The information in the following pages should be  

seen by all the department's scientists.

Please  distribute.

IF YOU USE ANTIBODIES, YOU SHOULD READ THIS BULLETIN

Electronic Posting Courtesy of  BIOALERT NEWS APRIL, 1995

THE FDA ABOUT TO CONTROL ANTIBODIES

The cooking.net">food and Drug Administration, FDA, is nearing its plans to implement a new antibody classification ruling which will designate numerous antibodies as Class II Medical Devices.  Many believe that this new regulatory action will have major repercussions in nearly every branch of biological and medical research. The FDA has started with the regulation of antibodies used for immunohistochemistry, but there are good indications to believe that this will expand to cover Flow Cytometry, Hematology, Cytology and even Molecular Biology including DNA/RNA probes.

The classification of primary antibodies as Class II Medical Devices  was the result of a reclassification petition by the College of American Pathologists (CAP). The meeting of the Hematology and Pathology Devices Panel, was held in Gaithersburg, MD, on October 21, 1994.  According to previous FDA rules, these antibodies by default were placed in Class III status. However, this was more a provisional status than a real Device classification, and consequently never enforced.

During the Classification Panel meeting the CAP group corroborated their support  for Class II as they had previously petitioned. At least five other groups including  a dissident group of  Immunopathologists within CAP itself, took a position contrary to that of CAP and supported Class I designation.  The Joint Council of Immunohistochemistry Manufacturers (JCIM), representing the manufacturers, also supported Class I designation. The JCIM position was also supported by The Health Industry Manufacturers Association (HIMA), the largest association of the health industry with a membership in excess of 700 health care companies.
At the end of the meeting, the official group of CAP obtained a victory, and all primary antibodies having clinical application for Immunohistochemistry were recommended to become Class II Medical Devices. No provisions were made to permit the availability of these antibodies for research use.

The  Panel Classification Meeting of October 21, 1994, was conducted in an unconventional manner.  Apparently, during the course of the meeting, the opinions of the delegates of JCIM were suppressed to the extreme that their position paper was not distributed to the Panel members.  Furthermore, the manufacturers presentation was kept under strict time control and the manufacturers were not allowed to respond to the arguments of CAP. In contrast, the CAP representation, advocating  in favor of Class II, were given unlimited  time for delivering their position and for general discussions.
This oppressive manner of conducting the meeting as well as several other irregularities of the meeting, prompted the filing of a complaint to the FDA by the  Washington law firm of Hyman, Phelps & McNamara, P.C,. on behalf of the oppressed parties. Attorney Jeffrey Gibbs, in his complaint filed with the FDA on January 9, 1995, lists the irregularities, and cites the rules violated during the meeting. The complaint reveals that the FDA officers present during the meeting did not clarify to the members of CAP and the Panel members that the requirements of safety and special controls they were pursuing to
accomplish by obtaining Class II could have been implemented even if the antibodies were designated Class I. Essentially, The College of American Pathologists and the Panel members  were misled by the FDA into believing that their goals were only possible if Class II was designated.

In the complaint, Mr. Gibbs requested that the recommendations of the Panel Meeting  be invalidated, the meeting be rescheduled, or  the antibodies be classified as Class I.  As of  April 10, 1995, three months after receiving the complaint, the FDA has not officially responded.

The significance of the outcome of this regulatory petition spearheaded by the College of American Pathologists is that, if designated as Class II Medical Devices, an extensive list of antibodies both polyclonal as well as monoclonal, including CD markers, will be subjected to an expensive process of Class II Medical Device approval.

The manufacturers as well as distributors of these antibodies argue that the approval cost of these antibodies will most likely be  $20,000 to $30,000 per antibody. They believe that approximately 90% of these antibodies do not produce sufficient sales to justify an expenditure at such level. It is thus believed that many of these antibodies will be removed from availability in the U.S. In addition, all manufacturers and many pathologists assert that these antibodies, when used for immunohistochemistry, are of low-risk to the public and should not merit the strict regulatory environment of Class II Medical Devices.

Upon closer examination of the products classified as Class II Medical Devices used in clinical laboratories, we find a major difference in the scope of regulation applied to antibodies and their auxiliary products used for immunohistochemistry.

In the case of devices for clinical labs, the complete device is the center of the regulatory action. For example, a kit like Hybritech's PSA is classified as a device. This does not designate any antibody to PSA, monoclonal or polyclonal, as a  Medical Device.  It is the complete kit (the defined device) which is licensed under the approval process. Therefore, the antibody by itself is not the device. Consequently, antibodies to PSA can be made and sold as antibodies without being an infraction to the previous FDA regulations.  Under the new ruling, however, it is different because it  targets  the antibodies
themselves and gives no provision for the supply of the antibodies outside of the ruling.  Under these new regulations, since the PSA antibody has clinical significance for immunohistochemistry, it becomes itself a Medical Device. Similarly, many other antibodies will be under the same set of rules.

In the last two versions of the Points to Consider, a document published by the FDA as a guide to the requirements of this ruling, they have unexpectedly included all auxiliary reagents used in immunohistochemistry as Class II Medical Devices.  This was unanticipated since there was no mention or discussion on this subject during the Panel Meeting held on October 21, 1994. Since the classification Panel never ruled on the auxiliary reagents, it is not understood their sudden appearance in the Points to Consider documents.  The improprieties of this inclusion may be a separate issue but the significance of this
addition goes beyond anything expected. These auxiliary reagents usually contain secondary antibodies labeled with either biotin, peroxidase, alkaline phosphatase as well as conjugates of avidin or streptavidin also conjugated to these tracers, and chromogenic substrates of these enzymes.  
This ruling designates all of these as Class II Medical Devices. This remains an unassembled puzzle for the manufacturers and many observers.

Overall, the number of antibodies which may be added to this list could be considerable.  It will surely include most of the CD antibodies available today as well as antibodies to tumor markers, infectious agents, and practically any antibody of general importance.  This appears to be a heavy regulatory weight over a broad range of products that are needed for general research by the U.S. scientific community.

Both manufacturers as well as many users fear that this will curtail research in the US and place the US scientist at a disadvantage in relation to their european and asian colleagues. Some independent pathologists are disheartened with the idea of increased regulation and fear that the prices of the antibodies will increase considerably. In the midst of this, the prevailing official position of the College of American Pathologists continues to support their original request for these antibodies to be Class II Medical Devices.

Altogether, the scope of this new set of rulings led by what appears to be a misled group of pathologists, is a difficult matter to assess. The detrimental effect it may have on research could be substantial and at this point it is difficult to predict if the gains of this new move will produce benefits commensurate to the loses inflicted to research and indirectly to healthcare. In the mind of many it is difficult to answer, with certainty, the lingering questions: Is this necessary? Is this really protecting the American public? Will the net result of these new antibody regulations be beneficial or detrimental to US healthcare?  If the scientific community does not voice their objections effectively the FDA will continue in their pursuit of controlling biologicals.

Whether or not the scientific community will accept the future limitations imposed on their work by the combined efforts and ensuing victory of the College of American Pathologists and the FDA, remains to be seen.

Ti H. Sllubon

The text of this document  is not copyrighted. Feel free to copy and distribute.

Please, help in the distribution of this information. Scientists should be aware of this pending problem.  
If you have a computer with telecommunication capabilities, download this document and post it to any Life Sciences
newsgroups including Medicine.  Post under the heading:  IF YOU USE ANTIBODIES, READ THIS.....
If you get a hardcopy of this document circulate to all scientific staff at your institution.