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December 2001
Vol. 4, No. 12, pp 25–27.
Rules and Regulators
Controversial bundles of joy
The FDA now requires “new drug” paperwork from fertility clinicians using the cytoplasmic transfer technique.

For the couple lucky enough to conceive without outside help, childbirth can be one of life’s greatest gifts. But for many others, bringing a bundle of joy into the world can be a source of infinite emotional and physical pain, frustration, and expense.

Every year, infertility affects about 6 million people in the United States—10% of the reproductive age population. Most cases of infertility, 85 to 90%, can be treated with conventional and relatively low-cost medical therapies such as medication or surgery of the reproductive organs. But some procedures, such as in vitro fertilization (IVF), can cost upward of $8000. Those who cannot be helped by these methods are left with limited options: adoption, surrogate parenthood, or remaining childless.

Often, the pressure to conceive can become so great that a couple having fertility problems will do just about anything to have a baby, no matter how untried a technique is, how strange its methods sound, or how low its chances of success. The fertility industry, for its part, has developed a variety of procedures designed to give couples a greater chance at success, depending on their particular difficulty.

Over the years, these procedures have strayed farther from the path of nature. Women have taken drugs to increase the output of eggs during ovulation, allowed fertilization to take place in a petri dish or test tube, watched their babies grow in another’s body, and so on. However, some experts believe that a relatively new technique, known as cytoplasmic transfer, might have pushed beyond the limits commonly considered to be acceptable.

Although proponents of the technique espouse it as the only hope for some couples to have children genetically related to them, those in opposition have called it unethical and possibly without scientific merit. In the past year, certain uses of the technique have become unlawful. In July, the FDA issued a letter reminding fertility clinicians that it has jurisdiction over the use of this particular procedure. Clinicians practicing cytoplasmic transfer, as well as several other techniques that had previously been performed without governmental oversight, are now required to fill out an Investigational New Drug application—and follow the same procedures required of developers of new prescription medications. These procedures require obtaining informed consent from patients participating in testing the technique, as well as conducting regimented Phase I-III clinical trials.

Many clinicians and advocates of reproductive research believe the FDA’s newly restrictive stance could prove to be a stifling addition for a field already strapped for support and resources, and limitations on the technique could narrow the options available even further.

Hope for the hopeless
According to its pioneering researchers, including a group of reproductive scientists at Saint Barnabas Medical Center in West Orange, NJ, cytoplasmic transfer was developed to help women with a type of infertility affecting the mitochondria in their eggs. Because the mitochondria are defective, the researchers theorized, the eggs cannot support a pregnancy once they are fertilized.

To combat this problem, the scientists inject cytoplasm from a donor egg into the egg of a woman seeking to conceive. The resulting egg is then fertilized with her partner’s sperm and implanted in the woman’s uterus. If all is successful, the zygote will develop into a healthy baby.

Since the technique’s inception in 1996, at least 30 children have been born through its use. Those children appear to be normal and healthy, and they possess genetic characteristics from their mother and father—a reality that would have been impossible had a complete donor egg been used instead.

“No other technique is available to these women [to have babies that are genetically their own],” said Henry E. Malter of the Institute for Reproductive Medicine and Science at Saint Barnabas Medical Center, speaking to MSNBC. “The parents are extremely happy.”

Questionable safety
But implications other than successful childbirth lie beneath this seemingly simple technique. Because mitochondria from the donor egg are transferred into the original mother’s egg, the resulting child ends up with genetic material from three parents: nuclear DNA from its mother and father and a small amount of mitochondrial DNA from the donor egg. Of all the children conceived with this technique, two have already tested positive for mitochondrial DNA from the donor egg.

Those opposed to the technique cite the fact that cytoplasmic transfer treads in novel territory: It is the first example of germ line modification (changing the genetic qualities of eggs and sperm) ever to take place in human beings. Other examples of human germ line modification, such as cloning, have been banned in the United States, and cytoplasmic transfer itself is illegal in many other countries. No animal studies have completely shown its effects on future generations, and no one knows what health or social consequences it may have on humans conceived through its use.

“This is human experimentation of an extreme sort,” said Ruth Hubbard, an expert in women’s reproductive health and a board member of the Council for Responsible Genetics, a nonprofit organization that monitors the development of new genetic technologies and advocates their responsible use. “We just don’t know what the outcome of this thing is going to be.”

Other experts point out that the number of “successful” cases is too small to prove anything. Only 15 cases were cited in a study published on cytoplasmic transfer by the Saint Barnabas researchers in the journal Human Reproduction (2000, 15, 207-217). The technique is still considered experimental, and so far, researchers are not sure exactly why or how it works. Hundreds of cases would need to be studied to determine if the procedure is indeed effective and for whom it should be used.

But some fertility researchers fear that exhaustive testing, such as what the FDA requires through an Investigational New Drug application, would be a financial impossibility for the poorly funded field of reproductive science. Unlike many other areas of research, the federal government does not fund reproductive science. Most clinics function independently, leaving it up to individual practices to pay the enormous costs of experimental trials.

“They are attempting to treat individual physician offices as manufacturers,” said Sean Tipton, a spokesperson for the American Society for Reproductive Medicine, the largest professional group of fertility specialists. “Your average reproductive medical practice does not have the resources of a large pharmaceutical company. It’s going to be difficult to meet some of the data demands [to get this approval].”

It is also difficult to determine what the FDA is trying to regulate, said Tipton. In the past, the FDA has had jurisdiction over drugs and tissues involved in fertility research to determine their safety and efficacy. Tipton says that his organization believes the FDA has a legitimate place in directing how tissues, such as a donor egg, may be extracted from the donor and tested for safety before use in a fertility technique. But he is concerned that it might be overstepping its boundaries by directing an actual procedure or the use of the tissue itself.

“The FDA has no place in what happens between a physician and a patient, in their office or the operating room,” Tipton said.

A new governing body
In part, the complaint of Tipton and others is that the FDA seems ill-suited to provide effective governance over this technique by covering it under statutes meant to refer to prescription drugs.

Mark Frankel, director of the scientific freedom, responsibility, and law program at the American Association for the Advancement of Science (AAAS), says that his organization believes a whole new governing body should be constructed to oversee the technique of cytoplasmic transfer and countless other technologies in development that have the potential for transmitting genetic changes to subsequent generations of humans. Its proposal is included in a published report available from the AAAS.

“What we have proposed in our report is that there be an oversight body established that would not only oversee this procedure, but would step back and try to generate some rational discussion as to whether or not this is something we ought to be doing in the first place,” said Frankel.

Frankel believes that cytoplasmic transfer and other germ-line-modifying technologies should indeed be regulated. And because the FDA is the only such regulating body at this time, he says that fertility practitioners should defer to its authority. But he is not convinced that the FDA’s position goes far enough.

“All the FDA will do is basically apply what its authority allows it to do, and its authority is really focused on safety and efficacy. It doesn’t look at social implications,” said Frankel. “There needs to be a broader public discussion of these issues so that we as a society can make these sorts of judgments as to whether or not we should continue.”

Meanwhile, cytoplasmic transfer will continue as long as researchers can meet the FDA’s requirements.

Christen L. Brownlee is an assistant editor of Modern Drug Discovery. Send your comments or questions regarding this article to mdd@acs.org or the Editorial Office by fax at 202-776-8166 or by post at 1155 16th Street, NW; Washington, DC 20036.

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