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  • by Sidney Wolfe and Kenneth Kaitin

Can we speed up the process for getting new medicines on the market while maintaining rigorous safety standards? In this photo a pharmacist is seen working in a lab where medicines are being produced at a Cipla manufacturing unit on the outskirts of Mumbai, India, Thursday, Feb 9, 2012. (Rafiq Maqbool/AP)

Introduction:

Developing and winning regulatory approval for new medicines can now take as long as it takes to raise a child to adulthood. But, can we make the FDA’s standards flexible enough to allow vital new drugs onto the market in a timely fashion, yet strict enough to protect us from potentially dangerous medicines?

Sidney Wolfe of Public Citizen’s Health Research Group and Kenneth Kaitin, a professor at the Tufts University School of Medicine look at challenges of developing — and approving — new medicines.

sidwolfecropSidney Wolfe, MD is founder of and senior advisor to Public Citizen’s Health Research Group and the editor of Worstpills.org.

In November 1898 Heinrich Dreser, a chemist at Bayer, presented the company’s newest product  at a medical meeting. The drug was, Dreser said, “10 times more effective as a cough medicine than codeine” with “only a tenth of its toxic effects”.

The new drug was thought to work better than morphine while at the same time being safe and non-addictive. Dreser had tested the drug first on animals, then on humans (Bayer employees, including himself). Some workers said the drug made them feel “heroic” (heroisch). Thus a brand name, HeroinTM, was born.

HeroinTM was a very successful new product for Bayer. Within one year, it was being exported to 23 countries. By 1902 it accounted for roughly 5 percent of Bayer’s net profits.

In the United States, manufacturers of over-the-counter cough syrups began lacing their medicine with heroin. Heroin was marketed as “the cheapest specific for the relief of coughs” and Bayer distributed free samples to physicians.

By 1913, the large number of heroin-related deaths and admissions into U.S. hospitals contributed to Bayer’s decision to stop making the drug.

Too little has changed in the pharmaceutical industry over the past century.  In 2007 Purdue paid $634 million in civil and criminal penalties for its illegal promotion of Oxycontin. As part of its marketing campaign, Purdue had instructed its sales representatives to tell health care providers that OxyContin potentially creates less chances for addiction than traditional narcotics.

Civil and criminal penalties paid by the industry for violations of the 1863 False Claims Act and other laws have skyrocketed over the past two decades. 

Purdue’s criminal promotion of Oxycontin is part of a growing trend in the pharmaceutical industry. Civil and criminal penalties paid by the industry for violations of the 1863 False Claims Act and other laws have skyrocketed over the past two decades. In 2012, annual total penalties reached a new high of $6.5 billion after only 7 ½ months of that year .

The Food and Drug Administration needs to take more care — not less — before allowing new drugs onto the market. There are 2 million serious adverse drug reactions (ADRs) – and 100,000 ADR-related deaths — every year in the United States, many of them preventable. There’s some variation year-to-year, but serious ADRs typically rank 4th-6th as a cause of death.

Last year the FDA approved the weight loss drug lorcaserin (marketed as Belviq) despite a 16 percent increase in heart valve damage in randomized trials. By contrast the European Medicines Agency refused to allow the medicine to be marketed in the European Union because “the benefits of Belviq did not outweigh its risks.”

After first rejecting another diet drug, Qsymia, in 2010, the FDA reversed course and approved it in 2012. Again the EMA’s concerns about the drugs potential for negative psychiatric and cardiovascular side effects have kept it off the market in Europe.

Thus, two more diet drugs, following in the footsteps of the now banned phenylpropanolamine (PPA), dexfenfluramine, sibutramine (Meridia) and others, were found by the EMA to be too dangerous to be used for weight loss for Europeans but are considered by the FDA to be “safe enough” for Americans. It’s not the resistance of Americans to the risks of these drugs but the intermittently dangerous malleability of the FDA that is the problem.

It’s not the resistance of Americans to the risks of these drugs but the intermittently dangerous malleability of the FDA that is the problem.

The approval process for drugs is heavily tilted toward establishing evidence of benefit, but statistically underpowered to detect all but the most commonly occurring harms. Consequently, a number of new drugs have been withdrawn when dangerous, sometimes fatal, side effects are discovered, often within their first seven years after release. Also, serious new adverse reactions or drug interactions that require stronger warnings are usually detected within the first seven years after a drug’s release.

