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stem cell mis-regulation

Big Surprise: FDA’s Final Stem Cell Guidelines Threaten the Existence of Stem Cell Clinics

Big Surprise: FDA’s Final Stem Cell Guidelines Threaten the Existence of Stem Cell Clinics

As widely reported yesterday, the FDA finalized the draft guidance documents concerning stem cells, or as the FDA refers to the category broadly, HCT/P’s.

The draft guidance documents proposed a couple years ago made it very hard for what I call unregulated stem cell clinics to operate. Based on recent FDA action against a couple of these clinics (see my prior post at http://rickjaffeesq.com/2017/09/22/sleeping-giant-awakens-fda-starts-final-push-eliminate-practice-medicine-stem-cell-clinics/),the tea leaves weren’t looking good for the FDA loosening-up the rules in the final version. Well, the final documents are out and the feds didn’t (lossen them up). The final guidance documents are at least as bad as the drafts, and in one important respect, worse.

Here is the main guidance document on minimal manipulation and homologous use.
https://pactgroup.net/system/files/GD_HCTs_20171116_UCM585403.pdf

The FDA also issued a final guidance document on same day surgical procedures, but practically speaking, that one is irrelevant, based on the main guidance document. And that’s because, per many of my previous posts, the two critical concepts which determine the legality/illegality of the delivery of HCT/P’s to patients outside of clinical trials are: homologous vs. non homologous use, and more than minimally manipulation (“MMM”).

What’s a Non Homologous Use? Answer: It’s what you’re all doing!

If there is one sentence in the FDA guidance document which sums up the FDA’s position on the use of HCT/P’s by the heretofore unregulated clinics, this is it:

“If an HCT/P is intended for use as an unproven treatment for a myriad of diseases or conditions, the HCT/P is likely not intended for homologous use only.” (Page 15 of “Regulatory Considerations for Human Cell, Tissues, and Cellular and Tissue-Based Products: Minimal Manipulation and Homologous Use”, here is the link again: https://pactgroup.net/system/files/GD_HCTs_20171116_UCM585403.pdf )

To remind you, if the use is non-homologous, (meaning not the same function as from where the HCT/P derived), it’s a drug, requiring the IND/NDA path, and the non-homologous use of which is a violation of the regulation, the law which leads to bad things.

Every unregulated stem cell clinic that I am aware of falls within this FDA statement, and I wouldn’t get my hopes up based on the FDA’s “likely” qualification. If you’re using an HCT/P to cure a disease and it’s not something like hematopoietic cells or bone marrow for blood conditions, blood related cancers, or immune system issues, your use is non-homologous according the guidance documents (draft and final).

When is an HCT/P More than Minimally Manipulated? Answer: Every process used on an HCT/P unless there is scientific proof to the contrary

The nastiest thing in the final guidance document is that the FDA has created in effect an irrebuttable presumption that anytime you do anything to an HCT/P, it’s MMM unless there is information that that the process is minimal manipulation, or as the FDA puts it:

“Please note that if information does not exist to show that the processing meets the definition of minimal manipulation, FDA considers the processing of an HCT/P to be “more than minimal manipulation”, (which basically makes the HCT/P a drug)

For structural tissue like fat, MM is defined by the FDA as “processing that does not alter the original relevant characteristics of the tissue relating to the tissue’s utility for reconstruction, repair, or replacement.”

For sure, when you separate the mesenchymal stem cell (“MSC”) from the adipose substrate, that’s MMM, let alone when the MSC is further processed into something like SVF or some other derivative product.

Prior to the draft guidance documents and even under the draft guidances, you were more or less free to argue that what you were doing to the HCT/P was not changing its relevant characteristics or MMM (more than minimally manipulating it), and then presumably force the FDA to prove that you were. Under the final guidance document, if there’s no “information” that what you’re doing is MM, then it’s not.

What Kind of Information is Needed Exactly?

Frankly, I’m not sure. Part of my uncertainty is there is some fuzziness, in my mind at least, about what are the relevant characteristics, etc. It’s an FDA created concept or administrative conclusion, rather than a biological fact or physical thing like a stem cell or HCT/P. Or it’s a question of where you draws the line. So is there a new business in creating “information” that some process doesn’t alter relevant characteristics?

How broad is the Guidance Document? Answer: Broad enough to cover basically any human tissue used by the unregulated clinics.

The guidance document covers almost every conceivable human tissue except some specific things like vascularized human organs, blood and blood components as listed in the regs, secretions or extracts like milk or other bodily fluids, bone marrow not MMM and a couple other things which are not of interest to the unregulated stem cell clinics. All other human tissue is subject to the guideline and the resulting restrictions. (See footnote 3 of page 2 of the guidance document for the list of excluded products).

So is there any Good News in the Final Guidance Document? Maybe, if you’re a Super Optimist

Perhaps to lessen the sting to the unregulated stem cell clinics, (or more cynically, to give them a false sense of hope), right in the beginning of the guidance document, the FDA says that in some cases it will use its enforcement discretion, and not enforce its interpretation of the regulations for three years to give stakeholders time to decide whether they are in compliance with the law or need to go the IND/NDA route. Later in the document, the FDA lists some factors which it will use to decide who it will not go after during these three years. (See pages 21-22).

The good of it is that autologous use lowers the risk.

The really bad of it is that high on the FDA hit list is non-homologous uses for serious and life threatening diseases and where the HCT/P’s are delivered by “high risk” methods like IV, infusion and some other methods. (See page 21 paragraph V B). The FDA considers the unapproved use of HCT’s for such life threatening conditions particularly nefarious since it might delay patients receiving “safe and effective medical treatment.” That’s an unfunny joke because the main, if not the only reason people seek out HCT/P treatment is because there are no safe and effective treatment for such conditions.

So basically, if you’re using HCT/P’s for curing or mitigating diseases other than blood or immune conditions, I’d say you’re not going to be the beneficiary of the FDA’s enforcement discretion largess.

Does that mean you should expect to receive a visit or letter from the FDA in the next year or three?

Not necessarily. There are hundreds of you clinics out there. It takes a lot of man-hours (sorry, person-hours) by many line investigators and back office federales to do each investigation. The FDA’s resources are insufficient to open up investigations and engage in the process of finding violations for anywhere near the number of clinics out there.

So what’s going to happen?

The FDA will continue with the administrative process of the high profile clinics which it has recently targeted. I think it will start the investigatory process with a few other high visibility clinics, as time and person-power permits. This will reinforce the message that the FDA is out there and remind the clinics that what they are doing is illegal (according to the FDA).

It will probably take almost a year or two before there is a judicial decision on the validity or enforceability of the guidance document. A safe bet is that the FDA will bring an injunction action against one of these clinics for not, in effect, closing. Injunction cases are tried to the judge, not a jury.

If the first case involves the Florida clinic where a nurse practitioner injected eyeballs with HCT/P’s and caused blindness, well you don’t have to have a crystal ball to know the result. Like I say, bad cases make bad law.

It’s going to interesting times for the unregulated stem cell folks.

More to follow.

Rick Jaffe, Esq.
rickjaffeesquire@gmail.com
www.rickjaffe.com

California enacts a new stem cell law, but it won’t do or change anything

California enacts a new stem cell law, but it won’t do or change anything

On Monday, October 2, 2017, Gov. Jerry Brown signed into law SB 512, which requires what I call the practice of medicine stem cell clinics to notify their patients that the use of stem cells by the clinic is not FDA approved. And that’s it!

Here is the link to the law:
http://leginfo.legislature.ca.gov/faces/billTextClient.xhtml?bill_id=201720180SB512

The law should be a welcome relief to the hundred plus California clinics that provide stem cell treatments to patients, because it does not affect their businesses at all. Any prospective patient who knows enough about his/her condition or disease to consider stem cells, knows that the therapeutic use stem cells is not FDA approved, and has probably failed conventional treatment, so lack of FDA approval is not a concern.

