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.
The Equal Employment Opportunity Commission (EEOC) has ramped up its vigilance over instances of genetic discrimination in the workplace. Last year, it filed its first class action lawsuit alleging violations of the Genetic Information Nondiscrimination Act (GINA), and this case has now settled. In the complaint, the EEOC charged that Founders Pavilion, a New York rehabilitation center, requested that job applicants provide a family medical history as part of its post-offer, pre-employment medical exams of applicants, in violation of GINA (ADA and Title VII claims were also advanced). Title II of GINA, passed by Congress in 2008 and enforced by the EEOC, prevents employers from requesting genetic information or making employment decisions based on genetic information:
Under Title II of GINA, it is illegal to discriminate against employees or applicants because of genetic information. Title II of GINA prohibits the use of genetic information in making employment decisions, restricts employers and other entities covered by Title II (employment agencies, labor organizations and joint labor-management training and apprenticeship programs - referred to as "covered entities") from requesting, requiring or purchasing genetic information, and strictly limits the disclosure of genetic information. The EEOC enforces Title II of GINA (dealing with genetic discrimination in employment). The Departments of Labor, Health and Human Services and the Treasury have responsibility for issuing regulations for Title I of GINA, which addresses the use of genetic information in health insurance.
The definition of genetic information in the statute is broad:
Genetic information includes information about an individual’s genetic tests and the genetic tests of an individual’s family members, as well as information about the manifestation of a disease or disorder in an individual’s family members (i.e. family medical history). Family medical history is included in the definition of genetic information because it is often used to determine whether someone has an increased risk of getting a disease, disorder, or condition in the future.
Details of the settlement:
As part of a five-year consent decree resolving the suit, Founders Pavilion will provide a fund of $110,400 for distribution to the 138 individuals who were asked for their genetic information. Founders Pavilion will also pay $259,600 to the five individuals who the EEOC alleged were fired or denied hire in violation of the ADA or Title VII.
The EEOC enforcement portfolio for GINA is relatively new. The EEOC filed and then settled its first GINA case last year, and it subsequently filed another case in September. The statistics on genetic discrimination complaints filed with the EEOC for 2012 reveal that of the 280 GINA charges investigated by the EEOC, approximately 59% found no reasonable cause, while approximately 13% did find reasonable cause. The trendline shows an increase in GINA complaints every year, and this is likely to continue. An emerging issue in the post-Affordable Care Act climate is a possible intersection of GINA data collection prohibitions with employer-provided wellness programs, which might involve making a health risk assessment (HRA) that impermissibly strays into the acquisition of genetic information in a manner that GINA prohibits. GINA’s relative invisibility in the civil rights toolkit of the EEOC will likely diminish over time.
A declaration of intent to conduct “gain-of function” experiments on the novel avian influenza A(H7N9) virus has been published by scientists who wish to alter the genetic composition of the viruses to determine what genetic changes/mutations correlate with altered function. Gain of function (GOF) experiments on pathogens alter existing properties and can result in the creation of more dangerous pathogens; the goal is to gain insights into the relationship between genetics (structure) and function. The H7N9 virus emerged earlier this year in China, and to date the World Health Organization reports 135 human cases, with 44 fatalities. This new effort to study H7N9 is proposed by a consortium of scientists, including Ron Fouchier and Yoshihiro Kawaoka, who were the principal investigators for the experiments on HPAI H5N1 viruses that produced viruses with potentially increased human to human transmissibility. Those earlier experiments raised such an alarm that publication of the research was halted in the U.S. while the NSABB federal advisory committee evaluated the risk of publication (both were eventually published). The proposed experiments fall into the category of DURC (dual research of concern), defined as such:
Dual use research of concern(DURC) is a subset of dual use research defined as life sciences research that, based on current understanding, can be reasonably anticipated to provide knowledge, information, products, or technologies that could be directly misapplied to pose a significant threat with broad potential consequences to public health and safety, agricultural crops and other plants, animals, the environment, materiel, or national security.
The declaration of intent by the scientists is presumably an attempt to increase transparency and invite deliberation at the front end of the process and avoid the panicked reaction that followed the announcements of the earlier H5N1 experiments in 2011. The authors also include materials outlining the biosafety precautions that would accompany the experiments. Early official reaction from the CDC and NIH declares that such experiments will receive extra scrutiny before U.S. government funding will be made available, according to recently issued federal guidelines for DURC issued earlier this year. The CDC has also issued specific biosafety guidelines for working with the H7N9 virus. The following kinds of gain-of-function experiments were announced in the letter:
•Immunogenicity. To develop more effective vaccines and determine whether genetic changes that confer altered virulence, host range or transmissibility also change antigenicity.
