Dilantin

Background

In 1998, two cancer research colleagues [Jerome B. Block, MD, and Steven Evans, MS] became convinced that the peer-reviewed literature strongly supported the role of various nutraceuticals in cancer risk reduction. (1,2) As a result, they decided to design and initiate a formal Clinical Study to evaluate the effectiveness of selected antioxidants and other evidence-based supplements for cancer risk reduction. During the next two-year period, they assembled an expert group of medical scientists as consultants who were well-acquainted with the science-based literature in combination with their own personal clinical experiences. The goal was to ascertain which supplements appeared to be most efficacious in contributing to cancer risk reduction. There was no preconceived notion of the number of supplements that might qualify nor any concern for their individual costs.

After 18 rounds of personal interactions and discussions, a consensus emerged for a supplement which was now labeled Formula #18. From the consultants' recommendations together with additional extensive literature review undertaken by the two cancer researchers, the final form of the Formula #18 supplement was completed by Evans and Block. Formula #18 contains 14 of the "best of the best" ingredients which have scientific and clinical evidence suggesting an effective role in cancer risk reduction. Table 1 lists its ingredients and quantities of each.

In 2000, the designers embarked upon an empirical Clinical Study to assess this supplement's usefulness for cancer risk reduction. Since controlling patent protection of this supplement was unlikely, conventional pharmaceutical corporations would not likely be interested in such a trial. (3) Consultants suggested a five year Clinical Study with perhaps thousands of participants similar to the design of the NIH SELECT Trial which would be an analogue to this Study (the SELECT trial is assessing two ingredients that also occur in Formula #18, namely selenium and vitamin E). The $180 million budgeted for the SELECT Trial suggested an approximate Study cost of over $200 million for the Formula #18 Study if it completely replicated the SELECT design. Without any external funding, this cost presented a barrier to Study initiation. The designers decided to embark upon the Study themselves, recruiting primarily by word of mouth, and scaling down the Study so that it could be supported by the designers themselves, if need be.

Study Protocol

Informed Consent. A signed Informed Consent is required of all participants in the Study which conforms to traditional informed consent documents used in classical clinical trials and which rigorously articulates that the effectiveness of this supplement remains unverified at the current time. The Informed Consent document required from all participants makes it abundantly clear that they must understand it is not yet known whether this supplement will achieve risk reduction, but it is the purpose of the Study to obtain data to address this question. In unmistakable terms, they are apprised that this composite supplement does not treat, cure, diagnosis, nor is as yet known, to prevent cancer or any disease. Obtaining such data is the point of the Study.

Inclusion and Exclusion Factors. Inclusion and exclusion factors were derived, consistent with conventional clinical trial designs, in which all pertinent, known or suspected disease-state interactions and drug-supplement interactions are listed so that potential participants with any of these conditions (e.g., undergoing radiation or chemotherapy) or on any of the listed drugs (e.g., Mirandon, Coumadin, Dilantin, etc.) are apprised at the onset of their ineligibility. An acknowledgment of the inclusion and exclusion factors must be signed by each participant. In addition, a Cancer Risk Questionnaire itemizing cancer risk factors is provided prior to enrollment, and no participant may join the Study without a minimum number of cancer risk factors as defined by this questionnaire since elevated risk defined by this Questionnaire is a required inclusion factor (otherwise Study participation is not justified).

Ongoing Monitoring. With every bimonthly shipment of the supplement, each participant is required to sign again an acknowledged review of the inclusion and exclusion factors, indicating their ongoing applicability to the participant. Another bi-monthly survey form itemizes potential side effects and reactions, along with open-ended inquiries which participants review, check, and return. Survey form responses are reviewed by the trial supervisor every month for every responding participant and are immediately followed up on a personal basis whenever necessary. An 800 number is provided for questions and information as may be needed by participants.