That’s why, until the FDA reforms its approval process, we at the Health Research Group urge doctors and patients to follow the seven year rule for safer prescribing. Except for true breakthrough drugs, don’t prescribe or imbibe any new drug for the first seven years after approval.

KennethKaitincropKenneth Kaitin, is professor of medicine and director of the Center for the Study of Drug Development at Tufts University School of Medicine.

In December 2011 a Harris Poll asked Americans which industries they consider to be “generally honest and trustworthy.” Drug companies came in with an 8 percent approval rating — lower than airlines, life insurance companies, and banks. The question is why?

In my view, the pharmaceutical industry has done a tremendous job of bringing many life-saving and life-improving drugs to market. Unfortunately though, a few companies have tarnished the image of the entire industry by engaging in questionable and sometimes illegal marketing behavior. Whereas it’s hard to defend these commercial practices, I think it’s important to look at the industry as a whole.

It’s worth noting that the U.S. pharmaceutical industry is under tremendous pressure, registering a net loss of jobs every year this century. Nearly 20,000 additional jobs have already been lost in 2013.

The old model for innovation and profitability in the industry was predicated on developing “high volume, low margin” drugs. A drug like Lipitor, owned and marketed by Pfizer, is a classic example. Lipitor lowers blood cholesterol levels and helps prevent strokes. Millions of people around the world take Lipitor and similar medications daily.

While under patent protection, drugs like Lipitor are hugely profitable for their makers. However once patent protection expires those profits virtually disappear, as the drugs lose about 80 percent of their value within a few months.

Under the old model, spending on research and development by drug companies increased exponentially over the past 40 years, while new drug approvals by the Food and Drug Administration now remains flat — generally 20-30 a year. As patents on Lipitor and other widely-used drugs have expired, companies have lost billions of dollars in annual revenue.

Industry’s focus on drugs to treat relatively small patient populations, however, may be an unsustainable business model.

One way the industry has responded is by shifting its focus to a new category of products: low volume, high margin medicines. For example, chronic myeloid leukemia (CML) is a relatively rare but potentially fatal cancer. Fortunately, there’s a drug — Gleevec — that is highly effective in treating the disease. Because the patient population is small, most health plans cover the high cost of treatment. As a result, Gleevec generates billions of dollars in revenue annually for Novartis, its developer.

Industry’s focus on drugs to treat relatively small patient populations, however, may be an unsustainable business model. As more of these drugs come onto the market, there is likely to be increasing resistance by payers (national governments in Europe and insurers in the U.S.), as well as patients and physicians, to the high cost of these treatments.

Currently it takes 15-18 years to develop, test and win approval for a new drug treatment. With long development times and low success rates (only about 16 percent of tested drugs end up getting approved by the FDA), research and development (R&D) costs have, by our calculation, soared to over $1.3 billion per new medication.

What we are already seeing is that several pharmaceutical companies have simply given up trying to develop new treatments for some of our most challenging diseases, many with a high degree of morbidity and mortality, because the R&D costs and risks are too high.

For example, it takes on average nearly 11 years for central nervous system (CNS) drugs that treat neuro-degenerative and psychiatric disorders to go from first testing in human subjects to receiving FDA approval.

The real challenge for all of these stakeholders is to look forward, identify the obstacles to development, and find the best path to bringing new medicines to waiting patients.

That’s more than twice as long as for anti-infective drugs. Moreover, the likelihood that a CNS drug will successfully make it through the human testing phase is only 8.2 percent. As a result, several companies recently announced that they have significantly reduced or eliminated their investment in CNS drug development. This is despite the fact that as our population ages, CNS diseases, such as Alzheimer’s disease, senile dementia and depression will become increasingly — and frighteningly — common.

In the face of these challenges, the landscape for bioinnovation is changing. We’re seeing dramatic growth in strategic alliances and collaborative partnerships, which bring together various stakeholders with an interest in new drug development: e.g., large and small pharmaceutical and biotech companies, academic medical centers, contract service providers, venture and investment capital funds, and patient advocacy groups.

In this new environment, all stakeholders will have a place at the table and will share in the risks and rewards of bioinnovation. The real challenge for all of these stakeholders is to look forward, identify the obstacles to development, and find the best path to bringing new medicines to waiting patients.

View slides from Wolfe and Kaitin’s Open Classroom presentations here

Watch video of Wolfe and Kaitin's presentations:

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