Food and Drug Administration
12420 Parklawn Drive
Room 1-23
Rockville, Maryland 20857
Re: Docket No. 97N-0066 -- Proposed Approach to Regulation of Cellular and Tissue-Based Products -- 62 Fed. Reg. 9721 (March 4, 1997)
Dear Sir or Madam:
These comments are submitted by the American Society of Clinical Oncology (ASCO) in response to the FDA document "Proposed Approach to Regulation of Cellular and Tissue-Based Products" and the accompanying document from the National Performance Review titled "Reinventing the Regulation of Human Tissue." ASCO is the national organization representing physicians who specialize in the treatment of cancer. As oncologists, we are the physicians who carry out the stem cell transplants that would be subject to FDA regulation under the proposed approach.
ASCO objects in the strongest terms to FDA's proposed regulation of stem cell transplants. This unprecedented proposal is unnecessary, would jeopardize the proper treatment of cancer patients and impede the development of new therapies, would substantially increase the cost of stem cell transplants, and exceeds FDA's legal authority. The proposed approach should not be adopted.
Background on Stem Cell Transplantation
Oncologists use hematopoietic stem cell transplants to restore the blood production and immune systems of cancer patients whose bone marrow has been extensively damaged by the disease or by intensive chemotherapy administered to treat the malignancy. Historically, the initial source of the stem cells was the bone marrow, and bone marrow transplantation remains an important procedure. More recently, stem cells have been obtained from the patient's peripheral blood or from the umbilical cord blood of infants. (In these comments, the terms "stem cell procedures" and "stem cell transplants" are generally used to refer to all of the procedures, regardless of the source of the stem cells.)
In an autologous bone marrow transplant, stem cells are harvested from the patient by extracting them from the posterior iliac crests through a large number of bone marrow aspirations. The patient is usually under general anesthesia during this procedure. The aspirated marrow is mixed with tissue culture medium, anticoagulated on occasion, purged, and frozen. The patient then undergoes high-dose chemotherapy, which destroys the patient's bone marrow as well as the target cancer cells. Subsequently, the frozen marrow is thawed and reintroduced into the patient by intravenous infusion. An allogeneic procedure is similar except that the bone marrow is harvested from an individual other than the recipient patient. Allogeneic transplants are typically used in leukemia patients whose bone marrows and immunological systems are compromised by the disease.
Although stem cells are found in great quantity in bone marrow, they are also present in the blood stream at about one percent of their level in bone marrow. In recent years, procedures have been developed to harvest stem cells from peripheral blood by apheresis -- an outpatient procedure that requires no anesthesia. Multiple sessions, each lasting a number of hours, are required to collect a sufficient number of stem cells. This method of acquiring stem cells has advantages over harvesting from bone marrow, including its less invasive nature. The transplant portion of the peripheral-blood stem cell transplant is the same as in the case of a bone marrow transplant. Thus, apart from the different source of stem cells, peripheral-blood stem cell transplants are essentially the same as bone marrow transplants. The same is true with respect to transplants using stem cells obtained from cord blood, which is a source that also has certain advantages.
More advanced stem cell procedures involve treating the stem cells after harvesting and before their infusion into the patient. This manipulation may be performed for various reasons, such as attempting to purge cancer or leukemic cells from the stem cell collection, purging immune cells from the stem cell collection to lessen the severity of graft versus host disease, or selecting out stem cells and growing them ex vivo.
As this brief overview indicates, stem cell transplants are medical procedures. Their use is the practice of medicine, not the manufacturing of biological products as FDA asserts. Transplantation procedures and their associated stem cells do not in any way resemble the products that FDA is chartered to regulate. Stem cells are collected and used on a patient-by-patient basis. The patients' oncologists and their institutions control each step in the procedure. Stem cell transplants do not involve products manufactured and distributed for broad use. The handling of stem cells used in transplants does not resemble even the handling of products by blood banks, since blood products are collected from many donors, stored for long periods of time, and redistributed to large numbers of previously unidentified patients who may be located over a wide area.