Health Care Provider Coordination. There is a notice that participants are required to sign prior to enrollment indicating they understand they have been directed and encouraged by the supervisors of this Study to keep all their health care providers aware of their Study participation.

Fee Assessment. A bi-monthly administrative fee to participate is assessed all participants during their participation in the length of the trial, with a guarantee that this Study fee is unchanged during the length of the trial and constant for all participants irrespective of how much supplement may be assigned (3-6 capsules daily according to protocol guidelines). Participants may cancel their involvement at any time for any reason, and Study fees terminate with such cancellation. The ethical basis for this model of fee-for-service was carefully considered and documented in the peer-review literature (4) to underscore the point that participants' interests are protected. The Formula #18 product is provided only within this Study setting and is not for sale nor made available to any individuals outside this well-defined Clinical Study arena.

Control Group. All participants receive the active supplement in this open-label Study. It was judged extremely unlikely that any participant compliance could be achieved during the five year Study if half the participants were required to ingest only a placebo. To achieve a control group, the designers are using overall epidemiological data for the US population as a whole, comparing rates of cancer incidence for comparable ages and gender as well as rates of recurrence for similar types and stages of cancers.

No Supplement Sales. Since this Study will address the potential effectiveness of this supplement combination, the supplement is not sold and will not be sold until such evidence of its effectiveness is in hand. At a minimum, five years will be needed for the Study to collect core data. The Study designers will not permit any sales of the supplement until final Study data support such an initiative.

Study Hypotheses. A core hypothesis of this trial is that after a one year period of enrollment using Formula #18, the cancer risk reduction benefits of the supplement should begin to materialize as reduced cancer occurrences or reduced recurrences among the participants. A second trial hypothesis is that this result will continue to hold (i.e., participants will continue to exhibit an ongoing cancer risk reduction effect).

Interim Results

Publication of interim data collected halfway through the Study was promised to participants since unfavorable trend data would prompt termination of the Study. Study Data collected to date is provided below:

Patient Characteristics. Enrollment has so far been essentially 50% men and 50% women. There are more participants who have had cancer (65%) than who have not (35%). Those with cancer had on average 8.2 risk factors among the 41 risk factors that the men could check and the 50 risk factors that women could check as provided on the Risk Questionnaire preceding enrollment. For those without cancer, 7.2 risk factors were checked on average. In summary, all participants have a documented statistically elevated risk for cancer or cancer recurrences. Since the Study has attracted only those at significantly increased risk, currently 99% of all participants are assigned the maximum dose level of six capsules daily.

Outcome Data. To date, there have accumulated 76 patients enrolled contiguously for one year or more. More than four out of five (83%) of this group (N=63) have remained enrolled at least two or more years with the longest contiguous time being over 3 years. So far, there have been no cancers at all reported in this group.

There also have been five patients who were enrolled at least one year but then dropped out. Of these five, two involved a couple who divorced and for financial reasons terminated, the third was an 80 year-old woman who suffered heart problems and was hospitalized, the fourth was a participant who terminated for financial reasons, and the fifth terminated from lack of interest. We had no reports of cancer from these dropouts. Not counted among the participants above are individuals terminated by the trial administrators (e.g., some participants began taking Coumadin for other medical conditions; this is an exclusion factor in the trial since the supplement includes both vitamin E and garlic which might affect Coumadin responses). None reported any cancer.

So far there have been three participants enrolled for under a year who had cancer relapses during that time interval. The first began the trial with active cancer and began chemotherapy again after five months on the trial, while the second participant was a cancer patient whose cancer progressed again after seven months on the trial. A third patient with active cancer had recurrences within five months of beginning the trial, with recurrences about every six months thereafter. The average enrollment of these three cases is approximately six months before cancer recurrence occurred. Since there are only three cases, these cases provide no useful data whether there was any comparative extension in the time before cancer progression for their active cancers. In summary, in all three cases, none had taken Formula #18 long enough (at least one year) while they remained cancer free. Since enrollment remains open, we note that there is also a cohort of participants enrolled for less than one year; data is not yet tabulated until this group reaches the one-year mark (although all remain cancer-free to date).

