The quality of a vaccine is closely linked to its manufacturing process, which must be rigorously controlled to ensure that batches of vaccines produced on different occasions are of reproducible and consistent quality. In general, quality is achieved by applying the current good manufacturing practice [cGMP] . . . Such principles also apply to the facilities and equipment in which products are manufactured. Accordingly, vaccine production is very highly regulated to ensure that the products are of consistent quality and safe and effective for the purpose(s) for which regulatory approval was granted.[i]
Before 1962, vaccines, drugs, and other such products did not undergo nearly the kind of scrutiny that they do today in order to become licensed. It wasn’t until the thalidomide disaster of the 1960’s that federal regulation of drugs came to be what it is today. As of 2003, the Department of Health and Human Services (DHHS) is “United States government’s principal agency for protecting the health of all Americans and providing essential human services, especially for those who are least able to help themselves.”[ii] This is a monumental undertaking and is why the DHHS is one of the largest government agencies with over 63,000 employees and an annual budge of $429 billion. It has a number of sub-agencies with their own areas of responsibility, including the Food and drug Administration. The history of these organizations bears some consideration because it is between the historical cracks in legislation and regulation that the current anthrax vaccine would slip.
In 1906, the first Food and Drug Act was passed, authorizing the federal government to monitor the purity of foods and safety of medicines. The 1906 Act was fairly light, even inadequate by most standards. False statements made about a drug by its manufacturer (i.e., public advertising) were not considered as misbranding by the courts. Additionally, the Act did not grant authority to ban unsafe drugs. For a drug to be legal under the 1906 law, it only had to meet the standards for composition of the United States Pharmacopoeia or the National Formulary. The Bureau of Chemistry – the forerunner to the modern FDA – enforced this law.
It wasn’t until 1938 that the Food and Drug Administration received broad statutory authority to regulate interstate shipment of unapproved new drugs for investigational use. This kind of federal regulation was a direct result of President Franklin Delano Roosevelt’s policies and the Great Depression. Prior to the Great Depression, the federal government exerted nothing even approaching the kind of regulatory authority that it does today.
The Sulfanilamide Disaster of 1937 brought the first modification to the 1906 act. Soldiers originally used sulfanilamide as a treatment for wounds. In powder form it was sprinkled over a wound as an antiseptic, to prevent infection. [This is one of the substances the Nazi doctors used in experiments named in the indictment at the Nuremberg Trials. Thus, their defense that what they did differed little from previous U.S. experiments.] A manufacturer decided to expand the anti-infective use of the drug by mixing sulfanilamide with diethylene glycol – diethylene glycol currently enjoys a more popular following among American consumers as anti-freeze in car radiators. The manufacturer marketed the mixture of glycol and sulfanilamide as an elixir for sore throats. No clinical tests were performed prior to marketing. There were 107 reported deaths from this product.
Subsequently, the Federal Food, Drug, and Cosmetic Act of 1938 was enacted, expanding the government’s control to include advertising and labeling of products. More importantly, it authorized the Food and Drug Administration (for the first time) to establish a regulatory system for obtaining pre-marketing clearance of an investigational new drug. Manufacturers were now required to submit a new drug application (NDA) containing evidence that a drug was safe for its intended use. Despite this grant of authority, the FDA was fairly ‘light’ (by modern standards) in its regulation. These regulations, which remained in effect without change until 1962, left the protection of human subjects almost entirely to the discretion of sponsors and investigators. For example, it did not require a notice for conducting investigational trials to be submitted to the FDA; it did not require pre-clinical safety studies prior to administration of a drug into humans; and, notwithstanding the Nuremberg Trials, the 1938 Act did not require informed consent of test subjects.
In 1962, thalidomide, a sleeping pill developed and widely used abroad for several years, was being studied for use in the United States. The FDA did not approve this drug for marketing in the U.S. because of the requirements in the Federal Food, Drug, and Cosmetic Act, and because of the refusal of an FDA medical officer, Dr. Frances Kelsey, to clear the drug on what she believed to be inadequate safety evidence provided by the manufacturer. Notwithstanding this, and even though the drug was restricted to investigational use in the U.S., the sponsoring pharmaceutical company widely distributed it to doctors for their use. [This practice continues to this day by some drug manufacturers.] Later, of course, thalidomide was learned to be a human teratogen which caused malformations in many European children. Children were being born without arms or with other severe deformities. A series of lawsuits demonstrated that, in general, prescribers of drugs had been relying on manufacturers for information pertaining to the drugs, and that this information in some instances had been based on inadequate testing, or even on deliberate falsification and deception. The Kefauver-Harris amendments of 1962 were finally enacted as a result of this incident.
