Design Management of Trials Crucial in Bringing Drugs to Market

MCLEAN, Va--The way clinical trials are planned and conductedoften means the difference between success and failure in winningFDA marketing approval for a drug or medical device, industryleaders said at a conference sponsored by the Cambridge HealthtechInstitute, Waltham, Mass.

Sheila Linder, MD, vice director, international clinical qualityassurance, Hoffmann-La Roche, Ltd., told the audience that mostmodern drug development programs are international in nature."A global clinical research team responsible for producinga major NDA within tight deadlines must efficiently make crucialdecisions based on project rationale and target profile,"she said.

Richard Ginsberg, MD, vice president for clinical trials, RocheLaboratory Corporation of America, Inc., noted that in 1962 anamendment to the Food and Drug Act was passed requiring "substantialevidence" of a drug's safety and efficacy for approval.

Since then, he said, the uncertainty and complexity of the clinicaltrials required to provide that evidence have increased, as havethe resources and time required to bring a drug to market (anaverage of $287 million and 14 years from laboratory synthesisto the pharmacy shelf).

The number of patients needed to accomplish this has also increasedmarkedly, and the return on a company's research investment hasdecreased because of shortened patent life.

These factors, combined with internal corporate factors such asuncertain leadership, poor intra- and extramural communications,and tightening deadlines, make it ever more important to see thatclinical trials are minutely managed at every step, Dr. Ginsbergsaid.

Small Biotech Companies

These problems are compounded for small biotechnology companies,said Robert C. Moen, MD, PhD, vice president for clinical developmentfor Genetic Sciences, Inc., Menlo Park, Calif, "because theyare always cash starved."

Such companies generally operate on a shoestring (less than a6 month cash reserve) and, as a result, are forced to concentrateon short-term strategies.

"They leap from one fundable milestone to another (a marketableidea, a pending patent, a proof of principle, an IND submission),"Dr. Moen said, and they have such a small pipeline that if onlyone project does not fare well, the company itself may fail. Forthese companies, he noted, planning of clinical trials is especiallycritical to avoid wasted time and money.

Small companies usually concentrate their efforts on efficacyor proof-of-principle studies to provide the means to raise money,he said. Only later are other pre-clinical study needs considered.

But Dr. Moen pointed out that this strategy may have a possibleadvantage. The company can piggyback preclin-ical toxicology andpharmacokinetics onto proof-of-principle studies. "The minimalincrease in time and resources required to simultaneously considerefficacy as well as these other regulatory needs can result insubstantial long-term savings in terms of cost and time."

Efficacy vs Effectiveness

Robert Epstein, MD, vice president for outcomes and performanceassessment, Merck & Co., talked about the difference betweenefficacy and effectiveness, which is, he said, in essence thedifference between a clinical trial and the "real world."

An efficacious treatment does more good than harm among thosewho receive it. An effective treatment does more good than harmin those to whom it is offered, he said. This seemingly minorsemantic distinction can mean the difference between a drug thatis ultimately successful and one that does not fulfill its sponsor'shopes: Efficacy is a regulatory question: can a drug work? Effectivenessis a question of the marketplace: does it work in the real world?

A clinical trial measures efficacy because virtually all the patientsactually receive the drug, at a carefully controlled dose; theyare monitored assiduously; and both the structure and processof care are rigidly controlled.

A drug given "out there" in the general population mayor may not be as effective as expected because of a number ofvariables, he said.

The drug may not be taken at the maximum effective dose becauseeither the patient cannot afford to pay for it or cannot toleratethe dose; it may be given in combination with other drugs; physiciansmay not know how to titrate the most clinically effective dose;the patient may not be completely compliant with the treatmentregimen; and tests to monitor the drug's efficacy may not be performedfor financial or other reasons.

Moreover, Dr. Epstein said, people who participate in clinicaltrials are not necessarily representative of the general population.They may be sicker and more highly motivated to continue an onerousand/or painful course of treatment, and they usually have morecomplete information about the drug.