Risk benefit assessment of APC

The first part of the article was carried in March 1-15 issue of EHM. In the second part of the article, Dr Krishan Maggon deals with the marketing, problems and challenges concerning activated protein C for the treatment of severe sepsis

Activated Protein C (Drotrecogin alpha, Xigris) attracted attention on Wall Street because there’s no comparable treatment for sepsis, also known as septic shock. With no competition, analysts predicted that drotrecogin alpha could easily become a star capable of generating more than $1 billion annually within a few years. As a result of the existing attitude towards drotrecogin alpha and despite its approval in Europe, Datamonitor expects its sales to fall well below analysts’ consensus forecasts of $300 million in 2002 - and significantly below the widely publicized forecasts of over $500 million.

Sales of drotrecogin alpha were $34.5 million in the fourth quarter of 2002. During the quarter, US sales of drotrecogin alpha were $26.9 million and sales outside the United States were $7.6 million. For the full year of 2002, drotrecogin alpha sales were $100.2 million. To date, drotrecogin alpha has been launched in 29 countries, most of which occurred late in 2002, including several launches throughout the European Union. Other countries include Argentina, Australia, Brazil, Colombia, India, Israel, Mexico, Norway, Peru, Romania, Singapore, South Africa and Switzerland.

Based on drotrecogin alpha’ cost and the revenues it has produced thus far, an estimated 14,000 patients have been given the drug in 2002, around 12000 in USA and 2000 outside USA mostly in Europe. Since drotrecogin alpha is marketed directly by Lilly, it is assumed that the normal distributors discounts is passed on to the hospitals. This discount may amount to $30-$40 millions. The hospitals are still figuring out the most appropriate way to use the drug, which situations and patients it is suited for, and how to pay for it. In Europe despite its approval by the EMEA, Lilly has to negotiate with national governments and their health systems deep discounts and agree on a price at which activated protein C will be available. In some cases such negotiations drag on for several years thereby delaying the marketing of the drug.

Problems

Lilly suffered its first setback in October 2001 when an FDA advisory panel was unable to recommend approval for drotrecogin alpha following a split vote. The panel were concerned that the Prowess study, on which the drug’s application was based, had the patient entry criteria changed halfway through the trial, which may have exaggerated drotrecogin alpha’s efficacy results. In Lilly’s Prowess clinical trial drotrecogin alpha only reduced the absolute risk of death by 6 per cent. It seems that, with a $6,800 price tag, this was insufficient to persuade physicians to prescribe the drug outside the most severe cases.

In 3.5 per cent of drotrecogin alpha-treated patients (compared to 2 per cent of placebo-treated patients), the drug also increased the risk of serious bleeding events. Such side effects have led to a laundry list of absolute contraindications for drotrecogin alpha including any ’active’ bleeding), imposing serious limitations on its potential market. But perhaps the worst drawback is the fact the drug must be started within 48 hours of the onset of sepsis: often sepsis is not recognized until much later.

Another obstacle to drotrecogin alpha’s widespread adoption is that it can be hard to identify candidates for treatment. The drug is intended for patients at a high risk of death from severe sepsis. Some physicians use it only if two or more organs fail, others prefer different criteria. It’s not always easy to tell when a patient is at an extraordinarily high risk of death from sepsis.

Drotrecogin alpha continued its fight back through the recent decision of US Medicare to grant reimbursement for it. The treatment became the first and only new medical product to be granted new technology status from the Centers for Medicare and Medicaid Services (CMS). This designation will allow hospitals that use drotrecogin alpha, Xigris in the treatment of Medicare patients with life-threatening severe sepsis to receive additional reimbursement. This development should help revive interest among hospital physicians, as it cuts the cost of the drug to $3,400.

In August 2002, drotrecogin alpha also received Marketing Authorization from the European Commission in all 15-member states of the EU. The drug is approved for the treatment of adult patients with severe sepsis with multiple organ failure when added to best standard care. The drug has a much clearer indication in Europe - for use in adult patients with two or more organs dysfunction. This will help physicians diagnose when the treatment is applicable, in contrast to the previous problem of a poorly defined illness. Drotrecogin alpha will also benefit from the wider European license, which does not confine its use to within 48 hours of the onset of the infection.

The company is recommending the that the use of drotrecogin alpha should be considered along with the use of vasodilators. Given the cool response to drotrecogin alpha in the US, its reception in the more cost-constrained European countries has been less welcoming so far. Drotrecogin alpha received a further blow at the hands of a report in the New England Journal of Medicine, which argued that the drug should not be widely used until a new study confirms its benefits. The report was based on the opinions of scientists at the Massachusetts General Hospital, the National Institutes of Health and the University of Texas Southwestern Medical Center.

Eli Lilly, nevertheless, continues to react to such setbacks. The company has launched the largest severe sepsis trial ever to take place, the Address study. The study will investigate the effectiveness of drotrecogin alpha in 11,000 adult severe sepsis patients who have a lower risk of death across approximately 1,000 clinical trial sites.

