The FDA is considering the merits of an assisted reproductive technology (ART) that has a goal of eliminating the transmission of genetically based mitochondrial diseases. Mitochondria, small DNA packages in the cytoplasm of the cell, are inherited in the maternally-provided egg during reproduction. For women who could transmit mitochondrial disease to offspring, this ART protocol involves the production of an altered egg, which has the nuclear DNA of the mother swapped into the egg of a woman without the genetic disease. Thus the egg is a genetic hybrid. Conventional in vitro fertilization (IVF) follows the manipulation of the egg. This technique has been dubbed "3-parent babies" because the child would inherit DNA from 2 females and one male. Is it safe? In the U.S., the FDA halted the use of a fertility treatment involving cytoplasmic transfer in eggs that was used in 2001, asserting its authority to regulate this technique as part of its ongoing supervision of the production and use of biologic products (e.g. cells, tissues, etc). Although technically genetic material is swapped around in order to “delete” the disease-causing genes, this is not quite the genetic engineering often imagined in which the nuclear genetic material would be deleted, supplemented or rearranged (”designer genes).” In fact, cellular structure makes this technique quite conceptually simple as the mitochondria are cellular organelles that exist outside the nucleus, facilitating a replacement scheme such as the one here. An Oregon scientist, Dr. Shoukhrat Mitalipov, has published experiments documenting success with the use of the technique in monkeys and would like to begin the use of the technique in humans. He would need FDA approval to begin any clinical trials in humans. In two days of open public hearings this week, the Cellular, Tissue, and Gene Therapies Advisory Committee of the FDA invited testimony from scientists and other commenters regarding the scientific, technical and clinical concerns for the use of mitochondrial manipulation technologies. They described their task:
The committee will discuss oocyte modification in assisted reproduction for the prevention of transmission of mitochondrial disease or treatment of infertility.
The FDA asserts its authority over the use of this technique as deriving from its role in regulating the production and use of biologic materials, from its ongoing review of protocols that involve genetic manipulation, as well as its goal of insuring the safety of human study subjects. In a briefing document prepared for the hearings, the committee cited a long list of potential safety concerns for both mother and child from the use of the mitochondrial replacement technique:
Potential risks to the women could include: 1) failure to become pregnant; 2) failure to deliver a child; 3) risks associated with the specific mitochondrial manipulation technology procedure; and 4) toxicities of the reagents used in mitochondrial manipulation technologies. Potential risks to their children could include: 1) mitochondrial disease (particularly in women with mitochondrial disease), as a result of carryover of abnormal mitochondria and heteroplasmy; 2) disorders due to nuclear mitochondrial incompatibility; 3) disorders related to aberrant epigenetic modifications ; 4) birth defects and other disorders associated with the specific mitochondrial manipulation technology procedure; and 5) toxicities of reagents used in mitochondrial manipulation technologies. There may be additional risks that are difficult to predict because of limitations in current knowledge.
The FDA will receive public comment on a draft guidance it has issued to those designing protocols for early-phase clinical trials with such techniques. The public comment period closes May 9, 2014. Although fertility clinics in the U.S. are not subject to extensive oversight from the FDA or any other agency, this proposed ART technique comes under FDA purview by its use, manipulation and transfer of biologic products into humans. Effectively, and critically, this technique is a germ-line modification of an embryo, meaning that the genetic manipulation will be carried into future offspring which inherit the replaced mitochondria. That fact heightens the concerns over the safety and ethical dimensions of potential use. Germline modification of embryos is prohibited in at least 40 countries, and there has been a kind of international consensus against use of these techniques. However, in a sign that a more nuanced regulation of certain ARTs may be developing, the UK is also considering whether to approve this use of this ART.
The FDA continues to monitor the emerging field of stem cell medicine, which offers the possibility of treating certain medical disorders by the application of new cells which replenish deteriorating tissues (e.g., Parkinson’s, heart disease, diabetes). The prospect of harvesting a patient’s own stem cells and administering them to sites of cellular stress is a new paradigm for disease treatment (autologous stem cell therapy). Nonetheless, such practices challenge existing legal regimes which regulate the introduction of pharmaceutical and biologic products into the marketplace. Regenerative Sciences, Inc., is a Colorado corporation that its Regenexx stem cell treatment, offered to patients suffering from a number of musculoskeletal conditions. The procedure involves withdrawing bone marrow from a patient, extracting the mesenchymal stem cells from the marrow, and processing the cells to create a therapeutic preparation for injection to a site of interest, with a goal of restoring function to impaired joints. Since 2008, the FDA has cautioned the company that its practice was likely violating the Federal Food Drug and Cosmetic Act (FDCA) because it involved the use of an unapproved drug and likely violating the a biological product under the Public Health Service Act (PHSA), because it used an unapproved biologic product. The FDA also inspected the Regenerative facilities in 2009, and found numerous departures from good manufacturing practices. The FDA then sued to enjoin the company from offering unapproved stem cell treatments and prevailed in federal district court in 2012. The court granted summary judgment on a motion by the FDA that the Regenerative stem cell preparation was both a drug and a biologic, and, as such, was both adulterated and misbranded, in violation of both statutes (see earlier post). The court issued a permanent injunction against Regenerative, prohibiting it from offering the stem cell treatment.
Now, the D.C. Circuit has upheld the district court’s decision, rejecting the defendant’s arguments that it was simply engaged in the practice of medicine, which is not regulated by the FDA, and is governed by state law. The appellate court affirmed the lower court’s finding that the stem cell preparation was both a “drug” and a “biologic” and required FDA approval before use in clinical medicine, noting that these existing laws do not interfere with the practice of medicine:
Appellants’ construction of the FDCA, by contrast, would allow states to gut the FDCA’s regulation of doctors, and thereby create an enormous gap in the FDCA’s coverage, by classifying the distribution of drugs by doctors as the practice of medicine. Given Congress’s intent that the FDCA’s “coverage be as broad as its literal language indicates," United States v. An Article of Drug . . .Bacto-Unidisk, 394 U.S. 784, 798 (1969), such a construction is not tenable.
Critics of these FDA enforcement activities argue that the application of the standard drug approval process to stem cell therapies (especially with the use of autologous cells harvested from the patient) undercuts innovation in the field. Proponents of FDA regulation argue that existing statutory responsibilities call for the agency to monitor the use of stem cell therapies, yet some concede that the use of autologous stem cell therapies calls for a novel regulatory policy that is especially tailored to these procedures, rather than the application of “one size fits all” FDCA and PHSA requirements.