A Long Road: 25 Years of Clinical Research

Originally Published MDDI August 2004

Clinical Research



Part 812 in 1980 recognized the need for clinical research laws for medical devices. Many revisions later, the industry's clinical trials practices came into their own.

Nancy J. Stark

I took my first job as a clinical research associate in May of 1980. I had never heard of clinical research, but I was a new graduate in biochemistry and I needed a job, so I agreed to work in the field. My boss warned me: “This will not be research as you know it in the laboratory.” 

In January of that year, something monumental had happened in the medical device industry. The Investigational Device Exemptions, 21 CFR Part 812, had been published. Clinical research in the device industry had come into its own.¹ The regulation became effective on July 18, 1980; I remember the date well because our regulatory affairs manager brought in a birthday cake to celebrate. The cake said, “Happy Birthday Part 812.”

I immediately fell in love with my new career. Clinical research is the perfect marriage of scientific investigation and human interaction. The best clinical research associates have both solid technical skills and an understanding of human nature.

Origins 

Drug manufacture had been regulated since the inception of the Food and Drugs Act of 1906, which prohibited interstate commerce of pharmaceuticals that were misbranded or adulterated.² But the clinical investigation of drugs wasn't regulated until 1963. FDA didn't want to regulate clinical research; it was a political hot potato. But if you remember the 1960s like I do, it was the era of civil rights, and the nation had suffered through the Tuskegee project, thalidomide investigations, and plutonium injections. For an excellent historical review of human subjects research in the United States, see the Department of Energy's October 1995 report from the Advisory Committee on Human Radiation Experiments. The report is available on the Internet at http://tis.eh.doe.gov/ohre/roadmap/achre/index.html. 

The sixties were an exciting, revolutionary, turbulent time of great social and technological change: assassination, unforgettable fashion, new musical styles, Camelot, civil rights, gay and women's liberation, a controversial and divisive war in Vietnam, the first manned landing on the moon, peace marches, flower power, great TV and film, and sexual freedom. America was in no mood for more unregulated human experimentation.

In this social climate, though, the regulations, 21 CFR Part 130—New Drugs, were published on January 8, 1963.³ But the medical device industry barely existed in 1963, and neither devices nor device clinical research were included.

Medical Device Amendments—1976

The Food, Drug, and Cosmetic Act wasn't amended until 1976 to include medical devices. I just so happen to have a copy of the 1976 law on my bookshelf. The whole of Chapter V, “Drugs and Devices,” is only 82 pages long, and the only mention of clinical research is under the description of Class III devices, the effectiveness of which “may be determined…on the basis of well-controlled investigations, including clinical investigations where appropriate, by experts qualified by training and experience to evaluate the effectiveness of the device….”⁴ The act spoke about clinical research as a sideshow or an afterthought, rather than a major step in the device development process.

Part 812—Investigational Device Exemptions

It wasn't until 1980 that medical devices got their own regulations for clinical research: the Investigational Device Exemptions, or IDEs, were published on January 18 of that year. We were all confused about what exactly it was that investigational devices were exempt from (all the other device regulations). The basic format consisted of seven major subparts: A) General Provisions, B) Application and Administrative Action, C) Responsibilities of Sponsors, D) IRB Review and Approval, E) Responsibilities of Investigators, F) Informed Consent (this subpart is now Reserved), and G) Records and Reports. 

As with all regulations, the preamble is as important as the regulation itself. Even today, I refer clients who test consumer products on their employees to question 42 on page 3470: “One comment argued that ‘institution' should not include a manufacturer because a manufacturer should not be required to create an in-house IRB.” FDA disagreed, stating, “A manufacturer must be subject to the requirements of institutional review if an investigation is carried out on the manufacturer's premises, for example, using employees as subjects of the investigation. Employees are entitled to the same protections, including IRB review, as other subjects.”⁵ Table I compares the regulation from 1980 to 2004.⁶

By my count, Part 812 has been amended on 22 separate occasions, as shown in the timeline in Figure 1. Each date may represent the revision of several paragraphs, and there have been more than 50 separate revisions to specific paragraphs. The revisions typically come in clusters. Here's a broad look at some of the most important ones.

May 30, 1980: Subpart F—Informed Consent Removed. The first major revision of Part 812 took place only five months after it was published. Subpart F—Informed Consent was removed and replaced with Part 50—Protection of Human Subjects. Publishing separate regulations for informed consent allowed FDA to have a common rule for devices, drugs, and other products regulated at the time. 

