Category: Blog

This year promises to be an auspicious period for some battles over the dissemination of biomedical research. Some companies seeking more freedom to promote their products have bristled at recent guidance documents from the Food and Drug Administration (FDA) regarding promotion of drugs and devices for off-label uses, claiming that they violate the First Amendment. Simultaneously, industry is divided over calls for increased transparency of clinical trial results. But as the FDA’s regulatory authority is weakened by First Amendment challenges, the need for clinical trial transparency becomes more urgent.

In the recent guidance documents, the FDA recommended that scientific articles used for off-label promotion be scientifically sound, come from peer-reviewed journals, and be distributed in unabridged form with the approved labeling and a comprehensive bibliography. Clinical practice guidelines used for marketing should be based on a systematic review of the evidence and “be developed by a knowledgeable, multidisciplinary panel of experts and representatives from key affected groups.” The FDA also recognized the growing importance of social media, describing the situations in which a company is responsible for comments on Facebook and patient-advocacy websites focusing on specific diseases and treatments. In early June, the FDA expanded this guidance process to include communications about new risk data for existing drugs. The FDA is concerned that companies might use incomplete new information to weaken the impact of warnings on the approved drug label.

Some companies have complained that these rules overly constrain their marketing practices and impermissibly infringe on commercial speech. These claims find some support in recent cases that have undermined the FDA’s regulatory authority over drug marketing. The First Amendment has emerged as a potent deregulatory weapon for corporations. Governments increasingly face First Amendment challenges to rules related to the marketing of regulated products, not only from the drug industry but also from companies selling tobacco, alcohol, and processed foods. These industries claim that the government violates a core principle of liberty — freedom of speech — by regulating how food, drugs, alcohol, and tobacco are sold. The FDA issued new guidance documents with these concerns in view.

In recent years, drug companies have paid billions of dollars in fines related to off-label promotion. Whether the First Amendment protects this activity remains an open question. The FDA’s position is nuanced. Under the law, a drug is viewed as “mislabeled” unless “its labeling bears adequate directions for use.” The FDA does not require labels to discuss all possible uses, which would be burdensome to the companies, but only those actually intended by the company. One way to prove this intention is to examine company statements about the drug, including promotional activity. Companies can make any truthful and non-misleading statement about their drugs, but when they choose to speak about any particular use, the label must bear adequate directions for that use. Speech is frequently used to prove elements of other crimes; examples include perjury, premeditated murder, and conspiracy.

Seen in this light, the recent draft guidance documents do not constrain First Amendment values. They provide safe harbors, listing circumstances in which the FDA will not consider actions to be evidence of intent to sell a drug for a particular use. And the guidance is quite lenient: a company can sponsor biomedical research for off-label use, refuse to submit that research to the FDA for an expanded label, but nevertheless widely distribute reprints of relevant journal articles to physicians and chat about them on Facebook and other social media. The FDA is keeping a respectful distance from the First Amendment, while gently reinforcing better practices, including peer review and disclosure of conflicts of interest.

If the Supreme Court’s interpretation of the First Amendment continues to constrain FDA influence over the dissemination of research, then even greater importance must be placed on improving research quality and providing the support independent research teams need to reanalyze clinical trial data. Studies have highlighted strategic weaknesses in the research enterprise, including failures in peer review, publication bias, the bias introduced by sponsors or investigators, and extensive financial relationships.

Transparency is an important tool for addressing these issues, and many stakeholders are working to improve transparency in biomedical research. The International Committee of Medical Journal Editors has adopted standards to improve the quality of the peer-review process, require registration of clinical trials before patient enrollment, and improve disclosure of conflicts of interest. The United States requires advance registration of many clinical trials; since 2007, summary results must also be published. Similar initiatives have been implemented in Europe and beyond, including a global clinical trial registry maintained by the World Health Organization. Advance registration and summary publication are important tools for reducing opportunities for publication bias and making it harder to hide negative studies.

The pressure is now building for two additional data-transparency goals: giving responsible independent researchers access to patient-level data to enable them to replicate studies and perform meta-analyses; and requiring the public release of clinical study reports submitted to governments for marketing approval, which have substantial informational value. Companies have traditionally protected these data as trade secrets, but major changes are underway.

In the United States, the FDA requested comments in 2013 on a proposal supporting a limited level of transparency for product-masked patient data. Product masking protects the identity of both the drug and the patient, which limits the data’s clinical utility for research. Currently, this effort appears to be on hold, awaiting results from a review by the Institute of Medicine. Meanwhile, transparency initiatives by some companies and legislative action in Europe may have reached the tipping point, with momentum growing for transparency that goes well beyond product-masked data.