But even beyond that, most clinics (and all of the clinics I represent) already inform patients about the non-FDA’s approval status of their treatments, and provide much more information to secure and document informed consent. Thus my conclusion that SB 512 won’t have any meaningful effect on these clinics. Nor will the law provide most stem cell patients with information that has heretofore been lacking.

The law also gets the California Medical Board into the picture, sort of. The board will have to separately identify complaints received and disciplinary/administrative actions taken against licensees who administer stem cell therapies. I suppose that may provide some useful information down the road, but I don’t think any of the California stem cell clinics will give this provision a second thought.

So in my view, the California stem cell clinics have nothing to worry about, so long as they post the required notice and give the patient the required form.

The institutional stem cell mafia (which is against the practice of medicine stem cell clinics) is likely to be wholly unsatisfied by the law because it does not restrict these clinics, and because the Mafioso doesn’t believe that non FDA stem cell treatment should be available outside of clinical trials, even with complete informed consent.

The real problem the practice of medicine stem cell clinics have is, of course, the recent spate of activity by the FDA and the likely content of the FDA’s four final guidance documents on autologous stem cell therapies. See my prior post at:
http://rickjaffeesq.com/2017/09/22/sleeping-giant-awakens-fda-starts-final-push-eliminate-practice-medicine-stem-cell-clinics/

I’m still expecting the issuance of these documents soon, but we’ll see.

Richard Jaffe, Esq.
rickjaffeesquire@gmail.com
www.rickjaffe.com

Landmark Texas Stem Cell Legislation Gets through the Texas Legislature!

Landmark Texas Stem Cell Legislation Gets through the Texas Legislature!

Over the Memorial Day weekend, the Texas Legislature passed amended HB 810, which allows access to autologous (yours) and allogenic (not your) stem cells. It is landmark legislation in that it is the first state law allowing access to stem cell treatments which are not FDA approved, and which do not fit within the narrow types of autologous stem cell treatments permissible under federal law.

Here is the amended bill awaiting the Governor’s signature. (The Governor has previously tweeted that he’s going to sign it)
ftp://ftp.legis.state.tx.us/bills/85R/billtext/html/house_bills/HB00800_HB00899/HB00810F.htm\

Bluntly speaking, the passage of HB 810 means that treatments which are illegal under federal law will be permitted, if given in Texas, at least under Texas state law.

That makes the Texas stem cell law analogous to the medical and recreational marijuana state laws, in that those state laws are in direct conflict with federal law. Another example of state laws in conflict with federal FDA law are the “right to try” laws which allow access to post phase 1 clinical trial drugs outside of FDA approved clinical trials, which is illegal under federal law.

Will the feds try to stop people from getting stem cells in Texas under the Texas law?

My guess is no for a variety of reasons. I don’t think the bill will open-up the floodgates to the kind of single doc small clinics based on the very severe limitations which the amended bill places of facilities and physicians seeking to do these treatments. For reasons which I’ll explain, you’re going to have to be big, well financed and well-connected to open-up a stem cell clinic in Texas which takes full advantage of the Texas law, meaning using cultured/expanded stem cells or umbilical or other allogenic (other people’s) stem cells.

The easy part of complying with the bill

To be eligible to receive stem cells under the bill, you’re going to need a certification from a physician that you have a terminal or chronic, incurable disease. That’s easy, since there are, regrettably, an overabundance of these types of conditions, anything from cancer, to MS, ALS and dozens more incurable diseases.

The patient is going to have to receive “informed consent” and maybe the Texas Medical Board will have a say in that, but that’s easy too. It’s experimental treatment, meaning that it hasn’t been proven by controlled clinical trials to be safe and effective. But these treatments are only going to be available for people with no other hope of cure, so informed consent won’t be much of an issue.

The Hard Part

The amended bill which came from the senate contained three onerous conditions. The first, which basically killed the whole bill, required that the treatments be in compliance with federal law. The whole point of the bill is to allow stem cell treatments not currently permissible under federal law, namely cultured/expanded autologous stems cells and umbilical cord and other types of allogenic stem cells. Fortunately, based on negotiations between the House and Senate, this provision was dropped, and that made the bill at least meaningful and possibly helpful to patients.

However, the House had to accept the other two Senate requirements to get the job done, and these limitations will mean that these type of stem cell treatments will probably only be available at a handful of places in Texas, at least for the foreseeable future. Here are the limitations on access to these treatments under the passed legislation:

1. Where you can get treated

The treatment will only be available at a hospital, medical school or ambulatory surgical center (“ASC”). In other words, you can’t get it at a regular physician’s office. Further, you can forget about getting these treatments at any medical school hospital because none of them (all of which do FDA approved research) are going allow the administration of non FDA approved drugs without FDA approval via the IND approval process (Investigational New Drug application). They get mega bucks from Pharma to do FDA clinical trials, and they’re not going to jeopardize that on so-called “unregulated human experimentation.”

The ASC (ambulatory surgical center) requirement was previously used by the Texas Legislature to eliminate or severely restrict abortions because individual physicians couldn’t afford to turn their offices into ASC level facilities. That might not be as much of a financial barrier in the stem cell arena since stem cell treatments are orders of magnitude more lucrative than abortions (hundreds of dollars versus 20k a pop for stem cells). Still, if a doc wants to provide these services, he/she will have to shell-out a few large, (as in millions) for up-front costs to create an ASC. That won’t be a problem for some of the popular off-shore stem cell clinics which had years to amass war chests awaiting their entry/reentry into the US market. Because of all the money in the field, ultimately, there will be players who will be able to either create ASC’s or partner-up with cash needy hospitals.

2. University or Big Hospital IRB Approval, Oversight and Paperwork Submission

The biggest impediment to unfettered access to unapproved stem cell treatments is that all stem cells under this bill must be given with IRB (Institutional Review Board) approval and oversight from a university/teaching hospital or large hospital IRB. As indicated, I don’t see any University IRBs granting IRB approval for the administration of non FDA approved drugs outside of clinical trials. But per previous, the lure of huge amounts of cash (and all these non FDA approved stem cell treatments are cash treatments) will induce at least some large but cash poor hospitals to try to set up an IRB and partner with or start their own HB 810 stem cell clinics.

The IRB requirement will stop every Tom, Doc and Harry from opening-up strip mall, doc-in-a-box facilities, and that’s probably not a bad thing. But it probably won’t stop the big off-shore or U.S, stem cell players.

Treatment will be expensive because the IRBs are going to have to maintain information about all patients treated and make annual submissions to the Texas Medical Board which takes time and money. The stem cell providers are going to have to give the hospitals and their IRBs their cut, while maintaining their substantial profit margins.

3. Texas Medical Board Approval of IRBs?

The bill allows the Texas Medical Board (TMB) to regulate the IRBs overseeing HB 810 stem cell clinics. I have a crystal ball and I’m getting a very clear picture that the TMB will decide to do so. Wait… I’m also seeing some language. Yes, I see the actual text of the TMB’s regulations of these IRBs. Here is what the TMB’s IRB regulations will look like:
In addition to being affiliated with a university or hospital per the bill, the IRB will also have to be accredited by the Association for the Accreditation Of Human Research Protection Programs, Inc. (AAHRPP) and be registered and qualified under the federal IRB statute (21 CFR part 56) dealing with human experimentation, or some other national accreditation organization recognized by the TMB.

Ok, my crystal ball isn’t that accurate, but I do know how to read the TMB’s current rules. The TMB already regulates IRBs overseeing the use of investigational agents, (Board Rule 198). What I’ve related above is what the TMB currently requires for IRBs supervising investigational agents. There is no reason to think that the Board will do anything other than apply this already existing board rule to stem cells.

4. Physician Compliance with Board Rules
The bill also states that a physician administering stem cell treatments must comply with all applicable medical board rules. That’s alittle vague for my taste. As an experienced Texas Board lawyer, it opens up all kinds of stumbling blocks and pitfalls. But we’ll leave that discussion for another day.

