My response to ‘Our Bodies, Our Cells’ Harvard Law blog post on stem cell deregulation

Over at the Harvard Law “Bill of Health” blog, Mary Ann Chirba and Alice A. Nobel posted a piece a few days ago that has generated a lot of discussion about FDA regulation of stem cell interventions.

Their piece really has two parts.

In the first part they go through the US v. Regenerative Sciences Inc. (RSI) case providing helpful and insightful perspectives on the history of the case and their prediction as to the likely outcome on appeal. They feel that the FDA will prevail.

In the second half of the piece, Chirba and Nobel build an argument for weakening of FDA regulation of autologous adult stem cell therapies. While I agree with them on the need for changes at the FDA (in my upcoming book I go out on a limb and call for 5 specific reforms at the FDA related to stem cells), I believe they do not make a strong case and that the specific proposed changes that they have put forth would do more harm than good.

Here is my comment on their post:

The historical and legal perspectives in the first half of the article are spot on and helpful.

However, parts of the later portion where you argue for weakening of the regulation of propagated adult stem cell therapies greatly concern me and you have left out some very important elements that are key to understanding the ongoing debate over the appropriate level of regulatory oversight for stem cell therapies. For example, you pretty much gloss over the safety concerns related to these stem cell interventions.

It seems to me that changes are definitely needed at the FDA in some respects related to stem cells such as expanded compassionate use of stem cells for patients with fatal diseases and a push for more openness. So we agree on a need for change at the FDA on stem cells. But the weakening of regulatory standards for propagated adult stem cell interventions would greatly increase patient risk. Further, as the numerous outstanding adult stem cell biotechs such as Athersys and Mesoblast have shown, in the stem cell field a company can have its innovation and be compliant too.

Your statement, “Conditioning the extent of regulation on the degree of manipulation may make sense on paper but is vague and confusing in practice, especially in the dynamic field of cellular therapies” is very puzzling.

In fact, the degree of manipulation is operationally (not just on paper) extremely important from a patient safety perspective and it makes perfect common sense that stem cells manipulated in different ways and to different degrees should be subject to different regulations. I do not see what’s vague or confusing about that at all.

On the other hand, your argument that smaller companies producing stem cell drugs should not be subject to the same regulations as larger companies is a dangerous one. Since when is the law variable depending on the size of the entity that should be following that law? Just as small and large drug manufacturers of pill (chemical) drugs have to follow the same rules to provide data on safety and efficacy, smaller companies selling stem cell drug interventions should have to follow the same rules and laws as big companies. To do otherwise would put patients at great risk. Don’t underestimate the number of patients collectively that stem cell clinics are treating and putting at risk these days: the numbers are in the many thousands and growing.

Paul Knoepfler

UC Davis

8 thoughts on “My response to ‘Our Bodies, Our Cells’ Harvard Law blog post on stem cell deregulation


  1. Thank you so much for your thoughtful comments on the piece recently posted by Alice A. Noble, J.D., M.P.H. and myself on the HealthLawProf and Harvard Law School’s Bill of Rights blogs. I’d like to follow up in two respects —

    1. We do not ask the FDA to “weaken” regulations or overlook known and potential safety concerns of autologous adult stem cell therapies. We discussed the need for “re-tooling” or “re-fitting” ASC regulations. Our suggestions about what revised regs should look like are deliberately generalized because, as we emphasize in our piece, what is most important at this point is that the FDA sit down and take a hard look at this — and do so with a group that reflects the full array of actors who are bound by and currently struggle with the 361/351 divide. This is not about “weakening” but “re-evaluating” for the sake of “improving” regulation of this area of HCT/P work.

    2. Our comments about minimal manipulation focused on how, not why it should be used for 351 v. 361 categorization. Our point is that, in practice, it can be difficult to discern what will and will not qualify as more or less than minimal manipulation. A sound regulation should have prescriptive and predictive value. Like statutory or common law, a regulation should be sufficiently flexible and therefore resilient in order to respond to new or evolving situations. However, it should also be sufficiently clear so that future actors can understand it and conform their conduct to it. We appreciate why the extent of manipulation matters; we asked “how can anyone reliably predict what qualifies as minimal manipulation in practice?” The FDA has provided some guidance, but not much. Thus, for a researcher, clinician, small or large entity, etc. it is sometimes if not often hard to tell where that line is and, consequently, it can be difficult to know when it has been crossed. This makes it too easy to stumble into 351 territory unintentionally and unknowingly. Having to seek guidance in advance or receive warning letters and shut-down notices on a case-by-case basis is not an effective or efficient way to regulate. It encourages actors to think in terms of “is it better to ask permission, or should I hope for the best and beg forgiveness if necessary?” The current state of affairs shows that the content and implementation of the current regulations can and should be improved.

    This is especially true for regulations that affect a patient’s ability to use her own cells, often to treat a serious condition with few if any effective treatments. Regulations address complex situations and, therefore, are understandably complicated. However, they should also fit the products, processes and actors being regulated and, despite their inevitable complexity, they should be comprehensible and their consequences should be predictable.

