Patricia F. Fitzpatrick Dimond Ph.D. Technical Editor of Clinical OMICs President of BioInsight Communications

Government funding, once the norm, is declining and pharma firms are in the driver’s seat.

On December 3, the Office of Health Economics (OHE) announced that it had released its comprehensive study assessing the cost of R&D for new medicines. In its review of research published over the last 30 years, the report describes an increase in costs, in 2011 prices, from $199 million per new medicine in the 1970s to $1.9 billion in the 2000s.

Causes for the increasing cost of drug development, according to the OHE report, include increases in out-of-pocket expenses, up nearly 600% from the 1970s to the 2000s, and falling success rates for clinical development as more relatively intractable therapeutic areas are tackled such as Alzheimer’s disease, autoimmune diseases, and oncology.

Success rates have declined from 1 in 5 in the 1980s to about 1 in 10 in the 2000s, with both more extensive regulation and more complex science affecting R&D times and the probability of coming up with a winning drug. The time spent researching a new drug and gaining approval grew, the report says, from 6 years in the 1970s to 13.5 years in the 2000s.

As Derek Lowe, a well-known biotech blogger, put it, “You get to spend the real money in Phase III: lots and lots of patients, all sorts of patients, in what’s supposed to be a real-world shakedown. Prepare to shell out more than you’ve spent in the whole process to date, because Phase III trials will empty your pockets for sure.”

Government Funding

In the face of the extraordinary time and cost pressures, companies are making changes to improve R&D efficiency, addressing those factors within their control, such as dumping drug candidates that clearly don’t have a chance of making it. A recent example of both a difficult disease area and hard-to-conduct clinical trials is Alzheimer’s disease, as cited in the OHE report. Last August, Pfizer and Johnson & Johnson decided to discontinue development of Alzheimer’s drug bapineuzumab after it failed in two late-stage clinical trials.

But nobody ever said drug development, especially for difficult diseases would be easy or cheap. That does not justify hiding unfavorable clinical data or stacking review panels to ensure favorable review. The rush to market has lead to an increase in misleading and/or incomplete clinical data that has, in some cases, supported marketing approval of drugs with lethal consequences.

“On the one hand, there are a lot of important industry-funded studies that are accurate, relevant, and useful,” commented Jerry Avorn M.D., a professor of medicine at Harvard Medical School and chief of the division of pharmacoepidemiology and pharmacoeconomics at Brigham and Women’s Hospital, who has specialized in spotting adverse events from drug use. “There is also a multiyear history of abuse and distortion.”

According to a recently published article in the Washington Post that attracted a lot of attention, the government once funded the lion’s share of drug development studies. But since about the mid-1980s, research funding by pharmaceutical firms has exceeded National Institutes of Health spending. Last year, the industry spent $39 billion on research in the United States, while NIH spent $31 billion.

Over a year-long period ending last August, the article noted, the New England Journal of Medicine (NEJM) published 73 articles on original studies of new drugs, encompassing drugs approved by the FDA since 2000 and experimental drugs. Of those articles, 60 were funded by a pharmaceutical company, 50 were co-written by drug company employees, and 37 had a lead author, typically an academic, who had previously accepted outside compensation from the sponsoring drug company in the form of consultant pay, grants, or speaker fees.

Marcia Angell, retired editor of the NEJM who spent 20 years as the publication’s editor commented, “It used to be that drug companies would hand their new drug over to an academic center to have it tested, and then they sat back and waited,” she said. “Now they’re intimately involved in every step along the way, and they treat academic researchers more like hired hands.”

It’s hard to know how much this involvement influenced clinical trial result interpretations that resulted in the approval of dangerous drugs, like Avandia, for example. “If you looked closely at the data that was out there, you could see warning signs,” said Steven E. Nissen, a Cleveland Clinic cardiologist who issued one of the earliest warnings about the drug. “But they were overlooked.” A Food and Drug Administration scientist later estimated that the drug had been associated with 83,000 heart attacks and deaths.

The FDA pulled the controversial diabetes drug from retail pharmacies beginning in November 2011 due to its cardiovascular risks. Avandia remains available to patients who’ve been safely using the drug, those who have had no success in controlling their blood sugar with other diabetes medications, and patients who have been informed of the risks and still choose to take it are enrolled in a special program to qualify to receive the drug, according to the FDA.

Pharma’s hands-on practices with regard to clinical data has begun to cost the industry some big money. Last July, in a civil settlement agreement, the United States alleged that GSK promoted Avandia to physicians and other healthcare providers with false and misleading representations about the drug’s safety profile, causing false claims to be submitted to federal healthcare programs.

It also alleged that GSK stated that Avandia had a positive cholesterol profile despite having no well-controlled studies to support that message. Further, the Department of Justice said, the company sponsored programs suggesting cardiovascular benefits from Avandia therapy despite warnings on the FDA-approved label regarding cardiovascular risks.

GSK agreed to pay $657 million relating to false claims arising from misrepresentations about Avandia.

Possible Solutions

To cure these drug development maladies, some have proposed that while the expense of clinical trials stays with the industry, a network of noncontractor industry-independent researchers should be established. These researchers should have the skills to evaluate trial design, statistical power, data analysis, and interpretation, not as regulators but as contributors to final research publications. In that way, analysis and interpretation stays in the hands of those reviewers “without a dog in the hunt.”

The NEJM and similar publications have taken steps to ensure that they have policies that not only call for authors to disclose their funding and financial associations, but also requires details about a company’s role in the research.

NEJM editor-in-chief Jeffrey M. Drazen, also a Harvard Medical School professor, said, “We spend a lot of time reworking language indicating that a drug is a blockbuster, when in fact the data show it’s just so-so.”

As the industry’s influence has grown, the journal and Drazen, who arrived at NEJM in 2000, have repeatedly made significant efforts to curb bias. In 2004, Drazen and editors at other journals made it much harder for companies to hide unflattering experiments, requiring drug makers to register a summary description of their trials in a public database.

Last August, U.S. Representative Edward J. Markey introduced a bill for the Trial Experimental Studies Transparency (TEST) Act.

The proposed Act broadens the scope of the current legislation mandating the posting of summary results data for certain clinical trials in to include all interventional clinical trials, regardless of Phase or FDA-approval status, including ex-U.S. trials.

Importantly, the Act would ensure that if a therapeutic strategy had been associated with adverse events, the information would appear in the database even if the product was abandoned by the original developer. In this way, other parties pursuing the same treatment approach with a different intervention would be aware of potential dangers.

It is hoped that these transparency requirements will keep the drug development business safer for everybody.

Patricia Fitzpatrick Dimond, Ph.D. ([email protected]), is a principal at BioInsight Consulting.

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