•Adaptation. To assist with risk assessment of the pandemic potential of field strains and evaluate the potential of A(H7N9) viruses to become better adapted to mammals, including determining the ability of these viruses to reassort with other circulating influenza strains.
•Drug resistance. To assess the potential for drug resistance to emerge in circulating viruses, evaluate the genetic stability of mutations conferring drug resistance, and evaluate the efficacy of combination therapy with antiviral therapeutics. Also, to determine whether A(H7N9) viruses could become resistant to available antiviral drugs, and to identify potential resistance mutations that should be monitored during antiviral treatment.
•Transmission. To assess the pandemic potential of circulating strains and perform transmission studies to identify mutations and gene combinations that confer enhanced transmissibility in mammalian models (such as ferrets and guinea pigs).
•Pathogenicity. To aid risk assessment and identify mechanisms, including reassortment and changes to the haemagglutinin cleavage site, that would enable circulating A(H7N9) viruses to become more pathogenic.
These proposed experiments – altering the critical variables of spread and virulence for the viruses, changing drug resistance and vaccine susceptibility – will likely produce viruses that are potentially more dangerous than those we currently know about. The stated goal of such work is to learn which mutations alter the risk profile of a virus – confer pandemic potential – and use that knowledge to design vaccines or discover antivirals that can respond to these viruses. Further, it is argued that ongoing surveillance efforts can be focused on identifying virus isolates that display such mutations and pose an elevated public health risk, although this point is contested by other scientists. It’s not clear whether the NSABB will be involved at this early stage – to date, it has not advised on the merits of funding specific experiments which can be characterized as DURC. The recent tightening of federal review of such research will be put to the test with these proposed experiments as the investigators seek U.S. funds. With respect to the publication of results, the influenza researchers anticipate the possible fallout:
To advance A(H7N9) virus research, findings should be shared in refereed publications. Investigators agree to adhere to guidelines for responsible communication of results and every effort will be made to put the results in context and reduce sensationalism.
The questions that were raised by the H5N1 influenza controversy - what criteria are to be used when evaluating the funding for DURC or what conditions need to attach to such funding – will now surface with this H7N9 research declaration – and their resolution might establish a template for future research proposals.
Several developments have followed last month's Supreme Court decision that invalidated Myriad Genetics patent claims to isolated genes; (AMP v. Myriad opinion). Within hours of the Court’s decision, several competitors announced plans to offer BRCA1 and BRCA2 genetic tests. Myriad has recently filed patent infringement suits against Ambry Genetics (California) and Gene by Gene (Texas), based on the assertion of patent claims from ten patents it holds to BRCA1 and BRCA2 related genetic materials and methods (including some with contested claims in the Supreme Court). The complaint against Ambry is here; the complaint against Gene by Gene complaint is here. The suits, filed in Utah federal court, could be an opening play to fully litigate these other patents or a maneuver to create licensing structures for these patented materials and methods. A strategy by Myriad to obtain a preliminary injunction against these companies would have to contend with the more rigorous scrutiny for such requests after eBay v. MercExchange (2006), where the Supreme Court reaffirmed the need to consider "public interest" in the award of injunctions, and the current climate might lend support for such an argument against any injunction. Ambry has indicated that it will “vigorously defend” its right to offer testing services.The Court’s invalidation of some of Myriad’s patent portfolio related to BRCA1/2 testing has clearly led to altered expectations regarding the state of the genetic testing marketplace. Evidence of this is the response from Senator Patrick Leahy, Chair of the Senate Judiciary Committee, to Myriad’s lawsuit, calling for the National Institutes of Health (NIH) to exercise “march-in” rights that it holds pursuant to the Bayh-Dole Act of 1980. That option applies to patents for which NIH provided federal funding (or other federal agencies). Apart from the march-in authority, the U.S. government retains a default mechanism, a compulsory license that allows it to use any patented invention (or authorize 3rd parties to do so) under the statutory authority of 28 U.S.C. 1498, which requires “reasonable and entire compensation for such use and manufacture.” Since the march-in authority has never been exercised by the NIH (see here), it is unlikely to respond to Leahy’s call. Nor is it likely that the government would regard the BRCA1/2 genetic testing controversies as critical enough to trigger the compulsory license mechanism. These disputes are likely to be settled more informally, and more quickly, as the high visibility of these tests will retain public attention and maintain pressure on Myriad to support the expansion of genetic testing options.