So here it is: Texas is poised to become the first state to allow the use of cultured/expanded stem cells, as well as umbilical and other allogenic tissue products outside of FDA approved clinical trials.

That is very good news for patients with terminal and incurable chronic diseases who chose to assume the risk of “unproven” treatment, (and I personally think this is a basic but heretofore unrecognized right). It’s bad news for the stem cell institutional Mafioso who wants to limit access to these treatment to FDA approved clinical trials.

The patient advocates (and the legislators) deserve a great deal of credit. They did an amazing and almost unbelievable job which will benefit many patients.

But my message to them is that it’s not over yet, even when the Governor signs the bill. The ball will go to the TMB’s court and there are many ways in which this can all go sideways.

So continued vigilance is the watchword.

Still, congrats on a job well done. Patients with incurable diseases owe you big-time.

Rick Jaffe, Esq.
rickjaffeesquire@gmail.com

Game Changing the Stem Cell Debate

Game Changing the Stem Cell Debate

It’s been almost a month since the FDA’s two day hearing on the draft guidance documents on autologous stem cells. Here is the short version of what happened:

The stem cell research industry, meaning the basic scientists and academic physicians employed at big institutions, and their acronym organizations like the draft guidances. They agree with the FDA that non-homologous, (roughly meaning therapeutic as opposed to replacement) autologous (i.e. my) stem cells (or any kind of autologous tissue or “HCT/P’s”) should only be available in clinical trials until the FDA grants marketing approval for some use. (What happens after approval, in terms of off-label use, is anyone’s guess).

Those institutional players cited four cases of harm to patients. Three were at one clinic where a non-physician injected stem cells into the eyes of the patients which resulted in loss of vision. The other case was someone who took stem cell tourism to the extreme, continent-hopping and injecting every manner of autologous and allogenic stem cells for his degenerative condition.

Testifying on the other side were clinicians providing non-homologous, autologous stem cell treatments to patients. These clinicians have treated or spoke about the tens of thousands of patients who have received various forms of therapeutic HCT/P treatment under the soon-to-be extinct practice of medicine exception (21 CFR 1271.15).

And then there were the HCT/P patients, many with life threatening, incurable or life altering conditions. They all testified in support of Americans having access to their own HCT/P’s in the U.S. It was heart wrenching and uplifting to hear their stories. I couldn’t begin to do justice to their plight and the power of their words, so I won’t try.

But, if there’s one thing I’ve learned about dealing the FDA on access to treatment issues, it’s that the government doesn’t really care about actual patients or even future patients, due to its deep concern about PUBLIC HEALTH and THE SAFETY OF THE PUBLIC, which are sort of like Platonic ideals, and which have only the faintest connection to actual patients and reality.

Powerful as it was, I don’t think the testimony of these patients will change the FDA’s mind on the core issue of a person’s access to his/her own body parts.

There were over six thousand public comments submitted to the FDA after the hearing. However, that’s orders of magnitude too small to make an impact on the FDA.

So after pondering the hearings, I feel like what Roy Scheider felt and expressed when he finally saw JAWS up close: “We’re gonna need a bigger boat.”

Between the media, which has been harpooning all these unregulated stem cell clinics, and the stem cell research industry’s greenlighting the draft guidance documents, we’re gonna need a bigger boat.

The bigger boat has to be a vehicle to reach a lot more people, like many tens of millions. Social media itself can’t do it.

To me, the obvious solution is a documentary. I’ve recently seen Vaxxed. These guys are now on a bus tour all across America. The documentary and the tour is having an impact, and that’s in spite of the fact that Andy Wakefield is a very controversial fellow who has been excoriated in the media.

I was involved in a couple of the documentaries about Dr. Stanislaw Burzynski. He’s also a very controversial fellow and gets a great deal of negative press. Nonetheless, the director/producer made a deal with the cable companies which resulted in the Burzynski documentary being available to something like 40 million cable viewers. Now those are the kind of numbers I’m talking about!

I think the right kind of documentary focusing on the patients and not having a polarizing protagonist could avoid some of the special challenges facing the producers of the two aforementioned documentaries. If done right, it could spark the interest of tens of millions who themselves or their family members are dealing with serious unresolvable medical conditions.

I have to believe that in the stem cell patient community there are media insiders, power players, and even celebs who support access to these treatments and would be willing to help. I also have the feeling that the money to make it happen would show-up.

The stem cell clinical community needs a game changer.

You know what they say: “Go big or go home.”

Rick Jaffe, Esq.
www.rickjaffe.com
rickjaffeesquire@gmail.com

More about the FDA stem cell hearings at:
http://rickjaffeesq.com/category/stemcells/

FDA Draft Stem Cell Guidance Documents Exposed as Improper Rulemaking, Bad Science and Heartless Public Policy

FDA Draft Stem Cell Guidance Documents Exposed as Improper Rulemaking, Bad Science and Heartless Public Policy

Today was a good day for people who want continued access stem cells outside of clinic trials, and also for people who want the FDA to allow faster access to this promising technology.

There was a wide spectrum of opinions. Some stem cell companies involved in clinical trials wanted the non-clinical trials clinics shut down. But at least there were representatives from some of these “unproven” clinics and interest groups who made some important points about the rights of patients and how the needs of patients are not being met by the current clinical trials model as it applies to stem cells. I heard a number like 250,000 people are not getting the stem cell treatments they need because of clogged research and regulatory hold-ups. There were numerous calls from very serious, highly credentialed people for the FDA loosen its death grip (my term) restricting access to these therapies, and the thrust of most of these presenters was that these draft guidance documents make thinks much worse.

 

The guidance document are really bad and deny access for many

And that was the big takeaway for me; that the guidelines were much, much worse than even I thought. I understood that the guidelines would make illegal the  21 CFR 1271.15 exempt same surgical procedures provided by many of the 600 plus unregulated stem cell clinics.

But what I didn’t understand until Monday’s hearing is that the FDA intends to radically change the rules so that, for example, the most popular form of breast reconstruction surgery post mastectomy (flap something) would become illegal under the new guidelines. Many other popular and widely successful procedures in other areas like orthopedics would be eliminated (outside of clinical trials). We’re not talking unboarded docs with no relevant experience who take a weekend course and starts shooting people up with stem cells. We’re talking about big-time breast reconstructive surgeons, highly regarded orthopedists and other highly skilled and specialized physicians who have successfully worked with tens of thousands of patients. If the FDA gets its way, according to these folks, Poof! These best practices transplant procedures are gone.

Fortunately, there were some very smart professionals making presentations, including an extremely knowledgeable law professor from Boston College, Mary Ann Chirba. She and several other people with regulatory expertise made the case that this whole guidance exercise was an illegitimate attempt to pass new rules without complying with the rulemaking requirements under federal law.  Works for me!

They and others honed in on the radical revisions to the two key preexisting terms/concepts used by the FDA to work its illegal magic: homologous use and more than minimal manipulation.

 

What’s a “main function?”

It was also pointed out that the guidance documents invented a new concept not existing in the statute or rule, namely the “main function” of a cell or HCT/P which is used as a way of forcing stem cell procedures from just registration under 362 into the IND/NDA drug approval path. It was argued persuasively by several regulatory experts that the creation of this new concept and its resulting transfer of many heretofore legal uses of stem cells into illegal new drug products turns the guidance documents into rulemaking without following federal administrative rulemaking procedures.

 

The FDA doesn’t understand what fat does

Another extremely cogent criticism made by a variety of people including Professor Chirba, other regulators and by both of the two top presenting stem cell researchers, Arnold Caplan and Keith March had to do with the FDA’s view of fat. According to the guidance documents, fat just has a structural function. But these presenters and especially March and Caplan showed that the FDA’s view was biologically unsound.  Fat has definite, known and extremely important non-structural uses, starting with energy storage and continuing to assistance in the healing function. The FDA’s unscientific, unsubstantiated restriction on fat allows it to find most of the important uses of fat and fat stem cells illegal as either non-homologous or as a more than minimally manipulated product. The FDA was absolutely and repeatedly pummeled on this point by my count, at least a half dozen very, smart experts.  I don’t see how even the FDA, which has a very particular agenda, is going to be able to hold on to its limitations/restrictions on fat/adipose tissue.