    In summary, this is not about “weakening” regulations, overlooking or under-estimating risks or abandoning degree of manipulation or other criteria. It is about improving current regulations so that they more accurately reflect, respond to and keep up with this critically important area of medicine. There is no perfect formula for balancing risks and benefits, or rights and interests. But there is also no reason (and for many patients, no time) to remain so far from perfect here.

    Thank you again for your interest in our work. We value your insights and it seems that we agree more often than not.- Mary Ann Chirba, J.D., D.Sc., M.P.H.


  2. Thanks for the detailed comment.

    Things have gotten substantially clearer these days regarding minimal manipulation even if I have to agree the FDA could do far better on clarifying this.

    Doctors today doing just a bit of homework know full well in the vast majority of cases whether what they are doing is 351 or 361. Of course many choose not to do any homework or receive proper training at all.

    There are a few key dividing lines. One is growth in culture. You grow the stem cells in culture, they are a 351 drug.

    Another is SVF, which is unambiguously a drug today. The doctors that I talk to know that. Some respect the FDA regs on this, but many others do not.

    An third huge issue is non-homologous use (e.g. using fat stem cells to treat MS), which is rampant at non-compliant clinics today even though it makes a product a 351.

    I do not believe that different regulations with lower hurdles for small clinics/doctors in private practice (vs larger companies) who are using laboratory grown stem cells or SVF would be helpful to anyone except the doctors and their bank accounts.

    On the other hand, the FDA could do far more on a proactive basis in the way of educational outreach to avoid punitive regulatory actions. It’s a piece of cake to identify non-compliant stem cell clinics in the US on Google. The FDA should be stepping in far earlier to make contact and educate. Then if necessary following continued non-compliance, the FDA needs to take action far faster.

    Realistically, I have to tell you that there are a lot of actors out there in the stem cell arena who lack good intentions and are just in it to make a quick buck. Others do have good intentions.

    The key goal is to help those with good intentions to succeed in getting safe and effective stem cell innovations to patients.

    As a heads up, you may not have intended it that way, but 100% of people that I have talked to interpreted your blog piece as definitely advocating weakening of regulations. Just see the first comment on your piece to know the take home message you sent.

    Let’s keep the dialogue going!
    Paul


  3. Clinics know the difference between 351 and 361 those that stumble do so with their eyes wide open. It is their business to know what regulations are in place before they engage in regenerative innovation. The practice of medicine might be applicable on a case by case basis but lets face it when a clinic is treating thousands of patients it is a business not an act of mercy. The comparison with pharma is unrealistic cost-wise as pharma costs are taken from chemical formulations through to human trials which is much more costly than just human trials. Some companies have gone the regulatory path with good success and their costs do not compare with those of bringing a new drug to market.

    The public can be harmed by cells grown in substandard labs, cultured extensively and delivered in suboptimal conditions. If these clinics were capable of self regulating or being governed by the practice of medicine it would already have happened…it hasn’t therefore some oversight is needed.

    Any adjustments should come through groups who have chosen to comply and build bridges rather than those who have set up business without FDA compliance


    • AMy it is the stage III that is expensive not the cost of basic science which is borne by public institutions.
      http://www.forbes.com/sites/aroy/2012/04/24/how-the-fda-stifles-new-cures-part-i-the-rising-cost-of-clinical-trials/

      Physicians cannot do these trials without investor/pharma backing. Please don’t bring up that the cost of 25,000 x 1000 patients a year equals millions as if that is all money the doctor is pocketing–it costs millions to do those thousand treatments. Fetal bovine serum or plasma, antibiotics, lab workers to babysit the cells, etc. these are not free with every dime going to MD pockets.

      I have asked several Linked In stem cell researchers what they thought the bottom line cost could be given an established company with an optimal process for autologous cells and they estimate about 10-15k might be possible. Duke is charging about 14k to expand auto umblical cord cells.

      Allogenic Prochymal and it’s proposed use for radiation sickness is going to go for 10K to the federal government. That is with a huge bioreactor doing a gargantuan process all at once, not a lab full of individual cells all being monitored and nurtured one at a time with all the difficulty that entails.

      All of that and CellTex was charging 7,500 for a single batch of 200 million cells given IV. Financially they don’t have the millions needed to do DB RCT stage III trials.

      that having been said I’d like to see that registry going and am thankful for Ricardo’s explanation of what delayed this.


      • Marie,
        Thank you for your thoughtful comments and the link. It would be compassionate to provide a pathway where all patients could have access to needed treatment through their insurance or medicare/caid. This requires trials and FDA approval. The phase 3 costing in the article is not what others I know have paid out to conduct phase 3 trials, not even close.

        A cGMP lab apparently costs 800,000 which is less than many MDs homes. Dr Rodriques sees the lab as overkill. the FDA doesn’t. What are the barriers to negotiation? What can be negotiated for change? It is far better to focus on problem solving than blaming don’t you think?

        Some Patients think the cells are great value and many are without options. At 7500 Celltex still makes money. Patients are willing to pay and they claim extraordinary benefits. I doubt that this is all placebo but their are other factors. Why not just do the trials, comply with standards and negotiate differences.