The use of stem cell transplants has cured thousands of cancer patients and prolonged the lives of many others. Bone marrow transplants have been performed since 1971 and have been standard therapy for certain conditions since the late 1970's. Peripheral-blood stem cell transplants have been performed for about ten years and have been standard therapy for certain cancers, such as lymphomas, for about five years. Improvements in the procedures and their extension to additional conditions continue to be rapid. All of this 25 years of progress in successful treatment has occurred without the regulations that FDA now asserts are necessary to make the procedures safe and effective.
Summary of FDA's Proposed Approach to Regulation
Although FDA's proposed approach is characterized as "reinventing the regulation of human tissue," as if existing requirements were being revised and improved, in fact the proposal would for the first time subject physicians performing stem cell transplants to federal regulation. The proposal would in essence establish three levels of increasing regulation for various types of stem cell transplants.
In the case of autologous procedures with minimally manipulated stem cells and family-related allogeneic procedures with minimally manipulated stem cells, FDA would require donor screening and testing for infectious agents. In addition, FDA would issue "good tissue practice" regulations, which would set forth requirements intended to prevent contamination and preserve stem cell integrity and function through proper handling and processing practices.
The next higher level of regulation would apply to non-family-related allogeneic procedures with minimally manipulated stem cells. These procedures would be subject to donor screening, testing for infectious agents, and the good tissue practice regulations, but in addition would be subject to processing controls established by FDA on the basis of the scientific literature. These processing controls would include "manufacturing" controls and "product" specifications. Examples cited by FDA of the kind of information that would be included in the standards include criteria for acceptance of a unit (such as volume, storage temperature limits, limits on microbial or other contamination, viable cell number, and functionality) and procedures for handling, transporting, storing, and thawing materials, and for when and how contamination and viability testing should be carried out.
The most intense level of regulation is proposed for stem cell procedures involving more-than-minimal manipulation of cells, non-homologous use of cells, or cells used for metabolic function. These procedures could be conducted only pursuant to an approved investigational new drug application (IND), in the case of clinical trials, or pursuant to an approved biologics license application (BLA), in the case of other uses.
There Is No Need for FDA Regulation
A striking aspect of FDA's document proposing the regulation of stem cell procedures is the virtual absence of any justification for the initiative. The principal "concerns" cited by FDA in support of the new regulatory apparatus are preventing the transmission of communicable diseases and assuring that stem cell procedures are safe and effective. But FDA has adduced no evidence whatever to suggest that communicable diseases are presently being transmitted through stem cell procedures or that stem cell transplants are unsafe or ineffective. Instead, FDA has proposed to subject physicians performing stem cell procedures to an extraordinarily burdensome and restrictive regulatory regime based solely on theoretical issues.
FDA regulation is not necessary to prevent the transmission of communicable disease through stem cell transplants. It is well-recognized by oncologists that stem cell transplantation carries with it the potential for transmission of communicable disease. Accordingly, it is already the universal practice to screen donors for risk factors and to test for contaminating viruses and bacteria. As a result, there has never been a documented case of a communicable disease being transmitted through a stem cell transplant. FDA's proposed regulations would add nothing useful to the procedures already followed by transplanters. It should be noted that infection control is a pervasive concern in medical procedures and hospital operations. Physicians and hospitals routinely take appropriate precautions to prevent the transmission of disease. There is nothing unique about the infection potential of stem cell transplants that justifies FDA singling out a small aspect of a hospital's activities, i.e., stem cell transplants, for direct federal control.
Similarly, there is no need for FDA standards or processing controls to regulate stem cell transplants. The medical literature contains information useful to transplanters in this respect, and private organizations, such as the American Society of Blood and Marrow Transplantation and the International Society of Hematology and Graft Engineering, have issued recommendations covering these topics to the extent that science permits. FDA could add nothing useful.
