome resistance of Hodgkin-Reed/Sternberg (H-RS) cells or to eliminate residual disease. Since H-RS cells are extremely sensitive to irradiation, RIT may be a potential approach. CD 30, is a monoclonal antibody or a humanized and a fully human anti-CD30 mAb is currently being evaluated in phase I/II clinical trials. These monoclonal Antibodies could engage the human immune system against the Hodgkin's Lymphoma and are capable of directly inducing apoptosis of H-RS cells. In addition, these monoclonal antibodies could be combined with conventional chemotherapy and are thus promising candidates for further development for the therapy of Hodgkin's Lymphoma.

The Food and Drug Administration(FDA) puts potential drugs and medical devices for all diseases through a rigorous set of clinical trials process known as Phased Clinical Trials before it will approve them for use with patients in the United States. These clinical trials are essential to the development of novel and improved treatment approaches for not only patients with cancer, but other diseases as well. Drug testing must go through 4 distinct phases of clinical trials to earn FDA approval.

Phase I trials are the earliest formal phase of clinical trials when testing a drug for treatment in humans and are done to find out the following: 1) the safe dose range and/or scheduling of the specific treatment regimen, 2) the side effects, 3)how the body copes with the drug, 4) the combination of drugs necessary for treatment.If the treatment shrinks cancer. The information from Phase I is used to established doses or scheduling of the drug, as well as its ability to produce anti-cancer responses, are utilized in subsequent trial phases.

Phase 2 or (Phase II) occurs with approx. 70 out of every 100 new treatments tested in phase 1. This series of trials may be done on people who either all have same the type of cancer or with several different types of cancer. Phase 2 trials determine if the new treatment works well enough to proceed on and test in phase 3. Questions that are answered include 1). which types of cancer it is the drug effective against, 2). more info about the side effects and how to manage them, 3.) more info about the most effective dose to use. Phase 2 trials are often larger than phase 1 and there may be up to 50 people taking part. If the results of phase 2 trials show that a new treatment may be as good as existing treatment, or better, it then moves to phase 3.

Phase 3 (phase III) trials compare the new treatments with the current standard or state of the art treatment available. Phase 3 trials are usually much larger than phase 1 or 2. This because differences in success rates may be small so, you would need very many results to show the difference. For example, 6% more people get a remission with a new treatment compared to standard treatment. If a phase 3 trial gave the new treatment to 50 people and the standard treatment to 50, on average, there may be 3 more remissions in the new treatment group. The 2 groups would not look that different. If they gave each treatment to 5,000 people, there could be 300 more remissions in the new treatment group. Sometimes phase 3 trials involve thousands of patients in many different hospitals and even different countries. Phase 3 trials are usually randomized which means the researchers put the people taking part into 2 groups at random. One group gets the new treatment and the other the standard treatment.At the end of this Phase information is processed and reviewed in what is know as a meta-analysis which consists of combining all the results from the phase 3 trials of a new drug or treatment. The purpose is to get a broader picture of how well a treatment works. Obviously the more data or information you have, the more accurate the results are likely to be. At the end of this Phase the drug or treatment is approved and the company receives its license.

Phase 4 (phase IV) trials although helpful are really is not necessary for they are carried after a drug or treatment has been shown to work and has been granted a license. The purpose of Phase 4 is to provide the pharmaceutical company with the info it will need to help market this newly licensed drug with the physicians and the marketplace. The main reasons pharmaceutical companies run Phase 4 is help then crystallize the information by:1). learning even more about the side effects and safety of the drug, 2). determining in more detail what the long term risks and benefits are, 3). and finally gain more insight into how well the drug works when it’s used more widely than it was in clinical trials.

CD 30 has completed the Phase 2 stage and truly more than half of Medarex's FDA quest for approval is over and the drug is well on its way to being used clinically barring any unforeseen disasters. From this moment on tweaking and refinement of the drug and its usage is the company's focus. Promising drugs as of 1997 have been "fast tracked" by the FDA. This means that it has determined that the drug or biologic is intended for the treatment of a serious or life-threatening condition. Furthermore having demonstrated the potential to address unmet medical needs for such a condition, the FDA will facilitate and expedite the development and review of the application for the approval of the product. As a matter of fact Medarex has a vaccine (MDX-010 in combination withMDX-1379, a melanoma vaccine, for the treatment of previously treated, unresectable Stage III and Stage IV metastatic melanoma) for a form of skin cancer, fast tracked in October 2004(www.tinyurl.com/9pdu3).