Many times, what is missing is more interesting than what is present. For example, in 1980, subjects were required to sign an informed-consent form, but not to date their signature. The requirement for signing and dating the consent form didn't appear until 1996.7 In another example, I was surprised to learn recently that Part 812 doesn't actually require an investigator to sign an informed-consent form, except in the case of obtaining oral consent from a subject.

January 27, 1981: 13 Revisions. In January 1981, FDA made 13 separate revisions to Part 812. Many of them had to do with institutional review boards (IRBs). 

812.42—FDA and IRB Approval Added. The relationship between significant- and non-significant-risk devices to full and abbreviated IDEs was (and remains) a source of continuing confusion. Significant-risk devices require full IDEs; non-significant-risk devices require only abbreviated IDEs. Section 812.42 clarified that both FDA and IRB approval were required for full IDE applications and supplements. We knew from other sources that non-significant-risk devices needed approval only from an IRB, which acts as an agent for FDA.

There are many other differences between full and abbreviated IDE requirements. For example, no protocol is required for abbreviated IDEs. Admittedly, it's impractical to get IRB approval without a protocol, but it would be helpful if the regulations were consistent with good clinical practices. 

812.65—Responsibilities and Procedures [of IRBs] Deleted. In another revision, Section 812.65 describing the responsibilities and procedures of IRBs was removed and replaced with Part 56—Institutional Review Boards. As with informed consent, publishing separate regulations for IRBs allowed FDA to have a common regulation for devices, drugs, and other products regulated at the time. 

812.66—Significant-Risk Determinations Added. Another major revision took place in 1981 with the addition of section 812.66. In this paragraph, FDA clarified that IRBs have responsibility for determining whether devices are significant risk. Other regulations tell us that the sponsor must make a contention (argument) to the IRB regarding the risk status of the device, but between the two of them, the IRB holds trump. 

April 26, 1985: 812.20—Application. Prior to 1985, the process for obtaining a full IDE for a significant-risk device was to submit an application to FDA, obtain its approval, and then submit the protocol to a local IRB for review (“…a sponsor shall not submit an investigation plan…to an IRB …before submitting an application to FDA…”). With the changes to the application process in 1985, FDA allowed more flexibility to the process. Now sponsors had a choice. They could submit a protocol to an IRB or to FDA first. If the IRB determined the device was significant risk, it was to notify the sponsor (through the investigator), who would then apply to FDA. This simple procedural change transferred much responsibility to the IRBs.

April 6, 1988: 812.20—Application [Environment Assessment]. Part 812.20 (9) was—happily—revised in 1988 to no longer require IDE applications to contain an environmental analysis report per Part 25. Now a sponsor could claim for categorical exclusion.
October 2, 1996: 812.47—Emergency Research and 812.38—Confidentiality. A significant provision was added to Part 812 in 1996, allowing for emergency research, i.e., allowing for research on persons who were medically unable to give informed consent. For the first time, there was a legal way to conduct research on trauma patients, comatose patients, Alzheimer's patients, car accident victims, or other patients who could not comprehend or give consent to participate in research. Before this time, such research could not be done legally in the United States. The provisions were intended to open up possibilities for important kinds of new product development. I remember they created such a sensation that newsletter editors would phone me, asking for interviews on the topic.

Concomitantly, Part 812.38 was modified to allow for public disclosure of information from IDE applications for emergency research. If you're interested in the information, you need only ask under the Freedom of Information Act. 

October 7, 1996: 812.1—Scope. The scope of Part 812 was changed in 1996 in a significant way: investigational devices became subject to Part 820.30—Design Controls. Never before had documentation of the design history or traceability of an investigational device been required, and the shift in policy served to finally bring the act of investigating a device into the product development process. Looked at from the manufacturing standpoint, a clinical study was now viewed as simply one more tool in the company's arsenal to verify and validate a design. In more than one corporate executive's eye, this change brought clinical research into the product development fold.

November 5, 1996: 812.140—Records. The records section was revised in 1996 with expanded definitions and requirements of investigators to keep records of each subject's case history. The definition of case history remains elusive: we know it includes case report forms, medical records, signed and dated consent forms, hospital charts, nurses' notes, and other documents; but what it includes and what it means are not the same thing. The issue matters because it is common for investigators to be cited for inadequate case histories.

