WASHINGTON - About 40 drug manufacturers, including a numberof biotech firms, have told the FDA that its proposed adverseexperience reporting regulations would add considerable time andcost to drug development and may not accomplish the intendedpurpose.

In comments submitted to the agency, the companies lodged anumber of criticisms about the regulations' fundamental design andreporting effort demanded of manufacturers. In addition, one largeteaching hospital that operates clinical trials questioned the reasoningbehind the regulations.

How the agency responds to these criticisms and incorporates any ofindustry's criticisms in the final regulations is pivotal. Officials fromFDA's Center for Biologics Evaluation and Research (CBER) willhost a satellite video conference today to explain how the final ruleswill be implemented.

The adverse experience reporting regulations, proposed by the FDAon Oct. 27, 1994, attempt to reduce inconsistencies in reportingrequirements between CBER and the Center for Drug Evaluation andResearch (CDER) as well as international protocols. But theregulations were primarily a response to unexpected deathsassociated with drug toxicity during a clinical trial. (See BioWorldToday, Oct. 28, 1994, p. 1.)

Several manufacturers quantified what they viewed as unnecessaryreporting requirements. Amgen Inc., of Thousand Oaks, Calif.,estimated that the new paperwork requirements would require"changes in procedure, development of new software and training ofboth new and old personnel" to comply with the regulations. Amgenfound the requirements so formidable that it asked the agency for asix-month extension so that the company could prepare for theenforcement.

DuPont Merck Pharmaceutical Co. estimated that its reportingburden would double. "By generating volumes of extra paperworkand diverting valuable human resources, the new rule could actuallyimpede rather than enhance FDA and industry sensitivity to detectpotential drug toxicity," according to comments submitted by JamieWarner, manager of regulatory affairs for DuPont Merck inWilmington, Del.

In 1994, DuPont Merck submitted 179 periodic new drug applicationsafety reports, either annually or quarterly, for 170 products and 104annual investigational new drug applications, producing a total of283 periodic safety reports. If the FDA implements the regulations asproposed, DuPont Merck estimated it would have to produce over660 periodic safety reports including 104 annual reports and over 560semiannual reports.

Amgen's comments about clinical study design are illustrative ofseveral manufacturers' criticisms of the regulations which they see asill-advised.

Sherri Brown, Amgen's senior safety officer, detailed the difficultyinvolved in providing estimates of the expected incidence of deathand serious adverse events in the study populations under review thatarise from underlying disease or concomitant medications.

"To make these estimates at all accurate or meaningful, a separateepidemiological study in the patient population and treatment settingunder review would be required," she stated.

Before Amgen opened clinical trials of Neupogen, a recombinantgranulocyte colony-stimulating factor, it reviewed relevant clinicalliterature about known morbidity associated with chemotherapy. Butthe company could not quantify true incidences until the clinical trialprogressed, Brown said.

Brown told the agency that Amgen is concerned that the regulationsstipulate that exceeding these estimates of morbidity "would lead tothe presumption that the events are associated with the use of thedrug until the sponsor is able to refute this assumption withappropriate data and evaluations.

"Since these estimates are likely to be inaccurate, helpful informationwill not be generated by comparing them to observed incidences,"Brown said.

Brown said she hoped the agency would permit each manufacturer todevelop specific monitoring plans prior to the initiation of clinicaltrials. Amgen said it expects the FDA to permit the sponsor toprovide the method of determining incidence rates and define thelevel that exceeds predicted rates.

The director of The Johns Hopkins University Center for ClinicalTrials, found considerable fault with the regulations' reliance oninstitutional review boards (IRB) to effectively monitor clinical trials."IRBs are ill-equipped to deal with isolated reports of adverse events,especially on the global scale," Curtis Meinert, professor ofmedicine, told the agency.

The proposed regulations "have the effect of requiring IRBs toreview safety reports in clinical trials under protocols never seen bythem. There will be little they can do other than to acknowledgereceipt of such reports."

"The impact of the changes will be to make individual IRBs into dataand safety monitoring committees. Data monitoring committees, evenwhen they have the proper statistical expertise, have difficultyinterpreting isolated events, absent denominator data and appropriatecomparison groups. There is no reason to believe IRBs will do aswell given their general charge and composition," Meinert stated.

Meinert estimated that the changes would increase the cost of theaverage clinical trial by $24 million. "That figure might be viewed asa small cost to pay if the changes were to result in reduced risks," hestated.

But Meinert said that was unlikely because the regulations have the"effect of removing investigator judgment from the reporting processand will, in the case of trials involving sick people, increase paperflow to IRBs by orders of magnitude." n

-- Michele L. Robinson Washington Editor

(c) 1997 American Health Consultants. All rights reserved.