 

The Big Guys say regulations are holding back progress

The two big-time researchers (Caplan and March) also made the point that the regulatory climate is holding back research. Caplan said that some bone marrow pioneers had observed that if they had the regulatory environment back then as what exists today, bone marrow transplants might never have taken off. Ouch!

Interestingly, Peter Rubin, the plastic surgeon who last Thursday presented the inspiring cases of reconstruction work from fat transfers, presented again. This time he was more critical of the FDA and stated that many of the most successful reconstructive plastic surgery procedures, including breast reconstruction would become illegal under the draft guidance documents. He and many other excoriated the draft homologous document which classifies fat tissue for breast reconstruction as non-homologous because the primary purpose of the breast is lactation. Several of the female presenters had some polite but pointed words to the FDA about that.  Most of the day’s presenters agreed that regulation/regulatory expense was delaying bringing this technology to patients.

 

The 3 Billion Dollar Player Weighs-in

The biggest dollar player was the California Stem Cell Institute which has a 3 billion dollar budget and 12 research centers. Its director spoke, and his message was clear, concise and right on the money (and with 3 billion, it should be). The FDA has to loosen-up its grip and find an intermediate path between unregulated stem cell clinics and full-on clinical trials, because there is a desperate unsatisfied need and that need will be satisfied  – just as water flowing down a hill will find a path –  with or without the FDA’s help. He was very persuasive. Reminds me of an old TV ad: “When EF Hutton talks, people listen.”

Interestingly, no one picked up on what I though was the most egregious over reach in the draft guidelines, namely that the FDA guidelines silently incorporated or read the homologous and more than minimally manipulated requirements from 361 registration facilities (1270.10) into the exemption for same surgical procedure places (1271.15). Under the actual rule (1271.15) same day surgical procedures can do non-homologous and more than minimally manipulation. At least those two terms are not in that rule. Legal Method 101 instructs that if terms are in 1271.10 but not in 1271.15, then the 1271.10 terms and restrictions cannot be read into 1271.15 which is what the FDA is doing based on its interpretation of “‘such’ HCT/P’s.” (Maybe too technical.  I’ll have more to say about that another time.)

 

Maybe there is a viable lawsuit

Something else I realized as a result of a couple of the astute presentations. I said in the last post that you can’t sue on a guidance document because it’s just the agency’s “current thinking.” However, if a guidance document is really disguised rulemaking without meeting the rule changing requirements, then maybe there is a lawsuit. Many presenters were clear about the fact that these guidance documents are disguised rule changes, so I’m now more optimistic about the chances of a legal challenge.

 

People are Mad and are going to do something about it

And speaking of possible legal challenges, while all of the presenters were very professional, very cordial, ostensibly courteous and complimentary to the FDA panel members on the dais, I sensed that quite a few, many in fact, were pretty upset by what the FDA is trying to do with the draft guidance documents.

So here is my prediction/wish/what I hope to make happen.  There won’t be one lawsuit filed if the draft guidelines go into effect. There will many lawsuits. I don’t think these folks are going to go quietly. My sense is that the big players, sophisticated players, like Rubin, the fellow who started a society and has 5800 members, the guy with dozens of clinics, they have seen too many good results to give up their most effective tools. All these guys either run or are closely connected to prestigious professional societies and  I predict that many of them are going to try to stop these guidance documents, in court or in Congress.

I hope for everyone’s sake the FDA really listened today, because people are mad as hell and they’re not going to take it. They want better and quicker access to this new technology, and my hope is they will get it.

Rick Jaffe, Esq.

www.rickjaffe.com

 

 

 

More on The FDA’s Stem Cell Public “Workshop”: Stem Cell Clinical Trials aren’t the Answer for Everyone

More on The FDA’s Stem Cell Public “Workshop”: Stem Cell Clinical Trials aren’t the Answer for Everyone

Not unexpectedly, the organizing theme of the FDA’s Stem Cell workshop  was that patients should only be able to receive their own stem cells for non-homologous use in FDA approved clinical trials until FDA marketing approval (i.e., until a New Drug Application is granted for some non-homologous use).

I’ve been involved in legal/policy issues relating to clinical trials for a long time. I understand that clinical trials is the standard of care for patients when FDA approved treatments (on or off-label) are not available for whatever reason.  Still, I’m here to tell you that from the perspective of patients with life-threatening/incurable diseases, clinical trials aren’t always the best answer for them. Here is why I think so.

  1. The Purpose of Clinical Studies is to Test Drugs, not to cure patients

 

The fundamental and indeed the stated purpose of a clinical trial is to test the safety and efficacy of a therapeutic intervention, not to cure a specific patient of a specific medical condition.

One of the presenters mentioned some empirical data indicating that there is a disconnect between this purpose and the patients’ understanding of the meaning and purpose of clinical studies. My take-away from what he was saying was that many people mistakenly believe that the primary purpose of a clinical trial is to get the patient better. That misunderstanding is consistent with my experience over the course of several decades interacting with patients on clinical trials.

That the purpose of clinical trials is to test interventions, not to cure patients has specific practical consequences for patients which sometimes mean that patients do not get optimal care for the good of the study.

 

  1. Some Phase 1 study patients may not get enough of the drug/intervention

In phase 1 or toxicity studies, patients are specifically told that the purpose of their participation is to study a drug’s toxicity, not to test the efficacy of the drug, and while the investigators hope the patient will obtain some benefit, that is not the goal of the patient’s receiving the drug.

Early patients in some phase 1 studies receive relatively low doses of the drug, based on what the investigators believe to be the therapeutic dose. Doses often get escalated in later subjects in a phase 1 study. I believe this is common in toxicity studies. It’s kind of like you shouldn’t buy a car that was made right before a holiday weekend or on a Monday. Sometimes, it’s not ideal to be one of the first study participants in a phase 1 study, because you may not get what the investigators expect to be an therapeutic dose.

 

  1. How are you helped by a placebo?

Some studies are placebo controlled. Obviously there is no therapeutic intent for those patients. In cancer and other life threatening diseases, placebo controls are no longer employed, and in some placebo controlled studies, placebo recipients are sometimes offered the study drug later or much later.  Still, if a patient is in a placebo controlled study. There’s a 50% chance the patient won’t receive the study drug (at least initially).

 

  1. In Phase 3 studies, you still might not get the study drug

You still might only have a 33-50% chance of obtaining the study drug in a phase 3 trials,

Most phase 3 studies compare the study intervention with FDA approved standard of care therapies. Patients are randomly selected into the different arms of the study, arms being the different groups that receive the study drug or the standard of care therapy. Some studies involve more than one standard of care control arm/option. If there are two different control arms, there is only a 33% chance of receiving the study drug and a 66% chance of receiving a therapeutic option which probably hasn’t worked too well.

 

  1. Most drugs in clinical trial drugs are not ultimately approved

It is true as reported at the Workshop that less than 5% of therapies entering clinical trials obtain NDA approval, but 1. There could be reasons other than efficacy why that happens, 2. Some agents just don’t work on a high enough percentage of patients to justify NDA approval but they do work on some, and if you’re one of those lucky people, you’re a happy camper. So I don’t see the fact that there is a low approval rate of study drugs as strongly supporting the banning of stem cells outside of clinical trials just because of that fact.

 

  1. What happens after the clinical trial is over for you?

Therapeutic interventions in clinical trials are usually given over a relatively short period of time and often there is some surrogate endpoint or target which is less than a complete cure. In cancer it’s called a response.  Let’s say you get a response, or the target improvement in pulmonary function or whatever the parameter the drug is intending to influence. You’re a responder but not cured. Can you still get the Intervention if you need it?

