June 9, 1998

Dr. Marlene Haffner
Director, Office of Orphan Drug Products Development (HF-35) FDA
5600 Fishers Lane
Rockville, MD

Re: Application #97-1053

Dear Dr. Marlene Haffner,

I'm writing in response to your November 24, 1997 letter rejecting the application (#97-1053) submitted by MAPS requesting orphan drug designation for smoked marijuana in the treatment of HIV-related wasting syndrome. I would like to bring to your attention several fundamental issues regarding the interpretation of the data you cited in your determination that the prevalence of HIV-related wasting, as MAPS defined it, was greater than 200,000 per year. Most importantly, I am proposing to change MAPS' definition of HIV-related wasting syndrome from HIV-related wasting to "involuntary weight loss of greater than or equal to 5% of body weight in patients with AIDS", thereby more clearly addressing FDA requirements that the patient population be no larger than 200,000 per year.

In your letter of November 24, 1997, you referred to data in a letter submitted by Dr. Alice Tang. You wrote, "Based on Dr. Tang's data, 39 to 53.7% of homosexual/bisexual or drug injecting HIV+ men developed a weight loss of greater or equal to 5%. If these percentage estimates are applied to all those who are HIV+, the prevalence of involuntary weight loss of greater than 5% baseline body weight in the presence of HIV infection will be greater than 200,000." My concern with the above analysis is that there are several aspects of Dr. Tang's data that are not accurately reflected in the statement.

First, Dr. Tang's data does not distinguish between voluntary and involuntary weight loss. This is a crucial fact since HIV-wasting was defined as involuntary weight loss. Weight loss that is voluntary does not in any way indicate HIV-related wasting or a need for treatment. The baseline weight for subjects in Dr.Tang's data base was simply their weight at the time they first enrolled in the study. Subjects then had their weight recorded at each subsequent interview, usually about every six months. Dr. Tang has no way to determine whether the subjects were over, under or at their ideal or normal weights at the time of entry into the study, nor whether changes in weight over time were voluntary or involuntary.

Second, the percentage estimates for prevalence cited in your November 24, 1997 letter are based not on annual percentages but instead reflect the cumulative incidence of weight loss over a 13 year period (in the homosexual and bi-sexual men cohort) and a 9 year period ( in the injecting drug user cohort). Dr. Tang's data for homosexual/bisexual men does show that 39% of her subjects experienced weight changes of greater than or equal to 5%. However, the 39% figures represents the cumulative number of subjects who experienced such a weight loss over the entire 13 year period of the study. Similarly, while Dr. Tang's data does show that 53.7% of the subjects in the cohort of drug injecting HIV+ men experienced weight changes of greater than or equal to 5%, the 53.7% figure represents the cumulative total over a nine year period.

Dr. Tang's figures for the annual prevalence of weight loss of greater than 5% very somewhat from year to year but average 3% in the cohort of homosexual and bisexual men and 8% in the cohort of injection drug users. If the total number of people infected with HIV were multiplied by the annual percentages observed by Dr. Tang in her cohorts, the total annual number of HIV+ people with weight loss of greater than 5% would remain well below 200,000. It must be kept in mind that these numbers are still an overestimate of the people who fit the definition of HIV-related wasting since Dr. Tang's data does not distinguish between voluntary and involuntary weight loss.

Furthermore, Dr. Tang has reanalyzed her data and has found that the weight loss identified in her subjects in the ALIVE cohort is in the majority of cases not linked to HIV-related wasting, AIDS, or most importantly, any need for treatment. As previously reported, of the 520 subjects in the ALIVE study of HIV+ injecting drug users, 279 (53.7%) developed a weight loss of >5% of their baseline weight over the nine years of follow-up. Dr. Tang conducted an additional analysis that indicated that only 120 of these 279 subjects ( 43% of those with weight loss or 23% of the total sample) developed AIDS over the nine year follow-up period. Most pertinent to the newly proposed definition, only 23 of the subjects with AIDS who also lost >5% of their body weight (representing 19% of those with weight loss of >5% and only 4.4% of the total sample) developed their weight loss AFTER their first AIDS diagnosis.

In the MAC cohort, 39% of the subjects (841/2131) developed a weight loss of >5% of baseline weight over the course of the 13 years of the study. Of that 39%, 641 developed AIDS during the follow-up period. This represents 76.2% of the subjects who developed a weight loss of >5%, or 30% of the total population. Of those with >5% weight loss who also developed AIDS, only 205 (32% of the total with AIDS or 10% of the total population) developed their weight loss after AIDS.

Dr. Tang's data do not demonstrate an annual prevalence of greater than 200,000 people with HIV infection with an involuntary weight loss of greater than or equal to 5% of their body weight. In any case, the portion of Dr. Tang's data that is relevent to the new, more restricted definition of wasting as "involuntary weight loss of greater than or equal to 5% of body weight in patients with AIDS" relates to the percentage of people with AIDS who experienced weight loss (still either voluntary or involuntary) of greater than 5% over the course of the entire study. In the ALIVE study, 39% of the AIDS patients remaining alive had ever experienced weight loss of greater than 5%. In the homosexual and bisexual cohort, only 16.4% of the cohort with AIDS had ever experienced weight loss of greater than 5%. These figures do not reflect annual incidence but rather measure whether any of the AIDS patients remaining alive at the time of the analysis had experienced a weight loss of greater than 5%, voluntary or involuntary, at any point during the entire period of the study.

I understand and appreciate FDA's need to ensure that orphan drug designation be limited to diseases with an annual prevalence of less than 200,000. As a result, the proposed change in the name and definition of the disease for which MAPS' seeks orphan drug designation to "involuntary weight loss of greater than or equal to 5% of body weight in patients with AIDS" is intended to result in a patient population of far fewer than 200,000 per year. The new definition focuses exclusively on the smaller population of AIDS patients and not on the larger population of patients who are only HIV+. This brings us back to the population I previously estimated of approximately 250,000 AIDS patients, of whom a maximum of between 16.4% and 39% have ever suffered from AIDS wasting as defined as "involuntary weight loss of greater than or equal to 5% of body weight in patients with AIDS."

Since the new proposed definition includes only AIDS patients who develop an involuntary weight loss of >5% after their AIDS diagnosis, the most relevant data from Dr. Tang's data sets concerns the percentage of AIDS patients in each study who developed a weight loss of >5% after their diagnosis of AIDS. In her ALIVE cohort, only 4.4% of the sample developed their weight loss after their first AIDS diagnosis. In the MAC cohort, only 10% of the sample developed their weight loss after their first AIDS diagnosis. Again, it must be kept in mind that the ALIVE study gathered data over a nine year period and the MAC study reports on cummulative findings over a 13 year period. These numbers demonstrate that there should be well under 200,000 AIDS patients per year who develop an involuntary weight loss of > than 5%.

I look forward to hearing from you at your earliest convenience regarding how I should proceed with my request that smoked marijuana be declared an orphan drug in the treatment of the newly defined AIDS wasting.

Sincerely yours,

[signature]

Rick Doblin
MAPS President
Public Policy Ph.D. candidate, Harvard's Kennedy School of Government