The primary objective of the Address trial will be to demonstrate that, compared to placebo and conventional care, drotrecogin alpha can reduce mortality at 28 days in adult patients with severe sepsis who have a lower risk of death. Given the continued lack of effective therapies for sepsis patients Eli Lilly will be hoping to expand the area in which drotrecogin alpha is used and possibly revive its fortunes.

As physicians get more experience with drotrecogin alpha, they will become increasingly comfortable with its use. Indeed, fast acceptance of drotrecogin alpha and use in an uncontrolled fashion might well have resulted in massive concern over complications and lack of expected efficacy, killing the drug before it had a chance to establish itself. Parallels can be drawn with the use of recombinant tissue plasminogen activator (rt-PA) for acute ischaemic stroke, which experienced slow uptake among physicians in the 1990s primarily because of price, safety concerns and stringent criteria for use of the drug. To counteract such concerns with drotrecogin alpha, Lilly has implemented a relatively aggressive promotional campaign focused on improving knowledge of sepsis among the physicians, nurses and pharmacists who will become involved in therapeutic decisions in this area.

Further publications that support the efficacy and safety of drotrecogin alpha would facilitate its uptake, and success stories, particularly ’miraculous turn-around’, would probably lead to a major increase in its use, despite the pricing concerns. Indeed, a recent follow-up study of the original phase III trial has shown that long-term benefits in mortality in high-risk patients with severe sepsis are sustained over 2.5 years.

Drotrecogin alpha is the first drug shown to cure those suffering from sepsis. Despite its extraordinary price, hospitals and insurers may not be able to refuse the drug to patients. Because of the grave consequences of sepsis and the effectiveness of the drug, hospitals and insurers may face lawsuits if they choose not to prescribe the medication. Major hospitals throughout the country are bracing for the expense of drotrecogin alpha. Some of these hospitals see approximately 10 patients per week with septic infections, as such, drotrecogin alpha could cost hospitals between $500,000 and $5,000,000 annually. Hospitals and insurers are said to be preparing for these expenditures.

Drotrecogin alpha’s main hold-up seems to be its high price ($6,800 for a four-day course). With antibiotic treatment serving less severe sepsis patients equally well, the drug was only used in the most severe (and less common) cases, with hospitals opting to use cheaper antibiotics for the majority of infections. Lilly could simply reduce the drug’s price to increase prescriptions but it could be difficult to reinstate drotrecogin alpha’s original book price once use became established. At present hospitals are reluctant to keep stocks of the drug in-house due to the price and 24 months shelf life of the drug. So rather than delivering drotrecogin alpha to hospitals via wholesalers in the USA/EU, Lilly delivers the drug as and when it is needed. The stability studies of the drug support a shelf life of two years when stored at 2-8 degree C and the reconstituted infusion solution should be used within 14 hours at room temperature.

Although it can deliver to any hospital in the US within three hours even this impressive delivery time is too slow. In the case of severe sepsis admissions, conventional treatment may well have already taken effect, so if drotrecogin alpha is not immediately available it may not be used. A sale or return policy would overcome this problem but may prove too expensive to warrant.

There is a very high risk of litigations in the USA about the use or non-use of drotrecogin alpha for treatment of Severe Sepsis. Hospitals and ER/trauma/ICU doctors may be sued for denying or delaying the use of drotrecogin alpha by relatives/family of who died or even for using drotrecogin alpha and failing to save lives. The company may be sued for giving discounts to hospitals for promoting its use by consumer health groups, HMOs, health insurances and federal and state governments for not passing on the discounts or overcharging or even not supplying the drug in time.

Marketing in India

Eli Lilly and Company India started marketing of drotrecogin alpha in May 2002. It is not known when Lilly filed for approval in India. An E-mail sent to Lilly India in January remained without response. Is it supplied from India or is ordered directly from a USA/EU facility or depot and what is the time lag between an order and delivery of the drug in ER/ICU? Has it been used in India and on how many patients? If patients order directly will they avoid paying import duty? Who will use it in India? Will the insurance cover the costs in India? There are moral and ethical issues raised about how hospitals will use it and how patients will contribute to the costs?

Lilly India should provide more information about its marketing strategy. Since it benefits only 6-10 per cent of severe sepsis patients, and these patients can not be pre-selected at present, strict guidelines are required that the 90 per cent of more of septic shock patients do not end up paying for activated protein C treatment without getting any clinical benefits. It is assumed that the filing in India by Lilly was done after FDA approval in November 2001. FDA fast track approval raised lot of controversy in the USA about the cost and low efficacy. If this was the case the Indian regulatory authorities seem to have approved drotrecogin alpha in a record time of few months and almost before or at the same time as the EU approval?

It indicates that as in the past, cost of the drug is no longer a hurdle in India and life saving drugs will now get automatic or real fast track approval in India if marketed in the USA/EU? Are there any restrictions for its use in India as in the USA and EU? I think the Drug Controller General of India should clarify the situation. The first application for oxaliplatin for colon cancer with a much better response rate and lower price took over two years to get approval in India. This life saving drug oxaliplatin was already approved in France and EU and has now become gold standard for treatment of colon cancer. In the recent past, doctors have preferred to surgical removal of cancer or radiotherapy rather than prescribe chemotherapy due to high costs to patients.