In drug studies, there is a serious issue of continued access to study drugs after the termination of the study. Drug companies are not required to provide study drugs after the conclusion of the participant’s time in the study. There is a movement afoot to change that. I don’t know whether that is an issue in autologous stem cell clinical trials, but it could or would be if the guidance documents become final because it would then be illegal (supposedly) for the person to have access to his/her stem cells after the study.

 

  1. The Biggest Problem with Requiring Clinical Trials for All Autologous Stem Cell Transplants

Here is the big one. The underlying assumption of the FDA’s and the Workshop’s position –that autologous stem cell transplants should only be available in clinical trials – is that any patient who wants an autologous stem cell transplant can enter a clinical study. That seems unlikely, but that’s just my gut feeling. I’m not familiar enough with the stem cell clinical trials to know whether there is a large unmet demand, but in many diseases like cancer, a relatively small percentage of patients enroll or can enroll in clinical trials. In cancer, I think it’s something like 3 or 4%, and I’ve seen numbers like 40% of cancer patients would enter a clinical trial if they could. There are many reasons why some patients aren’t eligible for clinical trials, tied to a variety of factors. Some are too sick for the protocol entry criteria. Some may have had a prior disqualifying treatment (like a previous clinical trial). But my supposition is that there are many more patients out there why would participate in clinical trials involving stem cells,  but can’t for one reason or another.

Assume that to be the case.

What are the policy implications and practical consequences?

On a policy level, there is going to be an arguably significant number of patients who have no therapeutic options. Of course the immediate response to that is what good is an unproven, possibly dangerous option? While it’s a fair question, it’s a better question for foreign interventions than a therapy derived from the person’s own body, because as stated, there are fewer safety concerns.

And, respectfully, I think it’s a too facile response by academics not facing no treatment options for a life-threatening condition. Let these guys who are so quick to cut-off treatment options come back after they have walked in the shoes of these terminal patients and their families.

What about the practical effect of the FDA’s plan to make illegal same day autologous stem cell procedures?

That’s easy and no crystal ball is needed. The cat’s already out of the bag, the cow has left the barn. Patients want the ability to use their own stem cells to treat a wide variety of medical conditions. Former Governor Rick Perry and Bart Starr believe in the therapy, and I dare say tens or hundreds of thousands of others do, and would try it in a heartbeat in there was no other reasonable alternative, whether or not there is an existing clinical trial for which they could qualify. If you’re the Governor of Texas, you can have someone shoot you up, consequences be dammed. Others will have to find other options.

It seems obvious that the effect of the FDA’s intended action will be to drive more people into stem cell tourism and to places which have less substantive and facility regulations than in the U.S. That’s not necessarily a good thing.

I hear one highly-regarded stem cell transplanter might suggest an expansion of the facility registration requirements (contained in 21 CFR 1271.10) to same day transplant facilities (exempt from that requirement under 1271.15). It would certainly enhance the safety profile of these clinics by providing some federal regulatory oversight. It’s a good and creative idea, but it would require a revision to the current regulations.

I have to believe there are far less draconian solutions to the legitimate safety, training and false or unsubstantiated claims concerns which worry the FDA and the institutional players. But maybe it’s time for some creative thinking, rather than a knee-jerk reaction to eliminate what seems to be much needed treatment options for many patients.

To my presenter friends and colleagues, looking forward to hearing what you have to say, (via the web anyway).

Best,

Rick Jaffe, Esq.

www.rickjaffe.com

 

 

 

 

The most important question at the FDA Stem Workshop was the one not asked

The most important question at the FDA Stem Workshop was the one not asked

I didn’t hear the first couple of presentations in the FDA’s Stem Cell workshop. However, I did listen from mid-morning to Dr. Irv Weisman’s closing.  Yesterday’s post was my take on the highlights.  http://rickjaffeesq.com/2016/09/08/really-tough-day-stem-cell-advocates/

Upon reflection, what is disturbing to me is what I didn’t hear, namely a discussion or even a mention of what I think should have been the most important question in the autologous stem cell public policy debate: whether autologous stem cell transplants should be treated differently by the FDA from other types of therapeutic interventions because the material comes from the person’s own body.

This question is both very simple and quite complex. It is complex because it involves not only scientific issues, but also public policy, legal jurisdictional issues, and even federal constitutional issues. And yet, I heard nothing about these issues from the FDA’s blue ribbon panel of thought leaders despite the extremely impressive academic credentials, accomplishments and experience of the workshop participants.

The question is also complicated because it’s only by virtue of the FDA’s as yet untested, convoluted and counterintuitive interpretation of its rules that it has arguable jurisdiction over most of the stem cell clinics it intends to put out of business with its draft guidance documents. (We’ll get into the legal weeds of statutory interpretation of the applicable rules later.)

The entire workshop’s discussion including the ethics presentations was predicated on the tacit premise that autologous stem cell transplants are just like any other therapeutic intervention. As I think about it, that tacit assumption led to a bizarre disconnect in the presentations.

Almost all of the presenters excoriated the use of stem cells therapeutics outside of clinical trials. Yet the most upbeat and heartwarming presentation, to me, was from the plastic surgeon, Peter Rubin who brought forth examples of fat transplants given to wounded warriors and breast cancer survivors. I don’t recall him saying that every one of his transplant patients were treated in clinical trials. I believe that many people receive autologous stem cells or fat HCT/P transplants for homologous use without FDA approval, including for reconstructive work such as he is doing.

Using a person’s body as the transplant material avoids many of the safety issues which occur from a foreign source, whether the source be another person’s stem cells, a chemical or an extract from a plant (like digitalis or vincristine,). Most non-self-interventions likely have L/D (lethal dose) toxicity limits and attendant serious safety concerns in terms of dosage and side effects. Not so with autologous HCT/P transplants.

Sure, in any transplant there are contamination issues, but that applies to any autologous (or allogenic) HCT/P or blood product transplant and thus is not unique to “unproven” stem cell transplanters. So if many of the safety concerns of drug therapies aren’t applicable to autologous stem cell transplants, then it all comes down to efficacy, and whether and how much proof is necessary for a person to be able to use material that comes from that person’s body.

Although none of the luminaries raised the issue yesterday, I think it’s worth asking why aren’t people allowed to use a technology or service which isolates and removes a body part (HCT/P’s)   and reintroduces all or a part of it back into their own body without federal government oversight.  Same day autologous transplants are basically medical procedures.  Normally the FDA is not in the business of regulating medical procedures because it’s the “practice of medicine” which normally is within the jurisdiction of the state medical boards.

I don’t think it’s crazy to ask why should the federal govenrment be involved in medical procedures regulated by state law, and I’m not alone in thinking that autologous HCT/P transplants should have different rules, that the new drug rules do not or should not apply, and that these procedures should be policed by the state medical boards.

In fact, it was the FDA’s position as well, until the proliferation of these “unproven” stem cell clinics. (I discussed this in my first post on the guidance documents http://rickjaffeesq.com/2016/04/21/stemcells/)

I think the presenters yesterday forgot the actual reason the FDA is doing this whole public exercise: to sell its reinterpretation of its own rules. It’s not clear to me that the courts are going to go along with it. Here’s why.

 

It’s always a good idea to start with the law

 

The primary specific source of stem cell regulation is 21 CFR 1271.

In short, stem cells or more generally HCT/P’s (Human Cell and Tissue and Cellular and Tissue Based Products) are categorized or regulated in three ways:

  1. Solely under 1271 (basically tissue facility registration)
  2. As new drugs requiring full IND/NDA approval and registration, or
  3. Not regulated by the FDA

21 CFR 1271.10 sets out the requirement for registration but not new drug approval, and applies if, among other things, the product is not more than minimally manipulated and is for a homologous use.

Here is this rule:  http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?fr=1271.10

 

What the FDA can’t regulate (at least until now)

 

21 CFR 1271.15 provides that the FDA doesn’t regulate the use of HCT/P’s if the extraction and reinsertion of the material is done in the “same surgical procedure.” Here is the exact language:

“(b) You are not required to comply with the requirements of this part if you are an establishment that removes HCT/P’s from an individual and implants such HCT/P’s into the same individual during the same surgical procedure.”