Limited patient-level data are now being made available to independent researchers. In May 2013, GlaxoSmithKline opened some of its patient-level data to responsible researchers, with an independent review panel acting as the gatekeeper. Johnson & Johnson followed suit in January 2014, partnering with a group at Yale. These programs are welcome improvements and should expand across the industry.

I believe that transparency should also extend to the clinical study reports submitted to the FDA and other drug-regulatory authorities. On April 2, 2014, the European Parliament adopted reforms to its rules governing human clinical trials, including a key provision requiring delayed release of clinical study reports submitted to the European Medicines Agency. The next day, AbbVie dropped its lawsuit against the agency, which had sought the release of clinical study reports on two AbbVie drugs. Other litigation remains pending, and the European Union may yet weaken these rules, but these events suggest that disclosure of clinical study reports may soon be the norm in Europe.

In public comments on the European reforms, the drug industry raised objections to the release of clinical study reports. Although companies have no trade-secrecy right to hide safety data on medicines, they make a reasonable point regarding the danger of substantial competitive harm from full transparency. Governments offer non–patent-based incentives for special categories of drugs, such as orphan drugs and biologics. These incentives have frequently rested on data exclusivity, prohibiting other companies from using data for regulatory approval purposes. To the extent that transparency disrupts data-exclusivity incentives and the timing of generic entry, both domestically and internationally, the law will need to be adjusted in order to restore the competitive position of the companies. The alternative is to delay data releases until many years after a drug is approved, but neither the progress of science nor public safety should wait for full transparency. The companies will also retain the full force of patent law to block premature generic entry. If this issue is resolved, the onus will be on the industry to articulate why clinical study reports should not be immediately released when a drug is approved.

After decades of criticism about bias in the clinical trial enterprise, new norms are being established that promote transparency. Additional transparency is particularly welcome in the United States, since the Supreme Court has increasingly constrained the FDA’s ability to regulate off-label marketing activities. In the deregulatory environment fostered by First Amendment challenges, clinical trial transparency is perhaps the best remaining option for informing physicians and protecting patients.

When a drug is found, after being approved by the Food and Drug Administration (FDA), to have unacceptably dangerous side effects or insufficient therapeutic benefits to outweigh its risks, patients can discontinue its use. But what if the approved therapy that is later discovered to be ineffective or unsafe is an invasive procedure or an implanted medical device? Patients who have already undergone the procedure were put at unwarranted risk, and those with an ineffective or dangerous implanted device must decide whether to leave it in their body or incur the risk associated with another procedure in order to remove it. In this sense, medical procedures and devices pose potentially greater harm to patients than drugs do.

Approval standards for high-risk medical devices, however, are generally less rigorous than those for pharmaceuticals. Only 1% of all medical devices reach the market through the premarket-approval route — the only pathway that requires the submission of clinical data. Research has shown that premarket approvals are often based on data from one small trial that used surrogate endpoints and included only short-term follow-up.1 Blinded, randomized, controlled trials (RCTs), in which the proposed therapy is compared with a placebo or a “sham” (nontherapeutic) intervention, are common for drugs but rare for medical devices. The lack of such trials for devices is due, in part, to the understandable reluctance to conduct a trial in which some patients are subjected to a sham procedure or implant. However, it has long been established that benefits do not have to accrue to all patients in a clinical trial.

In light of mounting evidence that medical procedures can produce a strong placebo effect that can be mistaken for actual effectiveness, I believe it is time for more frequent use of interventional trials in which patients are unaware of their randomized assignment.

For example, on the basis of unblinded trials, a catheter-based radiofrequency ablation of the renal arteries, known as renal-artery denervation, was thought to lower blood pressure. The recent SYMPLICITY trial, however, found renal-artery denervation had no beneficial effect on blood pressure beyond that achieved with a sham procedure.2 Although the reasons for this lack of benefit will be debated for some time, this important result would not have been discovered without the use of a nontherapeutic intervention.

The debate over the ethics of performing a sham procedure or surgery dates back more than 15 years to double-blind trials of fetal-tissue transplantation for Parkinson’s disease, discussed by Freeman et al. (1999). The sham procedure involved making twist-drill holes in the patient’s forehead and was considered necessary and ethical for determining whether there was an effect of treatment beyond the placebo effect (there was not). The institutional review board believed that the risks of sham surgery had to be weighed against the greater risks of mistakenly believing an invasive procedure to be useful because of its placebo effect. Indeed, had there been no trial including sham surgery, many Americans with Parkinson’s disease might be receiving craniotomies for only a placebo benefit.