March 14, 1997: 812.119—Disqualification of a Clinical Investigator. The clause regarding disqualification of clinical investigators was added in 1997. It placed a powerful tool at the sponsor's disposal for bringing recalcitrant investigators into compliance. For the first time, investigators who caused or attempted to cause false information to be submitted to FDA could be disqualified from participating in future clinical research. The disqualification list, affectionately known as “The Blacklist,” is published on the Internet. I have persuaded several investigators to cooperate with monitors by simply showing them the list.⁷

September 18, 1997: 812.36—Treatment Use of an Investigational Device. In 1997 came the addition of the treatment use provisions of Part 812. These provisions facilitated the availability of promising new devices to desperately ill patients as early as possible in the device development process and before general marketing. New devices for life-threatening conditions could be made available immediately after, or even during, clinical trials. 

February 2, 1998: 812.43, 812.110, 812.140—Financial Disclosure Provisions. The financial disclosure provisions were added to the regulations in 1998. These provisions tied Part 812 to Part 54 and required that trial sponsors disclose to FDA any equity interest in the device held by investigators, subinvestigators, spouses, or dependent children. At issue, of course, is that basic human tendency to bias our interpretation of events when there is a personal benefit at stake. 

November 23, 1998: 812.35—Supplemental Applications. Extensive additions were made to the clause addressing supplemental applications in 1998, delineating those types of changes to an investigational plan that required prior FDA approval, those types that could be made without prior approval but should be followed by a report within five days, and administrative changes that could be reported in an annual report. The provisions gave sponsors the flexibility to be managed “by exception,” i.e., to obtain prior approval or report promptly those changes to an investigational plan that had significant effects on patient safety or data integrity, but to refrain from cluttering up the reporting stream with minor events. 

Along the Way

Other major events have evolved more slowly, but should be mentioned here. Ethical mores have changed, too. The role of women of reproductive age, children, prisoners, and other vulnerable populations has taken a different place. Today, vulnerable populations are thought to have a right to participate in clinical research as much as others do. While the pregnancy of women must be established at the start of a study, pregnant women are not automatically excluded from clinical research. Prisoners have the right to participate in research on life-threatening illnesses, such as AIDS or hepatitis, for which there is no known treatment.

Regulators have joined together in global efforts to harmonize good clinical practices. ISO 14155, “Clinical Investigations of Medical Devices,” is an evolving global standard that sets the tone for conduct of clinical research in Europe. Data gathered under these standards are accepted by FDA.

The Global Harmonization Task Force, consisting of regulatory and industry representatives from the United States, Europe, and Japan, is establishing a new study group that will look at the requirements for clinical data to support medical device submissions. The goal is to harmonize the need for clinical research itself and to help ensure that all countries require the same quantity and quality of data.

A Slow Start

My corporate career lasted for about 10 years, first working for a big company, and then a small one.⁸ In 1990, I left corporate life to start Clinical Design Group. I thought the world needed a consultant in the clinical research field. But clinical research was so unimportant in the industry's mind in 1990 that I supported myself as a biocompatibility consultant. It would be 5 years before I won my first contract in clinical research. 

It wasn't only the industry that thought clinical research was unimportant, but the industry's most prominent trade journal as well. It shall remain unnamed, but I am compelled to say that it lost the first two clinical research manuscripts I sent them.

Today, clinical research is unimportant if you don't need to do it, and critically important if you do. Averaging between $100,000 and $1 million for a single trial, no one who needs clinical evidence to support an argument of safety, efficacy, or substantial equivalence can afford to take the subject lightly.

References

1.Federal Register, 45:13, 3732–3759, January 18, 1980. 
2.“Milestones in U.S. Food and Drug Law History,” [on-line] Available from the Internet: www.fda.gov/opacom/backgrounders/miles.html.   
3.Federal Register, 179, January 8, 1963.
4.Food, Drug, and Cosmetic Act of October 1976, Section 513 (3)(A).
5.Federal Register 45:13, 3740, January 18, 1980. 
6.Code of Federal Regulations 50.27 (a). 
7.“Disqualified/Restricted/Assurances Lists for Clinical Investigators;” [on-line] Available from the Internet: www.fda.gov/ora/compliance_ref/bimo/dis_res_assur.htm. 
8.3M Co. (St. Paul, MN), then Hollister Inc. (Libertyville, IL).   

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