These amendments contained several important new provisions to the FD&C Act. First, it required that all clinical testing of investigational drugs be conducted under applications submitted to the FDA (Investigational New Drug Applications). Additionally, sponsors were required to submit reports of pre-clinical studies to justify their proposed clinical testing in humans, obtain informed consent from test subjects prior to their entry into a study, and report all findings resulting from the investigational studies to the FDA. Second, Good Manufacturing Practices (GMP) were established. Any drug not produced in accordance with CGMP would be considered adulterated. Prescription drug advertising was also placed under the supervision of the FDA.
Finally, the 1962 amendments required that all new drugs, in addition to being safe, must be shown to be effective for their intended use, prior to marketing. The standard for scientific evidence acceptable for demonstrating substantial effectiveness was defined by Congress as:
adequate and well controlled investigations, including clinical investigations, conducted by experts qualified by scientific training and experience to evaluate the effectiveness of the drug involved, on the basis of which it could be fairly and responsible be concluded by such experts that the drug will have the effect it purports or is represented to have under the conditions of use prescribed, recommended, or suggested in the labeling.[iii]
The FDA had actually proposed new regulations before the 1962 amendments were enacted, and it issued final rules three months after the new law took effect. These regulations are the broad outlines of the investigational drug regulatory system that remains in effect today.
The former Division of Biologics Standards (DBS), currently the Center for Biological Evaluation and Research (CBER), was involuntarily transferred to the FDA from the Public Health Service in 1973. Its transfer was triggered by the failed Polio vaccine release, on the grounds that old-world style management encumbered it. The DBS was viewed as incapable of protecting the public health because it was too closely involved with the industry it was supposed to regulate (so-called “unholy marriages” between industry and government regulation). This was the same problem that existed with a number of industries and agencies, including the Atomic Energy Commission. The same agency was tasked with both promoting and regulating a given industry. The AEC was partly responsible for radiation exposure experiments on troops in the 1940’s. [AEC regulators actually wore protective suits during experiments while soldiers were completely exposed to the radiation from atomic bomb detonations.]
An important slip occurred between the time of the passage of the Kefauver-Harris Amendments and the time when the Division of Biologics Standards was transferred from the National Institute of Health’s/PHS’s DBS was put under the FDA. The FDA was charged with enforcing the Act and passing regulations to do so – which it did. However, a certain class of drugs, biologics (which includes vaccines and other blood products), were under the auspices of the DBS, which was under the Public Health Service, a different agency. Unfortunately, because of the hodgepodge manner in which agencies had sprung up, the DBS, which saw itself as controlled by the Public Health Service Act and also sought to promote the industry it was regulating, did not necessarily require efficacy data for approval of its products, namely, vaccines. Thus, it was not until some ten years later when the DBS was transferred under the FDA (because of the failed polio vaccine release mentioned above) and became the Center for Biological Evaluation and Research (CBER) that vaccines were truly required to show efficacy data – notwithstanding a law requiring it some ten years earlier.
When CBER finally came under the FDA, all of the previously licensed vaccines that had been given without the required efficacy data would be reviewed and placed into categories. Category I products were considered safe, effective, and not misbranded. Category II products were unsafe, ineffective, or misbranded. Category III products were split into A and B. Category IIIA products had inconclusive data, but the product would remain on the market pending further study and IIIB drugs were data inconclusive, product to be removed from the market. This review would take an incredibly long time and the review of the anthrax vaccine, licensed in 1970 without any efficacy data, would not be done until 1985.
With the creation of so many federal agencies came an increase in the administrative regulations over the industries the agencies were set to watch. The Supreme Court repeatedly deferred to these agencies’ decisions and upheld their regulations. Agencies such as the Equal Employment Opportunity Commission and the Food and Drug Administration (FDA) had increasing roles in their respective areas of concern. As part of the passage of regulations in its area of concern, the Agency first proposes a rule in the federal register for a period of time and invites comment on the proposed rule. The rule is then viewed in practice and left open for comment, then, if necessary, the rule is amended and a final proposed rule is ultimately published. While these regulations do not have the same force and effect as law, if they do not conflict with any preexisting laws and are not inconsistent with the agency’s charter, these rules in effect become law because they are binding upon persons, corporations, or agencies operating in the particular agency’s area of concern.