Expected Cancer Occurrences. The key finding to date is that for all those (N = 76) who remained cancer-free at least one year while taking Formula #18, there has been no report of cancer subsequently for the remaining time period with approximately 83% (N=63) of this group continuously enrolled for at least another year if not more. Given the significantly high-risk characteristics of this group both in terms of age, prior cancer history (i.e., 65% of the participants), as well as numerous specifically identified risk factors, one might have expected a number of recurrences or new primaries within this group by now. Although expected average presentation rates would be notoriously approximate, the 3% per year recurrence rate of those with cancer and a 1% per year rate for the high-risk non-cancer group would yield an expected approximation of five cancers by now in the current group. It is emphasized that this approximation does not have statistical significance nor validity at this point in the trial but is noted since it suggests a currently positive trend after the halfway mark for the Study.

Supplement Construction. Given potential variability in the required potency of ingredients in Formula #18, we employ an outside independent testing laboratory to evaluate each testable ingredient every time a batch of the supplement is produced, to insure quality control. This verification process is crucial since otherwise our data collection effort may just lead to "garbage out," if there is "garbage in" [by way of the supplement].

Administrative Fee. The cost of administering the trial without outside assistance may have been underestimated. The SELECT trial noted above is budgeted by NIH at $180 million for approximately 32,000 participants over the entire length of the trial (each participant is involved for five years). This translates to about $93 in administrative costs per participant per month, and there are no supplement costs involved in the SELECT Trial since the supplements are being donated. The Formula #18 Study assesses a fee per month. Initially it was calculated that there would be economies of scale for this Study which would not be realized in the SELECT Study. Regrettably, at a guaranteed unchanging Study fee per month per participant [there are no other fees such as mailing or handling], there has been a deficit every month since the Study began. We expect this to continue throughout the course of the Study, especially since our supplement ingredient costs have risen steadily over the years (ingredients have an estimated retail cost of over $213 per month's supply if purchased individually). Here too, economies of scale in supplement costs were not realized since the total active enrollment currently remains around 100 participants. With each supplement production run of only several hundred bottles at a time, supplement costs as well as Study administration costs remain high. Nonetheless the administrators set the original monthly fee to be $69 and remain committed to the original fee for participants for as long as they choose to remain in the Study.

Recruitment. Participant enrollment remains a challenge since recruitment by way of word of mouth is very slow. Although a number of oncologists expressed a willingness to encourage their patients to enroll, with one notable exception, this has not been productive to date. Study goals and the participation process must be introduced in the clinical setting by these physicians' nursing staff who interface with the clinicians' patients. Given the ever-growing burden on such personnel, there is little time or opportunity for them to introduce the Study's possibility. Frequently, clinicians familiar with our efforts have instructed their staff to make an effort to apprise potentially eligible patients, but typically this priority does not rise to the top of their staffs' pressing demands to address other patient care issues within their clinical settings. Enrollment continues primarily by word of mouth.

Participant Interactions. We have discovered a huge need to help neutrally assess the many supplements participants in the Study may already be taking. To help unify their supplement regimen, we have begun offering our Nutraceutical Assessment Review Service, waiving review fees to all Study enrollees to better address their overall needs. Since we do not sell any supplements and are only assessing Formula #18, we offer informed and unprejudiced advice about the supplements they take. Not infrequently we suggest that what they are taking or considering has been unfortunately hyped, with little or no data or peer-reviewed evidence for its consideration. At an approximately five-to-one ratio, products they ask about are indicated to be inappropriate, redundant, clearly unsafe, or sometimes simply terribly over-priced (we will suggest lower-cost quality alternatives if the supplement has merit from evidence-based sources). These reviews consume approximately two and a half hours per participant at the onset of enrollment, attesting to the innumerable supplements people have undertaken.

