A common feature of modern human clinical trials is a double-blind placebo test. In such a trial, neither the doctor administering the drug nor the patient knows who is receiving the active drug and who is receiving a placebo. The placebo effect is well documented and commonly understood as a mental expectation response to being told that you are receiving a powerful drug. Patients taking a placebo report a variety of responses: some patients on the placebo report feeling better; some report no response and no side effects; others report that they are feeling worse or only experiencing side effects. Some patients, who are not experiencing side effects, believe they are receiving the placebo tend to drop out of studies. Patient drop out is a serious problem and in response, the “active placebo” was developed.

Active Placebos

An active placebo is a placebo that causes the same side effects as the active drug, but does not treat the patient’s disease. This helps to convince patients that they are receiving the active drug in the trial, and makes them less likely to drop out (but more likely to report side effects and curative effects of the drug).  Active placebos are commonly used in pain trials, giving people symptoms like drowsiness, nausea, or dry mouth.

Patentability under §101

35 U.S.C. §101 requires that a patent be given for any “new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof…” The “useful” requirement of §101 has been used to exclude immoral inventions from patentability. While this category used to include things like gambling machines, today things like suicide machines or a letter bomb would be excluded on an immorality basis. Could an active placebo fail the utility test of §101?

§101 utility requires a practical or specific utility, operability, and a beneficial utility. An active placebo would meet the operability requirement by showing that it did in fact give some people side effects. Presumably, the side effects would have to come from a pharmaceutically active ingredient in the placebo, and not be a result of mental expectation from the patient. The placebo would also pass the practical or specific utility test because it is useful in clinical trials for reducing the likelihood of patient drop out. However, is the active placebo beneficial? It is a device used to trick people into thinking they are taking a curative drug, when in fact the pill does nothing but give them a stomach ache!

The beneficial utility test is a very low bar, and a device that deceives the public may still have a beneficial utility. Here, it may come down to how the claims are written. A composition or compound claim for a drug to induce headaches or nausea would almost certainly be allowed. However, a method claim to tricking patients and taking advantage of the placebo or mental effects of the drug might tip the scales in the other direction. In the European Patent Office, the patent may fail, partly because the EPO expressly allows examiners to consider the morality of an invention, but also because the EPO, under the European Patent Convention, would not grant any method claims filed on an active placebo as being a surgical method.

The use of active placebos presents many regulatory and legal issues that the Bioethics Committee should consider, including patent eligibility. Some other issues involve the informed consent doctrine, the ethics of “do no harm”, and the integrity of clinical trials.  No matter what the committee recommends, they will face a tough decision that could affect many clinical study participants in the future.

FDA approval for rBST and labeling policy
In 1987, Monsanto submitted to the FDA a new animal drug application for Posilac, a synthetic growth hormone that increases milk production in dairy cows (also known as an rBST or rBG). It took Monsanto over 6 years to bring rBST to market, and Monsanto supplemented the application with studies and reports documenting the safety and effectiveness of the drug. After reviewing those materials, the FDA approved Monsanto’s application for the use of Posilac in 1993. In January 1994, a Congressional task force concluded that the FDA’s position was adequately supported.

In addition to approving rBST for public use, the FDA had to determine whether milk from rBST treated cows should be labeled differently than regular milk. Besides enforcing requirements necessary to ensure that the labeling is not false of misleading, the FDA is prohibited from placing some additional requirements on labeling—the agency cannot require labeling based solely on differences in the production processes of identical foods. After an extensive agency investigation outlined above, the FDA found that there was no material difference between milk from rBST-treated cows and milk from non-rBST-treated cows, and accordingly it could not impose additional labeling requirements.

The standard for determining if two foods are the same is a materiality standard. Materiality relates to nutritional, organoleptic, or functional characteristics of the food. In general, the FDA has not found that foods from genetically modified organisms are different than their conventional counterparts. Therefore, the FDA could not require any additional labeling of rBST milk. This decision was specifically upheld in Stauber v. Shalala, when the Wisconsin district court determined that absent evidence of a material difference between milk from rBST-treated cows and non-rBST-treated cows, the FDA could not create any additional labeling requirements. Later, the FDA advised that milk from untreated cows could be labeled as such, but recommended the inclusion as a disclaimer that accompanying the statement “from cows not treated with rbST” with the statement that “No significant difference has been shown between milk derived from rbST-treated and non-rbST-treated cows.”

6th circuit finds rBST milk “materially different”
In International Dairy Foods Association v. Boggs, the 6th Circuit determined that Ohio’s 2008 law prohibiting the labeling of milk from non-rBST treated cows was unconstitutional under the 1st amendment. The court based this decision in part on its finding that the two milks were different, thus overruling the FDA’s prior determination. The court cites three reasons milk produced by rbST-treated cows is different: increased levels of the hormone IGF-1, a period of milk with lower nutritional quality during each lactation, and increased somatic cell counts in the milk. The court further noted that higher somatic cell counts indicate milk is poor quality and will turn sour more quickly.

The 6th circuit’s willingness to overturn the FDA’s determination could have important implications for other genetically modified foods on the market and those looking to enter the market, including genetically modified salmon. Companies spend enormous amounts of resources convincing the agency and the public that their products are safe to eat, have no environmental harms, and are overall the “same” as conventional foods. In fact, producers of genetically modified foods encourage labeling restrictions so that consumers cannot tell from the label which foods are genetically modified and which are not. The argument goes that since the FDA says the two types of food are materially the same, consumers should not be told that they are different in any way. Telling a consumer that a product is made from “cows not treated with rBST” creates an impression that milk from treated cows is worse, and thereby creates confusion.

As demonstrated by the Ohio case, specific regulations in each state can be the target of suits by consumers or producers of conventional foods. Companies will now need to continuously manage public and scientific opinion of their food products. In fact, genetically modified food producers will need to decide if they even want to pursue labeling requirements, when doing so could force them to defend the FDA’s materiality determination in 50 separate suits.