Compassionate access policies in the U.S. are fraying the ties between patients, and the drug companies, physicians and regulators that are essential for medical progress.

Now that the Josh Hardy case has let the social media genie out of the bottle, it is urgent that these groups, as well as lawmakers, work together to quickly create a system that is seen by the public as a fair way to adjudicate complex interests that can be both in conflict and legitimate (see Cover Story).

The result needs to be a process that is transparent so all the stakeholders understand the rules and the criteria for granting or denying access, and it must be applied in a way that the stakeholders can see the criteria have been applied objectively and with due diligence.

BioCentury has identified some basic principles that should guide responses to compassionate use requests no matter who does the answering (see "Decision Tree for Compassionate Use," A11).

Two broad ideas are at their core. First, access should be granted to as many patients who are out of options and could benefit as possible, even if access cannot be provided to all of them.

Second, when there are impediments to providing compassionate access, all the stakeholders have a responsibility to try to lift them.

The key to implementing these principles in a way that will make the outcome of tough decisions more equitable, easier to understand and therefore more acceptable, is the creation of an independent third party that can make recommendations based on a dispassionate assessment of the facts.

It also would be desirable to create sources of funding for compassionate access that can be used when provision of treatment is beyond the manufacturer's means. Compassionate access is in the public interest, so the public should help pay for it.

Ethical framework

The principles guiding decisions about compassionate access requests are the same regardless of differences among individual requests.

The starting point is the principle that compassionate access to experimental therapies should be restricted to patients with life-threatening or serious illnesses who have no acceptable alternatives.

A clinical trial is an acceptable alternative. Compassionate access should not be a ticket to avoid the risk of being randomized to standard of care or even placebo. Doing so would make it difficult, and in some cases impossible, to enroll patients in trials that are essential to determining safety and efficacy.

Patients who are eligible for a clinical trial therefore should not be granted early access, but rather should be given information about enrolling in appropriate trials.

The next question is whether granting early access could substantially slow or prevent FDA approval, which would mean slowing or denying access to the broader patient population.

In the case of Josh Hardy, FDA and Chimerix Inc. were able to create a pilot trial of the company's brincidofovir in a new indication, which enabled the medicine to reach the boy and create a pathway to a registration study in the second setting (see "The Josh Hardy Chronicles," A7).

But if risks to timely approval truly cannot be mitigated, compassionate access should not be granted. It is difficult to deny patients access to hope, but this must be done if providing an experimental treatment would imperil access by much larger numbers of future patients.

The next question is whether there is adequate supply of the experimental medicine to provide access to all eligible patients.

If supply is too constrained to meet demand, funds should be provided to increase supply if it is possible to do so. This could include a dedicated fund to pay for expanding production.

If supply cannot be increased even with the provision of additional money, capacity and personnel, but there is enough supply to help some patients, then an equitable access program should be created.

"Equitable" doesn't necessarily mean equal, nor must access be random. Depending on the circumstance, priority could be given, for example, to children, or patients most likely to have a cure, or those who are sickest.

Some advocates suggest that as a matter of principle, children should have priority over adults. Certainly, children should not be put at a disadvantage relative to adults.

The last question is whether providing compassionate access would impose a substantial financial burden on a company. Here again, the focus must be on finding solutions rather than identifying obstacles.

This could include a fund to pay for the cost of producing, quality testing and distributing the compound, and to pay companies to hire additional personnel to handle the pharmacovigilance required by FDA.

Answering tough questions

Clearly, the judgments that must be made to answer many of these questions are subjective, and they are based in part on risk calculations that will be different depending on who performs them.

For example, many drug company executives believe that compassionate access exposes drug development programs to substantial regulatory risk, a contention that FDA officials and patient advocates say is exaggerated.

Decisions about the effects of compassionate access on a drug development program must give a great deal of weight to the opinions of the company that is developing a drug. But to be credible to patients, their physicians and the public, an independent entity that does not have a financial interest should render an opinion.

In addition to taking some steam out of allegations that companies are putting profits ahead of patients, input from a trusted third party would shield drug company executives from demonization.

Similarly, when supply limitations cannot be overcome, third parties - not drug companies - should step in to develop and implement fair policies for allocating experimental drugs.

In light of the Josh Hardy case and another involving ovarian cancer patient Andrea Sloan - both of which generated physical threats against company employees - the third party idea is gaining some traction among patient groups and companies, and has been mooted by New York University ethicist Arthur Caplan as well.

The specific makeup of this entity, how it should be funded and where it should be housed is a topic for discussion. It needs to have representatives of industry, patients and regulators. And it needs a mandate to call on advisors who have sufficient expertise to make science-based decisions about the appropriateness of the requested medicine for a particular patient.

Finally, the system will require some sort of appeals process. It will be harder to wage protests if the facts of the decision can be transparently reviewed and it can be confirmed the rules were applied as intended.

The notion of an appeals process also suggests that at least part of the compassionate use pathway should be addressed through law and regulation. While some of the pathway probably could be hammered out by patient groups and companies, there are several reasons why it is likely that Congress will have to step in.

First, bipartisan legislation would show that the new system reflects broad public consensus.

Second, the overall environment for providing early access to experimental therapies would be improved by passing laws that create incentives and remove disincentives to compassionate access.

For example, it may be necessary to create a statutory safe harbor so that adverse event reports from use of a compound in uncontrolled settings or in indications the sponsor isn't seeking don't adversely affect FDA approval.

Finally, Congress would have to authorize a public fund and allocate money towards it.

Best practices

Companies that are developing medicines have responsibilities to obtain regulatory approval as soon as possible so their products can be disseminated as rapidly and widely as is necessary.

They also have a responsibility to help people along the way, and if they lack resources needed to do so, to seek those resources.

In the meantime, every company would be well advised to adopt and make public a compassionate use policy if its experimental drugs are likely to provide meaningful benefits over existing products for life-threatening or serious conditions.

Some companies have already done this.

For example, the Genentech Inc. unit of Roche states that compassionate access to investigational drugs is available to patients if they have a serious, life-threatening illness, and have "exhausted all available therapies typically used to treat the disease and [they are] no longer responsive to, or able to tolerate, these treatments." Patients must also have "no other viable therapy options, including participation in ongoing relevant clinical trials."

Genentech also says it will grant compassionate access only if it has "adequate supply of the investigational medicine," and, in the U.S., if an institutional review board (IRB) at the patient's treating hospital or clinic reviews and approves the use of the medicine for the patient.

- Unsigned Commentary represents BioCentury's Editorial viewpoint.


Chimerix Inc. (NASDAQ:CMRX), Durham, N.C.

Genentech Inc., South San Francisco, Calif.

New York University, New York, N.Y.

Roche (SIX:ROG; OTCQX:RHHBY), Basel, Switzerland

U.S. Food and Drug Administration (FDA), Silver Spring, Md.