        Phase 1 safety and Phase 2 basic efficacy are not so costly. When a trial intervention is shown to be overwhelmingly successful it is unethical to continue and the results can be published. If the treatments are as advertised it may not be costly to companies but could save the lives of poorer patients who only have access through insurance or govt funding.


  4. For the purposes of discussion of regulation of AUTOLOGOUS tissue, the FDA has made clear that as far as the 361 vs 351 determination “if it walks like a duck, it is a duck”- no matter how it got there. So if a tissue acts like a drug, it is a drug. I can understand that rationale.
    Manipulation (minimal manipulation or magic pixie dust sprinkling) is not the key determinant factor, resultant behavior of the tissue is.

    The problem for us concerned clinicians AND the FDA is that the regulatory apparatus attached to the 351 determination is very well suited to what it was designed for (mass production of synthetical molecular drug products), but not for autologous tissue. That is the irrational part I’m not OK with because it results in inconsistencies of enforcement, and the mis-application of an industrial set of procedural safeguards that is incongruous with the task at hand.

    INCONSISTENCIES- Several tissues clearly act like drugs despite differing levels of manipulation, yet are not classified as 351. To wit:
    * surgeon takes a piece of muscle from one part of the body and places it over a broken bone for use not as a contractile organ but as tissue cover and immune protection- a non-homologous and antibiotic effect.

    * PRP’s (plasma release products)- clearly a pharmaceutical product if there ever was one

    * In Vitro Fertilization- Includes heavily manipulated cells, culture expanded, and allogenic cells, all the bugaboos and red flags that would require cGMP.

    * Fat Grafting- Has SVF in it, acts like a drug. It is commonly accepted in the Plastic Surgery world that the virtue of fat is not that of a filler, but its medicinal effect.

    MIS-APPLICATION OS STANDARDS FOR AUTOLOGOUS 351-
    The procedural standard triggered by a 351 determination is only one- cGMP. It is overkill for most instances of autologous same day cell therapy.
    The situation is analogous to the therapy for breast cancer 50 years ago vs today.
    Back then, the scary word >cancerstem cell therapy< mean you get cGMP. Wehter it is embryonic, IPS, cultured allogenic cells, cultured autologous cells or autologousSVF reinjected in the same operative session.
    For autologous therapy this means compliance with a multitude of safeguards that have NOTHING to do with processing SVF. To wit:
    -You have to source a whole list of components that you would normally use in surgery. That means a chain of documentation and personnel to administer it.
    -You have to carry out, document and set a whole array of procedures, physical installations, etc. for communicative disease vectors that are meaningless because you are reinjecting the tissue to the same patient in the same operative session.
    -The letter of the law is so comprehensive that all the rules governing interstate commerce designed to cover the export of drugs to other states apply to your surgical extraction and reinjection of the patient's own tissue in the same operative session.

    The implications of this are not inconsequential. According to the FDA's own documentation on the set up and administration of a cGMP facility, minimum costs start at $800,000. This of course excludes consultants and ongoing administrative overhead. I can understand the necessity and expenditure for pertinent safeguards and regulations re. autologous therapy. However, complying for allogenic tissue sourcing, delivery, mass production, and interstate commerce NONE OF WHICH APPLY TO SVF is at once comical and ruinous.

    Clearly, there are other ways to ensure safety for a patient receiving autologous SVF therapy in the same operative session that do not make the physician comply with steps, procedures, documentation, and expense designed for the mass production, future delivery, and interstate distribution of allogenic tissue or chemical drugs. Getting rid of things that DO NOT APPLY is not weakening regardless of what you or others you consult with think.

    The world is not Black and White. It is not a case of virtuous and safety conscious FDA regulators vs. Anything goes, or even weakened safety. It is about getting rid of things that do not apply. And if you became familiar with implementing a cGMP facility and processing SVF you would quickly realize that while some things are pertinent and necessary, but so many are not.


  5. Dr. Rodrigues,
    I agree the world is not black and white however we live in a world where concrete knowledge is celebrated. There needs to be clear definition about what does not work and what needs to change in order to map a solution and ready it for application.

    I would think that removing things that do not apply could potentially reduce the capacity for medical error and costs. It simplifies research as well. Why does the FDA think you need to take these steps, and how could their concerns be answered?

    Perhaps an interesting but not stem cell related example could be the FDA interest in regulating fecal transplants for C-Difficile. Here there are time constraints, The suggested FDA protocol could render the transplant too little too late. There is some concern that relatives and/or patients may then self medicate. Obviously this needs to be thought through.

    For decision making to be effective it needs to be informed. You have the power to help this happen. For this you need to see all sides. Your expertise in a given field equip you with the tools to explain this clearly to others and to hear in return where the barriers are for them.

    Scientists have to spell out the obvious and argue for it just to win on a grant application. It is equally and perhaps more important here. There will be persons sitting on committees who know those who have sustained adverse effects in regenerative medicine or who have second hand media knowledge. Prevailing requires recognizing the roots of these objections and overcoming them while maintaining relationship.

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