The rule regarding testing on human subjects passed with little, if any, comment. Who could disagree with the principle that “no investigator may involve a human being as a subject in research . . . unless the investigator has obtained the legally effective informed consent of the subject[.]”[iv] In fact, almost every federal agency adopted the same or similar version of the regulation regarding human subjects and informed consent. This rule was passed by the Department of Health and Human Services (DHHS) in 1981. The full version of the FDA’s regulations are virtually identical to the full DHHS ones. They read that
no investigator may involve a human being as a subject in research covered by these regulations unless the investigator has obtained the legally effective informed consent of the subject or the subject’s legally authorized representative. An investigator shall seek such consent only under circumstances that provide the prospective subject or the representative sufficient opportunity to consider whether or not to participate and that minimize the possibility of coercion or undue influence. The information that is given to the subject or the representative shall be in language understandable to the subject or the representative. No informed consent, whether oral or written, may include any exculpatory language through which the subject or the representative is made to waive or appear to waive any of the subject’s legal rights, or releases or appears to release the investigator, the sponsor, the institution, or its agents from liability for negligence.[v]
Even the Department of Defense adopted regulations with much the same lack of fanfare in 32 C.F.R. 219.116-117. These regulations state, just as above, that “[e]xcept as provided elsewhere in this policy, no investigator may involve a human being as a subject in research covered by this policy unless the investigator has obtained the legally effective informed consent of the subject or the subject’s legally authorized representative.” The 2003 version of the DoD regulations are identical to the FDA’s. Everyone seemed to agree that when it comes to experimenting on human subjects, consent was a prerequisite. As an important corollary, DHHS also published some definitions of what research would be covered by the informed consent requirements. It is an extremely broad definition.
Research means a systematic investigation, including research development, testing and evaluation, designed to develop or contribute to generalizable knowledge. Activities which meet this definition constitute research for purposes of this policy, whether or not they are conducted or supported under a program which is considered research for other purposes . . . Research subject to regulation, and similar terms are intended to encompass those research activities for which a federal department or agency has specific responsibility for regulating as a research activity, (for example, Investigational New Drug requirements administered by the Food and Drug Administration).[vi]
This last “for example” is critical, as it repeats and reinforces the FDA’s requirements that using Investigational New Drugs for the purpose stated in the New Drug Application is research requiring informed consent. This deserves some explanation as it is crucial to understanding one of the reasons why the anthrax program was illegal.
The FDA regulates the manufacturers of drugs through the licensing and regulatory process, but it does not control the end-user of the product – i.e. a doctor, or in this case, the Department of Defense. Vaccines are subject to the requirements of the FDA under the Food, Drug and Cosmetic Act (FDCA, Title 21, Chapter 9) as prescription drugs and the requirements of the Public Health Service Act (42 U.S.C. 262) as a biologic. The two acts are not exclusive, but complimentary. Typically, a manufacturer submits a proposed New Drug Application with the FDA setting forth what “clinical protocol” or experiment it is going to do in order to demonstrate the efficacy of its drug. At the same time, the manufacturer also must comply with FDA regulations for how its manufacturing process takes place. Normally an approved drug must have a dual part license, a PLA (product license amendment) for the drug, and an ELA (establishment license amendment) for the facility. This ensures that the product meets the four necessary prerequisites for licensing: sterility, safety, potency, and efficacy.
The ELA helps ensure that the drug/biologic is sterile in its manufacturing process and potent. The FDA regulates this process in the facility by enforcing CGMPs (Current Good Manufacturing Practices). These practices are industry practices surrounding such procedures as sterility of the filtering systems, handling of the material, and random testing of the finished product to ensure uniformity from batch to batch. Potency is a good measure for quality control and to ensure efficacy of the manufacturer’s claims and proposed advertising. If random samplings of different batches reveal widely differing potency levels, it calls into question the consistency of the manufacturing process (a quality issue) and whether the drug can support the claims of efficacy. FDA inspectors, supposedly experts in the field, go check the facility to ensure compliance.