Indeed, the assumption underlying FDA's proposal -- that rigorously applied objective standards can and should be adopted -- is unsound. We do not fully understand why stem cell transplants succeed or fail, and standards to achieve success therefore cannot be written. A key part of the proposal is the establishment of standards to assure cell functionality, but this proposal exaggerates what is scientifically achievable. Various surrogate measures of cell functionality are currently used, but these are imperfect and cannot be regarded as definitive. Moreover, oncologists can in certain conditions ignore apparent inadequacies in cell functionality as indicated by the surrogate measures because they know that graft will be successful in the circumstances at hand.
Finally, there is no reasonable basis for FDA to impose special requirements for proving the safety and effectiveness of stem cell transplants through clinical trials that would be vastly more rigorous than the requirements applicable to medical procedures in general. Surgical and other procedures are typically developed and become established aspects of medical practice without the benefit of well-controlled clinical trials. By contrast, stem cell transplants have typically been conducted within the context of clinical trials until, based on such investigations and publications in peer-reviewed literature, their use for particular conditions has become accepted as safe and effective. In short, the oncology community already imposes a much higher standard of proof of safety and effectiveness for stem cell transplants than is generally observed in medicine. FDA's regulations are not necessary to insure the safety and effectiveness of these procedures.
The complete lack of any need for regulation of stem cell transplants is illustrated by FDA's proposed treatment of bone marrow transplants. Although the transplantation of stem cells derived from bone marrow raises the same theoretical issues as transplantation of stem cells derived from peripheral and cord blood, FDA has proposed not to regulate bone marrow transplants on the ground that they are already regulated by the Health Resources and Services Administration (HRSA) under the Transplant Amendments Act of 1990 (42 U.S.C. 274k). HRSA's only responsibilities under that Act, however, are to maintain a bone marrow registry and to issue limited standards relating to tissue typing, donor screening, and proper collection and transportation of bone marrow. Moreover, HRSA has in reality issued no standards to implement the Act.
HRSA's minimal authorized regulation of bone marrow transplants does not remotely resemble the comprehensive federal control that FDA envisions for other types of stem cell transplants through its proposed good tissue practice regulations and processing controls. The fact that FDA has found HRSA's essentially non-existent regulation of bone marrow transplants to be adequate to protect the public health demonstrates that the vastly more extensive controls proposed for transplants using stem cells from non-marrow sources are completely unjustified and unnecessary.
The Proposal Would Interfere with the Treatment of Cancer Patients
In contrast to the lack of benefit from the FDA's proposal, there would be clear adverse effects, including the following:
Retarding medical research -- FDA's proposal that each institution performing certain types of stem cell transplants should be required to obtain its own license (BLA) based on full clinical trials would impair the development of new methods of treatment. The time and expense necessary to obtain a BLA for a particular procedure would tend to freeze institutions into performing only that procedure without making modifications that would be outside the license and therefore could be conducted only under an IND. This result would be destructive to the development of new cancer therapies. Moreover, the very nature of a BLA is inconsistent with advancing science in this fast moving area. The phase 3 trials necessary for a BLA are so time-consuming that the procedure studied may well be obsolete before the trials are concluded. Stem cell developments can become outdated in six months. It is a seriously misguided notion that all procedures should be pursued through phase 3 trials, and FDA's proposal to demand that approach will stifle medical research and harm cancer patients.
Slowing dissemination of techniques -- Individual licensing of facilities for each procedure would limit the availability of procedures and would result in many patients being denied effective treatment. Currently, procedures that are recognized as safe and effective can be rapidly adopted by oncologists throughout the country. As a result, patients can generally access the procedures regardless of their geographical location or the nature of their health insurance. Under the FDA proposal, however, individual licensing of facilities based on their own clinical trials would result in extremely limited availability of new proven procedures. Patients whose location or insurance did not give them access to the few FDA-approved institutions would go without treatment. Cancer patients would be denied effective treatment as a direct result of FDA's regulations.
