FDA moving to expand access to experimental drugs

The FDA is taking steps to expand patients’ access to drugs that have not yet been approved for marketing, encouraging manufacturers to exclude fewer people from clinical trials and to publicize their policies about accessing drugs outside of clinical trials, according to a report from Government Accountability Office (GAO Report, GAO-19-630, September 9, 2019).

Clinical trials

Clinical trials often exclude patients by geography, age, or medical condition, and many stakeholders believe that the eligibility criteria are too narrow and exclude patients who are likely to be treated once a drug is approved, according to the GAO. Two recent laws have encouraged expanded access to pre-approved, or “investigational” drugs, the Federal Right to Try Act of 2018, which allows terminally ill patients and their doctors to request access to drugs without an FDA review process, and the FDA Reauthorization Act of 2017, which required the FDA to discuss and report on clinical trial inclusion and exclusion, and requires the GAO to report FDA’s actions to expand access to investigational drugs.

FDA efforts

The FDA has made efforts to make sure that historically excluded classes of people, like children, pregnant women, or patients with liver disease, can gain access to “investigational” drugs that have not been approved for marketing. The agency has met with stakeholders, reported on its meetings, and issued guidance on cancer drugs and on clinical trials more generally.

FDA issued four new draft guidance documents and one finalized guidance document in March 2019, aimed at expanding eligibility for cancer drug trials. Collectively, the guidance recommends that manufacturers attempt to include certain patient populations that have typically been excluded from participation, including children and adolescents; patients with HIV, hepatitis B or hepatitis C virus; patients with brain cancer; and patients with kidney, heart, or liver diseases. Rather than excluding these patients outright, FDA’s new guidance recommends ways to safely include them in trials, such as allowing testing on HIV-positive patients if they have not had an AIDS-defining infection within the past 12 months.

The FDA has more recently issued draft guidance that goes beyond cancer trials, recommending in June that manufacturers examine whether exclusion criteria are necessary to ensure safety or to achieve the study’s objectives, and avoid any unnecessary restrictions to a study’s population.

Despite the FDA’s efforts, drug manufacturers have not generally moved to expand eligibility for clinical trials. Only two out of ten surveyed by the GAO indicated that they had broadened their clinical trial eligibility criteria or intended to do so, while other drug manufacturers said that they had tried other ways to expand access to trials, such as reimbursing travel and hotel costs, or taking advantage of decentralized trials that took place in retail health clinics and patients’ homes, according to the report.

Beyond clinical trials, patients can also request access to investigative drugs through the FDA’s expanded access program or the federal Right to Try Act, and the FDA is taking steps to raise awareness about those programs. While the FDA has tried to use both programs to increase access to investigative drugs, it can only go so far, since neither program compels drug makers to provide access outside of a clinical trial.

The GAO received mixed feedback on the FDA’s program. Some physician and patient advocacy groups criticized it as too complex and burdensome, while others pointed out that the FDA approves most requests—99 percent in 2017—and that manufacturer’s approval is a bigger factor in preventing patient access.

The FDA has tried to simplify and improve the expanded access process, simplifying forms and enlisting an outside partner to help physicians and patients find drug manufacturers’ expanded access policies, according to the report. The FDA has also started a pilot program to assist oncologists with requests for investigative drugs, and created a streamlined process for institutional review board approval, both of which have been well-received by stakeholders.

The newer Right to Try Act also received mixed reviews in the GAO’s study, with some physicians and medical ethicists questioning whether the program, which eliminates FDA review, could compromise patient safety without solving the more common obstacle to improving access, which is manufacturers’ cooperation.

Drug manufacturers remain skittish about the FDA’s handling of adverse events that occur under the FDA’s expanded access program, despite recent guidance saying that such events have not prevented FDA from approving any drug. Two out of ten drug manufacturers said that recent the FDA guidance did not quell their concerns, and four in ten said that manufacturers’ concerns about the issue “may never be fully resolved.” FDA officials, for their part, told the GAO that data from the expanded access program has been commonly used to support drug approvals, and only very rarely has led to a clinical hold.

The GAO also tracked drug makers’ efforts to communicate with patients about access to investigative drugs, finding that 23 of 29 manufacturers surveyed communicated their position to potential patients. Nineteen said they would consider requests for investigational drugs outside of clinical trials, while four said they would not consider requests, with two citing safety concerns. Most of the manufacturers willing to accept requests included an estimated time frame for responses, and five mentioned specific drugs for which they would consider requests.