The treatment of drotrecogin alpha is now available in all major hospitals such as Apollo, All-India Institute of Medical Science, Wockhardt, Jaslok, Hinduja and Manipal. There is no debate about its use in patients who will benefit. The problems in identifying such patients mean that the drug will be used in patients who may not benefit from its use and die anyway. The costs to such patients family may be an intolerable burden.

The hospital ethical committees and ICU should have their own guidelines for the use of drotrecogin alpha and the ethical committees, regulatory authorities and health insurances should monitor the use of drotrecogin alpha. The cost of drotrecogin alpha treatment in India would be more than Rs 5 lakh including a 57 per cent duty. It is unethical to tax life saving drugs and almost every country exempts such drugs. Patients in India will eventually get a duty exemption in the near future.

As recent private hospitals bills now routinely range from Rs 1-5 lakhs for many patients, introduction of drotrecogin alpha will almost double or triple hospital bills As only about 0.2 per cent of the Indian population has health insurance cover, it means that poor patients will be denied the use of drotrecogin alpha even if they were to benefit from its use. The written informed consent of the patient and his family should be obtained prior to initiating treatment with drotrecogin alpha. This may of course be a moral and ethical dilemma for the family and an unacceptable financial burden.

Drug companies use discounts to influence hospitals and doctors. The hospitals can make huge sums from the difference between what they pay for the drugs and what they charge insurers, patients and government programs. Typically, doctors give patients prescriptions for drugs that are then filled at pharmacies. But the hospitals, buy the drugs themselves, often at prices discounted by drug manufacturers trying to sell more of their products, and then administer them intravenously to patients in their ICUs. The ICUs are very profitable for hospitals.

Corporate Hospitals in India generate additional revenues from drugs by supplying them in-house and some make it mandatory for the patients to buy medicines from the hospital’s chemist shop. A margin of 15-20% is charged for drugs. The discount on drotrecogin alpha given to hospitals may be in the range of Rs 40,000-100.000 per patient. Thus hospitals with say 100 patients with severe sepsis per month may earn between Rs 4-10 million per month or Rs 48-120 million per year from using drotrecogin alpha. Thus the hospital management may pressure ICU doctors to overuse drotrecogin alpha.

The practice also creates a potential conflict of interest for these hospitals/doctors, who must help patients decide whether to undergo or continue therapy if it is not proving to be effective, and which drugs to use. It is immoral and unethical for hospitals to make money from selling drugs than treating patients. It is a real conflict of interest situation and needs proper checks and balances in the light of emergence of profit driven corporate hospitals in India.

Lilly India should disclose the range of its discount to hospitals and these discounts should be shared with the health insurances and patients. Several hospitals in India are participating in ongoing trials with drotrecogin alpha in early stage severe sepsis. Lilly needs these trials to increase sales and switch patients responding to low cost antibiotics to very high cost drotrecogin alpha. Trials involving use with heparin will significantly increase risks to patients and should not be allowed in India.

Similarly studies so far have indicated no benefit of drotrecogin alpha in less severe sepsis and there is no rationale for additional studies in these patients. These clinical studies are another source of income for the hospitals as the sponsor pays the doctors per treated patient. The ethical committees must insure that a patient participating in clinical trials is not charged by the hospitals for treatment and stay. It is immoral and unethical for hospitals to make more money from clinical trials and testing of new drugs than treating patients. Once again, hospitals and doctors participating in clinical trials and paid by Lilly for doing clinical studies may have a tendency to over prescribe drotrecogin alpha. Hospitals launching their own Clinical Trials Services once again violate ethical and moral norms and conflict of interest. Several local pharma/biotech companies have offered/still offering huge rewards to doctors to prescribe specified drugs and this practice has not been checked under existing laws in India.

There is some risk of litigations in India about the use or non-use of drotrecogin alpha for treatment of Severe Sepsis. Hospitals and ER/trauma/ICU doctors may be sued for denying or delaying the use of drotrecogin alpha by relatives/family of who died or even for using drotrecogin alpha and failing to save lives. The company may be sued for giving discounts to hospitals for promoting its use by consumer health groups, HMOs, health insurances and federal and state governments for not passing on the discounts or overcharging or even not supplying the drug in time. The life sustaining care now possible in intensive care units alone consumes an astonishing $60 billion to $80 billion a year in the USA. That means that if one used every possible drug or device on every single patient, the system would quickly go broke.

Drotrecogin alpha should be rationed or withheld from a patient if it was probably of limited benefit and used on a patient who had a better chance of benefiting. Should drotrecogin alpha treatment be withheld when the cost outweighed the potential benefit to the patient? Withholding drotrecogin alpha treatment because of cost should be unethical when it would clearly benefit the patient. The decision to initiate drotrecogin alpha treatment should be rationale and as scientifically as possible so that any bias is taken out of its use.

The write is Pharma R&D advisor, based in Geneva. E-mail: maggonk@lycos.com