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HEALTH ddC: Problems & Promises Studies suggest excellent results from the drug when used alone and in conjunction with AZT, but activists are calling for a boycott of Hoffmann-La Roche products because of delays in making ddC available. by Kathleen Brockel, Atlanta NAPWA Treatment Advisory Committee “I had to build special shelving in my office to hold the four inch thick binders,” said Atlanta Infectious Disease physician Dr. Steve Marlowe, referring to the stack of paperwork requiredto enroll and moni tor patients in the Hoffmann-La Roche ddC expanded access program. Atlanta physician Rick Hudson enrolled the first patient in the country into the Roche's ddC expanded access program. It took him twelve hours to com plete the paperwork process. Then he was told by Roche that it would be 3 to 4 months before his patient would receive the drug. ddC is a nucleoside analogue (as are ddl and AZT) which has antiretroviral activity against HIV. ddC's efficacy has been suggested by increased CD4 counts, weight gain and reduction in p24 antigen levels. Reported side effects are generally attributed to higher doses (.06 & .03 mg/kg of body weight) of ddC used in phase I trials. Those side effects can include peripheral neuropathy (tingling, numbness or pain in the hands and feet, neutropenia-a type of low white blood cell count), thrombocytomenia (low platelets) and rash. The toxicities are nonexistent, or much less severe, in lower doses of ddC (.01 or .005 mg/kg of body weight). Current recommendations call for one or two ,375mg tablets taken orally three times per day. A person with HIV is eligible to get ddC through expanded access if he or she has experienced AZT treatment failure, AZT intolerance, or is ineligible for AZT. These are specific definitions set by Roche which outline criteria for lab val ues, symptoms, and time frame for eligi bility. (A summary list is printed in issue #113 of John James Treatment News available in the NAPWA office.) Expanded access programs are meant to allow access to potentially life enhanc ing and life saving drugs for people who are ineligible for standard, FDA approved drugs while those drugs are still in clinical trials. But, for a variety of reasons, peo ple are often not eligible to participate in expanded access programs. They may be taking other medications which might skew the results of a drug trial. Additional safety data on the drug is collected through the program, whereas efficacy data is collected through standard drug tri als. And drug companies are not allowed to charge for the drag through expanded access. “Patients die while doctors fill out forms” is the tag line coined by ACT UP New York’s “Boycott Roche” campaign. Boycott organizers charge that people with HIV are waiting as long as four to seven months to receive ddC through the expanded access program. They say that problems stem from Hoffmann-La Roche’s refusal to ask the government for a “national” IRB approval—experimental drag protocols must be approved by insti tutional review boards. Because there is no national IRB for ddC, physicians whose patients want to use the drag must get approval from local IRB's—through hospitals or research institutions. A sec ond obstacle is the paperwork required for each patient enrolled, a stack thicker than an Atlanta telephone directory. ACT UP calls for a boycott against Roche services and products (Valium, Librium, Dalmane and Roferon A) until demands are met to: replace local IRB approval with a national IRB; reduce monitoring paperwork from 6 pages every 2 weeks to 2 pages every 4 weeks; deliv ery of the drag in less than 3 weeks; and formal toxicity reporting procedure to physicians. David Rephun, ACT UP Boycott orga nizer met with Hoffmann-La Roche repre sentative Paul Oestreicher last week to discuss activists' demands. Rephun reported that Roche promised to stream line the expanded access process soon. But Rephun is concerned because Roche's promises have gone unfulfilled before. One day after this meeting, Oestreicher told us that Roche had already filed a new protocol with the FDA which will reduce the case report forms from 6 pages to 2. The FDA confirmed the filing. He also said that Roche approached the FDA last year for a National IRB, but was told that the FDA did not have the same experi ence with Roche as with Bristol Myers and would not approve it. ACT UP coun ters that the FDA says no such petition was submitted. The ddC expanded access program has been fraught with controversy since its inception last June. Initial criteria for accessing the drag required that patients be unable to take both AZT and ddl (another experimental anti-HIV drug). Hoffmann-La Roche eliminated the ddl fail criteria in September after consider able activist, physician and patient pres sure. Roche reports that 2,000 people are receiving ddC through this program and that 100 patients per week are being added, contrasted with more than 12,000 people enrolled in the ddl expanded access program. Roche’s Paul Oestreicher says such comparisons are not valid, as the Bristol Myers ddl program was in place a year before the ddC program. There are tens of thousands of people liv ing with HIV who are not able to, or choose not to, take AZT and could poten tially benefit from ddC or ddl treatment. But local physicians are frustrated. Dr. Marlowe (principal investigator for the AIDS Research Consortium of Atlanta’s [ARCA] study comparing ddC to AZT) said that he again spoke to Hoffmann-La Roche last week asking them to streamline the process for expanded access. Marlowe says he has not experienced the long delay in getting the drag that other physicians report. He speculated that this may be due to Atlanta being an experimental study site for the drug. Amy Morris, Executive Director for ARCA, said that ARCA physicians use that institution's IRB approval. Dr. Marlowe estimated that his patients have been waiting 10 