FDA considers a benefit-risk assessment for opioid analgesics

The FDA issued a draft guidance for the pharmaceutical industry when providing information in a new drug application (NDA) for opioid analgesic drugs. The FDA assesses risks and benefits of all drugs in the context of their labeled uses when reviewing NDAs. However, because of the widespread abuse of opioids the FDA will also consider the broader public health effect, including the risks related to misuse, abuse, opioid use disorders, accidental exposure, and overdoses for patients and others. The guidance details what data is required for the FDA to complete their benefit-risk analysis after receiving an NDA (Notice, 84 FR 29211, June 21, 2019).

Patient benefits. For the FDA to analyze patient benefits, pharmaceutical companies submitting opioid NDAs should show the efficacy and safety of the drug when used for its proposed indication. The NDA should provide a body of evidence supporting a finding of drug efficacy, what patient population was used and why, and a proposed duration of use for each proposed indication. In addition to efficacy, the companies should show the safety of the drug when used for its proposed use. The NDA should show drug safety by submitting supporting data of drug characteristics that mitigate adverse events associated with opioids, such as respiratory depression, sedation, and constipation. The FDA would also need data supporting any drug characteristics that mitigate risks of opioid use disorder.

Patient risks. In addition to the already known risks of opioids, the FDA will also consider questions about the risks to patients who are prescribed the drug and use it as labeled and directed by their physicians. The NDAs should provide data to support the answers to the following questions:

  • Does the drug have any risks not normally associated with opioid use? How serious are these risks, and can they be mitigated? Are the risks reversible?
  • Does the drug formulation cause any risks such as tablets that swell in the GI tract or stick to mucous membranes? For drugs formulated with abuse-deterrent properties, are there any risks associated with formulation?
  • Does the drug have characteristics that increase or decrease the risks of respiratory depression, sedation, or development of opioid dependence? Can packaging particulars or storage and disposal conditions mitigate the risks?
  • Is there evidence that typical adverse events associated with opioids occur at a higher rate?

Effectiveness and safety. The FDA considers the benefits and risks relative to other available treatment options for the prescribed condition. The comparative data of the drug to other treatment options is valuable, but the FDA notes, it is not required to be found superior to other options, to be approved for an ANDA. The FDA will consider the following questions when determining the effectiveness and safety of drugs in ANDAs:

  • Does efficacy data exist comparing the drug with other opioids or nonopioids for the condition? Does the drug have any advantages compared to other treatment options?
  • Does comparative safety data exist with other treatment options? Are there any safety advantages or disadvantages compared to other options?
  • What is the anticipated benefit-risk balance compared to other treatment options?
  • Does the drug have any other safety advantages over other treatment options?

Public health effects. The FDA proposed in the guidance that it would consider the greater public health effects of new opioids including patients and nonpatients. Nonpatients can be members of patient’s households, visitors to patient’s households and others. The risks are those related to misuse, abuse, opioid use disorder, accidental exposure, and overdose. The FDA will consider the following when analyzing public health effects:

  • Are there characteristics of the drug that increase or decrease risk of accidental exposure to children?
  • Are there characteristics of the drug that increase risk of misuse, abuse, and related adverse outcomes? Can the risks be mitigated?
  • Are there risks with the method of delivery?
  • Are there any potential unintended adverse consequences?
  • Safety of unintended routes of administration such as intravenous, intranasal, or inhalation
  • Discussion of anticipated use-specific subpopulations such as teens or patients with mental health disorders and how to mitigate such risks

Risk management. The FDA determined that there is a risk evaluation and mitigation strategy necessary for all opioid drugs intended for outpatient use to make sure the benefits outweigh the risks. The mitigation strategy requires training for all health care providers involved in the treatment of pain. To meet this requirement drug companies with approved opioid NDAs must provide grants to continuing education providers for development of these training courses. Any NDA must include any risk evaluation and mitigation strategies thought to be necessary to make sure the benefits outweigh the risks of the opioid drug.

U.S. pays nearly twice as much for drugs compared to other countries

A recent HHS analysis revealed that prices charged by drug manufacturers to wholesalers and distributors in the United States are 1.8 times higher than in other countries for the top drugs by total expenditures separately paid under Medicare Part B. U.S. prices were higher for most of the drugs included in the analysis, and U.S. prices were more likely to be the highest prices paid among the countries in the study (ASPE Report, October 25, 2018).