Under the plain meaning of this rule, all, most, many or some of what the “unproven” stem cell transplanters are doing is or was perfectly legal.

I have personal knowledge about this because around ten years ago, I contacted the FDA several times and asked them about this precise rule, on behalf of a client who wanted to do same-day autologous transplants and sought a legal opinion from me. I called the FDA several times, because sometimes you get different answers from an agency. Each time, I was told that the FDA doesn’t have jurisdiction over same-day autologous cell transplants. And so I gave my opinion clearing the procedure.

But that was before the 600 plus “unproven” stem cell clinics popped-up with all their purported claims of miracle cures. I’ve talked about this in a previous post. http://rickjaffeesq.com/2016/04/21/stemcells/ .

The point is that implicit in the words of 1271.15 –  the reinterpretation of which is the reason we are going through this FDA public show – is that autologous stem cell transplants are different from medical therapeutics involving a substance not originating in a person’s own body, and are regulated differently.

In fact, same-day, autologous stem cell transplants were not regulated by the FDA, until its regulatory interpretive epiphany precipitated by the wild west stem cell business.  That yesterday’s workshop didn’t even address the FDA’s prior position or the public policy and possibly constitution underpinnings of the actual language of the rule which divests the FDA from the business of regulating same-day autologous transplants, is disappointing, but not necessarily surprising, considering that the purpose of the workshop appears to be providing expert cover and justification for the FDA to make the draft guidelines final.

So how does the FDA get away with asserting jurisdiction over procedures which seem beyond its purview?  The answer is in its Adipose Draft Guidance document.

Here is the draft guidance document:

http://www.fda.gov/biologicsbloodvaccines/guidancecomplianceregulatoryinformation/guidances/tissue/ucm427795.htm

It’s a nifty trick: It interprets the phase “implants such HCT/P’s” as meaning that anything the unproven stem cell transplanters do beyond rinsing the material turns the HCT/P’s  into something other than the “such HCT/’s.” i.e. the HCT/P removed. Really!?

Here is the exact language where the magic happens:

“Limited handling such as rinsing and cleansing to  remove debris would allow the HCT/P from adipose tissue to retain the structural function, while other processing steps such as cell isolation, cell expansion, or enzymatic digestion generally would not.  Thus, if such other processing steps are performed that prevent the HCT/P from adipose tissue from remaining “such HCT/P,” the establishment manufacturing the HCT/P from adipose tissue would generally not be considered to meet the exception under 21 CFR 1271.15(b).”

It seems to me that the FDA’s interpretation is trying to backdoor the “more than minimal manipulation” idea contained in 1271.10 into the 1271.15 exemption from regulation and jurisdiction.  But the “more than minimal manipulation” language isn’t in 1270.15. It’s an agency add-in, years after the regulation was passed, and as stated, it was not the FDA’s original position.  The FDA’s textual jurisdictional reinterpretation seems far-fetched, inorganic and a somewhat desperate attempt to create jurisdiction over an activity which no one, including the FDA thought it had. Will it work?

In a fair fight; No, of course it wouldn’t work, but the FDA has the home court advantage on several fronts and these advantages might tip the scales.

First, in a court case, an administrative agency’s interpretation of its own regulations is given deference by the courts. I think the FDA’s position is attackable but you never know how far a court will bend over backwards to defer to an agency.

Second, you can’t sue the FDA on a draft or even a final guidance document because of non-intuitive and arcane non-finality rules of administrative law.

Ditto on warning letters. What that means practically is that if an “unproven” stem cell clinic keeps treating patients after receiving a warning letter, (which is basically an FDA cease and desist from engaging in illegal activity), the company can’t sue. It has to wait to see if the agency takes some kind of enforcement action. And here’s where it gets draconian.

Once there’s a warning letter, the doc or company is on notice that their actions are illegal, and specifically that they are violating what I call the FDA trifecta (introducing into interstate commerce an unapproved new drug, misbranding and adulteration).  Before the notice, or actual knowledge of the violation, we’re talking civil liability and/or at most a criminal misdemeanor, which means probation.

After the warning letter, if there are continuing “violations,” that’s an intentional criminal act which means felony and hard time.  So after a warning letter, the only safe play is to stop transplanting. (That’s what the Regenerative Science guys did after they got the warning letter. They sued, got thrown out of court, got sued by the FDA, fought the suit, but stopped doing stem cell transplants during the course of the litigation in case they lost, which they did.)

Bottom line is that docs and companies are disincentivized by the FDA and the system from challenging FDA action even if the action is or maybe outside of the FDA’s regulatory jurisdiction. But I’m hoping that if these guidelines go through and the FDA starts tossing out warning letters, some company is going to take a stand. I hope they do, and I’d like to be the one that smacks them down. Been there, done that, feels good (See chapters 2, 4 and 10 (on the first stem cell criminal investigation) in my book Galileo’s Lawyer).

So let’s get out of the legal weeds of administrative minutiea. It seems to me that the FDA is trying to exercise powers over same-day transplanters that it does not currently have. Maybe it should have that power, or maybe not. But whatever the ultimate policy answer should be, it needs to be discussed and studied. The luminaries yesterday didn’t do it, and I fear their myopic, one-sided view of the world and their ignoring of why autologous transplants are different and heretofore  beyond the purview of the FDA regulators needs to be discussed. Since it hasn’t been done in this workshop, the FDA needs to arrange a do-over with other more open minded, informed thought leaders.

There’s more to be said beyond these legal and policy points, but the hour is late and tomorrow is another day.

Rick Jaffe, Esq.

www.rickjaffe.com

 

 

 

 

 

 

 

 

 

 

A Really Tough Day for Stem Cell Advocates

A Really Tough Day for Stem Cell Advocates

The FDA’s Stem Cell “Workshop” just ended, and if you’re a person who wants continued access to stem cell therapies outside of clinical trials (or a transplanter of “unproven stem cell therapy”), it was a very depressing day. It was way worse than I had feared in my post yesterday.  http://rickjaffeesq.com/2016/09/07/fda-stem-cell-meetings-close-hand-stakeholders-sides-worried-one-side-really-worried/

Sure the two ethicists said that it was wrong and unethical to provide unproven stem cell therapy except in FDA sanctioned clinical trials. But the real punch came from two of the last speakers who discussed some horror stories of the severe harm caused by “unregulated” and “unproven” stem cell transplanters.

Stem Cell Horror Stories

Unregulated Stem Cell Therapy Causes Cancer

A Harvard fellow who co-wrote the recent oft-quoted case study of the stroke patient who traveled the world doing stem cells only to develop a stem cell treatment induced CNS tumor throughout most of his spinal column gave the gory details of the case, including a painstakingly detailed complete histology of the tumor. The only good news (if it can even be called such) is that, if I understood correctly, he concluded that the stem cells causing the tumor were not the patient’s but were the result of an allogenic transplant the patient received.

Unregulated Stem Cell Therapy Causes Blindness

The other presenter, an eye doctor, talked about three patients who received stem cells for macular degenerative disease. The procedures were performed in a South Florida stem clinic by a nurse practitioner, not under the supervision of a licensed physician. In each of the three cases, there was severe harm, requiring emergency surgery with catastrophic negative results to the eye sight of the patients. Of course these might be unusual and exceptional cases, but they will no doubt be used by the FDA to demonstrate the need for exactly the draft guidance documents which it is proposing to stop these medical horror stories from reoccurring.

FDA Implored to Stop the Maiming by Snake Oil Stem Cell Transplanters

Other members of the panel including leaders of disease advocacy/research entities all decried “unproven stem cell therapy” and implored the FDA to put these unethical stem cell purveyors of false hope out of business.

One panel member pointed out that the problem was just not in the U.S. and that there were these kinds of clinics in many parts of the world and because of the internet, it was easy to find out about them. One clinician lamented that when prospective patients call him and he has to tell them that he has no treatment options for them, the patients get mad and argue with him.