Compassionate Use Programs and FDA protocols for drugs or biologics in the midst of Clinical trial testing is another possibility which can help patients receive treatment before finally being released. A formal compassionate use program is a mechanism for getting an unapproved but promising new treatment to patients who would otherwise be unable to receive it. Compassionate use programs are for people who have a life threatening with "no comparable or satisfactory alternative drug or other therapy available to treat that stage of the disease in the intended patient population" (in the words of the FDA regulations). Formal compassionate use is a bit like a clinical trial in that you will still have to meet specific requirements such as the type and stage of disease, and usually you must be treated by doctors who participated in the clinical trials for the drug, but compared to trials, the requirements are somewhat relaxed. If you qualify for an open clinical trial of the treatment, obtaining it through compassionate use is not an option.

According to the FDA regulations, compassionate use programs are normally for drugs which are in phase III or have completed accrual to their trials (it takes significant time to allow the data to mature, compile it, and get it reviewed by FDA - often several years), but the regulations do say compassionate use might be possible for some drugs which are only in phase II testing. I presume there would still have to be applicable promising results - such as spectacular results from an ongoing phase II trial. If you just heard about the latest cancer cure for mice on the nightly news, it is likely that there will not be a compassionate use program. If there are reports of success in trials with your form of cancer most likely the company will have a Compassionate Use Program.

Although the FDA has to approve compassionate use programs, they normally do so without fuss. Whether there is a compassionate use program largely depends on whether the drug company has decided to have one. The decision depends on many factors including the cost which can easily run into the millions and whether there is an adequate supply of the drug (which is often an issue). In the past, campaigns by organized patients has sometimes made the difference. For instance, Genetech granted expanded access to the breast cancer drug, Herceptin, only after breast cancer activists conducted an intensive campaign. ("Demand Grows for Early Access to Promising Cancer Drugs",Journal of the National Cancer Institute, November 20, 2002). When a drug company decides to provide access to their unapproved drug outside of the clinical trial they most commonly do it in the following two ways:

1.) Expanded Access Programs (EAP): Drug companies in the late stages of drug development including the Phase III clinical trial stage, can offer Expanded Access Programs for patients who are not able to enroll in a clinical trial. The FDA generally approves these programs if the drug has demonstrated some effectiveness against a specific cancer in the on-going clinical trials.
2.) Single Patient Access(SPA): Patients who are not eligible for either clinical trials or an Expanded Access Program (if one exists) may be eligible to receive the unapproved new drug by applying for Single Patient Access. In this situation, the patient's doctor must first request permission for access to the drug from the drug company. If the company agrees, the patient's doctor works with the drug company to apply for FDA approval for use of the drug for the patient. The timeline for Single Patient Access varies. In an emergency, the FDA can walk the paperwork through in 24 hours.

Hopefully Amanda, this vivacious and courageous young women will have her plea for CD 30 honored by Medarex. Medarex will receive a tremendous amount of good publicity for free if they decide to go out on a limb for this young lady. This is a small biopharmaceutical company with just over 400 employees. The millions of dollars of publicity it will receive for free may bring this company notoriety and investors! In addition the FDA will easily support a Compassionate Use Program if Medarex decides to comply. Medarex, as a Medical Doctor I urge to help out this courageous young women, Amanda, who has been valiantly fighting refractory Hodgkin's Lymphoma for 7 years. It must be kept in mind that it cost pharmaceutical companies in the vicinity of 2 billion dollars to take a drug from conception to market. The road to market is expensive, tortuous and unbelievably difficult and is fraught with medico-legal gauntlets. Not withstanding the medico-legal and financial issues faced by all of us in the health care field, helping Amanda is simply the Hippocratic thing to do! Cheers to Medarex!

Francis X. Yubero, M.D.