Jeopardizing insurance coverage -- Many health insurers will not pay for services involving products subject to FDA approval if the particular item used in a procedure has not been approved by FDA. Therefore, in the case of the stem cell procedures, which FDA would subject to IND/BLA requirements, insurers may deny coverage for procedures conducted under INDs.
Increased administrative costs and burdens -- Even under the least rigorous form of the proposed regulation, good tissue practice regulations, there could be significant increased costs to institutions resulting from additional record keeping and similar administrative obligations. In addition, the regulations would impose manufacturing-type requirements unfamiliar to hospitals, such as the duty to investigate and formally assess errors. Specialized staff might be necessary to comply with these new requirements. In an era in which hospitals are under great pressure to control costs, there is no evidence to justify an elaborate and expensive government-imposed administrative system applicable to only a tiny part of a facility's operations.
Potential transfer of research control to commercial entities -- It is well-known that the cost of developing and submitting a BLA is very high. The resources necessary to do so may make it impossible for academic institutions and physicians to develop new stem cell procedures without the involvement of a commercial entity. This would in turn cause the course of stem cell development to be driven by the interests of such entities. This could retard the development of procedures that would not interest a commercial sponsor, for one reason or another, but would be of interest to oncologists and their patients.
Inappropriate requirements in the IND regulations -- FDA's existing IND regulations place significant restrictions on the sponsors of clinical trials. While these may well be appropriate in the case of commercial products, they could cause serious problems if applied to stem cell transplants as FDA has proposed. For example, FDA regulations generally prohibit charging for products subject to an IND. If these regulations would prohibit charging for a stem cell transplant subject to an IND, transplant research would come to a halt. FDA regulations also prohibit the sponsor of a clinical trial from representing in a promotional context that the subject of the investigation is safe or effective. Under this regulatory provision, physicians performing stem cell procedures under an IND could presumably not advise their patients that the procedures are safe or effective regardless of the state of the literature or accepted medical opinion -- a result that could seriously misinform patients and potentially cause them to reject curative therapy.
Denying treatment through imposition of the IND process -- At present, techniques for stem cell transplantation can be altered when particular patients present unusual circumstances. At most, these changes require clearance through a local institutional review board. Under the FDA proposal, however, altering a procedure to provide effective treatment would require filing an IND and a 30-day waiting period while FDA reviews the filing. This delay could jeopardize patient health. It is no answer that FDA might offer expedited review in emergencies, since the system should not require special treatment for the routine practice of good medicine.
FDA Lacks Legal Authority to Regulate Stem Cell Transplants
The FDA document does not explain in any detail the legal basis for the agency's assertion of authority over stem cell transplants. FDA asserts merely that cellular therapy is regulated by FDA as a biologic under the Public Health Service Act ("PHS Act") and the Federal Food, Drug, and Cosmetic Act ("FFDCA"). The document states that the rules on donor screening and testing to prevent the transmission of communicable disease, as well as the good tissue practice regulations, would be issued under section 361 of the PHS Act. The requirements for processing controls and for submission of INDs and BLAs would be issued under section 351 of the PHS Act and unspecified sections of the FFDCA.
Section 361 of the PHS Act
ASCO agrees that FDA has authority under section 361 of the PHS Act to issue appropriate requirements to prevent the interstate spread of communicable diseases through stem cell transplants. Section 361(a) authorizes FDA to issue regulations "necessary to prevent the introduction, transmission, or spread of communicable diseases from foreign countries into the States or possessions, or from one State or possession into any other State or possession." The particular requirements imposed must, of course, be reasonable.
FDA does not have authority under section 361, however, to issue the good tissue practice regulations it has proposed. According to the FDA document, these regulations are intended to preserve product integrity and function through proper handling and processing practices -- subjects that have no connection to preventing the interstate spread of communicable diseases. The FDA document attempts to make such a connection by claiming (on page 12) that inadequately controlled handling and processing can lead to impaired integrity and function of the stem cells, which can lead to a failed transplant, which can lead in turn to increasing the patient's susceptibility to communicable disease or requiring a repeat transplant with its risk of communicable disease. In other words, FDA's ostensible reason for regulating stem cell transplants through good tissue practice regulations has nothing to do with the transplants themselves, or with successfully treating a patient's cancer, but is intended merely to prevent cancer patients from acquiring a communicable disease as a result of an unsuccessful transplant.