 They should all be delicensed!

The day’s moderator was Irv Weisman, who is one of the biggest names in academic stem cell research. In his summary, he suggested that U.S. physicians who perform unregulated stem cell transplants abroad to skirt U.S. regulations be delicensed.

To listen to these guys, it would appear that stem cells given outside of clinical trials have never helped anyone. In one sense that might be true. If all you care about is scientific data from well-designed FDA clinical trials, then they are right.  Anecdotal evidence is not science, and all seemed to agree that all the non FDA trial data which is published is not worthy of consideration because of design flaws.

There is a Consensus

The absolute, universal consensus of today’s workshop was that stem cells should only be available in the U.S. in FDA approved clinical trials, until such trials prove that there is a safe and effective non homologous use for them. And anyone who provides “unproven stem cell therapy” to patients outside of clinical trials is a greedy, unethical charlatan who should lose their medical license…That’s a tough message, but no doubt a welcome one for the FDA since the elimination of non-homologous autologous stem cell therapy outside of clinical trials is the purpose and end result of the four draft guidance documents.

One thing I am clear on: the positions taken today by the people the FDA considers the thought leaders in the field really, really need to be addressed by the stakeholders on the other side next week, head on.

I’m going to give this a good think over the next day or two and maybe make some suggestions to my presenter friends.

Stay tuned.

Rick Jaffe, Esq.

 

FDA Stem Cell Meetings Close at Hand: Stakeholders on Both Sides are Worried, but One Side Should be Really Worried.

FDA Stem Cell Meetings Close at Hand: Stakeholders on Both Sides are Worried, but One Side Should be Really Worried.

Next Monday and Tuesday, September 12 and 13th is a widely acknowledged big day in the stem cell world; it’s the two day public hearing on the FDA’s four draft guidance documents.  (Here is a link to the FDA’s announcement. http://www.fda.gov/BiologicsBloodVaccines/NewsEvents/WorkshopsMeetingsConferences/ucm462125.htm.  The entire event will be live broadcast via a link on this FDA page.

The draft guidances are a big deal because, as I’ve said before,  http://rickjaffeesq.com/2016/04/21/stemcells/,  they will make illegal almost all autologous cell transplants outside of FDA approved clinical trials, including the ever popular stem cell transplants from adipose tissue.   It’s been reported that there might be over 500 U.S. clinics physicians/clinics doing some form of autologous stem cell transplants for a wide variety of conditions, so you can bet that this new industry is watching closing and worrying. They have plenty to worry. Let’s start with what’s out there.

 

The lines are drawn 

For at least the past year, there has been what I would call an institutional attack on the clinical use of autologous stem cells, and by that I mean the use of autologous stem cells outside of FDA approved clinical trials. Thought leading papers, especially the New York Times have run articles against the stem cell clinics both here and abroad. The most recent article, in July, 2016, http://www.nytimes.com/2016/07/28/upshot/stem-cell-therapies-are-still-mostly-theory-yet-clinics-are-flourishing.html?_r=0  seemed more like a retweet or bump of an article by one of the main anti-stem cell talking heads, Paul Knoepfler, a PhD who works at U C Davis.  Just google “stem cells and false hope” and see what comes up. Knoepfler published an article which is the source of the now widely reported 500 or 600 plus clinics in the United States performing autologous stem cell transplants outside of clinical trials.  But other news media outlets have also taken up the call to ban the clinical use of stem cells until they go through the complete drug approval process. http://www.webmd.com/a-to-z-guides/features/stem-cell-treatments-false-hope-warning-signs

Apart and together with the media outcry are ethicists and public policy position papers decrying the unregulated stem cell business.  (Here is one from the Texas Baker Institute http://bmcmedethics.biomedcentral.com/articles/10.1186/s12910-015-0069-x ).

The knock on the clinical stem cell business is that it is unproven and untested and hence might be dangerous or ineffective and shouldn’t be given outside of clinical trials until proven safe and effective. This is same criticism leveled against the “right to try” state and federal legislative initiatives. (See my post on the federal right to try:: http://rickjaffeesq.com/2016/05/24/federal-right-try-hopefully-not/ ‎

 

Maybe the Really Important Meeting Is Not What We Think It Is

What hasn’t received as much attention from the stakeholders is the stem cell workshop which will take place tomorrow. Thursday September 8th which I think will be as or more important.  http://www.fda.gov/BiologicsBloodVaccines/NewsEvents/WorkshopsMeetingsConferences/ucm518541.htm.

This workshop will be presentations from the scientific/policy/ethics luminaries and thought leaders. From what I can tell, none of them are directly involved in the clinical use of stem cells beyond what is in accordance with FDA approved use. My guess is that all of the speakers are against the clinical use of stem cells except in clinical trials, and until they pass through the full approval process.

The two lectures  I’m most interested in hearing about are : Jonathan Kimmelman, PhD, Ethics, Evidence, and Regulatory Approval for Cell-Based Interventions and  Massimo Dominici, MD, Dissecting Unproven Cellular Therapies: The International Society for Cellular Therapy (ISCT) Position.

 

My guess is that, consistent with the talking heads in the past media articles, their conclusion will be that it’s unethical and dangerous to allow the unregulated use of autologous stem cell transplants outside of clinical trials and before FDA approval.

 

Why this is important is because I think the FDA is going to cite the workshop position papers as a reason to make the draft guidance documents final without substantial changes. And these speeches will justify the FDA’s position to make adipose stem cell transplants illegal outside of clinical trials.

 

Why do I think that’s going to happen? Well first the obvious. That’s the import of the draft guidelines and the FDA has had a few years to think about the problem. The problem is that the originally thought-to-be tiny regulatory loophole in 21 CFR 1271.15 (which says that autologous same day procedure transplants aren’t regulated by the FDA) has mushroomed into an entire industry with all kinds of wild west claims and with virtually no barriers to entry stopping any doc from cashing in. That has the FDA very, very nervous.

 

But beyond the obvious and the din of media and institutional based criticism of the field, there is a broader FDA context, which I am aware of because I do a lot of stuff beyond stem cells.

Let’s look at two other big things the FDA is working on right now.

 

FDA tries to tame the Wild West of Dietary Supplements

 

A month ago, the FDA released its long awaited revised draft guidance on dietary supplement NDIs (New Drug Ingredients).  The guidance document is highly restrictive and, if enacted, will severely limit access to dietary supplements.  (See my recent blog on this http://rickjaffeesq.com/2016/08/16/maybe-glass-still-less-half-full-water-might-start-leaking/

The FDA’s concerns about supplements is basically the same as its concerns with stem cells, namely unsubstantiated claims for products which haven’t been adequately tested for safety and efficacy.  The proposed solution: make supplements with “new dietary ingredients” (broadly defined) subject to rigorous testing. Sound familiar?

 

Pharmacy Compounders Get Unwanted Federal Attention

 

Second, in 2012, a compounding pharmacy literally killed over 60 people from a contaminated batch of a compounded product. Up until that time, compounders were largely unregulated by the FDA and were overseen by the state pharmacy boards. But many compounders were blurring the lines between a compounded drug for patients and drug manufacturing.

 

As a result of the outcry over these deaths, there were congressional hearing, new legislation, new regulations, and proposed draft guidances. Bottom line. Increased regulation and scrutiny of these pharmacies by the FDA. This example is different from the NDI supplement and stem cell guidance documents in that there was actual severe harm, but it still shows that if the FDA believes there is an abuse and a regulatory vacuum, they will regulate.

 

Of course, autologous stem cells are different from supplements or compounded drugs for the obvious reason that the source is the person’s own body, which presumably eliminates contamination from the source issues. But it doesn’t address the claims issue which I think is at the heart of the FDA’s and institutional opposition to the clinical use of stem cells. And admittedly, there are probably still some safety issues, and most likely some training issues, because anyone with a valid medical license can become a stem cell transplanter, and it’s a lot easier logistically than doing brain surgery which requires a real surgical center. In fact, stem cell transplants are commonly done in regular medical offices. Some might view that as not a good thing.

