Controlled studies to evaluate GDD to satisfy critics. What does that entail?

Controlled studies to evaluate GDD to satisfy critics. What does that entail?

A number of supporters of GDD have over the years opined to me: we need to have controlled studies because the critics dismiss GDD, or your treatment approaches due to lack of sufficient evidence.. The question raised to me, as if I had not previously considered it.

Background. I will start by my credentials. Scholar GPS rating for my career: #10 in MRI, #14 in Medical imaging, and in the top 0.05% of accomplishments of all scholars on all subjects. The dominant text book in Abdominal MRI in multiple editions, for all time of Abdominal MRI. So my response to begin with: not a single critic, perhaps not even a collective gaggle of 5 critics, have that level of accomplishment. None do.

Possible study designs:

Most recently a physician expert suggested to me (in regards to defending chelation) 3 groups; i) no chelator (sham/ placebo),ii) full dose chelation, andiii) half dose chelation. Charge 1/2 of standard charge, 10 subjects in each group. 5 chelation sessions.

The problem with a sham/placebo comparison: it is unethical in my opinion to charge someone for a session where they are getting no treatment. If you end up then not charging them, then the knowledge is evident that they did not get chelator. Who would fly to North Carolina and get no treatment?

The issues:

1. All entrants to the study must have all expenses covered, to avoid bias and to ensure double blinding (no one knows if there is treatment or no treatment performed, neither patient nor investigators).

2. The GDD condition is relatively rare. 1 in 10,000 for all comers, which means individuals with GDD will invariably have to travel some distance and stay at a hotel. So airflight, accomodations, and meals need to be factored in regarding study cost.

3. Salary support for all members of the investigation team, from physicians, to nurses to technologists.

4. Serum cytokine studies should be performed for all studies.

5. 24 hr urines pre and post chelations should be performed for everyone.

6. Even marginally significant results would require 50 patients for each group. I would suggest a placebo and standard DTPA chelation as we do it now (escalating chelator/ decreasing steroid over chelation sessions).

7. Who should compose the GDD patient group: i) all comers, ii) only patients with 1 GBCA with GDD development within 3 months iii) only patients with 3 or fewer GBCAs with GDD development with the last GBCA injection 3-6 month apart.

8. Each patient should get at least 10 chelation sessions, since a broad array of patients would require at least 5 chelations to experience notable benefit. I have estimated for each GBCA the person needs 5 chelation sessions to approach near cure. All chelations need to be consecutive, with no gaps, eg: no between chelations placebos.

9. There is significant heterogeneity of disease severity among patients.

   
   
   
   

Entities of comparable rarity and other potential studies:

1. The most comparable entity to GDD is severe Acute Hypersensitivity Reaction (AHR) with either iodine contrast and CT or gadolinium contrast and MR. No controlled study of this type for these entities has ever been performed. Comparisons of empiric different strategies have been performed, but they have not looked at a placebo comparisons.

2. No prospective study of supplements have ever been performed.

3. Meta-analysis of multiple studies for most supplements and vitamins have suggested no benefit to the vitamins and supplements. But bias of patient type likely confounds these studies.

4. No studies of similar entities with similar incidences have ever been done, for multiple reasons, expense and time-consumption of such a study, and likelihood that no useful information will be acquired are the major explanations.

Additional complicating factors:

1. Research of this type is generally only performed in university settings.

2. University provides Institutional Review Board )IRB)

3. All investigators already receive salary support for academic time, which ranges from 50K- 800k, with most in the 100k- 200 K range.

4. Direct access to other research groups

5. As formal medicine prefers to ignore GDD, and grant reviewers for such a study from a major granting organization (such as NIH) who would be considered 'MR safety experts' are radiologists whose knowledge of safety is based on they do a lot of GBCA enhanced MR studies (ie: no actual knowledge of safety, but preferring to ignore safety) the likelihood of success at getting a grant in the present environment approaches 0.

