Please login to the form below

Not currently logged in

A work in progress

Questions remain about the FDA's Risk Evaluation and Mitigation Strategy as more drugs are required to participate

USAMore than two years after the effective date, questions remain about issues ranging from who should have input into the initial development of a Risk Evaluation and Mitigation Strategy (REMS) to how a REMS should be evaluated once it is in place. One thing is clear, though: the number of drugs and biologics for which REMS are required is steadily increasing and industry needs to be both familiar with the existing programme and ready to change as it evolves.

In all, the Food and Drug Administration (FDA) has approved new REMS and revisions to REMS for nearly 130 products since the programme came into effect. The federal agency required REMS for approximately 30 per cent of the new medicines it approved between January and June 2010. Many drug sponsors are now required to submit proposed REMS as a component of their marketing applications. In addition, the FDA has begun to explore class-wide REMS, beginning with a focus on opioids and TNF blockers. (The agency maintains a regularly updated list of REMS programmes at

And it is not just companies launching new products that need to be ready to face the possibility of a REMS; the 2007 legislation gives the FDA the authority to require a REMS for a product that is already on the market if new safety data comes to light.

More than half the time, a REMS consists solely of printed safety information called a MedGuide that must be dispensed with each prescription. The FDA requires medication guides when it believes they are necessary to prevent serious adverse events or inform patients about a known risk of serious adverse events, or when they are needed in order to provide the patient with instructions for using the product.

In most cases, the MedGuide must be distributed to patients each time the medication is dispensed, even if it is in an inpatient setting. Companies are required to assess the effectiveness of their own MedGuides at several intervals – 18 months, three years and seven years – after approval of the REMS, although not much guidance has yet been provided by the agency about how that should be done.

In addition, about 40 per cent of the time, a REMS also has components above and beyond the MedGuide. In these cases, a REMS may include a communications plan aimed at healthcare providers, which most often takes the relatively simple form of sending letters to doctors, pharmacists and others involved in getting the medicines to the patient. However some REMS, including one designed to address safety issues surrounding Genentech's rheumatology drug tocilizumab, include more burdensome provisions about communicating with doctors, such as requirements that the safety information be displayed at medical conferences and published at specified intervals in predetermined medical journals.

A handful of the REMS put in place so far require healthcare providers and pharmacists to be given special training regarding the drugs and some impose a restricted distribution network. A REMS can also require the prescriber to monitor patients, either immediately after drug administration or over a longer period of time.

Rethinking REMS
As burdensome as it can be, the REMS programme has some clear benefits. First and foremost, it has the potential to increase patient safety, an outcome that is obviously desirable for all parties involved. Secondly, by mitigating a product's risks, the programme makes it possible for the FDA to approve drugs and biologics that it might otherwise have to keep off the market.

However, while most stakeholders agree that there is a fundamental need for the programme, many also believe that the programme – as it exists now – is inefficient and in some cases inequitable.

The trade group Pharmaceutical Research and Manufacturers of America (PhRMA), for example, has called on the FDA to make a number of changes, including providing more transparency about how it decides whether a REMS is necessary, communicating with companies earlier in the REMS review process, ensuring that different divisions at the FDA use similar procedures when evaluating the programmes and making it easier for companies to make minor revisions to REMS already in operation.

Industry has also argued that given that drug companies have no direct contact with the patient who ultimately receives the drug, it is unreasonable to hold a manufacturer responsible for whether or not a medication guide is put into the patient's hand along with the filled prescription.

Many stakeholders believe the programme is inconsistent and fragmented. "Because each REMS is created independently by the affected medication's manufacturer, REMS lack standardisation in programme design and implementation," explained Illssya Levins, president of the Center for Communications Compliance.

"The resulting growing number of disparate programmes leads to administrative, logistical and workflow challenges for the healthcare system. The inconsistency that results from such 'silo' programmes leads to provider confusion, administrative inefficiencies in implementation, workflow inefficiencies and burdens on the healthcare system. FDA recognises this and has committed to addressing these issues, but in the meantime companies must sort out these problems as they're designing REMS elements."