The PLA sets forth the clinical protocol for the product. This includes what studies and data the manufacturer will use to demonstrate effectiveness. In other words, a company cannot simply claim they made a product cleanly and safely, that covers the ELA – one half of the license – they have to show the product does what it is advertised to do. This PLA will set forth how the product will be used (or has already been used) and the data from those controlled studies. Initially, in most cases, animal studies and basic research will be used to gather data. The company will then submit a New Drug Application (NDA), for completely new drugs, or an Investigational New Drug (IND) application for drugs already licensed that the company is seeking to modify somehow. The PLA, and ultimately license for a drug, is so specific, that any change requires a modification to the existing license. The PLA gives the company an “indication” for using the drug. The “indication” in the license will include the route of administration of the drug (taken by injection or by mouth, for example), the number of shots or pills to be taken (twice daily or once a month?), what form it will be in if necessary (pills, liquid, caplets), dosage (20, 30 or 40 mg, for example), and what exactly the drug is designed to prevent, cure, or ameliorate.
In the typical course of business, the drug will have advanced from the “experimental” stage to the Investigational New Drug (IND) stage, whether it is a new drug or an existing licensed drug, where some animal studies or other data exists indicating the drug’s likely effect. At this point, in order to gain licensure and prove efficacy in human beings, there must be two well-controlled human studies to prove efficacy of the drug. This point cannot be overstated: before a manufacturer can prove efficacy of a drug for its licensed indication, it must have two human studies. This means that no company manufacturing a drug as a pretreatment for chemical warfare can ever get beyond the Investigational stage. As two Army doctors pointed out in an article in 1992,
For products designed to protect against chemical and biological agents, a clear demonstration of efficacy would require exposure to humans to these lethal agents. Since this practice would be unethical and immoral, these products never advanced beyond the investigational stage.[vii]
This requirement proved to be the insuperable obstacle for any DoD contractor trying to make a vaccine as a pretreatment for biological warfare agents – because it would be unethical to test drugs on human beings as pre-treatments for chemical warfare. HOWEVER, if there were an already existing vaccine that could be used as a pretreatment for a chemical or biological agent and it was licensed for some other purpose, the DoD could use that without being subject to FDA regulation, which brings us full circle to the question of whom the FDA regulates.
The FDA requirements above all apply to manufacturers, not the end-user. Thus, as an example, let us suppose that there is a drug we will call PB that is used to block a particular chemical from being produced by the brain in patients with a certain disease, we will name MG. Let us suppose this has been licensed for many years and shows no side-effects on these patients in the dosages they take for 35 years of licensed use. Now, let us suppose that the DoD gains knowledge about a certain nerve agent named SM that, as its mechanism of attack, causes the brain to massively produce the same chemical that our licensed drug, MG, blocks the production of. The agent is usually delivered in bombs in aerosol form. The DoD could, it would appear, buy large quantities of this drug and give it to troops in order to prevent the effects of the nerve agent SM. This use of the drug is considered off-label and investigational. This is because the drug is normally used (and has been licensed) to fight a particular disease, not be a prophylaxis against a nerve agent, and so there is no licensed indication for the drug as a pretreatment as a nerve agent. There is certainly no proof of efficacy for this use. Thus, the manufacturer could certainly not advertise the product as a pretreatment for the hypothetical SM without incurring the regulatory wrath of the FDA, but what about the DoD? The DoD could use the drug in such a fashion, provided it obtained informed consent from the individuals it was giving the drug to. While the FDA would have no way to regulate an end-user relationship normally, the FDA is responsible for monitoring IND applications and clinical trials under an IND application. If the above drug were not licensed fully and the DoD intended to use the drug and track who it was given to and when and how many times and record that in servicemembers record books, that would be research as defined under FDA, DHHS, and even the DoD’s own regulations. Research requires informed consent. Such administration of the product, vaccine or drug, would have to be performed under an IND clinical protocol.
On the eve of the Gulf War, the DoD was up against the regulations requiring informed consent, with the concomitant intelligence and history showing that Saddam Hussein (a) possessed such agents and (b) had previously used chemical (and perhaps biological) weapons on minorities in his own country. The DoD therefore lobbied the FDA for a waiver from the requirements of Rule 50.23(d) of the FDA’s regulations.[viii] This would happen for a number of licensed, investigational, and even experimental products, with servicemembers having no say in the matter.
Endnotes
[i] GAO Report T-NSIAD-99-148 (April 29, 1999)
[ii] Quote from the DHHS website, http://www.hhs.gov/about/profile.html.
[iii] 21 U.S.C. §355(i) (2000)
[iv] 45 C.F.R. 46.116 (2000)
[v] 21 CFR 50.20 (2000)
[vi] 45 CFR 46.12 (2000)
[vii] Col. Garland E. McCarty and Lt. Col. Gregory P. Berezuk, Military Medicine, Vol. 157, p. 404 (August 1992)
[viii] 21 CFR 50.23(d) (1990)