Another important lesson on the value of sham controls came from vertebroplasty, a procedure in which bone cement is injected into a fractured vertebra for treatment of a compression fracture. Vertebroplasty became popular in the early 2000s, on the basis of observational studies and a nonrandomized trial. Fueled by position statements from various U.S. radiologic and neurologic surgical societies arguing the benefits of these procedures, the number of vertebroplasties performed in Medicare patients nearly doubled between 2001 and 2005, increasing from 45.0 to 86.8 per 100,000 enrollees.3 In 2009, however, RCTs that included a group assigned to receive a nontherapeutic procedure found that pain relief in the sham-procedure group was no different from that in the group that received the actual procedure.4 These examples establish not just ethical precedent but also the importance of comparing device-based interventions and surgeries with equivalent sham control.

It’s important to understand the power of the placebo effect. Researchers at the Institute of Medical Psychology in Munich recently quantified that power for various types of placebo treatments in studies of migraine prophylaxis. They found that 58% of patients had a positive response to sham surgery and 38% had a positive response to sham acupuncture, while only 22% had a positive response to oral pharmacologic placebos.5 This research shows not only an astonishingly high response rate for sham procedures but also a significantly higher response rate for placebo physical interventions than for placebo drugs. These results highlight the importance of devising a control that will sufficiently distinguish the specific effect attributable to the placebo.

Not all device trials necessarily require nontherapeutic controls. For example, after a therapeutic benefit beyond the placebo effect was established, subsequent iterations of a device would not need to be compared with sham control. In addition, trials with only objective endpoints, such as mortality, do not need a nontherapeutic control. Interventional studies that would most appropriately be conducted as blinded RCTs include early studies of new technology and studies whose primary outcome measure is susceptible to a placebo effect, such as pain.

For example, percutaneous coronary intervention (PCI), a widely used procedure for treating stable coronary artery disease, has never been investigated in a blinded trial. Some non-blinded RCTs have shown that PCI has a beneficial effect on anginal symptoms, but there appears to be no difference between PCI and medical therapy in rates of the objective endpoints of nonfatal myocardial infarction and death due to cardiac causes. It is possible, therefore, that the perceived symptomatic benefit is actually a placebo effect and not attributable to PCI. Although a blinded trial would be relatively straightforward if two groups of patients were randomly assigned to a cardiac catheterization procedure, as was done for renal-artery denervation, such a study has yet to be performed, and the important question of PCI’s actual clinical benefit, therefore, remains unanswered.

Subjecting patients to sham procedures is not without risk, and it gives rise to ethical concerns about “unnecessary” invasive procedures that will have no actual therapeutic effect. I believe, however, that the examples above show that sham interventions are ethical when the benefits of information from a sham-control trial exceed the risks of using an intervention not shown to be more therapeutic than a sham. Moreover, the risk associated with performing unnecessary procedures should be weighed against the risk of mistaking a placebo effect for therapeutic benefit and therefore subjecting thousands or millions of patients to a procedure that actually does them no good. In a controlled trial, patients are informed of and consent to the risks; when an ineffective procedure is accepted into practice, however, patients who subsequently undergo it most certainly have not knowingly consented to an ineffectual procedure. Without careful use of nontherapeutic controls, we may be subjecting millions of Americans to harm from risky, invasive procedures without benefit. Ethical concerns regarding a placebo group should, of course, be acknowledged and addressed by institutional review boards and through informed consent, as they are in drug trials and have been in the examples above.

In the SYMPLICITY trial, the risks were weighed and managed. There were risks associated with the sham control, which included a femoral-artery puncture and renal angiography. However, the finding that the procedure lacks any apparent benefit will spare many patients from undergoing a risky procedure that apparently has only a placebo value. There are clear benefits of preventing ineffective procedures and devices from gaining widespread use, which means that true therapeutic benefit should be established before FDA approval.

The SYMPLICITY trial thus adds to mounting evidence that medical procedures can have a substantial placebo effect. This knowledge may require Congress to articulate a clear standard for establishing true therapeutic benefit for FDA approval, to ensure that all devices we provide to our patients are safe and effective.

But I must explain to you how all this mistaken idea of denouncing pleasure and praising pain was born and I will give you a complete account of the system, and expound the actual teachings of the great explorer of the truth, the master-builder of human happiness.

No one rejects, dislikes, or avoids pleasure itself, because it is pleasure, but because those who do not know how to pursue pleasure rationally encounter consequences that are extremely painful.

Nor again is there anyone who loves or pursues or desires to obtain pain of itself, because it is pain, but because occasionally circumstances occur in which toil and pain can procure him some great pleasure. To take a trivial example, which of us ever undertakes laborious physical exercise, except to obtain some advantage from it?

But who has any right to find fault with a man who chooses to enjoy a pleasure that has no annoying consequences, or one who avoids a pain that produces no resultant pleasure?