Side Effects. There has essentially been no negative side effects in participants with two exceptions. The first case involved two simultaneously enrolled rectal cancer patients who had just completed a regimen of rectal radiation. In both of these unique cases, there was immediate diarrhea in both individuals, and their participation was terminated within the first days. The second case involved a participant who experienced bloating and gas which arose essentially at the same time as the supplement was initiated, and careful monitoring enabled us to terminate the Study participant virtually immediately.

Not surprisingly, since the supplement is likely to be boosting the immune system in a somewhat substantial manner, numerous unsolicited comments from participants continue to accrue monthly about its apparently favorable impact on the reduction of upper respiratory tract infection, on added stamina, etc. The extremely high compliance and retention rate (approximately 94% per year) may be due in part to this indirect favorable impact which is perceivable by the participants. They bring personal and concrete knowledge regarding how frequently they may have caught colds or their past stamina and can directly compare their "before Formula #18" history to their "after Formula #18" experience in such cases.

Summary

For those remaining at least one year on Formula #18 cancer-free, no cancer occurrences have subsequently occurred among this group so far, with 83% of these patients already enrolled two or more years. It is thus possible to undertake and maintain, albeit with challenges, private Clinical Studies to assess the effectiveness of a supplement for a specific need. Such efforts should be more widely implemented in order to obtain useful data that will provide evidence-based guidance in the use of nutraceuticals for prevention and health maintenance.

References

1. Block JB and Evans S. Clinical evidence supporting cancer risk reduction with antioxidants and implications for diet and supplementation. JANA Vol. 3, No. 3, fall, 2000.

2. Block JB and Evans S. A review of recent results addressing the potential interactions of antioxidants with cancer drug therapy. JANA 1:11-20,2001.

3. Evans S and Block JB. Why funding for nutraceutical clinical trial research will remain minimal. JANA 1:12-15, 2000.

4. Evans S and Block JB. Ethical issues regarding fee-for-service funded research within a complementary medicine context. J Alt and Comp Med Vol. 7, No. 5, 2001.

RELATED ARTICLE: Notice of Open Enrollment for a Clinical Study for Prevention of Cancer Re-occurrences or New Cancers

Enrollment has opened for a Clinical Study testing the usefulness of a recently developed dietary supplement designed for (1) patients who have had cancer who wish to prevent reoccurrences, or for (2) those individuals who are unaffected with cancer but are at increased cancer risk. Interim Clinical Study results are reported in this issue of the Townsend Letter.

The supplement contains 14 minerals, vitamins, herbs and food extracts, all backed by pre-clinical studies and medical scientific data supporting a potential cancer risk reduction role. Participants entered in the study are charged a fixed administrative fee per month while participating, but may terminate participation at any time. The supplement is available only through Study participation.

* Participants must not be currently undergoing active chemotherapy or radiation (Tamoxifen is acceptable). Inclusion and exclusion criteria are provided prior to enrollment.

* Everyone enrolled receives the active supplement (a complete list of ingredients is provided).

* Supplement ingredients are confirmed by independent national lab testing for every batch run.

* In-depth consultation is provided to all participants, thus limiting enrollment to 95 more applicants.

For information, enrollment material, and all informed consent documents

Email: sevans@gsm-usa.com

Fax: 402-556-5743 (leave a name and address) or

Voice mail: leave a name and address at 1-800-207-4819 to obtain a copy of all information or

Questions: leave a name and number at 800-207-4819 and a medical researcher will call you back

by Steven Evans

Genetic Services Management, Inc.

Correspondence:

Steven Evans, President

GSM Genetics Services Mgmt. Inc.

418 N. 38th St.

Omaha, Nebraska 68131 USA

402-551-1020

Fax 402-556-5743

COPYRIGHT 2005 The Townsend Letter Group
COPYRIGHT 2005 Gale Group