Let me preface this by saying that there are no crystal balls or sure things in the biotechnology sector. Even when you think you have everything down and you suspect you can read the reaction of the Food and Drug Administration or its panel with your eyes closed, something will come out of left field to humble you.

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With that being said, the biotech sector is still a stomping ground for some of the most mind-numbing and heart-stopping gains you'll ever see. For example, if you had ridden clinical-stage cancer drug developer Pharmacyclics up from the market bottom in 2009, you'd have an eye-popping 16,671% return as of Friday's close. While returns like these aren't typical in the biotech sector, you can, if you know how to navigate the sector, find clinical-stage companies that are setup to dramatically (and I do mean dramatically!) outperform the broad-based S&P 500.

How to be a successful biotech investor
Back in March, I outlined three important ways investors could use the biotech sector to their advantage over the long term.

One method was to seek out established pipelines, such as is the case with Gilead Sciences (GILD -0.22%). It's true that Gilead has seen huge gains in the wake of impressive data for its oral hepatitis-C drug hopeful sofosbuvir, but the real allure of Gilead is its multiple FDA-approved drugs, its recurring cash flow, and impressive pipeline diversity.

Another pathway to success is by picking out biotech ETFs that spread your risk around among multiple companies if you're not comfortable just picking one or two. This, too, has been a strong strategy of late, with the SPDR Biotech ETF up a whopping 41% over just the trailing 12-month period.

The final pathway, and the one that seems to carry the greatest risk and reward, is seeking out clinical-stage biopharmaceutical companies with diverse pipelines. The problem with clinical-stage companies is they carry a lot of risk if a mid- or late-stage drug fails, since they often have little to no recurring cash flow and count on milestone payments and secondary offerings to drive their cash balance higher. Conversely, it takes only one or two successes to pump a clinical-stage company into buyout territory or make a significant impact on its valuation.

Three solid clinical-stage long-term companies
Today, I'm going to highlight three that I believe are could be the perfect fit for the long-term, risk-taking biotech investor.

What makes for a successful clinical-stage company, in my eyes, is diversity and opportunity. If I gave you the opportunity to buy a company with three clinical-stage drugs or 12, which would you choose? As for me, I'd go with the company boasting 12 clinical-stage candidates. Why? Because choice breeds potential and helps spread around your risk, much as a biotech ETF spreads out your risk among numerous biotech stocks. Here are three companies that I think do an exceptional job of spreading around their risk and optimizing their potential despite having very few FDA-approved drugs.

Isis Pharmaceuticals (IONS 1.12%)
Despite only one FDA approved treatment -- Kynamro, to treat homozygous familial hypercholesterolemia -- Isis has 23 ongoing clinical-stage trials and an addition seven preclinical studies. Add that up and you, as an investor get 30 chances at success. To me that sounds like much better odds than a coin flip or a company with just two or three compounds in its pipeline.

In addition, Isis also develops the majority of its therapies with its antisense technology platform. In other words, it's using proprietary technology, which can't be duplicated and gives it royalty rights should any drugs make it to market. This has been a key component of how it's been able to gain upfront milestone payment funding from its 12 partners without having to turn to secondary offerings. Just recently, Isis announced its fourth collaboration with Biogen Idec (BIIB 3.40%) in developing neurological therapies that could be worth as much as $4 billion and gave it $100 million upfront. All told, Isis has easily more than $6 billion in potential milestone payments that could be earned across its pipeline.

With a constant stream of clinical data across five major therapeutic areas (cancer, cardiovascular, inflammation, metabolic, and rare disease), Isis is perhaps the most intriguing of all clinical-stage biopharmaceutical companies.

Nektar Therapeutics (NKTR -2.11%)
Don't let the 24% implosion on Friday fool you, Nektar Therapeutics is sound as a pound! Nektar currently has nine FDA-approved therapies as well as 19 clinical-stage studies ranging from preclinical in nature to being under review by the FDA.

Like Isis, Nektar discovers its experimental drugs on its own proprietary polymer conjugate technology platform. This platform gives Nektar a unique edge in that it can leverage its technology to unlock royalty rights on numerous drugs while also having the capability to develop in-house drugs of its own. Currently, Nektar is testing NKTR-102, an in-house cancer-fighting drug that's delivered 21% to 22% unconfirmed and confirmed response rates in mid-stage metastatic breast cancer and platinum-resistant ovarian cancer trials.

Nektar also has the ability to jettison those royalty rights for cash to fund further research. In January 2012, Nektar sold its royalty rights to Cimzia and Mircera for $124 million, which allowed it to get rid of $215 million in convertible debt. Although the cash flow may seem erratic now, consider Nektar's proprietary technology and 19 ongoing trials a future source of huge cash flow potential.

ImmunoGen (IMGN)
Last, but certainly not least, we have ImmunoGen (IMGN), with its targeted-antibody payload, or TAP, technology, which allows chemotherapy toxins to hop aboard an antibody and be released when they come into contact with a targeted cancer cell that exhibits a specific protein signature. The end result is the destruction of cancerous cells without harming healthy cells that don't possess this protein signature.

ImmunoGen currently has one FDA-approved therapy with Roche named Kadcyla to treat HER2-positive breast cancer in patients who have taken and stopped responding to Herceptin and taxane. Beyond that one approval, ImmunoGen also has 17 ongoing clinical-stage studies and one preclinical study, as well as six partnerships with some of the biggest names in the pharmaceutical industry, including Sanofi, Bayer, and Amgen.

ImmunoGen's TAP technology is showing promise in early and mid-stage trials across a number of cancer types, including breast cancer, small-cell lung cancer, and diffuse large B-cell lymphoma, to name a few. With a wide variety of cancer-treating possibilities and plenty of ongoing milestone potential, the sky is the limit for ImmunoGen.

The takeaway
If you're beginning to notice a trend, it's that proprietary and game-changing technologies are key components to clinical-stage biopharmaceutical success. Having the ability to leverage your technology through royalties and across a wide range of compounds gives these companies a far better chance of success.

You'll also notice that these three companies give investors more "rolls of the dice" than your average clinical-stage biotech company. Sure, you can go out and buy a large pharmaceutical company like Roche, which has 113 ongoing clinical studies in addition to its existing pipeline of products, and do just fine. However, you could also buy all three of these companies and gain access to a combined 11 FDA-approved compounds and 67 clinical and preclinical stage studies and take part in a potentially huge growth opporunity! The more rolls of the dice you have, the better chance you have of being successful -- it's just that simple.