This rationale is a transparent pretext for FDA regulation and does not reflect an actual effort to prevent the interstate spread of communicable disease. Patients who suffer unsuccessful stem cell transplants are indeed subject to opportunistic infections due to their lack of an effective immune system. Since these patients are hospitalized prior to, during, and after such infections, however, they are simply the victims of a nosocomial infection and cannot reasonably be viewed as part of the interstate spread of disease. Moreover, there is no reason to believe that the FDA standards and processing controls would reduce the incidence of engraftment failure. Failure currently occurs in 2-3 percent of transplants, but the reasons for failure are not understood. In the absence of that understanding, it is impossible for FDA to draft standards that would reduce or eliminate transplantation failure.
Section 351 of the PHS Act
Similarly, there is no legal basis under section 351 of the PHS Act for FDA to issue processing controls or to require the submission of INDs or BLAs for stem cell transplants. Section 351 applies only to biologicals that are sent "from any State or possession into any other State or possession," that are in foreign commerce, or that are within the District of Columbia. In addition, the section pertains only if the biologicals are offered for "sale, barter, or exchange." Thus, unless the stem cells are sold, bartered, or exchanged in interstate commerce, FDA lacks authority to regulate them under section 351. FDA's assertion that physicians who carry out certain types of stem cell transplants would need to have approved INDs or BLAs under section 351 has no legal basis in the absence of interstate transportation and sale of the stem cells.
The Federal Food, Drug, and Cosmetic Act
The FDA document also cites unspecified portions of the Federal Food, Drug, and Cosmetic Act as authority for the proposed regulations, but this Act also applies only if the regulated product has moved in interstate commerce. Although the recent FDA document does not explain how this requirement would be satisfied in the case of ordinary stem cell transplants, a previously circulated FDA proposal offered a highly convoluted and attenuated theory for FDA jurisdiction based on FDA's authority over misbranded drugs that are held for sale after shipment in interstate commerce. As we interpret the theory, FDA is arguing that some articles used in a transplant procedure move in interstate commerce, that these articles are therefore components of the final stem cell "product," that the physicians involved are holding this "product" for sale to their patients, that the "product" is misbranded because it fails to bear adequate directions for use as is required for all non-exempted drugs, and that the only basis for exemption recognized in FDA regulations is that the product be an approved drug or biological. Through this circular reasoning, FDA apparently argues that stem cells used in transplant procedures can be regulated.
FDA's theory is fundamentally flawed. A drug is not required to bear adequate directions for use if a physician is simply administering it to his own patients. United States v. Evers, 643 F.2d 1043, 1052-53 (5th Cir. 1981). Thus, even if there were validity to FDA's highly questionable assumptions that stem cells for transplantation constitute a product and that drugs and other articles used in connection with transplants are components of that product, the theory is not sufficient to give FDA authority over transplant procedures. Oncologists are free to conduct stem cell transplants on their own patients without FDA regulation.
Conclusion
FDA should not regulate stem cell procedures undertaken within an institution, among a group of collaborating institutions, or in any other setting where the cells are procured from a donor for a preselected recipient under the direction of physicians caring for these patients. Any FDA regulation of stem cells should be limited to the processing of stem cells by entities that have commercial-type operations. FDA's proposed approach, which would regulate physicians and hospitals conducting stem cell transplants, is not justified by any existing problems, would not provide any advantages over the current system while imposing significant additional costs, would impede the development of new cancer therapies, would limit the access of cancer patients to proven therapies, and would be illegal. The proposed approach is a threat to good medicine and should not be adopted.
Sincerely,
John R. Durant, M.D.
Executive Vice President | 