6. Turn around time for grant funding is generally 2 years in the very best of circumstances. First submission is generally rejected, and with revision it is approved the next year - in the best of circumstances. .

The circumstance I am in:

1. In private practice I do not have any salaried academic time. So whereas other physicians would receive on average $100K - 200 K for research, I receive $0 salary for research, and all research expenses I have paid for.

2. Additional researchers would either have to work for free, or I would have to pay them. Almost no one works for free.

3. No on site IRB.

4. No easy access to 'normals' individuals getting GBCAs but experience no symptoms (gadolinium Storage Condition).

Type of research study that would be appropriate:

1. 50 subjects in each of 2 arms.

2. Chelations need to be consecutive, and spaced 1-4 weeks apart, otherwise re-equilibration Flare will be extreme, and confound any result.

3. 5 chelation sessions the very minimum number based on the pattern of Gd removal from the body, 10 more appropriate

4. If a placebo is used, the study really needs to be done as a cross-over study. So 2 arms: arm 1: receives 10 sessions of chelation consecutively followed by 10 of placebo; arm 2 receives 10 sessions of placebo followed by 10 of chelation.

5. 50 subjects x 2= 100. 20 sessions for each. So a total of 2000 sessions.

6. Estimated costs to refund and pay for studies each patient $4000 per session.

7. 2000 sessions at $4,000 per session $ 8 million cost for this study.

The type of study that is of value and feasible:

1. DTPA with steroids, as I have written it up, is the only validated approach to treat GDD. So this forms 1 arm.

2. Comparison with another strategy that possesses these three features: i)chelating agent has high safety profile; ii) chelating agent has a high stability constant with Gd; and iii) documented in vivo Gd removal in humans.

3. oral HOPO possesses these qualities. So a double blind study comparing an iv injection of DTPA with an oral placebo in arm 1, and iv injection of placebo and oral HOPO in arm 2, is a feasible study.

4. Patients would accept paying for treatment that does involve at least one effective chelator for each session.

5. This would be an ethical study.

So this is where we stand right now:

1. I am perhaps among the top 3 radiologists who have shown the clinical value of GBCAs in clinical studies, so essentially none of the critics are anywhere close to this level of expertise showing GBCAs are useful.

2. I have dedicated the last 7 years of concerted thoughtful effort into showing that GDD unquestionably exists. Denying this is willful, and inexcusable ignorance.

3. The same for the treatment regimen of DTPA with steroids. Denying thi is willful and inexcusable ignorance. No critic for this has anywhere close to the level of expertise that I have, that I have garnered through working with experts in chelation science and cytokines.

4. All of my research on this subject matter have been at my own expense over the last 7 years. Whereas in a university setting I had received in the range of $50K - $150K for every year for 24 years. For the last 7 years in private practice I received $0. In actuality, based on my accomplishments in the university, this was money well spent: that almost no other radiologist would have accomplished that much for the academic salary they received. Perhaps there may be up to 5 radiologists where the institution and the world gained that amount of knowledge contributed in Radiology for the academic money spent.

5. If a cross-over study is performed this will be at least $8 million- which also does not include any salary for me.

6. A feasible study is comparing two arms, one an established effective treatment and the second a potential alternative effective treatment.

7. These type of studies have never been performed for other similar entities with similar occurrence rates: 60 years of iodine contrast use, and 35 years of GBCA use and no well-performed definitive studies have ever been performed to evaluate severe AHR and treatment (minor empiric comparisons have been done, but nothing definitive). So I am expected to come up with a study for GDD and treatment all on my own and my expense? The dark humor is breath-taking.

8. So the world may have to accept, that one of the greatest experts on all the subject matters, who has written at least 17 major peer-reviewed articles (and counting) on these subjects.... and this is about as good as it gets in a flawed, biased human-generated health care system.

9. I am not sure how much longer I will continue to follow this path.

   
   
   
   
   
   

   Richard Semelka, MD