Of the many steps it takes to get a medical device or new drug to market, the clinical trial is perhaps the most critical.
Drug and device makers have a lot riding on such trials, which can often take several years and millions of dollars to complete.
Clinical trials can make or break a company.
Sicor Inc., which was based in Irvine and is now part of Israel’s Teva Pharmaceutical Industries Ltd., was forced to reorient itself from a biotechnology company to a generic drug maker in 1994 when its Protara cardiovascular drug failed a clinical trial.
Larger device and drug makers usually are able to withstand some trial setbacks or delays because they have larger, broader product pipelines.
Earlier this decade, Edwards Lifesciences Corp., an Irvine heart valve maker, raised mild concerns when it voluntarily halted a feasibility trial for its less-invasive heart valve in 2005 after the death of at least one patient.
Edwards then worked with the Food and Drug Administration, which regulates domestic clinical trials, to develop an easier insertion procedure and restarted that feasibility trial.
Results from that trial led to a large, closely watched clinical trial for Edwards’ less invasive Sapien heart valve that’s been going on for roughly a year. Edwards expects to continue the study through the third quarter of 2009, the company said in an e-mail.
Allergan Inc., an Irvine-based maker of Botox and other drugs, stopped a trial for memantine, a pill to treat glaucoma, at the beginning of this year after a third-phase study showed no significant benefits versus a placebo.
After learning that a trial to check if memantine restored the function of damaged nerves would take five years, “given that we had other opportunities, it didn’t make sense” to continue, said Scott Whitcup, Allergan’s executive vice president of research and development.
Shortly after the company abandoned the trials, Allergan Chief Executive David Pyott compared mem-antine’s development “to drilling a 20,000-foot-deep hole in the seabed and discovering that there’s no oil there.”
Trial Phases
Trials begin with what’s called “pre-clinical” work.
On the pre-clinical side, Spectrum Pharmaceuticals Inc., an Irvine drug developer, has done work on animals, including mice, dogs and rhesus monkeys. The company also has used pig hearts, which are similar to human hearts, for cardiology drug testing.
“We want to get a species that is closer to man, and the larger the animal, the closer they are to man,” said Rajesh Shrotriya, chief executive of Spectrum, which began selling Fusilev, its first branded cancer drug, last month.
After the pre-clinical work is done, a drug or device maker moves to a first-phase trial. During first-phase trials, a drug candidate is given in a very small dose to a healthy human subject and various tests are done, including X-rays, blood testing and EKGs, to establish safety.
There are some exceptions: Spectrum, which is an oncology-focused company, does all of its trials on cancer patients. That’s because cancer drugs are often carcinogenic themselves, Shrotriya said, and would be dangerous to test on healthy people.
Second-phase trials are generally larger, featuring 100 to 400 patients.
“Those tend to be in patients with the disease you’re trying to treat,” Whitcup said.
Goals in second-phase trials also include finding optimal dosages and what Whitcup called a “proof of concept.”
“You’re trying to determine if the drug is safe and effective and what are the best endpoints to measure, to demonstrate efficacy and the right patients to include in the third-stage clinical trial,” Whitcup said.
If second-phase results are satisfactory, the drug or device moves to third-phase trials, which Whitcup called the “confirm” part of the process.
Pharmaceutical third-stage trials are often large, taking in as many as 1,000 patients, and companies generally run a pair of third-stage studies. Such trials are the last ones done prior to submitting a request for approval to the FDA or a foreign regulatory body if the drug is going to be marketed outside the U.S.
“For most drugs, you see multiple trials, usually four to five at a minimum for a brand-new drug,” Whitcup said.
Clinical Teams
When conducting a trial, companies can either do it in-house or bring in outsiders, such as consultants or contract research organizations. Contract research organizations are companies that drug and device makers bring in to perform various tasks.
“We’ve elected to do most of our studies, I’d say, well over 90%, with internal people,” said Nick Tarantino, vice president of global clinical research and development for Advanced Medical Optics Inc., a Santa Ana-based maker of eye devices and contact lens solutions. “We feel that we probably get just a little more value” with our own people, he said.
Spectrum also prefers handling clinical trials with its own internal team.
“If I hired a consultant to do our trial, first of all, I’ll have to educate this consultant (on) what my drug is,” Shrotriya said.
Keeping a trial in-house, according to Shrotriya, is a time and money saver.
“For big companies, they are OK. We just can’t afford to give over any work,” Shrotriya said.
Allergan, which is much larger than Spectrum, uses consultants and clinical re-search organizations, particularly for first-phase trials.