 

Perhaps interestingly, in the 1997 FDA modernization act, there were advertising restrictions placed on compounders as a compromise solution, but those restrictions were ruled unconstitutional by the U.S. Supreme Court.  (Western Stateshttp://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/PharmacyCompounding/UCM155167.pdf.  Because of Western States, my guess is that the FDA is not going to offer a compromise by limiting stem cell advertising because of its past negative experience.

 

For all these reasons, I think the FDA’s mind in pretty much made up. Tomorrow’s stem cell workshop will provide a nice piece of cover, and I expect it to be relied upon by the FDA when the final guidance documents come out.

 

The FDA has to give stakeholders the right to comment, but there’s no law that says the FDA has to really listen.

 

Circling back to the dietary supplement NDI draft guidance document, the original one came out many years ago, but due to the enormous public outcry complaining about them, the original draft guidance was rescinded. That bought the field many years of a guidance free existence. Sometimes that’s about as good as you can get, and I think with the stem cell draft guidance documents, that’s as good a strategy as any I’ve heard.

 

 

Rick Jaffe, Esq.

 

S 2689: Congress to the rescue on stem cells? (Not)

S 2689: Congress to the rescue on stem cells? (Not)

In my last post on stem cells, I painted a pretty bleak picture. Based on warning letters and recent FDA guidance documents, the clinical use of autologous stem cell therapeutics is essentially over. The only way patients are going to be able to receive autologous stem cell transplants for non-homologous use is either in FDA approved clinical trials or outside the United States.

This hasn’t gone unnoticed in Congress. In March, 2016, a bill was introduced, by Senator Mark Kirk and others which purports to help. It doesn’t. It creates an illusion of a solution that changes nothing. The bill does not address the core problem which is that autologous stem cells, even if cultured, should not be regulated as drugs, because under any reasonable analysis, they are not. As I suggested in my previous article, the feds are clamping down on stem cells because of the claims made by transplanters and because of the culturing of stem cells. The FDA’s response is draconian and the Kirk bill doesn’t help in any meaningful way.

Under the proposed bill, ostensibly a new regulatory pathway is created. But before we talk about the new path and why it’s nonsensical window dressing, let’s briefly review the traditional approval path. Under current FDA law, to get a drug approved, a drug sponsor needs to file an IND (investigational new drug application). This is a very big deal in terms of time, expense and volume of paperwork. All available information about the safety and efficacy of a drug must be submitted. Usually this information comes from animal studies.  (However, if there is controlled clinical use or foreign studies, such data is submitted which could bypass phase 1 and go right to phase 2 studies.)

All available pharmacokinetics information (basically mechanism of action and interactions) must also be submitted. A protocol setting out all of the details of the dosage, entry criteria, contraindications, endpoints, and a myriad of other aspects of intended use information must be included in the application. In addition, the proposed informed consent form must be submitted for FDA review, as well as information about the study’s IRB (Institutional Review Board). Also, the sponsor must include information about the principal investigators and sub investigators who will administer the investigational drug to the patients/study subjects. Basically, the IND has to convince the FDA that it is safe to administer the drug to humans, and there is some reason to believe that the drug will work as well in humans as it did in animals, (or in humans if there is prior controlled clinical use). In other words, that there is some reasonable expectation of efficacy.  After the IND is submitted (which usually consist of tens of thousands of pages), the FDA has 30 days to review the filing. If the sponsor doesn’t hear from the FDA in that time, the trials can proceed. Oftentimes, the FDA has questions which have to be answered, which begins the back and forth between the sponsor and FDA. This process can move with the alacrity of the shifting of tectonic plates.

Under the Kirk bill, a supposedly new and streamlined drug approval path is created. It’s called “conditional approval.” The bill gives the FDA one year to come up with some kind of framework to conditionally approve a stem cell application, if the sponsor demonstrates preliminary evidence of safety and a reasonable expectation of efficacy, short of phase 3 levels of proof. See section 351B (a) of the proposed bill. https://www.congress.gov/114/bills/s2689/BILLS-114s2689is.pdf).

On its face, this test seems similar to what is required to obtain an IND, except the Kirk bill seems to assume that the treatment has already been used on humans and there is some legitimate clinical trials data supporting safety and efficacy.

Hmmm. Odd. I thought the bill was supposed to make it easier for a person to get his/her own stem cells? But this seems to require more evidence of efficacy than might otherwise be required of a sponsor to obtain a regular old IND.

These two Kirk bill requirements (preliminary evidence of safety and controlled clinical evidence of a reasonable expectation of efficacy) of course give the FDA complete discretion in determining whether the proposed study meets the criteria. If the sponsor succeeds in this threshold showing, then it has five years to submit the data in an NDA (new drug application).

However, in detailing the additional requirements for obtaining “conditional approval”, Section 351B (b) (8) requires that that the sponsor submit an IND in order to treat any patients under the “conditional approval.”

OK, so everything which has to be submitted in a regular IND has to be submitted for “conditional approval” because you can’t get conditional approval without submitting an IND.

So in substance and paperwork requirements, the bill seems more cumbersome than the requirements for an IND, at least an IND with a couple different protocols.  So what’s the point of the conditional approval thing?  I haven’t figured that out yet.  Seems that the Kirk bill is a waste of time and energy, despite the fact that something like 80 organizations support it. Maybe the devil is in the details. One could always hope that the FDA will actually come-up with a more streamlined process to allow patients to receive stem cells, but I’m just not feeling it from what is in the bill.

My underlying problem is that I don’t think a person’s cells are drugs or should be regulated/prohibited as “unapproved new drugs.”  There seems to be something fundamentally odd and wrong about the federal government regulating a person’s own tissue when the tissue or part of it is reinjected. I get that the separation should be done in a sterile and effective way, (read that the cells aren’t contaminated or destroyed by the separation process) and that the centrifuges should be validated and FDA cleared. But regulating a person’s own biological material which is removed and then reinjected, well that just seems crazy intrusive, or just plain crazy to me, except in the Bizzaro regulatory world.  But actually, the FDA used to agree with my view, in part at least, because up until the first warning letter in 2012, the FDA interpreted 21 USC 1271.15 as stating that separating stem cells from tissue or structure was the practice of medicine and not subject to FDA regulation as long as the product was reinjected in the same surgical procedure. The FDA only changed this reasonable position based on the perceived abuse by stem cell transplanters  (my interpretation).

In that regard, I also get that government agencies might or should be concerned about these exaggerated claims. But the state medical boards can and do police physicians based on their web sites and information conveyed to patients. I think the state medical boards are in a better position to handle enforcement actions against unsupported claims. And of course, this is more in-line with the seeming intuitive notion that a person’s tissue or cells are not drugs just because the material is removed and reintroduced into the body. Both the FDA and the FTC have the statutory jurisdiction to go after the transplanters for false claims if they think the medical boards aren’t doing their job. But prohibiting what is essentially a surgical procedure seems like an unnecessary and complete overreaction to the problem.

So what needs to be done? It’s not complicated. Congress should statutorily overturn the FDA stem cell guidance documents and warning letters by passing a law that autologous stem cell transplantation is the practice of medicine, even for non-homologous use, and even when the cells are cultured/expanded.  Let the state medical boards police the autologous stem cell transplant physicians in terms of their claims and therapeutic use. Texas is already doing just that. Organizations or other sponsors can still do clinical trials. People will still enroll in trials the way they do now, (or did before the warning letters) because of the financial incentives to the patients in enrolling in clinical trials (the “drugs” are free and so are many associated costs). But at least those who decide to have their own stem cells reinjected in their bodies will have the option to do so without government interference, and in my view, that’s a good thing.

Any brave Congress folk willing to take on the FDA?

Richard Jaffe

rickjaffeesquire@gmail.com