The FDA has admitted that the programme needs fine-tuning, with agency officials maintaining that they weren't given enough time to develop the programme before they were required by law to implement it. Given that the FDA is chronically under-resourced, the burden of the programme on the agency is no doubt significant and improvements and clarifications are likely to come more incrementally than many in the industry might find ideal.

Seats at the table
The ongoing process of refining the REMS programme is likely to be both enhanced and complicated by the fact that the agency is receiving input from multiple stakeholders, including industry, health insurance companies, hospitals, doctors, nurses, pharmacists and patient groups. When the FDA invited interested parties to speak at a public hearing about REMS in July 2010, more than 70 presentations were made by various stakeholders, demonstrating how many parts of the healthcare system are affected by the programmes.

Some outside stakeholders want the process of developing a REMS to be opened up to more than a closed loop between the FDA and the drug sponsors. The American Society of Clinical Oncology (ASCO) recently took issue with the REMS that was developed by Amgen and the FDA for the company's erythropoiesis stimulating agents and has asked that ASCO be brought to the table for future discussions about REMS for oncology drugs. Other groups have been demanding a seat at the table too. The American Pharmacists Association, for example, has asked for more involvement of pharmacists and prescribers in the early stages of REMS development.

The hospital network Kaiser, while not necessarily seeking to be in on the discussions about specific REMS, has also made it clear that it aims to have a voice in the programme overall. The company submitted a major petition on REMS issues to the FDA last year and made multiple presentations during the July public hearing.

Stakeholder involvement
The very fact that the FDA conducted the hearing indicates that the agency is interested in giving  outside stakeholders some input at least into how the overall REMS programme is structured and possibly in certain circumstances into the development of specific REMS, although the agency has pointed out that there are confidentiality requirements that could make the latter proposition difficult.

Meanwhile, many physicians want to be part of the conversation about REMS in order to try to reduce the burden of the programme which, in addition to the other requirements, stipulates that doctors must keep thorough records of their REMS-related activities and allow drug companies to audit them. The FDA is required by law to take into account the burden on physicians in implementing the REMS programme, but PhRMA has taken the agency to task for not being transparent about its procedures for doing so.

A recent survey of physicians conducted by Sermo found that 83 per cent of haematologists/oncologists viewed the Erythropoiesis-Stimulating Agents REMS as a barrier to utilisation. Sermo quoted one respondent as saying: "I would rather not even prescribe a drug than generate more work for me or my staff."

Some stakeholders even worry that REMS could decrease rather than increase the amount of safety information transmitted to patients.

The National Comprehensive Cancer Network REMS Work Group issued a statement that said, in part: 'To meet some REMS requirements, providers must spend additional time on administrative tasks like registration, training, verification and documentation, which may take away valuable time from patient-care activities, including thoroughly presenting the benefit/risk ratio for a proposed therapy.'

All in all, the REMS programme has already had a powerful effect on the US pharma industry, but it is clearly critical for the FDA to continue to learn from experience and revise the programme with the needs of multiple stakeholders in mind. As FDA Principal Deputy Commissioner Joshua Sharfstein said during recent remarks to Congress, the REMS authority is still "a work in progress."


Kate FodorCorrespondent
Contact Kate Fodor at

To comment on this article, email

10th March 2011


Subscribe to our email news alerts


Add my company
Havas Life Medicom

We are a fully integrated agency that is 100% dedicated to creating standout communications in healthcare. Our success starts by...

Latest intelligence

Millennials: the wellness generation
Looking at the results from a global healthcare research study focusing on the patients of the future...
The problem with clinical trials (and how virtual insight-gathering can help)
While still the gold standard of research, clinical trials are often riddled with issues that limit their applicability to broader populations or delay market access....
The rise of digital healthcare – fuelled by open innovation in healthtech hubs
How the ever-increasing uptake of digital solutions is enhancing patient engagement, increasing access to care and lowering the cost of drug development...