Medicare Part B

Drugs typically administered to patients by healthcare practitioners are covered and paid under Medicare Part B, which is part of the fee for service traditional Medicare benefit. Under Part B, providers buy and bill for these drugs. Medicare pays suppliers and providers based upon the Average Sales Price (ASP) for each product, as reported by manufacturers to CMS. Physician offices that buy and bill Part B drugs are paid 106 percent of the drug’s ASP, and hospitals are reimbursed either at 106 percent or 77.5 percent of ASP, depending on the hospital outpatient department’s participation in a safety net drug pricing program. Spending on Part B drugs has doubled since 2006.

The analysis and results

Data was compiled on the top drugs based on total Medicare reimbursement to either physician offices, hospital outpatient departments, or overall under Medicare Part B in 2016. Countries included in the analysis included: the United States, Austria, Belgium, Canada, Czech Republic, Finland, France, Germany, Greece, Ireland, Italy, Japan, Portugal, Slovakia, Spain, Sweden, and the United Kingdom. The analysis identified thirty two Medicare Part B drugs among the top twenty drugs in spending for each setting. These thirty two drugs accounted for $18 billion in spending, out of a total $27 billion on Part B drugs across these settings. The main analysis reports on twenty seven Part B Drugs.

Across the twenty seven drugs in the study, the U.S. ex-manufacturer prices were 1.8 times than average international ex-manufacturer price. There was not any one country that consistently had the highest or lowest prices compared to the U.S. for twenty of the drug products; U.S. prices exceeded the average international price by more than twenty percent. In addition, for nineteen of the twenty seven products the U.S. prices were higher than any other country. Excluding the U.S., Germany and Canada had the highest prices for six drugs and Japan for five drugs. France and the United Kingdom had the lowest prices for four drug products. Japan, Sweden and Slovakia had the lowest prices for three drug products each. Finally, the analysis calculated that the Medicare program and its beneficiaries spent an additional $8.1 billion (47 percent more) on these twenty seven products that it would have, if payments based upon ASP were scaled by the international price ratios.

Overall, prices and reimbursement rates for Part B drugs are significantly higher for the U.S. providers than purchasers outside the U.S., except for a few outlier cases. The amount by which U.S. prices exceeded those of international comparators varied significantly by product, and there was no clear pattern as to which countries were consistently paying lower prices. The analysis suggests that Medicare Part B could achieve significant savings if prices in the U.S. were similar to those of other large market based economies.

Kusserow on Compliance: OIG toolkit for calculating opioid levels and opioid misuse risk

The OIG toolkit provides detailed steps for using prescription drug claims data to analyze patients’ opioid levels and identify certain patients who are at risk of opioid misuse or overdose. It is based on the methodology that OIG has developed in its extensive work on opioids. This provides technical information to support the OIG’s public and private sector partners, such as Medicare Part D plan sponsors, private health plans, and State Medicaid Fraud Control Units. It is intended to assist OIG partners with analyzing their own prescription drug claims data to help combat the opioid crisis. It provides steps to calculate patients’ average daily morphine equivalent dose (MED), which converts various prescription opioids and strengths into one standard value. This measure is also called morphine milligram equivalent (MME). The toolkit includes a detailed description of the analysis and programming code that can be applied to the user’s own data. The resulting data can be used to identify certain patients who are at risk of opioid misuse or overdose. Users can also modify the code to meet their needs, such as identifying patients at other levels of risk. The toolkit has three chapters:

 

(1) Analysis of Prescription Drug Claims Data,

(2) Explanation of the Programming Code To Conduct the Analysis, and

(3) Programming Code.

 

Opioid abuse and overdose deaths are at epidemic levels in the United States. As one of the lead federal agencies fighting health care fraud, the OIG is committed to supporting public and private partners in its efforts to curb the opioid epidemic. These partners include Medicare Part D plan sponsors, other private health plans, State Medicaid Fraud Control Units, State prescription drug monitoring programs, and researchers. They can use this toolkit to analyze claims data for prescription drugs and identify patients who may be misusing or abusing prescription opioids and may be in need of additional case management or other follow-up. This toolkit can also be used to answer research questions about opioid utilization.

Copies can be obtained by contacting the Office of Public Affairs at Public.Affairs@oig.hhs.gov.

Richard P. Kusserow served as DHHS Inspector General for 11 years. He currently is CEO of Strategic Management Services, LLC (SM), a firm that has assisted more than 3,000 organizations and entities with compliance related matters. The SM sister company, CRC, provides a wide range of compliance tools including sanction-screening.

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Copyright © 2018 Strategic Management Services, LLC. Published with permission.