Whitcup said, however, that Allergan wants to make sure it has “a lot of expertise” internally when it comes to trials.
Edwards has an internal clinical research group and contracts with outside consultants as needed, the device maker’s spokesperson said.
Clinical trials aren’t cheap, although prices do vary among drug and device makers.
“It costs a lot,” Shrotriya said, giving a general price range of $5,000 to $60,000 per patient, depending on the trial’s complexity.
Whitcup said a large third-phase clinical trial with 2,000 patients enrolled could cost up to $40 million for certain diseases.
Clinical trial costs are part of a company’s research and development expenses.
Advanced Medical said its trial costs are on the low end of the spectrum; Tarantino said the device maker may run a small pilot trial with few patients at one or two sites that may cost some $25,000.
“And then, we’ll do various other stages. Then, the final stage, which is for registration, could be as high as $2.5 million total. The average is probably somewhere around $1 million,” Tarantino said.
Advanced Medical’s clinical trials generally are smaller. Tarantino, an optometrist, said that from a regulatory point of view, the company only needs to demonstrate results from its devices in somewhere around 300 subjects.
Drug and device companies, as well as the investigating doctors and facilities, generally carry malpractice and liability insurance in case things go wrong, although clinical trial participants sign waivers that are designed to release liability.
Advanced Medical also has supplemental insurance for clinical trial sites outside the U.S., Tarantino said.
“We live in a very litigious society,” Shrotriya said. “Everybody (carries insurance). There’s an overkill of insurance.”
Spectrum has several clinical trials under way. They include later-stage trials for EOquin, which treats bladder cancer, and SPI-1620, which is being studied for breast cancer treatment.
Clinical trials are conducted in a highly regulated environment, particularly in the U.S.
“I would say the conduct of clinical trials for the registration of new drugs is probably one of the most regulated areas, period,” Whitcup said.
The FDA has rules covering a variety of topics when it comes to new drugs. Whitcup said those included rules covering patient enrollment, endpoints, measuring endpoints, data collection, data analysis and how the data’s put together in the submission.
Allergan mainly deals with FDA officials at the agency’s operation in suburban Washington, D.C., rather than its Irvine operation, when it comes to operating its clinical trials. The company does deal with the Irvine branch, mainly when it comes to audits, Whitcup said.
When it comes to setting up a good trial, experts say that how it is designed and establishes a product’s validity is key.
“I’m a strong believer that subtleties in the design of your trial are the difference between getting a drug improved and a drug failing,” Whitcup said.
Well-designed and conducted trials, Whitcup said, “have a lot of pieces.” Those include having good science, understanding the disease, understanding participating investigators and statistical analysis.
Edwards said it felt that its partnership with doctors and clinical teams at top academic research centers that frequently engage in investigational device studies is “very important, as is ready access to the study’s desired patient population.”
Pitfalls, Safeguards
On the other hand, there are also some pitfalls to avoid.
For instance, bias in terms of how a study is conducted and how data is generated is an “anathema” to the process, according to Tarantino. To minimize any chance for bias, Advanced Medical sets up its studies with masking and randomization.
Drug and device makers also have built in safeguards for their trials.
For instance, companies work with institutional review boards that outline and enforce processes designed to protect patients, including screening criteria, patient evaluation and monitoring and follow-up testing.
Patients, before participating in trials, generally have to sign forms, including disclosure about the drug candidates’ experimental nature. It’s called “informed consent.”
Edwards called this disclosure “critical to patient protection.”
Drug and device makers also work with independent ethics committees to monitor clinical trials.
In addition, Allergan’s Whitcup said one safeguard specific to his company is that its drugs are generally delivered locally, whether through an eye drop, an implant or even Botox, which is injected into a specific area, thus minimizing systemic exposure for participants.
If something does go wrong, a drug or device maker is required to let the FDA know immediately in case of what’s considered a “serious adverse event,” such as the death of a trial participant.
Medical device and drug makers are also conscious of the international markets. In fact, most devices are first sold overseas before they are taken to the U.S. market.
Whitcup characterized the differences between how trials are done in other areas of the world as subtle.
For example, European regulators favor trials where a new drug goes against an existing approved therapy, Whitcup said.
“In the U.S., they are more accepting of a placebo-controlled study,” he said.
When it comes to Japan, “one difference is that they want a fairly sizable exposure to patients of Japanese ancestry. They want to know that your drug is specifically effective in Japanese patients,” Whitcup said.
But Tarantino said that the FDA is interested in seeing how a medical device works across patients from a cross-section of races and geographies.