to 14 days for application approval and then a week for the drag, down from a 3 to 4 week delay at the onset of the program. It appears that an individual’s source of medical care greatly impacts his or her experience with ddC delays. One NAPWA member reports that he waited nine weeks for the drag. At the Grady Infectious Disease Clinic, Nurse Practitioner Gail Parker reported that she began the paperwork process for a patient last October and the patient has yet to receive the drag. Delays were due to the monstrous paperwork and the lengthy process for IRB approval—Grady goes through Emory’s IRB. She is hoping that the second Grady patient she is currently enrolling will move along more expedi tiously. At another government funded hospital no patients have been enrolled, but an anonymous source there reported that the patients, reviewed for eligibility due to AZT failure, were then found ineli gible due to other specific medical prob lems. Physician Toni Rossi has enrolled 10 patients into expanded access, but she has an employee in her office specifically assigned to complete the burdensome paperwork. Rossi pointed out that while Bristol Myers allows physicians to stock the required forms to apply for ddl expanded access, Hoffmann-La Roche requires physicians to order the forms on a case-by-case enrollment basis. Rossi says her patients are getting the drag 2 to 3 weeks after the application is complet ed. ARCA's Morris has contacted Hoffmann-La Roche several times on behalf of ARCA physicians frustrated with expanded access obstacles. She said that the government has a responsibility to address problems with expanded access programs by outlining firm guidelines which speak to issues about case report forms, National IRB approval, incentives for drag companies to establish such pro grams and financial costs of the programs. She reported that the U.S. Public Health Service is circulating such guidelines cur rently, but no one would give her any definitive time table for adoption. So, is anybody in Atlanta getting ddC? Yes, some people have participated in ARCA’s now closed ddC vs. AZT study—although Grady reported no par ticipants. ARCA is now enrolling patients in a ddC vs. ddl study. NAPWA is aware of a number of peo ple purchasing ddC through buyers clubs. The health care providers interviewed said only a handful of patients reported pur chasing the drag in this method. Buyers club sources are: Fort Lauderdale (305) 568-3001; San Francisco (415) 626-2316; Los Angeles (213) 748-1295. Cost ranges from $50 to $70 for a month's supply. In-stock supplies vacil late. Each of these clubs reported that the drug they are providing had been analyzed for comparison against the Hoffmann-La Roche drag. Hoffmann-La Roche has, in fact, begun the process of filing a New Drag Application (NDA) with the FDA for Market approval of ddC as both a single agent and for combination therapy with AZT. This means that the FDA will now review all clinical data that has been gath ered on both safety and efficacy to deter mine if ddC can be sold as an anti-HIV compound. Roche’s Oestreicher says that the NDA could be tens of thousands of pages and will be completed by mid-year. The FDA has promised a speedy review, but has offered no timetable for actual approval. Oestreicher declined to speculate about what Hoffmann-La Roche would charge customers for ddC. Physicians interviewed were encour aged that another anti-retroviral other than AZT might be available by prescription soon. Community based use and prelimi nary results of trials investigating the effi cacy of ddC in combination with AZT have been widely reported in AIDS treat ment news letters throughout the country. The San Francisco-based "John James AIDS Treatment News" reported in its Nov. 23, 1990 issue on ACTG Trial 106. In the trial 48 volunteers with AIDS or ARC who had less than 200 T-cells took various combinations of AZT and ddC. This small study reported increased T-4 cells and weight gain with no new oppor tunistic infections appearing after the first few weeks of treatment. The O.I.'s that did appear in the first few weeks may, of course, have been developing prior to the onset of the therapy. Word is that the full data from the study will be published in a medical peer review journal next month. While this small study offers some information on combination therapy, further studies will be necessary for conclusive proof. Roche’s Oestreicher said that more than 500 patients have been enrolled in a ddc/AZT combination study in the ACTG system. Dr. Rossi noted that combination thera py was an interesting concept, but that she had no experience with patients using both drags together. Persons getting ddC through expanded access programs are not allowed prescriptions of AZT due to AZT fail criteria. Project Inform's Terry Beswick said the implication of combination therapy approval is astounding because it may throw a monkey wrench into the whole AZT standard-of-care model. It may mean that all current drug trials using AZT sin gle agent therapy would be revised for AZT/ddC therapy. Project Inform initiated a nationwide advocacy campaign to call for early review of ddC and ddl data. Beswick added that the information put out by Hoffmann-La Roche indicated that the NDA proposes "the use of ddC for the treatment of AIDS and ARC patients as an alternative to AZT therapy." This description does not specify if the drug company will indicate a T-4 cell range for labeling. He speculated that it may be restricted to people with 200 T- cells or less as there may not be sufficient data on people with 200-500 T-4 cells. Physicians who wish to enroll patients into ddC expanded access should call (800)332-2144. Anyone who wishes to sign on to ACT UP's "Boycott Roche" campaign should call (212) 532-3821 or stop by the Atlanta NAPWA office. Additional info on ddC studies is also available at the NAPWA office, 98 6th Street. 874-7926. Southern Voice/March 28, 1991 25