These are my notes from class meeting 8 of Harvard Law School’s Food and Drug Law course, led by Prof. Peter Barton Hutt on January 17, 2017. Reading for today’s class meeting is pp. 77-78, 135-139, and 1123-1192 of Food and Drug Law 4th Ed..

History of regulation of biologicals

Federal regulation of biologicals began in 1902, as explained in lecture 1. For 70 years, it was administered by the Division of Biologics Standards (DBS), located in what’s now the NIH. People eventually began to wonder whether NIH had a conflict of interest, in that some NIH researchers worked on developing vaccines, so NIH might be predisposed to believe that its vaccines were safe and effective. Finally in 1972 the DBS was transferred to FDA. With this move came a big change. Until then, DBS had been mostly concerned with pure science; its only regulatory role was in the decision of whether to approve a biological or not. FDA brought with it many other regulatory concerns, for instance enforcing Good Manufacturing Practices, which no one in DBS had thought about previously. FDA merged biologicals and drugs into one unit in 1982, then split them again in 1988, yielding CDER and CBER.

Definition of biologicals

During the years when DBS was part of NIH, there were debates over how regulation of biologics related to regulation of drugs, and who had jurisdiction over what. In an effort to resolve this and harmonize biological regulation with the FD&C Act, Congress included language in the Public Health Service Act of 1944, which is still the statutory source of FDA jurisdiction over “biological products” today. That 1944 Act, as currently amended, offers the following definition:

“biological product” means a virus, therapeutic serum, toxin, antitoxin, vaccine, blood, blood component or derivative, allergenic product, protein (except any chemically synthesized polypeptide), or analogous product, or arsphenamine or derivative of arsphenamine (or any other trivalent organic arsenic compound), applicable to the prevention, treatment, or cure of a disease or condition of human beings.

So whereas the regulatory definition of “drug” is largely a functional test, the definition of biological is this enumerated list, plus the open-to-interpretation words “or analogous product”. FDA has historically used the “analogous product” phrasing to regulate whatever it believes are biologicals, and the courts have largely upheld this. The one exception was that the original 1944 Act did not include blood, and the courts held that blood was not “analogous” to anything else in the list; Congress subsequently added blood to the list.

This definition has led to some strange and arbitrary delineations. For example, whether a protein is a biological depends on its length (number of amino acids), method of production (in living cells or by chemical synthesis), and intended use (drug vs. vaccine or allergen). FDAMA in 1997, however, required the biologics license application (BLA) and new drug application (NDA) processes to be parallel, thus bringing biologicals and drugs under basically the same regulatory regime, so these distinctions mean less than they used to. Within FDA, the current division of what products are regulated by CBER vs. by CDER dates to an FDA leadership decision in 2003.

Differences between biologicals and drugs

Biologicals are natural substances, and so batch to batch they are never identical. So whereas drugs are regulated by chemical composition, biologics are regulated by 1) establishment (the facility where they are produced), and 2) method (how they are produced). This leads to some peculiarities. There was one instance where a factory collapsed or burned down, the manufacturer built a new factory next door to it and wanted to resume production, and FDA insisted that they needed to do a new clinical trial to show safety and efficacy of the product as produced by the new establishment.

Although regulation of pioneer drugs and pioneer biologicals is similar, there is a big difference between the regulation of generic drugs versus “biosimilar” biological products.

“Biosimilars” are a category created by Congress in 2009 with the Biologics Price Competition and Innovation Act. They are defined as being “highly similar”, recognizing that having been produced in living cells or organisms, they cannot be as identical to a pioneer biological as a generic drug (say, a synthetic small molecule) can be to a pioneer drug. The criteria for approval are stricter and require new clinical trials to show safety and efficacy. This is all hypothetical, however, because so far no company has ever filed an application for a biosimilar.


If an organ or tissue is not manipulated or is “minimally manipulated” then it is exempt from FDA regulation. If it is more than minimally manipulated then a BLA is required. Removing cancer cells from bone marrow is classified as minimal manipulation, however, adding a drug to bone marrow prior to transplant is considered more than minimal manipulation. Yet addition of drugs to bone marrow is sometimes clearly necessary, and the cost and time required to obtain a BLA for such a procedure is prohibitive, thus creating a conflict for doctors who must carry out their obligation to provide the best care to the patient. The de facto compromise is that drug companies cannot market their drugs as additives for bone marrow transplants, but physicians can use the drugs for this purpose off-label. In other areas, the compromise has been that U.S. patients travel to Canada to get transplants done.

Regulation and supply of vaccines

Vaccines are the original biological and were the impetus for biological regulation to begin in 1902. The impact of vaccines on human health is tremendous, and they continue to occupy a major place in FDA.

Yet several factors combine to make vaccine development incredibly economically difficult. First, the BLA process is enormously expensive. But unlike an NDA for a drug, obtaining a BLA is not even the end of the road. For biologicals, manufacturers must submit substantial new data to FDA for every new facility or new method employed. FDA can hold individual batches of product for review prior to release. And FDA often requires manufacturers to upgrade and incorporate new manufacturing processes as they become available. All of those factors make producing vaccines very expensive. Meanwhile, revenue from vaccine production is also very limited. Vaccines are given just a few times (usually one primary inoculation and a few booster shots in one human lifetime) rather than taken regularly like many drugs. About 50% of the vaccine market is childhood vaccines procured by the federal government, which uses its market power to keep prices down. And on top of all this, even the safest vaccines inherently have some very low but nonzero rate of serious adverse events (usually allergic reactions, sometimes fatal), and the courts have allowed consumers to sue manufacturers when they are injured or made sick by vaccines, even when the manufacturer had FDA approval and fully complied with all regulations. The federal government provides the National Vaccine Injury Compensation Program as an alternative to torts, but lawsuits do still happen and can on occasion be astronomically costly.

That’s the U.S. market; there is of course an international market for vaccines but the economic opportunities are not much greater anywhere else.

The net result that as of 2004, there were only five major vaccine producers in the U.S., and for several vaccines that everyone routinely gets, there is only one supplier [Sloan 2004]. This makes the market highly vulnerable to disruptions in supply.

Many of the regulations go out the window for flu shots. A new flu shot is issued each year for the upcoming flu season, so there is no opportunity to do clinical trials, and FDA recognizes this and exempts them from this requirement.

Mandating vaccines

States require vaccines in order for kids to attend public schools. Parents can opt out by home-schooling their children, though this doesn’t remove the public health threat, as those kids can still go to the library or playground, etc, plus 48 states offer religious exemptions under which unvaccinated children still can attend public schools. For instance, here are the Massachusetts regulations. Mississippi and West Virginia are the two exceptions.

Religious objections to vaccines are on the decline, however, and more of the failure to vaccinate children today is due to the mistaken belief that vaccines cause autism.

Recombinant DNA

After cloning was invented, scientists convened the 1975 Asilomar conference where they set out strict guidelines for research using recombinant DNA and a moratorium on certain uses thereof until safety could be established. These guidelines were followed, despite never becoming law.